280

CMEinfo presents
a definitive multimedia course

NEUROLOGY FOR
NON-NEUROLOGISTS
directed by Martin A. Samuels, MD
BRIGHAM AND WOMEN’S HOSPITAL/HARVARD MEDICAL SCHOOL
 Neurology for Non-Neurologists
Provided by:
Oakstone Publishing, LLC
_____________________________________________________________________________________________________________________________________

Updated for rerelease: June 30, 2018

Date of Original Release: June 30, 2016
Date Credits Expire: June 30, 2021

TARGET AUDIENCE:
The activity was designed for Internists, family physicians, emergency physicians, Psychiatrists,
Physical Medicine and Rehabilitation physicians, obstetricians/gynecologists (who act as
primary care physicians), adolescent medicine physicians, geriatricians, Resident and Fellows in
the above specialties and Nurse Practitioners and Physician Assistants in the above specialties.

ESTIMATED TIME TO COMPLETE:

It is estimated that it should take the average learner 33 hours to complete the activity.

ACCREDITATION:
Oakstone Publishing, LLC is accredited by the Accreditation Council for Continuing Medical
Education (ACCME) to provide continuing medical education for physicians.

Oakstone Publishing, LLC is accredited as a provider of continuing nursing education by the

American Nurses Credentialing Center's Commission on Accreditation.

DESIGNATION:
Oakstone Publishing, LLC designates this enduring material for a maximum of 33 AMA PRA
Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of
their participation in the activity.

Contact hours: 33

Successful completion of this CME activity, which includes participation in the evaluation
Successful completion of this CME activity, which includes participation in the evaluation
component, enables the participant to earn up to 33 MOC points in the American Board of
Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will
earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME
activity provider’s responsibility to submit participant completion information to ACCME for
the purpose of granting ABIM MOC credit.

SPECIAL PREREQUISITES FOR PARTICIPANTS: There are no prerequisites for

participants.

METHOD OF PARTICIPATION: Review Video/Audio program, score 70% or greater on the

required posttest to assess the knowledge gained from reviewing the program and complete the
comprehensive activity evaluation.

280
____________________________________________________

LEARNING OBJECTIVES:
At the conclusion of this activity, the participant will be able to:

 Recognize and name the most common neurological signs and symptoms, for example,
fatigue, tremor, dizziness.
 Differentiate between common neurological conditions and those conditions that are
more serious in order to determine optimal care.
 Perform a thorough neurological examination and take a complete history.
 Apply the American Academy of Neurology guidelines for the management of common
neurological disorders.
 Assess relevant treatment options and apply them as appropriate.
 Analyze appropriate and cost-effective imaging and laboratory studies and their
indications and contraindications when evaluating a patient.
 Predict and manage patient expectations regarding prognosis and rehabilitation.
 Identify methods, support, and resources for patient self-management for those patients
with chronic neurological conditions, for example multiple sclerosis, Parkinson disease.
 Identify the social networks of interpersonal connections that influence positive outcomes
in post-stroke patients.

FACULTY AFFILIATIONS DISCLOSURE:

Oakstone Publishing, LLC has assessed conflict of interest with its faculty, authors, editors, and
any individuals who were in a position to control the content of this CME activity. Any
identified relevant conflicts of interest were resolved for fair balance and scientific objectivity of
studies utilized in this activity. Oakstone Publishing’s planners, content reviewers, and editorial
staff disclose no relevant commercial interests.

Disclosure information for all individuals in control of the content of the activity is located
on the disclosure slides in the PDF and printed syllabus.

WARNING:
The copyright proprietor has licensed the picture contained on this recording for private
home use only and prohibits any other use, copying, reproduction, or performance in
public, in whole or in part (Title 17 USC Section 501 506).

280
____________________________________________________
CMEinfo is not responsible in any way for the accuracy, medical or legal content of this
recording. You should be aware that substantive developments in the medical field covered
by this recording may have occurred since the date of original release.

© 2018 Ebix, Inc. DBA Oakstone Publishing. LLC.

CMEinfo is a registered trademark of Oakstone Publishing, LLC.

280
 Neurology for Non-Neurologists
Faculty List

Course Director:
Martin A. Samuels, MD
Chair of Neurology,
Brigham and Women’s Hospital;
Miriam Sydney Joseph Professor of Neurology,
Harvard Medical School,
Boston, MA

Speakers:

Nazem Atassi, MD, MMSc Rebecca C. Burch, MD

Associate Professor of Neurology, Assistant Professor of Neurology,
Harvard Medical School; Harvard Medical School;
Associate Director, Associate Neurologist,
Neurological Clinical Research Institute Brigham and Women’s Hospital
Massachusetts General Hospital, Department of Neurology;
Boston, MA Staff Neurologist,
John R. Graham Headache Center,
Aaron L. Berkowitz, MD, PhD Boston, MA
Director, Global Neurology Program,
Brigham and Women’s Hospital; Louis R. Caplan, MD
Assistant Professor of Neurology, Neurologist,
Harvard Medical School; Beth Israel Deaconess Medical Center;
Health and Policy Advisor in Neurology, Professor of Neurology,
Partners in Health, Boston, MA Harvard Medical School, Boston, MA

Shamik Bhattacharyya, MD Michael E. Charness, MD

Department of Neurology, Chief of Staff,
Brigham and Women’s Hospital, VA Boston Healthcare System;
Harvard Medical School, Boston, MA Professor of Neurology,
Faculty Associate Dean,
Kate Brizzi, MD Harvard Medical School;
Instructor in Neurology, Professor of Neurology,
Instructor in Medicine, Palliative Care, Associate Dean,
Massachusetts General Hospital, Boston University School of Medicine,
Harvard Medical School, Boston, MA Boston, MA
Kirk R. Daffner, MD, FAAN Galen V. Henderson, MD
J. David and Virginia Wimberly Director of Neurocritical Care,
Professor of Neurology, Department of Neurology,
Harvard Medical School; Brigham and Women’s Hospital,
Chief, Boston, MA
Division of Cognitive and Behavioral
Neurology, Albert Hung, MD, PhD
Director, Assistant Professor of Neurology,
Center for Brain/Mind Medicine, Harvard Medical School;
Brigham and Women’s Hospital, Associate Neurologist,
Boston, MA Brigham and Women’s Hospital;
Associate Director,
Amar Dhand, MD, DPhil Massachusetts General Hospital
Assistant Professor of Neurology, Movement Disorders Unit,
Brigham and Women’s Hospital, Boston, MA
Harvard Medical School;
Network Science Institute, Joshua P. Klein, MD, PhD
Northeastern University, Chief, Division of Hospital Neurology,
Boston, MA Department of Neurology,
Brigham and Women’s Hospital;
Steven K. Feske, MD Associate Professor of Neurology,
Associate Professor of Neurology, Harvard Medical School,
Harvard Medical School; Boston, MA
Chief, Cerebrovascular Division,
Brigham and Women’s Hospital, Eudocia Quant Lee, MD, MPH
Boston, MA Associate Neurologist,
Division of Cancer Neurology,
Michael Ganetsky, MD, FACEP, Department of Neurology,
FACMT Brigham and Women’s Hospital;
Assistant Professor of Emergency Center for Neur0-Oncology,
Medicine, Harvard Medical School; Dana-Farber/Brigham and
Core Medical Toxicology Faculty, Women’s Cancer Center;
Harvard Medical Toxicology Fellowship, Assistant Professor of Neurology,
MA/RI Poison Control Center; Harvard Medical School,
Director, Medical Toxicology Boston, MA
Consult Service,
Department of Emergency Medicine,
Beth Israel Deaconess Medical Center,
Boston, MA
Jennifer L. Lyons, MD Lakshmi Nayak, MD
Chief, Division of Neurological Infections Director, Center for Central Nervous
and Inflammatory Diseases, System Lymphoma,
Department of Neurology, Center for Neuro-Oncology,
Brigham and Women’s Hospital; Dana-Farber Cancer Institute;
Assistant Professor of Neurology, Neuro-Oncologist,
Harvard Medical School, Division of Neuro-Oncology,
Boston, MA Department of Neurology,
Brigham and Women’s Hospital;
Robert M. Mallery, MD Assistant Professor of Neurology,
Instructor in Neurology and Harvard Medical School, Boston, MA
Ophthalmology,
Harvard Medical School; Aaron P. Nelson, PhD, ABPP
Associate Neurologist, Chief of Neuropsychology,
Brigham and Women’s Hospital; Brigham and Women’s Hospital;
Assistant Ophthalmologist, Assistant Professor,
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA
Boston, MA
Peter Novak, MD, PhD
Tracey A. Milligan, MD, MS, FAAN Division Chief, Autonomic Neurology,
Vice Chair for Education, Distinguished Director, Autonomic Laboratory,
Clinician, Department of Neurology, Department of Neurology,
Brigham and Women’s Hospital; Brigham and Women’s
Assistant Professor of Neurology, Faulkner Hospital,
Harvard Medical School, Boston, MA Harvard Medical School, Boston, MA

Edison K. Miyawaki, MD Mary Angela O’Neal, MD

Department of Neurology, Assistant Professor of Neurology,
Brigham and Women’s Hospital; Harvard Medical School;
Assistant Professor of Neurology, Clinical Director of the Neurosciences,
Harvard Medical School, Boston, MA Brigham and Women’s Hospital;
Program Director, Women’s Neurology,
William J. Mullally, MD Department of Neurology,
Associate Chief of Clinical Neurology, Brigham and Women’s Hospital,
Brigham and Women’s Boston, MA
Faulkner Hospital;
Director of Sports Neurology, Milena Pavlova, MD
Department of Neurology, Department of Neurology,
Brigham and Women’s Hospital, Brigham and Women’s Hospital;
Boston, MA Assistant Professor of Neurology,
Harvard Medical School;
Medical Director,
Faulkner Sleep Testing Center,
Boston, MA
Sashank Prasad, MD Chizoba Umeh, MD
Associate Professor of Neurology, Instructor in Neurology,
Harvard Medical School; Harvard Medical School; Associate
Chief, Division of Neuro-Ophthalmology, Neurologist,
Department of Neurology, Brigham and Women’s Hospital,
Brigham and Women’s Hospital, Boston, MA
Boston, MA
Henrikas Vaitkevicius, MD
Thomas B. Sabin, MD Neurocritical Care Unit,
Professor and Vice-Chair, Brigham and Women’s Hospital;
Department of Neurology, Assistant Professor of Neurology,
Tufts University School of Medicine; Harvard Medical School, Boston, MA
Lecturer on Neurology,
Harvard Medical School, Boston, MA Nagagopal Venna, MD
Associate Professor of Neurology,
Reisa A. Sperling, MD Harvard Medical School;
Professor of Neurology, Director of Neuro-Infectious
Harvard Medical School; Diseases Clinic,
Director, Center of Alzheimer Head, Division of
Research and Treatment, Comprehensive Neurology,
Brigham and Women’s Hospital; Massachusetts General Hospital,
Director, Neuroimaging for the Boston, MA
Massachusetts Alzheimer’s Disease
Research Center, Victor Wang, MD
Massachusetts General Hospital, Division Chief, Pain Neurology,
Boston, MA Brigham and Women’s Hospital,
Boston, MA
James M. Stankiewicz, MD
Clinical Director, Gregory T. Whitman, MD
Partners Multiple Sclerosis Center, Otoneurologist,
Brigham and Women’s Hospital; Massachusetts Eye and Ear Infirmary;
Assistant Professor of Neurology, Instructor in Otolaryngology,
Harvard Medical School, Boston, MA Harvard Medical School, Boston, MA

John F. Sullivan, MD
Neuropsychiatrist,
Brigham and Women’s Hospital;
Instructor in Psychiatry, Harvard
Medical School, Boston, MA
 Oakstone Publishing, LLC
Neurology for Non-Neurologists

Book
Topic/Speaker Page #
Taking a Neurological History
1
Martin A. Samuels, MD
The Mental Status Examination
6
Aaron P. Nelson, PhD, ABPP
The Neurological Examination:
Cranial Nerves, Motor, Sensory, Coordination, and Reflexes 35
Martin A. Samuels, MD
SENSORY COMPLAINTS
Approach to the Patient with Dizziness
41
Gregory T. Whitman, MD
Treatment of Dizziness
65
Gregory T. Whitman, MD
Approach to the Patient with Spells
72
Louis R. Caplan, MD
Fatigue
81
Thomas D. Sabin, MD
Migraine and Other Headache Syndromes
100
Rebecca C. Burch, MD
Headache as a Symptom of Systemic Disease
121
Rebecca C. Burch, MD
Neck and Arm Pain
141
Shamik Bhattacharyya, MD
Low Back and Leg Pain
162
Shamik Bhattacharyya, MD
Spinal Cord Neurology
184
Shamik Bhattacharyya, MD
Approach to the Problem of Chronic Pain
211
Victor Wang, MD
EPILEPSY
Epilepsy
229
Tracey A. Milligan, MD, MS
Seizures as a Symptom of Systemic Disease
258
Tracey A. Milligan, MD, MS
NEURO-OPHTHALMOLOGY
Visual Disturbances
275
Sashank Prasad, MD
Eye Movement, Lid, and Pupil Abnormalities
295
Robert M. Mallery, MD
MOVEMENT DISORDERS
Parkinsonism
322
Chizoba Umeh, MD
 Oakstone Publishing, LLC
Neurology for Non-Neurologists

Book
Topic/Speaker Page #
MOVEMENT DISORDERS
Tremor
349
Albert Hung, MD
Hypokinetic Movement Disorders
(Other than Parkinson Disease) 366
Edison K. Miyawaki, MD
Hyperkinetic Movement Disorders
385
Edison K. Miyawaki, MD
STROKE
Prevention of Stroke
408
Steven K. Feske, MD
Impact of Social Networks in Stroke
445
Amar Dhand, MD, Dphil
Treatment of Acute Stroke
462
Galen V. Henderson, MD
CANCER NEUROLOGY
Primary Brain Tumors
511
Lakshmi Nayak, MD
Neurological Aspects of Systemic Cancer
553
Eudocia Quant Lee, MD, MPH
NEUROLOGICAL INFECTIONS
Encephalitis
579
Jennifer L. Lyons, MD
Meningitis
591
Jennifer L. Lyons, MD
HIV Neurology
602
Nagagopal Venna, MD
NEUROMUSCULAR DISORDERS
Neuropathies
620
Mohammad Kian Salajegheh, MD
Muscle and Neuromuscular Junction Disorders
649
Mohammad Kian Salajegheh, MD
Motor Neuron Diseases
689
Nazem Atassi, MD, MMSc
MULTIPLE SCLEROSIS AND AUTOIMMUNE DISORDERS
Multiple Sclerosis
710
James M. Stankiewicz, MD
Autoimmune Neurology
734
Henrikas Vaitkevicius, MD
 Oakstone Publishing, LLC
Neurology for Non-Neurologists

Book
Topic/Speaker Page #
BEHAVIORAL NEUROLOGY
Evaluation of Cognitive Impairment
791
Kirk R. Daffner, MD
Alzheimer Disease
814
Reisa A. Sperling, MD
Delirium and Confusion
831
Joshua P. Klein, MD, PhD
Neuropsychiatry
848
John F. Sullivan, MD
NEUROIMAGING
Principles of Neuroimaging
858
Joshua P. Klein, MD, PhD
BORDERLANDS OF MEDICINE AND NEUROLOGY
Neuro-Rheumatology
879
Shamik Bhattacharyya, MD
The Neurology of Acid-Base Disturbances
908
Martin A. Samuels, MD
Neurocardiology
960
Martin A. Samuels, MD
Neurohematology
1029
Martin A. Samuels, MD
SLEEP DISORDERS
Insomnia
1069
Milena Pavlova, MD
Excessive Sleepiness
1085
Milena Pavlova, MD
Sleep Problems in Neurological Diseases
1102
Milena K. Pavlova, MD
BRAIN INJURY AND TOXINS
Traumatic Brain Injury and Concussion
1123
William J. Mullally, MD
Metabolic Encephalopathy
1147
Martin A. Samuels, MD
Coma and Brain Death
1153
Martin A. Samuels, MD
The Neurology of Alcohol
1168
Michael E. Charness, MD
Neurotoxicology: Central Nervous System Toxins
1192
Michael Ganetsky, MD
 Oakstone Publishing, LLC
Neurology for Non-Neurologists

Book
Topic/Speaker Page #
BRAIN INJURY AND TOXINS
Neurotoxicology: Peripheral Nervous System Toxins
1214
Michael Ganetsky, MD
SPECIAL TOPICS
Neurorehabilitation
1239
Sabrina Paganoni, MD, PhD
Autonomic Neurology
1265
Peter Novak, MD, PhD
Women’s Neurology
1300
Mary Angela O’Neal, MD
Palliative Neurology
1327
Kate Brizzi, MD
Neurology in Global Context
1346
Aaron L. Berkowitz, MD, PhD
What My Mistakes Taught Me
1376
Martin A. Samuels, MD
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

Disclosures
• None

1
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Neurological History

The Object of the Neurological

History
• What is the pace of the process?
– Acute
– Subacute
– Chronic
– Episodic
• What is the localization of the process?
– Brain
– Spinal cord
– Roots
– Nerves
– Neuromuscular junction
– Muscle

2
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Which Brain Gives the History?

• The Patient

• Relatives

• Co-workers

• Police

The Open Ended History

• The Rogerian technique

• Beware of the medicalized history

– Vertigo
– Lyme disease

• Beware of the “classic” description

• Beware of vague terms

– Numbness may actually be weakness
– Blurry vision may actually be double vision

• How to handle the internet

3
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Principle of Pseudo-acuteness

• Chronic illnesses may present acutely

• Examples:
– Double vision
– Cognitive decline
– Weakness

Avoid Pseudoquantification
Examples:
– How bad is your headache, where 0 is absent
and 10 is intolerable?

– How bad is your backache?

– How dizzy are you?

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dizzy?
Martin A. Samuels

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

5
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Mental Status Examination

March 14, 2014

Aaron Nelson PhD, ABPP

Division of Cognitive and Behavioral Neurology
Brigham and Women’s Hospital
Harvard Medical School

Disclosures
• None

6
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Frontal Lobes
• Primary Motor Cortex
• Expressive language
• Attention
• Executive function
• Planning and execution of
complex actions
• Anticipation of outcomes
• Behavioral modulation
• initiate, maintain, shift

• Comportment (social behavior)

• Reasoning, judgment,
insight

7
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Temporal Lobes
• Primary auditory cortex
• Olfaction
• Language
comprehension
• Memory
• Emotion

Parietal Lobes
• Primary somatosensory
cortex
• Sensory integration
• Guidance of proximal limb
movement
• Spatial distribution of
attention
• Body schema representation
• Graph construction
• Aspects of language,
calculations

8
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Occipital Lobes
• Primary Visual Cortex
• Perception of Form
• Perception of Color
• Perception of Depth
• Perception of Movement

Objectives of the MSE

• Localization of cerebral dysfunction through
application of knowledge of brain/behavior
relationships
• Syndrome recognition and differential diagnosis
• Systematic measurement of mental function
• Estimate disease severity
• Assess functional implications of mental state
abnormalities
• Gauge treatment response
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE Caveats
• Relationship between test performance and
cognitive function is complex
• MSE performance is influenced by intelligence,
educational background, socio-cultural factors
• MSE findings are rarely pathognomonic in terms of
lesion localization in the usual sense; many aspects
of higher cortical function reside in complex, widely
distributed networks
• Test behavior and “real life” behavior are imperfectly
correlated

Premorbid baseline makes a difference

10
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Estimating Premorbid Baseline

• History
• Educational background
• Vocational history
• Interests & hobbies
• Examination
• Breadth of vocabulary
• “Hold tests” (e.g., lexical knowledge)
• “Best performance” method

MSE SCHEMA
• Level of Consciousness *
• Comportment *
• Attention *
• Executive Functions
• Orientation
• Memory
• Language *
• Visuospatial Function
• Mood *
* Indicates that abnormality in this sphere is likely to affect mental status in a
global fashion

11
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language
• Visuospatial Function
• Mood

Level of Consciousness
• Alert – Drowsy – Somnolent – Stuporous – Comatose
• Severe impairment
– Damage to brainstem reticular formation
– Bilateral thalamic lesions
– Bilateral hemispheric lesions
• Milder impairment
– Unilateral lesions
– Toxic/metabolic derangement
– Dementia
– Encephalitis
– Depression

12
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

GLASGOW COMA SCALE

Eye Opening
Never 1
To pain 2
To verbal stimuli 3
Spontaneously 4
Best Verbal Response
No response 1
Incomprehensible sounds 2
Inappropriate words 3
Disoriented and converses 4
Oriented and converses 5
Best Motor Response
No response 1
Extension (decerebrate) 2
Flexion abnormal (decorticate) 3
Flexion withdrawal 4
Localizes pain 5
Obeys commands 6

Delirium
• onset usually acute (hours to days)
• clouded consciousness
– decreased alertness
– dulling of cognitive processes
• diurnal waxing/waning course
• usually bespeaks acute medical problem
– toxic
– metabolic
– organ failure
• patients with early dementia vulnerable
• impaired attention limits exam

13
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language
• Visuospatial Function
• Mood

Comportment
• + Symptoms (Orbitofrontal?)
• Impulsivity/disinhibition
• Emotional dysregulation; belligerence
• Hypersexuality
• Perseveration
• Utilization behavior (environmental dependence)
• Witzelsucht (inappropriate humor)
• - Symptoms (Dorsolateral?)
• Abulia
• Apathy
• Withdrawal
• Affective flattening
• Violation of social rules
• Decreased empathy
• Diminished insight
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language
• Visuospatial Function
• Mood

Attention
• Simple Attention
– Digit Span
– Months of the year forward
• Vigilance/Sustained Attention
– Continuous performance tasks
• Speed of Processing
– Response latencies and reaction time
– Timed tasks
• Working Memory
– Digit span backward
– Months of the year in reverse

15
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Digit Span
Forward Backward
5-8-2 2-4
6-4-3-9 6-2-9
4-2-7-3-1 3-2-7-9
6-1-9-4-7-3 6-1-8-4-3
5-9-1-7-4-2-8 7-2-4-8-5-6
5-8-1-9-2-6-4-7 8-1-2-9-3-6-5
2-7-5-8-6-2-5-8-4 9-4-3-7-6-2-5-8

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language
• Visuospatial Function
• Mood

16
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Executive Functions
• Overall regulation/modulation of behavior
– Initiate, maintain, and flexibly shift in response to
environmental contingencies
• Capacity for abstract thinking
– Identification of commonalities
– Planning future goal-directed behavior
– Anticipation of consequences/outcomes
– Formulation of future “rules” to guide behavior
• Self-observational capacity

Testing Executive Functions

• Motor programming
– Alternating graphomotor patterns
– Luria serial hand positions (fist, side, palm)
• Cognitive flexibility/Response inhibition
– Motor go/no go paradigm
– Stroop Test (overcoming prepotent response)
• Verbal abstraction/Concept formation
– Similarities, Proverbs, Idiomatic expressions
• Verbal fluency
– Letters, Categorical fluency

17
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alternating graphomotor patterns

Stroop Test

18
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Verbal abstraction
• Similarities
– apple/banana
– boat /car
– tree/fly
• Proverbs
– A stitch in time saves nine
– A rolling stone gathers no moss
• Idiomatic Expressions
– a chip on his shoulder
– a heart of gold

Disorders associated with deficits in executive function

• Traumatic Brain Injury
• Frontal Lobe Tumor
• Vascular Injury
– ant cerebral a. infarction
– ant communicating a. (ACoA) aneurysm rupture > SAH
• Toxic Conditions/Infection (e.g., HIV, EtOH)
• Frontotemporal Dementia
– Behavioral variant
– Progressive nonfluent aphasia
– Semantic dementia
• Other Degenerative Dementias (PSP, HD)
• Normal Pressure Hydrocephalus (NPH)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions

• Orientation
• Memory
• Language
• Visuospatial Function
• Mood

Orientation
• Time and Location
– Year, Month, Date, Weekday, Season
– Location, City, State
• Personal context
– “Why are you here today?”
– Symptoms of concern
– Relevant medical history
• Extrapersonal context
– Recent/upcoming holidays
– Recent significant family life events
– Recent major news events

20
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation

• Memory
• Language
• Visuospatial Function
• Mood
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Memory Processes
• Acquisition (aka encoding, registration)
• Recall (aka retrieval after a delay interval)
• Recognition (cueing; multiple choice)

• Primary memory impairment

(assumes relative preservation of acquisition)

– Failure of retention
– Abnormally fast rate of forgetting
– Loss of information from storage

Tests of Anterograde Memory

• Word list
– MMSE (3 words)
– MoCA (4 words)
– CERAD (10 words)
• Brief story
– Anna Thompson (Wechsler Memory Scale)
– Fishing story
• Hidden objects
– Personal items from patient
– Office items
– Currency

22
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CERAD Word List

• Butter • Three Drilled Immediate
• Arm Recall Trials
• Shore • Delayed Recall
• Letter – (10 minute filled interval)
• Queen • Delayed Recognition
• Cabin – 10 targets + 10 foils
• Pole
• Ticket
• Grass
• Engine

WMS Logical Memory

Anna/ Thompson/ of South/ Boston/, employed/ as a
cook/ in a school/ cafeteria/, reported/ at the City
Hall/ Station/ that she had been held up/ on State
Street/ the night before/ and robbed/ of fifty-six
dollars/. She had four/ small children/, the rent was
due/, and they had not eaten/ for two days/. The
police/, touched by the woman’s story/, took up a
collection/ for her/.

23
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Three Words Three Shapes Memory Test

Mesulam

• Direct copy
• Incidental recall
• Drilled recall to criterion
• 5 minute delay
• 15 minute delay
• 30 minute delay
• Multiple choice
recognition

24
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Testing Retrograde Memory

• Personal history (autobiographical memory)
– Personal history (family, medical, school, work)
– Personal info (SS#, DOB, address, phone)
• Episodic memory (personal events)
– This morning, yesterday, recent holiday, vacations
• Historical information (non-personal)
– US Presidents
– Wars and disasters
– Sporting events
– Fact Knowledge (semantic memory)

Disorders associated with a high incidence of

memory dysfunction
• Alzheimer’s disease and other dementias
• Traumatic brain injury
• Frontal lobe tumor
• Alcoholic Korsakoff’s syndrome/thiamine deficiency
• Viral encephalitis
• Anoxia/Hypoxia
• Surgical resection of the temporal lobes
• Occlusion/Infarction of posterior cerebral artery
• Rupture/Clipping of ACA aneurysm
• Paraneoplastic limbic encephalitis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory

• Language
• Visuospatial Function
• Mood

26
 Language
• Speech characteristics: discourse
• Comprehension: discourse; commands; yes/no
questions
• Naming: available objects; responsive
• Fluency: alpha letters; categories
• Repetition: words & phrases
• Praxis: limb/body to command/copy
• Reading, Spelling, Writing

Naming Errors
Circumlocution
Whistle = police blower
Wheelchair = push the...thing...
Phonemic paraphasia
Comb = crome
Igloo = exemo
Verbal/Semantic paraphasia
Dart = arrow
Pear = apple
Perceptual
Harmonica = factory
Pretzel = snake
 Broca’s Aphasia
Exam
dysfluent, dysarthric, effortful, telegraphic
output
relative sparing of comprehension
repetition is impaired
Associated Findings
right hemiplegia
frustration, agitation, depression
Lesion
implicates L post. frontal lobe (area 44)

Wernicke’s Aphasia
• Exam
fluent, paraphasic, empty output
severe impairment of auditory comprehension
repetition is impaired
• Associated Findings
hemiplegia rare
absent insight (indifference)
• Lesion
implicates L superior temporal lobe (area 22)

28
 MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language

• Visuospatial Function
• Mood

Visuospatial Function
• Spatial attention: cancellation; bisection; search
• Perception: design matching; design copying;
object recognition; color recognition
• Construction: drawings to copy & command, puzzle
assembly, block design
• Directional orientation: R-L pointing; map
locations; route-finding
Strub & Black The Mental Status Examination in Neurology

30
Intersecting pentagons

Clock Drawing

December 1993 June 1995

31
 MSE SCHEMA
• Level of Consciousness
• Comportment
• Attention
• Executive Functions
• Orientation
• Memory
• Language
• Visuospatial Function

• Mood

Mood self-report measures

• Patient Health Questionnaire (PHQ-9)
– http://www.integration.samhsa.gov/images/res/PHQ%20-%20Questions.pdf

• Generalized Anxiety Disorder 7 item scale (GAD-7)

– http://www.integration.samhsa.gov/clinical-practice/GAD708.19.08Cartwright.pdf

32
 Neuropsychiatric Inventory
delusions apathy
hallucinations disinhibition
agitation/aggression irritability/lability
depression/dysphoria aberrant motor behavior
anxiety sleep disorders
elation/euphoria appetite & eating disorders

Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients.

Neurology. 1997 May;48(5 Suppl 6):S10-6.

Mood and other psychiatric factors

• Is this a primary psychiatric disorder?
– Anxiety
– Depression
– Hypomania and Mania
– Psychotic spectrum disorder
– Suboptimal effort and Malingering
• Depressive pseudo-dementia
• Pseudobulbar palsy (damage to corticobulbar tracts)
– Motor Neuron Disease
– Multiple Sclerosis
– Amyotrophic Lateral Sclerosis
• Hallucinations and Delusions in neurological disorders
– Epilepsy
– Reduplicative paramnesia and Capgras syndrome
– Dementia (e.g., FTD, LBD)
– Acute toxic states and delirium
34
 The Brigham Department of Neurology
Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

Disclosures
• None

35
 The Neurological Examination

Overview of the Neurological

Examination
• Mental Status
– Psychiatric
– Neurological
• Cranial Nerves
• Motor
• Sensory
• Coordination
• Reflexes

36
 The Psychiatric Mental Status
Examination for Non-Psychiatrists
• Affect

• Mood

• Thought
– Content
– Process

The Neurological Mental Status

• Level of consciousness
– Attentive, confused/delirious, stuporous, comatose
• Language
– Fluency, comprehension, repitition
• Memory
– Episodic, semantic, working, procedural
• Visuo-spacial skills
– Representations of extra-personal space

37
 Cranial Nerves
• I. Olfaction
• II, III, IV, VI, VIII. Eyes, pupils, lids
• V. Facial sensation
• VII. Facial movement
• VIII. Hearing/vestibular function
• IX, X. Swallowing, palatal sensation
• XI. Sternocleidomastoid and Trapezius
• XII. Tongue

Motor Exam
• Power
– Patterns of weakness; symmetry
• Tone
– Increased tone (e.g. spasticity), decreased
• Bulk
– Neurogenic atrophy

38
 Sensory Exam

• Primary modalities
– Noxious (e.g. temp); non-noxious (e.g. proprioception)
• Secondary modalities
– Graphesthesia, two-point discrim., stereognosis
• Screening test for axial proprioception
– Romberg test

Coordination and Gait

• Hypotonicity
– Passive limb movement, overshoot
• Dysmetria
– Finger-nose, heel-shin, mirror test
• Dysdiadochokinesia
– Rapid alternating movements
• Fine motor tasks
– Finger on thumb tapping
• Gait
– Wide-based
 Reflexes

• Proprioceptive
– Muscle stretch (aka tendon jerks)
• Nociceptive
– Plantar, corneal, abdominal, cremasteric, anal
• Anti-gravity
– Four limb (decerebration), two limb (decortication)
• Release
– Sucking, rooting, grasping, palmomental

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

Approach to the Patient
with Dizziness
Gregory T. Whitman, M.D.

No relevant disclosures.

@gregwhitman

41
 What is “dizziness?”
• An imprecise term.
• Abnormal sense of acceleration, velocity,
position, orientation.
• In the U.S., we add abnormal gait/balance,
because symptoms such as the above tend to
perturb gait/balance.

@gregwhitman

• Timing
• Triggers
• Targeted Eye Exam

• Head Impulse
• Nystagmus
• Test of Skew

@gregwhitman
 Dizziness History
Quality
• Vertigo, oscillopsia, hearing, presyncope,
lightheadedness, faintness.
• Disequilibrium, abnormality of gait.
Temporal pattern/timing
• Episodic, constant, monophasic, progressive,
duration.
Aggravating factors/triggers
• Better or worse lying down, upright, hunger.
Associated symptoms
@gregwhitman

Anatomy

NASA/JPL-Cal Tech @gregwhitman

43
 Dizziness Exam
• Orthostatic symptoms and vital signs.
• Dix-Hallpike, supine roll tests.*
• Dynamic visual acuity test (near card, 2Hz. passive
yaw).
• Hearing.
• Neck ROM (yaw, pitch, roll).
• Fukuda stepping test (50 steps, arms outstreched).
• Associated ear and brain signs.
*Neuro-Ophthalmology Virtual Education Library (NOVEL)

**Epley maneuver
@gregwhitman
(Whitman and Baloh)

Dizziness Lab Tests

• VNG with calorics—oculomotor function,
horizontal canal/CN VIII.
• Rotational testing in the dark—horizontal
canal/CN VIII; confirmatory of VNG findings.
• cVEMP and oVEMP—otolith organs/nerves.
• CDP—balance function.
• vHIT—in theory, test all semicircular canals.

@gregwhitman
 Common Diagnoses
• Benign paroxysmal positional vertigo (BPPV)
• Meniere’s syndrome
• Vestibular migraine
• Acute vestibular neuritis
• Bilateral vestibular hypofunction
• Small vessel ischemia of the brain
• Anxiety
• Dysautonomia
• Mal de debarquement

@gregwhitman

BPPV - Overview
• Prevalence of 1-3%, one year incidence 0.6 %.
• Triggers: lying down, sitting up, rolling in bed,
extension of neck (“top shelf vertigo”).
• Freely floating debris in semicircular canals.
• Associated with vitamin D deficiency.

@gregwhitman

45
 Posterior canal BPPV
• Dix-Hallpike--nystagmus is:
delayed
torsional (upper poles of eyes toward ground),
upbeat
paroxysmal (dizziness occurs in parallel)
fatigable. (not always).
• Epley & similar maneuvers “work,” but you
may have to repeat.
@gregwhitman

Physiology of Dix-Hallpike
Sitting up Head back – neck extended

Gravity

Debris settles due to

gravity—endolymph flow
results in slow phases
@gregwhitman down, fast phases up.
 Horizontal canal BPPV
• Dix-Hallpike induces predominantly horizontal
nystagmus.
• Supine Roll Test
• May resolve with sleeping on the “non-dizzy”
side.
• Symptoms can be severe in part due to long
duration of paroxysms, often leading to
nausea.

@gregwhitman

Anterior Canal BPPV

• Paroxysmal positional downbeat nystagmus.
Try to ensure that the nystagmus is
paroxysmal.
• Treatment: Deep head hanging maneuver—
often many repetitions.
• Downbeat can also be due to posterior fossa
lesion, craniocervical lesion, or familial ataxia.
• Follow until signs and symptoms resolve.

@gregwhitman
 BPPV – tips
• “I keep waking up with vertigo.”
• Dizziness on lying down, rolling in bed.
• Recurrent vertigo Think of BPPV.
• Acute phase often disabling.
• Nonspecific symptoms can linger while upright.
• First few steps often abnormal on getting out of
bed; gait often markedly abnormal if bilateral.
• BPPV aggravates migraine.
• Symptoms vary from one bout to another.
• Post BPPV syndrome can last at least 6 weeks.

@gregwhitman

Meniere’s syndrome
• Prevalence 0.1-0.2%, etiology unknown.
• Spontaneous attacks of vertigo lasting more than 20
minutes, and some last hours.
• Asymmetric, low frequency hearing loss.
• Tinnitus, ear fullness, altered hearing, may correlate
with with vertigo.
• Vertigo after a high sodium meal.
• Usually should test for retrocochlear lesion.

@gregwhitman

48
 Meniere’s Audiogram

@gregwhitman

Asymmetric hearing loss—ruling out a retrocochlear lesion:

•PTA should be close to SRT (e.g., within 5 dB); PTA can be =
average of hearing levels at 500, 1000, 2000 Hz. (Normal < 20 dB).
•When in doubt, order MRI IAC with gado or if MRI cannot be done: ABR.

“In the intention-to-treat analysis (ie, all 60 patients), the mean number of vertigo attacks
in the final 6 months compared with the 6 months before the first injection (primary outcome)
decreased
From 19.9 (SD 16.7) to 2.5 (5.8) in the gentamicin group (87% reduction) and
From 16.4 (12.5) to 1.6 (3.4) in the methylprednisolone group (90% reduction).”

@gregwhitman

49
 Migraine - Overview

• Prevalence of 9-15%, maybe higher.

• Episodic headaches, some with nausea and/or
photophonophobia.
• Rule out other mechanisms.

@gregwhitman

Vestibular Migraine - Overview

• Prevalence 1-4%.
• Recurrent “spontaneous” attacks of vertigo.
• Migraine.
• 5 dizziness episodes, lasting ≥ 5 minutes .
• Migraine related symptom(s) in ≥ 50% episodes.
• No better explanation.
• “Possible” vestibular migraine may be on the
differential, even if all of above not met.

@gregwhitman
 @gregwhitman

Vestibular migraine – tips

• Diagnosis of exclusion--you can’t be confident
until symptoms improve or resolve.
• Focus on visual symptoms (photophobia,
auras, visual motion sensitivity).
• Ask about caffeine and sleep apnea.
• Migraine may aggravate motion sickness.
• BPPV may aggravate migraine.

@gregwhitman
 Acute vestibular neuritis
• May be due to viral invasion or reactivation.
• Onset over minutes–hrs., fluctuates acutely.
• Gait/balance dysfunction.
• Acutely: horizontal +/- torsional nystagmus
(slow phase of horizontal toward affected ear).
• Spontaneous nystagmus fades quickly.
• Abnormal head impulse test.
• Acutely, falls toward lesion, turns toward lesion.
• Symptoms may become chronic.

@gregwhitman

@gregwhitman

52
 Vestibular neuritis – tips
• Similar to a first attack of Meniere’s—in Meniere’s,
the signs “clear” more quickly e.g., vestibular
neuritis does not vanish on day 2.

• Recurrent vestibular neuritis is rare—if the history is

“recurrent vestibular neuritis,” think BPPV or
Meniere’s.

@gregwhitman

@gregwhitman

53
 Bilateral Vestibular Hypofuncton -
Diagnosis
• Disequilibrium (especially in the dark).
• Oscillopsia (and abnormal dynamic visual acuity).
• Romberg.
• DDx: autoimmune disease, syphilis, Lyme,
diabetes mellitus, amidarone.

@gregwhitman

Semicircular canal dehiscence

• Vague dizziness.
• Dizziness triggered by loud sounds (Tullio).
• Autophony: hearing heart beat, eyes move.
• Audio: “better than normal” bone curve (threshold
less than 0 dB) i.e., pseudo-conductive pattern.
• VEMP: thresholds low, amplitudes high.
• Temporal bone CT must be protocoled correctly.
• May be associated with Chiari malformation.
• Surgical candidates are rare, but they’re out
there…

@gregwhitman
 Small vessel cerebral ischemia
• Can’t be well measured, so it’s mostly a
postulate.
• Cognitive, balance and gait impairment.
• In some cases, similar MRI pattern associated
with atrial fibrillation.
• If asymmetrical, consider extracranial carotid
artery narrowing.
• Hypothetically, dysautonomia may potentiate
ischemia.
@gregwhitman

Dysautonomia - diagnosis
• OH, VVS, and POTS.
• Lightheadedness on prolonged standing, with
heat, exercise, and/or 1st thing in morning.
• ? Triggered by head trauma, viral illness.
• Diagnosis often made clinically based on
orthostatic vital signs/symptoms.
• Consider: CBC, B12, TSH, ANA, Lyme,
hemoglobin A1C, urine catecholamines.
• Rule out Cardiology problems (e.g., CAD).
@gregwhitman

55
 Chronic subjective dizziness / PPPD
/functional dizziness/anxiety disorders
• Dizziness anxiety, and anxiety disorders
dizziness; often must diagnose both.
• Dysautonomia (e.g., POTS) may be an
aggravating factor--opens treatment options.
• Excessive visual dependence may be an
important element.
• Consider SSRI/SNRI.
• Exercise often helps.
@gregwhitman

@gregwhitman
 Mal de debarquement syndrome
• Continuous sensation of motion e.g., rocking,
after a cruise, flight, long road trip, etc.
• Associated disequilibrium / abnormality of gait.
• Improves in moving vehicles.
• Anecdotally, benzodiazepines during motion
exposure may prevent recurrence (unproven).
• Treat associated migraine and/or anxiety.
• New treatment approaches attempt to exploit
effects of optokinetic stimuli to “readapt” the
VOR.

@gregwhitman

Vestibular schwannoma
• Dizziness not a major, early feature, but can be
(…even then, hearing symptoms still appear
within months).
• Unilateral or asymmetric tinnitus and/or
hearing loss.
• Audio: Asymmetric SNHL, impaired word
recognition out of proportion to increase in
pure tone thresholds.
• Tumor growth is characteristically slow.

@gregwhitman

57
 Cervicogenic dizziness
Curr Opin Neurol. 2015 Feb;28(1):69-73.
Cervicogenic causes of vertigo.
Hain TC
SUMMARY:
Little progress has been made over the last
year concerning cervicogenic vertigo. As
neck disturbances combined with dizziness
are commonly encountered in the clinic,
the lack of a diagnostic test that establishes
that a neck disturbance causes vertigo
remains the critical problem that must be
solved.

@gregwhitman

Cervicogenic dizziness
• Pain doctors avoid bilateral facet joint
injection.
• Worth checking neck range of motion.
• Rule out myelopathy.
• If the patient has neck problems, treat; and as
a bonus, you may help the dizziness.

@gregwhitman

58
 Treatment of Dizziness
Gregory T. Whitman, M.D.

@gregwhitman

Benign paroxysmal positional

vertigo (BPPV)
Epley maneuver for posterior canal BPPV

Log roll for horizontal canal BPPV Head straight back for anterior canal BPPV

@gregwhitman

59
 Vestibular neuritis - treatment
• Limit vestibular suppressants within 1 week (meclizine
is notorious).
• PT then home exercise program.
• One option (no particular protocol widely accepted):
– 60 mg daily x 5 days with daily antacid.
– 40 mg x 2 days.
– 30 mg x 2 days.
– 20 mg x 2 days.
– 10 mg x 2 days.
– 5 mg x 2 days.
• Ramsay Hunt (VII & VIII) some physicians give
prednisone x a few extra days + antiviral with little
evidence. @gregwhitman

Bilateral vestibulopathy- treatment

• Vestibular physical therapy.
• Limit vestibular suppressants.
• No swimming alone.
• Try to avoid future aminoglycoside use.

@gregwhitman
 Meniere’s disease treatment
Main goal: stop vertigo.
•“Spread out” sodium consumption e.g., 500
mg per meal, 2000 mg per day.
•≤ 1 caffeinated beverage/day.
•≤1 alcoholic drink per day.
•Stay hydrated.
•Diuretics e.g., TMT-HCTZ, acetazolamide,
spironolactone if sulfa allergic.
•IT corticosteroid or gentamicin.
•Surgery for very small % of patients.

@gregwhitman

Vestibular migraine - treatment

• Regular nutritious meals, fluids, sleep.
• Avoid caffeine.
• Migraine preventative medications.
• As needed vestibular suppressants.
• One view: “Treat the headaches / photophobia,
and as a bonus, you may alleviate the
dizziness.”
• Acetazolamide seems to help migraine and
Meniere’s.

@gregwhitman
 Dysautonomia - treatment
• Fluids and if no hypertension, sodium.
• Avoid excessive heat, especially early in day.
• Compression stockings (including abdomen).
• Exercise including leg muscle strengthening.
• De-intensify meds where possible.
• Fludrocortisone, midodrine, and
pyridostigmine.

@gregwhitman

Chronic Subjective Dizziness /

PPPD
• Yoga, meditation
• Cardio exercise
• Sertraline and other SSRI

@gregwhitman

62
 Cervicogenic dizziness
• Many possible mechanisms—use the other
symptoms as a guide.
• Experiment with various pillows.
• Cautious physical therapy.
• Surgery referrals where appropriate.

@gregwhitman

Vestibular Physical Therapy

• Particle repositioning maneuvers
• Balance retraining
• Lower extremity strengthening
• Visual treatments comparable to VOR re-
adaptation

@gregwhitman

63
 Side Effects
• Many medications have dizziness as a side
effect.
• Think of hypotension.
• Assess effects of psychiatric medications on
the brain.

@gregwhitman

@gregwhitman

64
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment of Dizziness
Gregory T. Whitman, M.D.

@gregwhitman

No relevant disclosures.

@gregwhitman

65
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

**Epley maneuver
(Whitman and Baloh)
@gregwhitman

Benign paroxysmal positional

vertigo (BPPV)
Epley maneuver for posterior canal BPPV

Log roll for horizontal canal BPPV Head straight back for anterior canal BPPV

@gregwhitman

66
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Vestibular neuritis - treatment

• Limit vestibular suppressants within 1 week (meclizine
is notorious).
• PT then home exercise program.
• One option (no particular protocol widely accepted):
– 60 mg daily x 5 days with daily antacid.
– 40 mg x 2 days.
– 30 mg x 2 days.
– 20 mg x 2 days.
– 10 mg x 2 days.
– 5 mg x 2 days.
• Ramsay Hunt (VII & VIII) some physicians give
prednisone x a few extra days + antiviral with little
evidence. @gregwhitman

Bilateral vestibulopathy- treatment

• Vestibular physical therapy.
• Limit vestibular suppressants.
• No swimming alone.
• Try to avoid future aminoglycoside use.

@gregwhitman

67
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meniere’s disease treatment

Main goal: stop vertigo.
•“Spread out” sodium consumption e.g., 500
mg per meal, 2000 mg per day.
•≤ 1 caffeinated beverage/day.
•≤1 alcoholic drink per day.
•Stay hydrated.
•Diuretics e.g., TMT-HCTZ, acetazolamide,
spironolactone if sulfa allergic.
•IT corticosteroid or gentamicin.
•Surgery for very small % of patients.

@gregwhitman

Vestibular migraine - treatment

• Regular nutritious meals, fluids, sleep.
• Avoid caffeine.
• Migraine preventative medications.
• As needed vestibular suppressants.
• One view: “Treat the headaches / photophobia,
and as a bonus, you may alleviate the
dizziness.”
• Acetazolamide seems to help migraine and
Meniere’s.

@gregwhitman

68
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dysautonomia - treatment
• Fluids and if no hypertension, sodium.
• Avoid excessive heat, especially early in day.
• Compression stockings (including abdomen).
• Exercise including leg muscle strengthening.
• De-intensify meds where possible.
• Fludrocortisone, midodrine, and
pyridostigmine.

@gregwhitman

Chronic Subjective Dizziness /

PPPD
• Yoga, meditation
• Cardio exercise
• Sertraline and other DDRI

@gregwhitman

69
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cervicogenic dizziness
• Many possible mechanisms—use the other
symptoms as a guide.
• Experiment with various pillows.
• Cautious physical therapy.
• Surgery referrals where appropriate.

@gregwhitman

Vestibular Physical Therapy

• Particle repositioning maneuvers
• Balance retraining
• Lower extremity strengthening
• Visual treatments comparable to VOR re-
adaptation

@gregwhitman

70
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Side Effects
• Many medications have dizziness as a side
effect.
• Think of hypotension.
• Assess effects of psychiatric medications on
the brain.

@gregwhitman

@gregwhitman
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurological spells- their

diagnosis and evaluation
Louis R Caplan MD
Professor Neurology
Harvard Medical School

Disclosures
• Reports no commercial interest
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Turns
The Australians wonderful word for
attacks and temporary spells

“Turns”- usual suspects

• First differentiate “general non-focal”
symptoms from focal ones
– General
• Light headedness, blurred vision, distant
hearing, lack of mental clarity
– Focal
• Unilateral motor, sensory, cerebellar symptoms
• Aphasic
• Hemianopic

73
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non focal “Turns”

• Syncope or near syncope ( determine relationship
to positional changes, fluid balance, activities etc
and past fainting or near fainting)
• Vestibular
• Metabolic- hypoglycemia and hyperglycemia;
intoxications; other less common metabolic
• Non-convulsive seizures
• Sleep-related (rare)

Focal “Turns”
• TIAs
• Migraine
• Seizures
• Psychiatric- swoons, falls, odd fits etc
• Local pressure palsies or transient localized
numbness
• Metabolic especially hypoglycemia
• Transient global amnesia (TGA)
• Paroxysmal hemimovement disorders
• Tumor-related attacks
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Differential diagnosis of focal

“Turns”
• Details of the spells- abruptness of onset, duration,
number of spells and over what period of time,
accompaniments such as headache, movements
• Age of onset
• Risk factors
• Family History
• Setting and precipitants of spells
• Labs and Imaging (brain and vascular)

TIAs
• Usually begin and end abruptly
• Are most often brief- last less than a minute to one
hour
• All symptoms, signs occur concurrently
• Are most often unilateral and hemi rather than one
limb
• Symptoms are negative- loss of function (eye as an
example and limbs
• Most often ( but not always) develop in older
individuals with stroke risk factors

75
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

TIA
• Importance of Imaging- do the
findings correlate with the
symptoms?
– Brain
– Neck and intracranial vessels
– Heart
– Aorta

TIA
A diagnosis of TIA does not reflect
– Whether or not a brain infarct has
occurred
– The cause and mechanism of the brain
ischemia
– The prognosis for further ischemia

76
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

TIAs
• Patients with TIAs have a much higher risk of
stroke than those who do not have TIAs
• The risk of stroke is highest during the first hours
and days after the TIA
• TIAs and stroke have the same etiologies
• The prognosis for developing a stroke and the
treatment depends mostly on the cause (cardiac-
cranio-cerebral arterial disease-hematological) not
on silly ABCD or other scores
• Each TIA patient needs a very urgent thorough
evaluation by an experienced stroke physician

Migraine with aura

• Begins with positive phenomena- visual or tactile
• Positive features spread slowly within the initial modality
• Negative features follow in the wake of positive
• The spread is slow and does not honor anatomical vascular
supply areas
• When one modality is cleared or nearly cleared a second
modality may begin
• A third dysfunction e.g aphasia, high level visual
abnormlities can follow
• Auras last on average 20-30 minutes but may last an hour
• Headache often follows after the aura has ended but
headache can precede or accompany the aura

77
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Migraine with aura

• Patients tend to be younger and more often
women but older individuals - migraine
accompaniments of the elderly- are a prominent
group
• Attacks are often spread over years
• Headaches with and between attacks are
common
• Family history is often positive

Seizures
• When sensory ( Jacksonian) spread very quickly
• Smell, taste, chewing and other automatisms are common
• Often followed by lethargy or decreased alertness or amnesia
• Abnormal movements may accompany or precede the reduced
function but can be absent or easily missed
• Brief lapses in attention are common (seconds to a few
minutes)
• Seizures usually last only 1-3 minutes
• The time span during which the attacks have occurred may be
many years

78
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

TGA
• Similar precipitants to migraine- hot bath, dip in cold
water, sex, severe effort, emotional sudden trauma
• Repetitive queries
• Often a change in behavior- overactive pacing or
unusually quiet
• Severe antegrade amnesia plus retrograde amnesia that
graduall clears after the attack
• Normal cognitive function and no neurological signs
other than memory-related during the attacks
• Most often lasts 30 minutes to up to 8 hours
• Tiny DWI+ lesons in lateral hippocampi especoally the
left

Less frequent causes of focal turns

• Hypoglycemia- diabetics; sweating and decreased alertness,
and hunger are coomon; if hemiplegia usually persists
• Toxins- usually associated are decreased alertness and lethargy
and the onset and termination are gradual
• Paroxysmal movement disorders are familial and begin early
in life and occur over a long duration
• Psychologically mediated- circumstances and secondary gains-
mostly swoons. Motor deficits and amnesia-aphasia are
prolonged and not transient
• Tumor ( or subdural-related) attacks are usually motor and are
only diagnosed with imaging

79
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Evaluation
• Most essential is a thorough history and an account
from others who were there
• Brain and especially vascular imaging are very
useful in uncertain cases
• Cardiac evaluation especially of cardiac rhythm and
echocardiography are important if a TIA is a
prominent consideration
• Lab tests- CBC, blood sugar, toxic screen are
occasionally useful

80
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Fatigue

May 16,2016

Disclosures
• Reports no commercial interest
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Other Names for Chronic Fatigue

• Post viral fatigue syndrome
• Benign myalgic encephalomyelitis ****
• Chronic fatigue immune dysfunction syndrome (CFIDS)
• Royal Free disease
• Icelandic disease
• Yuppie flu (Tahoe Epstein-Barr Virus implicated)
• “Chronic fee syndrome”
• Neurasthenia (Beard 1869)
• Phlegmasia
• Chronic brucellosis
• Imaginary invalidism
• Vagotonia
• Chronic hypoglycemia

Yet Another Name!

• The prestigious Institute of Medicine designated
a new name in hope of getting this disorder
more widely accepted as a serious physiologic
disorder by the medical profession.
• SEID=Systemic exertion intolerance disease.
Lots of negative reaction from patients who
always preferred the more “medicalized” Myalgic
Encephalomyelitis.

• IOM Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:

Redefinnig an Illness. Washington DC: The National Academies
Press;2015

82
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The New SEID Criteria

• Must have all three:
• 1- Substantial reduction or impairment in
the ability to engage pre-illness levels of
occupational, educational, social or
personal activities that persists for more
than 6 months and is accompanied by
fatigue, which is profound, is of new or
definite onset (not lifelong), is not the
result of ongoing excessive exertion, and
is not substantially alleviated by rest.

SEID Diagnostic Criteria (con’t)

• 2-Postexertional malaise.
• 3-Unrefreshing sleep.
At least 1 of the following 2 manifestations is
also required:
• 1 -Cognitive impairment.
• 2- Orthostatic intolerance.
Some exclusionary diagnoses are now
treated to be comorbidities.

83
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Outbreaks
• 1934 Los Angeles-Nurses caring for acute
polio patients came down with a new disease
but their patients, consorts and other close
contacts were spared. There was fatigue and
“weakness” with sensory complaints and
progressive disability. The official detailed
report states “certain observers were of the
privately expressed opinion that hysteria
played a large role in this outbreak.
• Gilliam, AG Epidemiologic study of an epidemic diagnosed as poliomyelitis occurring among
the personnel of the Los Angeles County General Hospital during the summer of 1934. Public
Health Bulletin. US Treasury Dept; 19381 publication No. 240

Royal Free Infirmary Cases

84
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Outbreaks Punta Gorda Florida

• A house to house survey was made and

no African American members of this tiny
community were affected! The same
phenomenon was noted in a South African
outbreak.

• Poskanzer DC. Et al N Eng J Med 1957;257:356-364

Evaluating Fatigue

• Six million medical visits !

• Medical bills tally over a billion dollars.
• 19,000 totally disabled in USA.
• >400 support groups.
• Physicians response to these patients
varies widely.

85
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Chronic Fatigue Syndrome Criteria #1

• A diagnosis of exclusion, whose very existence
is contentious with no pathogenic agent, no
target organ, no definitive physical finding, no
pathologic tissue changes and no diagnostic
test! Fatigue is tri-modal.
• Must have:
– Clinically evaluated unexplained persistent or
relapsing fatigue that is new or of definite
onset.
– Is not the result of ongoing exertion.
– Is not substantially relieved by rest.
– Results in marked reduction in previous levels
of occupational, social or personal activities.

Criteria for CFS #2 (after Fukada et al Ann Int Med 1994)

• Concurrent occurrence of four or more of the
following features, all of which must have
persisted or recurred during 6 or more
consecutive months of illness-not predating the
fatigue.
– Sore throat.
– Self reported decrease in short term memory and
concentration.
– Tender axillary or cervical nodes.
– Muscle pain.
– Multijoint pain without redness or swelling.
– Unrefreshing sleep.
– Change in headache.
– Post-exertional fatigue lasting>24 hours.

86
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Physical Examination

• Look for throat redness and cervical nodes

(suggesting post-viral fatigue).
• Determine blood pressure and pulse while
supine and then while standing for a 5
minute period.

CFS overlap with other

unexplained conditions
• Irritable bowel syndrome.
• Temporomandibular disorder.
• Multiple chemical sensitivity.
• Tension headache/ chronic daily
headache
• Interstitial cystitis.
• Post-concussion syndrome.

• Aaron LA Ann Intern Med 2001;134:868-681

87
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Medical Diseases
*Metabolic
– Renal failure
– Hepatic failure
– Protein wasting enteropathy
*Cardiovascular
-Chronic failure and aortic stenosis
-Bradyarrhythmias
-Orthostatic intolerance or neurally mediated
postural tachycardia
*Rheumatologic
*Nutritional (extreme diets/homeless)

Medical Diseases (con’t #2)

*Endocrine
• Hypothyroidism and apathetic hyperthyroidism
• Hypopituitarism
• Hypoadrenalism
*Hematologic
-Chronic anemia esp. B 12 deficiency
-Lymphoma and myeloproliferative disorders
*Drugs
-John Brust lists 154 in his book “ Neurologic
Complications of Drugs” Butterworth-Heineman 1996
-Beta blockers and interferons produce a very
similar syndrome

88
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Medical Diseases (con’t #3)

• Infections
– Both Lyme disease and mononucleosis cause
fatigue while active and commonly produce
long periods of post-viral fatigue.
– HIV/AIDS
– Tbc, brucellosis and other smoldering
infections and parasitic invasions.

Neurally mediated hypotension

• Post-exertional fatigue and
lightheadedness.
• Symptoms usually worse while upright.
• There is >30 mg Hg fall in BP on tilt table
often with bradycardia.
• Often young well conditioned women.
• May respond to increase salt intake, β-
blockers.
– Rowe RC Lancet 1995;345:623-4

89
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Orthostatic postural tachycardia ( POTS)

• Failure of rapid clearance of nor-epinephrine
from synaptic clefts. Plasma nor-epi is high
because there is decreased clearing at the
synapses due to lack of nor-epi transporter.
• May follow a viral illness sometimes with
features of an acute autonomic neuropathy.
• Fatigue may be accompanied by postural
wooziness, palpitations, leg weakness, altered
mentation, pain, abdominal bloating with early
satiety, diarrhea and vascular headaches.
• Legs may turn violacious on prolonged standing.
• Sine qua non- Pulse increases by 30 after
standing for 5 minutes without a fall in BP.

Diagnosis of Fatigue-Neurologic Disorders

*Multiple sclerosis
– Up to 40% of MS patients have fatigue as
their chief complaint!
– Stops them from normal daily functions.
– PET scans have shown decreased
metabolism in frontal lobes and basal ganglia.
– May respond to Amantidine or Modafinil.
*Parkinsonism
*Chiari malformation
-questionable neurosurgical intervention.
(Not myasthenia, myopathies or other diseases
with actual paralysis.)

90
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Fatigue after penetrating brain injury correlates with ventromedial cortical lesions in
yellow an orange. Pardini et al Neurology 2010;74:749-754

Psychiatric disorders
*Depression if chronic before the onset of CFS
– Share non-restorative sleep GI symptoms and poor
prolonged mental concentration with CFS.
– They also have the debilitating effects of
deconditioning

*Hypochondriasis and somatization disorder

*Generalized anxiety

*Malingering

91
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Laboratory Studies
• Bloods –CBC, ESR, electrolytes, calcium,
phosphorous, CPK, LFT’s, thyroid panel, protein
electrophoresis. A full rheumatologic study
should be done when musculoskeletal
tenderness and pain are prominent.
• Lyme, VDRL, EBV capsid antigen may also
help.
Imaging many patients have small scattered T-2
hyperintensities in the frontal lobes, but these
are not sufficiently diagnostic to justify MRIs.
MRI should be done when suspicion of multiple
sclerosis is present.

92
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Laboratory Testing that Might be Considered

but is Not Diagnostic for CFS
• EEG with sleep study.
• Lumbar puncture.
• Nerve conductions and EMG.
• Neuropsychological testing.
• Immune state (NK cells/CD4-CD8
ratio/interlukins)

93
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathogenesis
• Immunologic- heightened immune system
activation (increased globulins).
• Endocrine- abnormal pituitary adrenal
axis. Lowered corticotrophin releasing
factor.
• Decreased N-acetyl aspartase in the right
hippocampus and increased flow in the
right thalamus and basal ganglia on
functional imaging.
• Viral -a long and disappointing list.
The latest :Xenotropic murine leukemia virus (XMRV)-a retrovirus

94
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Resulted in retractions and job loss. HSV, EBV, CMV, HTLV-ll and HHV-6 have
also gone by the boards.

Acquired Narcolepsy:
a possible medical model for SEID
• Pandemrix vaccine (but not Focetria)
produced 1300 cases of narcolepsy during
the H1N1 flu epidemic of 2009-10.
• Vaccine induced antibodies to hypocretin
receptor (and to the viral nucleoprotein)
• These ABs breech the BBB and and bind
to receptor sites on hypothathalamic
neurons and disturb hypocretin release
which creates narcolepsy.
• Wekerle H, Sci Trans Med 2015:7(294fs27)

95
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

A Theoretical Model
• Increase in immune substances( TNF
&interleukins)>>>Circumventricular
organs>>>
• Hypothalamus>>>Abnormal pituitary
adrenal axis, sleep disturbance, dysphoria
• Frontal and medial temporal
cortex>>>cognitive and behavioral
changes.

96
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non-pharmacologic Treatment 1
• Tai Chai (Wang et al NEJM 363:8,2010)

• Symptomatic
– Pain
– Sleep
– Postural tachycardia or hypotension
– Depression

Non- pharmacologic therapy 2

• Graded supervised exercise program.
Deconditioning alone causes weakness, loss of
muscle bulk and changes in muscle metabolism.
• Cognitive behavioral therapy. (Increases frontal cortical
volume on MRI !!! Lange et al Brain 2008,131,2172)

• Sage advice to prevent the patient from having

“sickness” become a full time job and going
broke on useless treatments. There are more
than 300,300 hits if you Google CFS.
• Prognosis of CFS is very poor, only a small %
are normal in 5 years, underscoring the
importance of separating out the post-infectious
fatigue and the other imitators.

97
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pharmacologic Treatment of CFS

Amitriptyline- for many years the only

formally studied effective agent.
Amantidine- borrowed from MS.
Minacipran (Savella) is the most
recently approved agent and is a selective
serotonin and norepinephrine uptake
inhibitor. Has all the side effects of the of
the other serotonergic drugs such as
suicide risk in the young and serotonin
syndrome(no MAO inhibitors or tryptins).

Pharmacologic Treatment
• Cyclobenzaprine (Flexeril) is a centrally acting
muscle relaxant with common side effects of
drowsiness, dizziness and dry mouth.
• Fluoxetine (Prozac) selective serotonin uptake
inhibitor side effects include anxiety and
serotonin syndrome.
• Duloxitine (Cymbalta) another SSRI actually
approved for RX of fibromyalgia. Note suicidality
in young patients.
• Pregabalin (Lyrica) is a more potent gabapentin
(Neurontin) with a similar side effect profile i.e.
somnolence and “dizziness” are most common.
Suicidal thinking can occur.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thank you!

99
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurology for Non-Neurologists

Migraine and Other Headache

Syndromes
Rebecca Burch, MD
John R. Graham Headache Center
Department of Neurology
Brigham and Women’s Faulkner Hospital
Harvard Medical School
Boston, MA
[email protected]

Disclosure

• Dr. Burch reports no commercial interest.

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Questions

• How are headaches diagnosed?

• How can the most common headaches be

differentiated?

• What are the typical treatment strategies for

the most common forms of primary
headache?

Headache Classification

• International
Classification of
Headache Disorders
(ICHD)
• Third edition now in use
• Find it at:
https://www.ichd-3.org/

101
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• 1) Primary Headaches
– Migraine
– Tension-type
– Cluster headache and Primary
trigeminal autonomic 90%
cephalgias (TACs)

• 2) Secondary Headaches
– Tumor
– Meningitis
– Giant cell arteritis

In the clinic

• A 28 year old woman consults you with

recurrent, disabling, throbbing headaches
occurring intermittently for 8 years.
• Headaches occur with menstrual periods, last
48 hours, are associated with vomiting and
photo and phonophobia.
• Benign past medical history
• Her neurologic examination is normal

102
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ICHD Diagnostic Criteria For

Migraine Without Aura
A. Lasting 4 to 72 hours
B. Two of the following
• Unilateral location
• Pulsating quality
• Moderate or severe intensity
• Aggravation by or causes avoidance of routine
physical activity
C. At least one of the following:
• Nausea and/or vomiting
• Photophobia and phonophobia
D. At least five attacks fulfilling the three bullet points above
E. No evidence of organic disease

ICHD Diagnostic Criteria For

Tension-Type Headache
A. Lasting 30 minutes to 7 days
B. Two of the following
• Steady, pressing quality
• Bilateral location
• Mild to moderate intensity
• No aggravation by routine physical activity
C. No more than either mild photophobia OR
phonophobia
D. At least five attacks fulfilling the three bullet points
above
E. No evidence of organic disease

103
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Differentiating Migraine from

Tension Type Headache

• 40% of migraine patients have bilateral pain

• 50% of the time, pain is nonthrobbing
• Stress is a common trigger for migraine
• Neck pain may be present in both disorders
• Probable migraine vs tension-type headache

• A common diagnostic error

Lipton et al. Headache. 2001;41:646-657.

Pryse-Phillips et al. Can Med Assoc J. 1997;156(9):1273-1287.

One Year Prevalence of Migraine

Age & Sex

30

Females
Migraine Prevalence (%)

25
Males
20

15

10

0
20 30 40 50 60 70 80 100

Age (in years)

• Peak prevalence at age 40 years

• Greatest impact on ages 25 to 55 years
Lipton et al. American
• One in 4 households has a migraineur Migraine Study II. Headache.
2001 Jul-Aug;41(7):646-57

104
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Migraine aura
• Focal neurologic event(s)
– Typical aura: visual, sensory, dysphasic speech
– Hemiplegic migraine: One of the above plus motor
weakness

• Usually precedes headache…but not always

– May include at least one symptom developing
gradually over ≥5 minutes and lasting ≥5 and ≤60
minutes, aura symptoms occurring in succession,
aura symptoms unilateral or positive

• May be positive or negative, spreading, reversible

• May also occur in the absence of headache

Migraine aura

• Essentially all patients with any kind of aura

ALSO have visual aura
• So to identify aura it is only necessary to ask
about visual aura
– Visual aura is not visual blurring
– Visual aura is not visual sensitivity
• Migraine aura vs prodromal symptoms

Eriksen et al. The Visual Aura Rating Scale for Migraine Aura Diagnosis. Cephalalgia
2005;10:801-810.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Migraine with aura: Implications for

use of estrogen
• Migraine with aura associated with increased
risk of stroke, heart disease, other vascular
outcomes
• Exogenous estrogens increase stroke risk
– No contraindication to exogenous estrogen
in women who have migraine without aura
– Exogenous estrogens contraindicated in
women who have migraine with aura
• Assessment of risks and benefits should be
individualized
Schürks M et al, BMJ 2009; 339:
doi:10.1136/bmj.b3914

An unhappy young man

• 29 year old man with no prior personal or

family history of headache began to have
intermittent head pain 2 weeks ago
• Now having 2 headaches a day; one at 4 PM,
the other 2 hours after he goes to bed
• Behind his right eye. Sharp, 10/10, no
nausea, vomiting or other symptoms except
his right eye waters. Lasts 30 minutes.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ICHD Diagnostic Criteria For Cluster

Headache
A. At least five attacks fulfilling criteria
B. Severe or very severe unilateral pain lasting 15–180
minutes
C. Ipsilateral autonomic symptoms
• conjunctival injection or lacrimation, nasal congestion
or rhinorrhoea,
• eyelid edema, miosis, or ptosis
• forehead and facial sweating or flushing
• sensation of fullness in the ear
OR a sense of restlessness or agitation
D. One every other day- eight per day
E. Not better accounted for by another ICHD-3 diagnosis.

Cluster headache

• Episodic and chronic forms

• Circadian, circannual periodicity
• Attacks often occur at predictable times
• During a cluster period, may be triggered by
alcohol, sleep
• Misdiagnosis, diagnostic delay common
– Dental pathology often suspected
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cluster Headache Treatment

• Acute
– Triptans
• Sumatriptan injection
• Zolmitriptan nasal spray +/-
– 100% Oxygen via non-rebreather face mask, 12-
15 Liters, over 10-15 minutes
• Preventive
– First line: Verapamil, up to 240-720mg daily
– Alternative: Lithium, start at 100-300mg/day,
follow levels
• Bridge
– Steroid taper over 10-14 days Cohen AS, Burns B, Goadsby P. JAMA. 2009
Dec 9;302(22):2451-7.
– Occipital nerve block Tfelt-Hansen PC, Jensen RH. CNS Drugs.
2012 Jul 1;26(7):571-80.

Trigeminal Autonomic Cephalalgias

Disorder Duration Frequency Gender Acute Preventive/Bridge
(F:M) Treatment Treatment

Cluster 15-180 Every other 1:3-7 Oxygen, SC verapamil,

min day to (trending sumatriptan, topiramate,
8/day towards NS valproic acid,
women) sumatriptan lithium,
or methylergonovine,
zolmitriptan corticosteroids
Paroxysmal 2-30 min 1-40/day 2-3:1 None indomethacin
hemicrania (trending
towards
men?)
SUNA 2-600 sec Dozens to 2:1 None lamotrigine,
hundreds topirimate,
per day gabapentin,
indomethacin?
SUNCT 5-240 sec Dozens to 1:2 None lamotrigine,
hundreds topirimate,
per day gabapentin

108
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Managing migraine and tension

type headache

• Abortive treatment
– Virtually all patients require
• Preventive treatment
– A subset of patients with migraine and
tension type headache qualify
– An underused intervention!

Reasonable lifestyle modifications

• Regular meals

• Adequate sleep; Standardized

sleep and wake times

• Regular exercise and maintenance

of normal weight

• Limit or avoid caffeine, watch

alcohol

• No good evidence for dietary restrictions - lots of

anecdote

109
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Options for acute therapy

• Disorder • Common treatments

Tension-type HA NSAIDs, mild analgesics

Migraine NSAIDs, mild analgesics

Ergot derivatives
Triptans
(barbiturate combination
analgesics)
(Other combination analgesics)

Cohen et al. High-flow oxygen for cluster headache: a randomized controlled trial. JAMA 2009;22:2451-7.

Triptans

• There are seven of them Sumatriptan

– All available orally (2 as orally
disintegrating tablets) Zolmitriptan
• Results are similar when Naratriptan
comparable doses are used
Rizatriptan
• Nonetheless, patients usually
have a favorite Almotriptan
– Two available as nasal sprays Eletriptan
– One available as subcu injection,
nasal powder Frovatriptan

Loder E . Triptan therapy in migraine. N Engl J Med 2010;363:63-70

110
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Triptans: Side Effects and

Contraindications

• Common side • Contraindications

effects – Ischemic heart disease
– Tingling – Coronary vasospasm
– Warmth – Poorly controlled
hypertension
– Flushing
– Multiple risk factors for
– Chest discomfort coronary artery disease,
– Dizziness unless workup is fully
negative
– Drowsiness
– SSRI/SNRI use may NOT
be a contraindication

Optimizing abortive therapy

• Use adequate dose
• Use early/at mild stage of headache
• Consider combinations if triptan monotherapy
is ineffective
– Anti-emetics
– NSAIDs
• Avoid overuse
• Avoid opiates and combination treatments for
first line therapy

111
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rescue therapy

• Humane Options include:

• Necessary • Injectable or nasal spray
• Practical triptans
– Keep patients out of • Phenothiazine PR
the ED • Indomethacin PO or PR
• Nonoral formulations • Opiates (not a sin here)
helpful • Injectable or nasal spray
DHE
• Sedatives
• Steroids

When is preventive treatment

indicated?
• For migraine or tension-type headache:
– Headache frequency > 1/week
– Failure, contraindication to, or troublesome
side-effects from acute medications
– Overuse of acute medications
– Special situations
• e.g. headaches with profound disability
or consequences

Ramadan NM, et al. Evidenced-based guidelines for migraine headache in the primary care setting: pharmacological management for
prevention of migraine. http//www.neurology.org. Silberstein SD & Goadsby PJ. Cephalalgia 2002;22:491–512.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Goals of Migraine Preventive

Therapy

• Reduce headache-related disability

• Reduce headache frequency, duration and
intensity by at least 50%
• Improve response to abortive medications
• Reduce abortive medication requirements

• NOT “No headaches”

Preventive Medications
• Tension-type HA • Tricyclics, NSAIDs

• Migraine • Beta blockers: Propranolol, timolol

• AEDs: divalproex sodium,
topiramate, gabapentin
• Neurotoxins: onabotulinum toxin A
• Other: TCAs, ACEIs, ARBs,
memantine
• Nonpharmacological:
Biofeedback, CBT, Vitamin B2,
magnesium
Italics: FDA approved

113
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Common Preventive Medications

Evidence Medication Usual Daily Comments
Level = FDA Dose
Indication
B Atenolol 50-100 mg
A Propranolol 80-240 mg
A Metoprolol 50-150 mg
U Verapamil 180-480 mg Downgraded, favorable AE profile

A Divalproex 250-1500 mg FDA pregnancy category X

sodium
U Gabapentin 300-1800 mg Downgraded, favorable AE profile

A Topiramate 25-150 mg FDA pregnancy category D

B Amitriptyline 10-150 mg Downgraded but strong clinical
impression of benefit
B Venlafaxine 37.5-150 mg Well tolerated, not sedating
C Cyproheptadine 2-8 mg Pediatric population, sedating
Rizzoli, P. Acute and Preventive Treatment of Migraine, Continuum Neurol 2012;18(4):764-82

Comparison of American,
Canadian, and European guidelines

• Areas of agreement: highest level in all

– Divalproex
– Metoprolol
– Propranolol
– Topiramate
– *Amitriptyline

Loder E et al. Headache. 2012

Jun;52(6):930-45
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment principles
• Choose treatments based on comorbidity and
side effects, possibility of pregnancy
• Patient buy-in is essential
• “Start low, go slow”
• Adequate treatment duration and dose
• Quantify treatment effects (headache diaries)
• Reevaluate treatment at regular intervals

Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.

Chronic Migraine
A Primary Headache Syndrome
(Organic causes of headache are excluded)

Headache occurs > 15 days a month

Lasts > 4 hours a day

Migrainous > 8 days a month or more

1-3 % of the world’s population: more common than epilepsy and virtually
all other neurologic diseases

115
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment of chronic migraine

• Prevention emphasized
• Watch use of abortive medication in order to
avoid medication overuse headache
• Onabotulinum toxin type A FDA-approved for
prophylaxis
– The dose for treating chronic migraine is 155
Units IM, 0.1 mL (5 Units) per injection site.
– Every 12 weeks

Fig 1.—Fixed-site, fixed-dose injection site locations: the (A) corrugators, (B) procerus, (C)
frontalis, (D) temporalis, (E) occipitalis,
(F) cervical paraspinal, and (G) trapezius muscle injection sites.

Blumenfeld et al. Method of injection of onabotulinum toxin A for

chronic migraine. Headache 2010; doi: 10.1111/j.1526-
4610.2010.01766.x

116
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

What’s new in migraine: CGRP

monoclonal antibodies
• Calcitonin gene related peptide
– Widely distributed throughout the nervous
system; highly conserved in vertebrates
– Elevated in blood and saliva during attacks
and interictally in people with chronic
migraine
– Infusions provoke migraine
– Blockade prevents migraine
• Four antibodies developed; one FDA
approved

Antibodies in development
Galcanezumab Erenumab* Fremanezumab Eptinezumab

Target Ligand Receptor Ligand Ligand

Subclass Humanized Human Humanized Humanized
Half-life 25-30 days ~ 21 days ~45 days ~32 days
Dosing 120 mg, 240 70 mg 675 mg SQ 100 mg
schedule in mg SQ mg 140 mg quarterly, 675 300 mg
phase 3 monthly SQ monthly mg/225 mg SQ IV monthly
studies monthly
Selected -4.2 days vs - -3.4 days vs -6.27 days 225 mg -5.6 days vs
results, 3.0 days -2.3 days -6.09 675 mg - 4.6 days
active vs -3.46 days placebo
placebo

*FDA approved

117
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Adverse events
• Tolerability appears good
– Discontinuation due to AE < 5%
– Injection site reactions common
• Long term safety unknown
– CGRP may be important fail-safe mechanism in
ischemic emergencies
– Three deaths in active arms of trials (?unrelated to
treatment)
• Studies have excluded complex, refractory patients
so generalizability is uncertain
• Cost is a concern – will probably be used in addition
to, not in place of, many existing treatments

Syndrome of medication overuse

headache

• Occurs in patients with pre-existing headache

• Self-sustaining rhythm of predictable and
escalating headache frequency and
medication use
• Poor response to appropriate symptomatic
and preventive treatments
• Medication withdrawal results in escalation of
headache
• Opiates, combination analgesics worst
offenders

118
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of MOH therapy

• Start prevention
• Taper medications most likely to cause rebound
• Substitute acute medications that do not cause
rebound
• Rational medication combinations

Be aware of:
Opioid and barbiturate abstinence syndromes
Increasing headache during withdrawal period

When to refer to a headache

specialist

• Diagnostic uncertainty
• If the diagnosis is challenging to manage eg
idiopathic intracranial hypertension
• Medication overuse headache
• When multiple acute or preventive strategies
have failed
• Significant psychiatric comorbidities
• High resource utilization

119
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary: Take home points

• Recurrent, debilitating headaches are likely

migraine until proven otherwise

• Prevention is an underused intervention

• Medications with high risk of medication

overuse should be avoided

120
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurology for Non-Neurologists

Headache as a Symptom of
Systemic Disease and Other
Secondary Headaches
Rebecca Burch, MD
John R. Graham Headache Center
Department of Neurology
Brigham and Women’s Faulkner Hospital
Harvard Medical School
Boston, MA
[email protected]

Disclosures

• I have no relevant disclosures

121
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Objectives

• List signs and symptoms of secondary

headaches

• Review common presentations of systemic

disease in the headache clinic

• Discuss diagnostic testing options and when

testing is appropriate

Primary vs Secondary Headache

in the ICHD

• Part 1 Primary headaches

• Symptom based definitions
• Organized according to
phenomenology

• Part 2 Secondary headaches

• Etiology based definitions
• Organized according to underlying
cause

122
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Causes of secondary headache in the

ICHD: Headache attributed to…

• Trauma or injury to the head and/or neck

• Cranial or cervical vascular disorder
• Non-vascular intracranial disorder
• A substance or its withdrawal
• Infection
• Disorder of homeostasis
• Disorder of the cranium, neck, eyes, ears, nose,
sinuses, teeth, mouth or other facial or cervical
structure
• Psychiatric disorder International Classification of Headache
Disorders 3

Approach to diagnostic testing

• Primary headaches most represented in
health care settings
• Yield of diagnostic workup in migraine is low
– Meta analysis: If criteria for migraine are
met and neurologic exam is normal, 0.18%
chance of imaging changing management
• How to know when to test?
• How to know what tests to order?

123
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Red flags for secondary headache

History and physical: Headache characteristics:
• Neurologic symptoms or signs • Headache triggered by
(e.g., altered mental status,
weakness, diplopia, papilledema, exertion or Valsalva
focal neurologic deficits) maneuver
• Immunosuppression (HIV) or • Worse with positional
cancer
changes
• Meningismus or nuchal rigidity
• Onset of headache after age 50 • Thunderclap headache
or in young children (severe headache that
• Systemic symptoms (e.g., fever, peaks within a few seconds)
weight loss, scalp artery tender) • Progressively worsening
• Red eye and halos around lights headache
• Head or neck injury
• Recent travel (foreign, domestic)
• Different
• Pregnancy
Kuruvilla and Lipton. Curr Pain Headache
Rep (2015) 19: 17

Causes of secondary headache in the

ICHD: Headache attributed to…

• Trauma or injury to the head and/or neck

• Cranial or cervical vascular disorder
• Non-vascular intracranial disorder
• A substance or its withdrawal
• Infection
• Disorder of homoeostasis
• Disorder of the cranium, neck, eyes, ears, nose,
sinuses, teeth, mouth or other facial or cervical
structure
• Psychiatric disorder International Classification of Headache
Disorders 3

124
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1

• A 56 year old woman presents with a

constant throbbing occipital and vertex
headache, 7/10, L>R
• Intermittent L temporal aching lasting 2-24
hours
• Radiation to or from the neck with worst
headaches
• Also reports knee pain with negative
orthopedic workup, debilitating fatigue, night
sweats, pain in both arms, and pelvic pain.

Case 1, continued
• MRI brain – nonspecific white matter lesions
• ESR – 39
• CRP – 38.5
• Platelets – 395
• ANA negative
• Started on prednisone and had immediate
improvement in symptoms other than
headache
• Referred for temporal artery biopsy
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1, continued
• MRI brain – nonspecific white matter lesions
• ESR – 39
• CRP – 38.5
• Platelets – 395
• ANA negative
• Started on prednisone and had immediate
improvement in symptoms other than
headache
• Referred for temporal artery biopsy-> healing
giant cell arteritis

Giant cell arteritis

• Systemic vasculitis of medium and large arteries

• More common in white women, smokers
• American College of Rheumatology Classification
requires 3/5 of the following:
– Age at disease onset >=50 years
– New headache
– Temporal artery abnormality (TTP, decreased
pulses)
– Elevated ESR >=50 mm/hour
– Abnormal artery biopsy
Hunder GG et al. Arthritis Rheum
1990;33:1122---8.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Giant cell arteritis: Diagnosis

Diagnostic test Comments
ESR (typically>60) Historical test of choice; must be
adjusted for age; normal in 17%
CRP More sensitive than ESR, no
adjustment needed
Platelets Thrombocytosis predictive of
positive biopsy, ocular
complications
Temporal artery biopsy Gold standard; may need bilateral
if single side is negative; “skip
lesions”
Temporal artery ultrasound Noninvasive; monitoring disease
activity

Giant cell arteritis headache:

diagnostic challenges
• ICHD criteria:
– New headache and GCA has been diagnosed
– 2 of the following:
• Headache and GCA are temporally related in onset
• Headache follows GCA clinical course or resolves
within 3 days of starting high dose steroids
• Headache is associated with scalp tenderness or
jaw claudication

• BUT:
– Headache can mimic migraine and other primary
headache
– Residual headache may occur and require treatment

127
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Vasculitis

• Headache occurs • Headache occurs

early: late:
– Giant cell arteritis – Polyarteritis nodosa
(48% initial, 90% – Microscopic
eventual) polyangiitis
– Primary angiitis of the – Wegener's
CNS (PACNS) granulomatosis
– Takayasu arteritis – Churg-Strauss
– Cogan's syndrome syndrome,
– Systemic lupus
erythematosus
– Sjögren's syndrome
– Behçet's syndrome

Reversible Cerebral
Vasoconstriction Syndrome
• Single or recurrent thunderclap headache
• Diffuse segmental constriction of cerebral arteries,
resolving within 3 months
• Normal CSF
• May be accompanied by ischemic or hemorrhagic
stroke including SAH (30%), cerebral convexity SAH
(20-25%), cerebral edema, or TIA

Ducros A,Reversible cerebral vasoconstriction

syndrome. JAMA Neurol. 2014,Mar;71(3):368.

Ducros A et al The clinical and radiological

spectrum of reversible cerebral vasoconstriction
syndrome. Brain. 2007 Dec;130(Pt 12):3091-101

128
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

RCVS

• 60% have at least one risk factor, including

– Pregnancy or post-partum
– Serotonergic or vasoconstrictive
substances (SSRI/SNRI, triptans, nasal
decongestants, catecholamine secreting
tumor)
– Illicit drug use (cocaine, marijuana,
methamphetamines, ecstasy)
• Treated with calcium channel blockers

Differential diagnosis of
Thunderclap headache
• Intracerebral/subarachnoid hemorrhage
– Bleeding arteriovenous malformation
– Unruptured intracranial aneurysm (“sentinel
headache”)
• Reversible cerebral vasoconstriction syndrome
• Cerebral venous sinus thrombosis
• Hypertensive emergency
• Spontaneous intracranial hypotension (CSF leak)
• Bleeding into intracranial mass
• Pituitary apoplexy

129
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Workup for thunderclap

headache

• Intracranial vascular imaging now

recommended for thunderclap headache if
CT/LP are negative
• Vascular imaging may be negative in 20% of
patients
– Repeat after 2 weeks
• Benign causes of thunderclap headache may
not exist
– Consider empiric calcium channel blockers
if no cause found

Case 2

• A 54 year old man presents with near

continuous headache for the last 3 months
• 2/10 baseline with daily increases to 4/10 and
to 5-6/10 a few days a week. Worsens with
activity. Oxycodone helps.
• Pulsating, midline occipital and bifrontal
• Associated with nausea and photophobia
• Triggered by bright lights and hunger

130
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2, continued

• Also reports episodic hand numbness, rare

horizontal diplopia
• He and family report slowed processing,
repeating questions/conversations, poor
comprehension, and word finding problems
• MRI brain with and without contrast was
normal

Case 2, continued
• Lumbar puncture:
– Opening pressure 18 cm H20
– WBC 37, RBC 27 tube 1
– Glucose <10, Total protein 322
– Gram stain: many polys, suspicious for
yeast
– Cryptococcal antigen positive

• HIV antibody positive

131
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Headache in the
immunocompromised patient

• Many causes: HIV, chronic steroid use,

immunosuppression, hematologic malignancy
• Any new headache requires workup
• Low threshold for imaging (MRI) and lumbar
puncture
• Immunocompromised patients may have
meningitis but little immune reaction

Workup for immunocompromised

patients with new headache
Serum Cerebrospinal fluid
• Complete blood count with • Opening pressure
differential • Glucose
• Total protein
• Disease specific:
• Cell counts
– Toxoplasma serology
– Treponemal antibody • Disease specific:
– Interferon release assay – Cryptococcal antigen and
fungal culture
(TB)
– AFB stain and Mycobacterial
culture
– PCR for JC virus, VZV,
HIV, EBV, CMV
Sheikh, H. U. and Cho, T. A. (2014), Clinical
Aspects of Headache in HIV. Headache. – VZV antibodies
54: 939–945.

132
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Headache in patients with HIV

• Opportunistic infections and neoplasm much
more likely with CD4 counts <200 cells/µL
• Most causes similar to those in patients without
HIV
• Aseptic meningitis can occur at seroconversion
or viral rebound
• Low grade meningitis associated with CSF
pleocytosis can cause chronic headache
• Headache is a side effect of some antiretrovirals
Sheikh, H. U. and Cho, T. A. (2014), Clinical
Aspects of Headache in HIV. Headache.
54: 939–945.

Headache associated with systemic

infection

• “Headache in systemic infections is usually a

relatively inconspicuous symptom, and
diagnostically unhelpful.” - ICHD
• What about Lyme disease?
– Neuroborreliosis associated with headache
in case reports
– Headaches more common in those with
central nervous system involvement (54%
vs 19%) and flu-like illness (58% vs 19%)
in hospitalized patients with lyme.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3
• A 31 year old woman presents with slowly
increasing frequency of headache for the last
6 months, with acute worsening 2 months ago
• Now occurring 4-5 days/week
• Headache is bilateral frontal and temporal,
dull, occasionally throbbing
• There is associated mild nausea but this is
not temporally linked to headache

Case 3, continued

• Also reports fatigue, poor sleep, diffuse joint

pains, and weight gain

• MRI brain shows a pituitary lesion. Followup

imaging confirms a pituitary adenoma

• Pituitary labs show TSH of 9, otherwise

normal

134
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Headache related to endocrine or

nutritional abnormalities
• Hypothyroidism
– Headache reported by 30% of hypothyroid
patients
• Hyponatremia
• Fasting
• Vitamin D deficiency?
– Vit D levels in migraine: Few studies, conflicting
– Cross sectional data suggested those with normal
vit D levels taking statins had less migraine
– Vit D + simvastatin RCT for prevention of migraine
showed 8 fewer migraine days/month in treatment
group vs 1 additional day in placebo group.
p < 0.001
Ishii M, Continuum (Minneap Minn). 2014 Jun;20:560-79.
Buettner C et al Ann Neurol. 2015 Dec;78(6):970-81

Headache associated with

pituitary tumors

• Headache associated with endocrine abnormality

requires dedicated pituitary imaging
• Headache presenting complaint 37-70% of the
time
• Factors associated with headache
– Rapid growth
– Hormonal activity
– Cavernous sinus invasion (Knosp grade)
– Evidence on tumor volume
conflicting Yu B et al Cephalalgia. 2016 May 6.
Rizzoli et al Neurosurgery. 2016
Mar;78(3):316-23

135
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Synthesis: When to test

• Neurologic findings
• Systemic signs or symptoms
• Worrisome patient characteristics
• Atypical historical elements

• All trigeminal autonomic cephalalgias

• All “Other primary headaches”

Uncommon (but interesting!)

primary headaches

• Exertional headache
• Cough headache
• Headache associated with sexual activity
• Stabbing headache
• Hypnic headache
• Primary thunderclap headache
• New daily persistent headache

136
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

When to consider imaging a patient

with migraine

• Unusual aura
– Unusual, prolonged, or persistent aura
– Basilar-type
– Hemiplegic
– Aura without headache

• Increasing frequency, severity, or change in clinical

features

• Late-life migraine accompaniments

• Headaches always on the same side

• Significant anxiety contributing to headache

After RW Evans

Synthesis: What tests to order?

• Testing is always based on clinical suspicion

• Testing rules out a disorder
• There is no serum, CSF, or imaging test to
diagnose migraine, tension type headache, or
other primary headaches
• “Scattershot” approach likely to yield false-
positives
– Caution with testing for Lyme, autoimmune
disease

137
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Synthesis: Serum testing

Test Rationale
CBC Infection, hematologic malignancy,
giant cell arteritis (platelets)
ESR/CRP Giant cell arteritis
Blood cultures Meningitis
TSH Hypothyroidism
Lyme Lyme disease
ANA Autoimmune disease
Vitamin D, B12 Deficiency may be common
HIV CDC recs for all aged 13- 64 years
Iron studies People at risk for anemia
CADASIL, MELAS Extensive white matter lesions on
MRI

Neuroimaging: What test to get?

• MRI generally superior to CT
– Better look at posterior fossa
• Sensitivity for neoplasm 92% vs 81% for
CT
– Superior imaging of vascular structures
– Radiation risks of CT are not minor
• Contrast if concern for neoplasm, infection,
intracranial hypotension
• Possible role for C-spine imaging
Kuruvilla and Lipton. Curr Pain
Headache Rep (2015) 19: 17

138
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuroimaging: What test to get?

• MRA
– Dissection
– Aneurysm
– Vasculitis
– Headaches with autonomic features
• MRV
– Papilledema
– Clinical suspicion of increased ICP
– Pregnancy or postpartum

When to consider a lumbar

puncture? Concern for…
• Infection involving the CNS
– Meningitis, encephalitis
• High or low intracranial pressure
– Positional headache, worse with Valsalva
or straining, papilledema on exam
• Neoplastic process
– Lymphoma, carcinomatous meningitis
• Intracranial hemorrhage
• CNS angiitis

139
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

New Daily Persistent Headache

Workup

• Imaging: MRI of the brain with and without

contrast, MRV, and MRA of the head and
neck (if headache presents with a
thunderclap onset).
• Laboratory screening: ESR, Lupus antibody,
Lyme, and viral titers (IgG and IGM for EBV,
HH6, Parvovirus, and cytomegalovirus),
VDRL, thyroid function, complete blood count,
and serum chemistries.
• If above negative, consider LP to check
opening pressure. Rozen T. Curr Pain Headache
Rep. 2014;18D7]:431

Summary: Take home points

• Be alert for red flags and be vigilant about

“making the history fit”

• Headache is typically a non-specific symptom

of systemic disease but more common in
some conditions

• Targeted testing rules out possible underlying

etiologies of headache

140
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neck and Arm Pain – A

Neurological Perspective

Shamik Bhattacharyya MD MS
Brigham and Women’s Hospital
Harvard Medical School

Disclosure
No relevant disclosures for this presentation

141
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

A Common Problem
• Majority of population will experience neck
pain
• One year incidence estimated at 10-20%
– Higher in office and computer workers
• Prevalence is higher women and in urban
areas, higher-income countries with peak in
age group 35-49
• Most types of neck pain spontaneously remit
and have a relapsing-remitting course

Classifying Neck Pain

• Time categorization
– Acute: <6 weeks
– Subacute: <3 months
– Chronic: >3 months
• Distribution:
– Axial
– Axial and upper extremity
• Cause of neck pain
• Shorter duration predicts better outcomes
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

What causes neck pain?

• Axial neck pain
– Cervical strain/cervicalgia
– Cervical spine degenerative disease
– Traumatic neck injury
– Referred pain from other causes
• Axial neck pain plus extremity symptoms
– Cervical radiculopathy
– Cervical myelopathy
– Brachial plexopathy (more shoulder pain)

Cervical Strain
• Common diagnosis of unclear pathophysiology
– Likely many different causes
• Pain, stiffness, and tightness spread over the
neck, shoulder, and upper back
– Often tightness over the trapezius muscles
• Loss of lordosis of cervical spine
• Generally resolves in less than six weeks
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cervical Spine

Anterior view Mid Sagittal View

Images from Gray’s Anatomy 40th edition

Cervical Spine

Vertebral Body Joint

Posterior Cervical Muscle

Images from Gray’s Anatomy 40th edition

144
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cervical Spine Degenerative Disease

• A broad term to describe number of
abnormalities
– Discogenic changes with herniation of disc
– Bony misalignment
– Facet joint arthropathy
– Ligamentous hypertrophy or laxity
• Cervical spine degenerative disease present in
majority of older adults
• Poor correlation between symptoms and
radiology

Discogenic Pain
• More severe pain often lasting more than six
weeks
• Axial neck discomfort with range of motion in
different directions
• Associated muscle tightness/pain worse with
immobility such as when reading or working
or driving for prolonged periods
• Hard to correlate with specific disc findings or
levels on MRI
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Facet Joint Pain

• Risk factors:
– Flexion/extension injury such as in car accident
– Occupations such as electrician or plumber with
prolonged postures holding neck extended
• Pain can be midline/paraspinal with radiation to
occiput, shoulder, or upper back
• No specific imaging finding
• Intra-articular injection of anesthetic and
subsequent relief can be diagnostic

Cervical Radiculopathy
• Generally presents with neck and arm pain
• Sensory symptoms in some cases:
– Burning, tingling, numbness
• Weakness of the arm and hand occurs less
commonly
• Generally caused by impingement of spinal
nerve – distribution of symptoms depends on
the nerve root

146
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cervical Radiculopathy

• Disc herniation responsible for

only about a quarter of cases.
• Combination of degenerative
changes usually lead to nerve
impingement
• Compression of dorsal root
ganglion is likely important

N Eng J Med (2005); 353: 392-399

Cervical Radiculopathy
Root Pain Sensory Weakness
Medial scapula, lateral upper Arm abduction,
C5 Lateral upper arm
arm and elbow external rotation
Lateral forearm, thumb, and Thumb and index Elbow flexion and
C6
index fingers fingers wrist extension
Elbow extension,
Medial scapula, posterior arm Posterior forearm,
C7 wrist flexion, finger
and forearm, middle finger middle finger
extension
Shoulder, medial forearm, little Intrinsic hand
C8 Little finger
finger muscles

• C7 nerve root is likely most commonly affected followed by C6

• C6 radiculopathy causes decreased biceps reflex
• C7 radiculopathy causes decreased triceps reflex

147
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Spurling Maneuver

• Positive test is reproduction of radiculopathy symptoms

• Sensitivity is about 50% and specificity around 80%

Spine (2003); 28: 52-62

Shoulder Abduction Test

• Positive test is alleviation of radiculopathy symptoms

• Sensitivity is about 40-50% and specificity around 80%

Image from McGraw-Hill Companies, Inc.

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neck Distraction Test

• Positive test is alleviation of radiculopathy symptoms

• Sensitivity is about 40% and specificity around 90%

Spine (2003); 28: 52-62

Abduction-Extension Test

• Positive test is reproduction of radiculopathy symptoms

• Sensitivity likely around 80%

Eur Spine J (2013); 22: 1522-1525

149
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Imaging and Electrodiagnostics

• Cervical radiculopathy is a clinical diagnosis
without a “gold” standard
• In patients with low risk of inflammatory or
neoplastic etiologies:
– Treat with conservative management
– Reasonable to image at 6-8 weeks for progressive
or disabling symptoms
– EMG/NCS useful to supplement equivocal or non-
diagnostic imaging

Imaging
• MRI preferred imaging modality because nerve
and surrounding structures can be directly
visualized
• Generally non-contrast imaging is sufficient
unless suspicion for inflammatory or neoplastic
causes
• Degenerative changes are highly prevalent in
older adults and must be correlated to signs and
symptoms
• In patients who cannot get MRI, CT myelography
can be used.

150
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MRI of Cervical Spine

MRI of Cervical Spine

Arrows at neuroforamina for exiting nerve roots

151
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MRI Cervical Spine

• Moderate narrowing at bilateral neuroforamina

• Patient had signs and symptoms of right sided
radiculopathy despite more significant compression on
the left side

Electrodiagnostic Studies
• Nerve conduction studies (NCS) and EMG
performed together
• NCS alone is not sufficient and useful for
excluding other etiologies such as carpal tunnel
syndrome
• EMG changes take at least two weeks to develop
from start of symptoms
• Varying estimates of sensitivity between 30-70%
with higher yield when weakness present
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cervical Degenerative Myelopathy

• Neck pain and evidence of spinal cord
dysfunction
• Neck pain can be clinically similar to other
causes
• Spinal cord dysfunction
– Stiffness of gait and instability often the first
symptoms
– Numbness/paresthesias in the hands or truncal
sensory level
– Increased tone and reflexes

“Red Flag” Symptoms

• Anterior neck pain is atypical of
musculoskeletal neck pain
• History of cancer, fever, unexpected weight
loss, and immunosuppression
• Neck pain in association with proximal
shoulder and hip pain in older patient
suggests polymyalgia rheumatica or possibly
giant cell arteritis
• Neck pain following significant trauma such as
fall or major car accident
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Canadian C-Spine Rule

Developed to be used in
awake and alert patients in
stable condition

Rheumatoid Arthritis

Also known as cranial settling

154
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Some Other Causes

• Herpes zoster: Initially causes cervical
radiculopathy with rash appearing later
• Thoracic outlet syndrome: Numbness,
weakness, and swelling of an arm
• Shoulder musculoskeletal injury with regional
pain

Case I
• 50 year old woman with six months of achy
pain in the left side of the neck worsened by
driving
• No pain, weakness, or numbness in the arms
• Exam:
– Pain in left side of neck and shoulder worsened
with rotating neck to the left by 15 degrees
– No numbness or weakness in left arm
– Also pain worsened with pressure in focal region
of left trapezius
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis
• Most cases of cervical strain resolve
spontaneously within six weeks
• Prolonged course and worsening with neck
motion suggests cervical spine degenerative
disease
• Trigger points indicates myofascial pain pattern
• Unlikely to have nerve compression
• Cervical degenerative disease – discogenic
versus facet arthropathy. Concurrent myofascial
pain.

Imaging

• Cervical degenerative disease at multiple levels

• Imaging does not further localize which segment is causing pain
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case II
• 55 year old man with two years of neck pain
– Sharp pain at base of neck radiating upward to
occiput and to shoulder blades
– Worsened with head movement (rotation or flexion)
– Sense of tingling in bilateral fingertips
• Exam
– Limited range of motion to about 20 degrees in
either lateral direction or in flexion/extension
– 3+ left patellar reflex; 2+ right patellar reflex
– Mild weakness in left hamstring

Diagnosis
• Long standing worsening neck pain provoked
by neck motion indicates cervical
degenerative disease
• Findings of hyperreflexia and left leg weakness
with history of hand tingling suggestive of
cervical degenerative myelopathy
• Cervical degenerative disease – likely spinal
cord compression.

157
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Imaging

• Multilevel degenerative disease

• Spinal cord compression at C3-4 level

Treatment
• Despite prevalence of condition, few robust
clinical trials to guide practice
• Existing data confounded by heterogeneity of
underlying pathology and natural history
• Significant practitioner and regional variation
in approach to neck pain

158
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment – Non-Pharmacologic
• Posture modification
– Avoiding long periods of immobility of neck such
as prolonged driving or holding phone for hours at
work
– Decreasing weight over shoulders
• Exercises
– Gentle range of motion exercising holding the
head at each end position for a few seconds
– Shoulder rolls
• Use of cervical collar discouraged

Persistent Neck Pain

• Referral to physical therapy for more
regular/intensive stretching exercises
– Evidence of benefit from therapeutic exercises
• No adequately controlled studies to provide
firm recommendation for medications
– Acetaminophen and NSAIDs first line agents
– Muscle relaxants at night such as cyclobenzaprine
– Tricyclics helpful for more chronic axial neck pain
– Other neuropathic pain medications also used
(gabapentin, duloxetine, pregabalin)

159
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Persistent Neck Pain

• If opioids used for acute pain, limit quantity to
as short a duration as possible (generally no
more than seven days in initial episode)
• Unclear evidence of benefit versus risk for
spinal manipulation, massage, manual
therapy, laser therapy, traction
• Important to set expectation of improvement
and treat comorbid sleep and mood disorders

Interventional Management
• Cervical Medial Brach Block: Anesthesizes the
facet joint and can provide marked relief in
patients with facet pain (diagnostic and
therapeutic)
– Followed sometimes by radiofrequency
neurotomy for more prolonged relief
• Epidural steroid injection: For persistent
radiculopathy. May be repeated one or two
times. Risk of vascular or neural injury.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Surgery
• Referral appropriate:
– Radiculopathy with weakness/numbness that is
persistent beyond six to eight weeks
– Refractory radicular pain
– Evidence of myelopathy
• Utility of surgery for chronic neck pain is
controversial and lacking evidence. Some
surgeons operate if clear evidence of single
level disease.

Conclusion
• Neck pain is common and can be managed in
most cases by primary care doctors
• Neck pain with upper extremity paresthesias and
pain likely from radiculopathy
• Axial neck pain has more heterogenous causes
• MRI is the preferred imaging technique for
cervical radiculopathy and obtained for axial neck
pain with persistent symptoms
• Neck pain can generally be treated by
combination of physical therapy and analgesics

161
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Low Back Pain

Shamik Bhattacharyya MD MS
Brigham and Women’s Hospital
Harvard Medical School

Disclosure
No relevant disclosures for this presentation

162
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Low Back Pain

• Very common condition
– Most will experience in lifetime
– One quarter of Americans have experienced back
pain within past three months
• Many do not seek medical care
• A major public health focus with estimated
total costs around $50-100 billion

Causes of Back Pain

• Musculoskeletal back pain
• Disc herniation
• Spondylolisthesis
• Facet arthropathy
• Radiculopathy
And many
• Cauda equina
more…
• Osteomyelitis
• Vertebral fracture

163
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Finding a Cause
• Back pain symptoms are non-specific and do
not reliably correlate with specific spinal
anatomical abnormalities
– Largest group making up about 85% of patients
• Unclear if classifying cause makes a difference
• 70-90% improve within seven weeks

A Pragmatic Approach
• Divide low back pain into three categories:
1. Nonspecific low back pain
2. Back pain with associated neurological
symptoms in legs
• Radiculopathy
• Cauda equina syndrome
3. Back pain associated with systemic disease
• Vertebral osteomyelitis
• Bony metastases
• Ankylosing Spondylitis

164
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nonspecific Low Back Pain

• Variable descriptions
– Achy pain with sharp exacerbations
– Can be midline or in the paraspinal regions
– Margins are diffuse with extension to low thoracic
regions and into proximal legs
• Risk factors:
– Heavy lifting or twisting
– Obesity
– Poor conditioning

NEJM (2001); 344: 363-370

165
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Facet Joint Pain

Nat Rev Rheumatol (2013); 9:216-224

Facet Joint Pain

Nat Rev Rheumatol (2013); 9:216-224

166
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Facet Joint Pain

• More important cause of pain in older adults
• Pain generally worsens with back extension
and rotation towards the affected joint
• Improvement of pain with forward flexion
• Anesthetic injection of the medial branches
innervating facet joint (medial branch block)
often improves pain and can aid diagnosis

Nonspecific Back Pain

• Muscular or ligamentous injury causing
localized pain
• Degenerative disc disease
• Spondylolisthesis and spinal column instability
• Sacroiliac joint pain
– Causes posterior low back and gluteal pain
• Piriformis syndrome
– Buttock pain worsened with sitting

167
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lumbosacral Radiculopathy
• Often provoked by physical activity or injury
• Aching low back pain with sharp, severe
radiating pain down the leg (usually unilateral)
• Pain extends below the knee
• Other neurological symptoms
– Paresthesia in legs
– Numbness in dermatome
– Weakness in myotomal distribution

Lumbosacral Radiculopathy
• Caused by irritation of nerve root
– Neuroforaminal stenosis
• Disc herniation often responsible for acute
radiculopathy
• Frequent accompanying degenerative changes such as
facet arthropathy and spondylolisthesis
– Canal stenosis with nerve root compression with
disc herniation

168
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Straight Leg Test

• Positive test is reproduction of radiculopathy symptoms.

• Sensitive for radiculopathy at the L5 and S1 nerve root levels
• Ipsilateral test (>80% sensitive) but not specific
• Contralateral test is more specific
NEJM (2015); 372:1240-1248

Lumbosacral Radiculopathy
Root Pain Sensory Weakness
Thigh and medial Hip flexion, knee
L3 Thigh
knee extension, hip adduction
Knee extension, foot
L4 Anterior and medial leg Medial lower leg
dorsiflexion
Toe extension; foot
Lateral leg, dorsal
L5 Lateral leg and dorsal foot dorsiflexion, eversion,
foot
inversion; hip abduction
Sole of foot, lateral Knee flexion, hip extension,
S1 Posterior leg, sole of foot
ankle foot plantarflexion

• L4-L5 and L5-S1 levels are most susceptible to injury

• L3 and L4 radiculopathy cause decreased patellar reflex
• No reliable reflex correlate for L5 radiculopathy
• S1 radiculopathy causes decreased ankle jerk

169
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lumbosacral Radiculopathy
• A clinical diagnosis and with compatible
history and examination, no further diagnostic
tests necessary
• Imaging obtained:
– Persistent radiculopathy symptoms at 4-6 weeks
(majority of cases resolve spontaneously)
– Progressive weakness or numbness
– Urinary retention or saddle anesthesia

Imaging
• MRI without contrast is the preferred modality
– Visualizes soft tissue structures such as disc, bony
elements, and exiting nerve roots
• In cases when MRI cannot be obtained
– CT myelography (intrathecal contrast injection)
visualizes nerve root compression
• X-ray can show dynamic instability in different
postures
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Persistent Right S1 Radiculopathy

• Anterior spondylolisthesis at L4
on L5
• Does not correlate with clinical
syndrome of S1 radiculopathy
L3

L4

L5

S1

Persistent Right S1 Radiculopathy

L3
Impacts descending nerve
L4 roots in the canal

L5

S1

171
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

EMG/NCS
• Changes take at least 3 weeks to appear
• Varying sensitivity of test
– Insensitive for sensory predominant syndrome
including numbness and radiating pain
– More sensitive when weakness is present
• Complementary information to imaging when
there is ambiguity about cause of weakness or
for investigation for neuropathy

Lumbar Stenosis
• Narrowing of the lumbar canal and
compression of intraspinal nerves
• Neurogenic claudication
– Pain in legs provoked by walking or standing and
improved by sitting or leaning forward
– Symptoms are often asymmetric
– Sensory loss and weakness can occur often
involving multiple roots
• Low back pain can be mild
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Severe Lumbar Stenosis

• Cauda equina syndrome
– Involvement of bilateral lumbosacral nerve roots
– Genitourinary dysfunction
• High lumbar canal stenosis causes conus
medullaris syndrome
– Mixed findings of myelopathy and radiculopathy
with increased tone or Babinski sign

Lumbar Stenosis
• Diagnosis based primarily on history
• Examination can show:
– Variable findings involving multiple nerve roots
– Physical activity in the office such as walking can
elicit symptoms (such as weakness)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Imaging
• MRI is preferred imaging modality
– Not specific, many have canal stenosis without
symptoms
– Others can have “moderate” radiologic stenosis
with significant symptoms
• CT myelogram can image canal in patients
who do not tolerate MRI

Neurogenic Claudication

174
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Back Pain from Systemic Disease

• Generally infrequent to present primarily with
back pain but can happen
• Quality of back pain often does not distinguish
dangerous causes of back pain
• Asking for “red flag” symptoms increases
likelihood of finding these causes

Risk Factors
• Patient history:
– Cancer
– Unexplained weight loss
– Age older than 50
– Intravenous drug use
– Recent infection
– History of osteoporosis

175
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Risk Factors
• Clinical Characteristics
– Failure to improve after one month or escalating
pattern
– Fever
– Morning stiffness and improvement with exercise
– Alternating buttock pain
– Awakening in second part of night only with back
pain

Last three characteristics suggest ankylosing spondylitis as a possible etiology

Vertebral Osteomyelitis

Enhancement on post-contrast imaging

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ankylosing Spondylitis

Corner related osteitis. STIR (left); T1 (right).

Ann Rheum Dis (2012); 71: 1278-1288

Diagnostic Steps
• Classify into one of the three groups
– Nonspecific back pain
– Back pain with neurologic symptoms/signs
– Back pain with red flags
• Imaging indicated for those with red flags or
symptoms suggestive of spinal stenosis
• For those with persistent symptoms for one to
two months or progressive symptoms, obtain
imaging of lumbar spine

177
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nonpharmacologic Therapy
• Acute low back pain
– Exercise: Unclear benefit of early physical therapy.
General recommendation is for gentle activity rather
than bed rest.
– Massage: Low quality evidence for improvement
– Superficial heat: Heat wrap likely improves pain relief
and disability
– Lumbar support: Likely no difference in pain/function
– Insufficient evidence for multiple other therapies

Nonpharmacologic Therapy
• Chronic low back pain
– Exercise: Likely provides benefit in improving pain
intensity and function
– Mind-body techniques: Likely benefit from
biofeedback, cognitive behavioral therapy, and
relaxation techniques
– Massage: May improve pain level
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nonpharmacologic Therapy
• Radiculopathy
– Exercise: Likely provides mild benefit
– Multiple other techniques such as traction,
massage, and acupuncture have insufficient
evidence for efficacy

Pharmacologic Therapy
• Acute low back pain
– Acetaminophen: Conflicting evidence.
Randomized trial did not show benefit but some
observational studies support use
– NSAIDs: small benefit in pain intensity
– Muscle relaxants: Small benefit in pain
– Corticosteroids: No clear benefit
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pharmacologic Therapy
• Chronic low back pain
– NSAIDs: Small to moderate benefit
– Acetaminophen: Insufficient data
– Duloxetine: Small benefit in pain and function
– Tricyclic antidepressants: Unclear if any benefit
– Opiates: Moderate benefit but high risk of harm
and ineffectiveness with long term use. Tramadol
may have benefit.
– Gabapentin/pregabalin: Unclear if any benefit

Opiate Therapy – SPACE Trial

Opioid therapy does not provide improvement in pain function or intensity

over non-opioid group

180
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pharmacologic Therapy
• Radicular pain
– Diazepam: Brief duration therapy may be helpful
– NSAIDs: Likely benefit
– Acetaminophen: Likely benefit
– Glucocorticosteroids: Unclear benefit
– Pregabalin: Uncertain benefit
– Inadequate data to assess other therapies such as
muscle relaxants

Interventional Therapies
• Epidural Steroid Injections
– Best data support use for short term benefit in
radiculopathy
– No clear benefit in lumbar spinal stenosis or
chronic low back pain
• Medial branch block: Used as a
diagnostic/therapeutic measure for facet
related pain
– Can be followed by radiofrequency ablation

181
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Surgery
• Surgical referral:
– Radiculopathy: Persistent disabling symptoms of
generally at least six weeks duration failing
conservative measures.
– Lumbar stenosis: Indicated with
weakness/numbness or disabling pain
– Chronic low back pain: Unclear how to select
patients. Generally disabling pain for at least one
year with significant degenerative disease on
imaging. Symptoms often persist.

Failed Back Syndrome

• Persistent disabling pain despite surgery
– Muscular/ligamentous pain not intervened on
– Incorrect surgical level
– Surgical complications
– Progressive degenerative disease
– Arachnoiditis
• Spinal cord stimulation with epidural lead
placement may be an option for pain
reduction
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Conclusion
• Back pain is common and occurs from varied
causes
• Most instances of back pain resolve
spontaneously without any intervention
• Axial low back pain is generally treated
medically
• Radiculopathy and lumbar stenosis may be
treated surgically if symptoms are persistent
and disabling

183
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Spinal Cord Disorders

Shamik Bhattacharyya MD MS
Brigham and Women’s Hospital
Harvard Medical School

Disclosure
No relevant disclosures for this presentation

184
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Length: 45 cm (17.7 in)

Weight: 30 grams

• L1-2 interspace disc

• 40% below this level but
almost always above L2-
3 disc space

Images from Gray’s Anatomy 40th edition

Images from Lippincott Williams & Wilkins library

185
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Images from Lippincott Williams & Wilkins library

• Cervical spinal roots exit

near the corresponding
vertebra
• Thoracic spinal roots
descend for one to two
vertebral body lengths
before exiting
• Longer distance for lumbar
and sacral nerve roots

Images from Gray’s Anatomy 40th edition

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The anatomical level of spinal cord segment and

vertebral body segment do not correspond to
each other

T8 vertebral body ~T9 spinal cord

segment

Images from Lippincott Williams & Wilkins library

187
 Continuum (2015); 21:13-35

188
 Images from Gray’s Anatomy 40th edition

Spinal cord lesions can cause symptoms at that segment

or any level below

189
 Common Complaints
• Progressive weakness (can be symmetric or
asymmetric)
• Bladder urgency/hesitancy; bowel incontinence
• Subjective sense of numbness below a level
(such as numb from waist down)
• Difficulty walking
• Painful spasms

Signs
• Flexor pattern weakness in legs – hip flexion,
knee flexion, foot/toe dorsiflexion
• Extensor pattern weakness in arms – shoulder
abduction, elbow extension, wrist/finger
extension
• Numbness below a level in the back –
“sensory level.” Test both with sharp and
vibration

190
 Signs
• Decreased rectal tone
• Reflexes can be increased/decreased
depending on acuity. Acutely decreased and
later increased
• Upgoing toe (Babinski response)
• Tone can be increased/decreased. Acutely
flaccid and then hypertonic

Myelopathy is a clinical diagnosis. Imaging has variable

sensitivity depending on etiology.
 Imaging
• CT: Good to examine bony spine structures such
as for fractures. Does not show spinal cord
parenchymal changes.
• MRI: Better definition of parenchymal structures
and spinal roots.
– Best to localize spinal lesions clinically and image
focused area (such as cervical MRI or thoracic MRI)
– Whole spine imaging has low sensitivity for
pathologies other than cord compression or
multiple metastatic cancer lesions

Imaging
• CT myelography: Largely superseded by MRI.
Injection of contrast into intrathecal space.
– In patients who cannot get MRI, can image
subarachnoid space for compressive lesions of the
spinal cord
Does this patient have myelopathy from degenerative
spine disease?

Spondylotic Myelopathy
• Commonly affects the cervical spinal cord
• Spondylosis: Age-related degenerative changes
– Begins with disc dessication leading to
– Herniation of disc accompanied by
– Development of osteophytes impinging along
ventral aspect of spinal cord accompanied by
– Ligament calcification and facet arthropathy

193
 Spondylotic Myelopathy

• Most common cause of myelopathy in adults

over age 55
• Most common cause of non-traumatic
paraparesis in adults

Threatening, treatable, and time-dependent diagnosis

194
 Spondylotic Myelopathy
• Cervical spondylotic changes occur in over
90% of adults over 65.
• Of those with symptoms of neck pain, only 5-
10% have findings of myelopathy
• Of those with imaging evidence of spondylosis
and spinal cord compression, only 23% will
develop clinical myelopathy when followed for
3.5 years

Spondylotic Myelopathy
• Pathogenesis not only from mechanical
compression
– Symptoms not predicted well by degree of stenosis
alone
• Other hypothesized factors:
– Repetitive stretch injury from flexion/extension
movement in narrowed canal with distorted
anatomy
– Chronic cord ischemia from compression of artery
and microvasculature

195
 Risk factors
• Male gender
• Repetitive occupation injury
• High performance aviators and athletes
• Ossification of posterior longitudinal ligament
particularly common in Asian
• Down syndrome
• Rheumatoid arthritis and Ankylosing
Spondylitis
• Familial clustering reflecting genetic
predisposition

Clinical Presentation
• Progressive gait dysfunction most common
– Feeling of imbalance, stiffness, and sensory
changes (despite normal strength testing)
• Clumsiness of hands or fine motor movements
(such as writing or typing errors)
• Neck pain (may not be present)
• Parasthesias in the extremities
• Bladder dysfunction is less common (~15-20%
of patients)
 Examination
• Commonly seen as spastic gait
• Increased tone particularly in legs
• Increased reflexes (such as ankle clonus). Note
common concurrent neuropathy in older
population makes reflexes alone unreliable
• Upgoing toes
• Decreased proprioceptive and vibratory
sensation

197
 Management
• Natural history unclear of untreated
spondylotic myelopathy
– Some suggest stability while others show steady
progression of deficits
• Neurologic status deteriorates in about 20-
62% of patients
• Wide variability in natural history

Prognostic Factors
• Some evidence that milder disability may
stabilize with conservative treatment
• Shorter history of symptoms may be
associated with clinical stability (low-quality
evidence)
• Unclear area of the field

198
 Management
• Conservative advice:
– Hard or soft cervical collar
– Pain control
– Activity restriction with avoidance of heavy lifting,
jumping, or repetitive neck movement
• None of these compared with each other in
randomized trial

Surgery
• Multiple approaches based on anatomy
– Anterior approach: Cervical discectomy usually
with fusion of adjacent vertebrae
– Posterior approach: Laminectomy with fusion
– Anterior-posterior approach
• Complications:
– Dysphagia, recurrent laryngeal nerve palsy
– C5 root weakness
– Instability at sites of fusion

199
With mild myelopathy, conservative management with
careful monitoring may be appropriate while
progressive symptoms likely require surgery.

Does this patient have transverse myelitis?

200
 Transverse Myelitis
• Term first used in 1948 by English neurologist
A.I. Suchett-Kaye for reporting a case of
paralysis following pneumonia
• Confusing term that has come to mean
virtually any inflammatory myelopathy
• At present, specific etiology favored over the
term transverse myelitis

Clinical Presentation
• General signs/symptoms of myelopathy with
sensory loss, weakness, bladder/bowel
dysfunction, pain
• Usually progresses over hours to days
• Acute presentation with diminished reflexes
and flaccid tone – can be confusing with
peripheral nerve etiologies like Guillian-Barre
Syndrome

201
 Acute Investigation
• Urgent imaging of entire spinal cord with MRI
to exclude compressive lesion
– Often followed by focused dedicated imaging of
region of interest with contrast
• Usually followed by lumbar puncture testing
for:
– Cell count, glucose, protein
– Oligoclonal bands and IgG index

Multiple Sclerosis
• About 85% of patients
with MS will experience
myelitis
• 20-40% will have
myelitis as presenting
symptom
• Typically short segment
with ovoid appearance
 Multiple Sclerosis
• With compatible imaging, test for:
– Brain MRI (often there are asymptomatic lesions)
• Myelitis + brain MRI lesions = high risk of
developing MS
• Myelitis + normal MRI + negative oligoclonal
bands on CSF = lower risk of developing MS
• Patients with first attack need follow-up
imaging at 6 month or 1 year following event

Neuromyelitis Optica (NMO)

• Increasingly recognized
cause of myelitis
• Associated with
– Longitudinally extensive
myelitis (>3 vertebral
segments)
– Has relapsing-remitting
course often with
incomplete resolution

203
 Neuromyelitis Optica
• Associated with anti-Aquaporin 4 antibodies
(aquaporin expressed on astrocytes)
• Core clinical characteristics
– Optic neuritis
– Myelitis
– Area postrema syndrome: Unexplained intractable
hiccups and nausea/vomiting
– Symptomatic narcolepsy or thalamic/hypothalamic
lesions
• If positive, treated with steroids + plasma
exchange acutely and rituximab long term

Most patients with unexplained myelitis should be

tested for anti-Aquaporin 4 antibody from serum
 Other Inflammatory Diseases
• In Sjogren Syndrome, often positive anti-AQP4
antibody
• In systemic lupus erythematosus, myelitis can
be anti-AQP4 positive or negative
• In sarcoidosis, difficulty to diagnose.
– Serum ACE elevated in less than 50%. CSF ACE
may be more helpful
– Search for other systemic disease. 5-10% will have
isolated neurosarcoidosis

Paraneoplastic Disorder
• Associated with number of cancers mostly
carcinomas
• Often insidious in onset over weeks
• In the majority, myelopathy precedes cancer
diagnosis by about a year
• Can have normal cell count but isolated
elevated protein in CSF
• May or may not have known paraneoplastic
antibody

205
Suggested Diagnostic Evaluation for Inflammatory Myelitis

Brain MRI

Anti-Aquaporin 4 Antibody

Anti-Ro/La, ANA, anti-phospholipid antibody

Copper, Vitamin B12

CSF VZV IgG and PCR

Serum treponemal antibody

CSF West Nile Virus Serology (in appropriate season)

Serum Mycoplasma Serology (for evidence of recent infection)

CSF HSV1/HSV2 PCR

In majority of cases, treat empirically with high dose

corticosteroids (1000 mg IV methylprednisolone daily
for 3 to 5 days) and/or plasma exchange.

206
Does this patient have autonomic storm?

Autonomic Dysreflexia
• Typically associate with severe spinal cord
injury at T6 level or above
• “Storms” triggered by noxious stimuli below
the level of injury
• Syndrome is secondary to exaggerated
sympathetic outflow from poor
parasympathetic autonomic response
– Parasympathetic neurons in sacral region (below
level of lesion typically)

207
 Typical Findings
• Arrhythmias
• Severe hypertension (systolic blood pressure
can reach >250 mmHg)
• Sweating
• Tremors
• Temperature dysregulation – hyperthermia or
hypothermia

If untreated, autonomic dysreflexia is uncomfortable

and can be life threatening (such as hypertensive crisis
or intracranial hemorrhage).

208
 Find the Source
• Often the trigger is in genitourinary system or
in lower body
– Bladder distension/blocked urinary tract
– Severe constipation
– Urinary tract infection
– Pressure sores
– Occult bone fracture
– Pain

Treatment
• Sit the patient upright
– Typically, with spinal cord injury, patients lose
ability to regulate orthostatic pressure
– Sitting upright orthostatically lowers blood
pressure
• Treat inciting source
– Focus investigation on constipation and urinary
tract
– Treat pain aggressively
– If necessary, use adrenergic blockade

209
 Conclusion
• Important to recognize spinal cord disorders
as cause of progressive paraparesis –
screening with lumbar MRI for leg weakness
often misses myelopathy
• Cord lesions can produce symptoms at that
segment or below
• Progressive gait disorder is often the
presenting feature of spondylotic cervical
myelopathy.

Conclusion
• MRI is the preferred imaging method for
spinal cord
• Myelopathy is a clinical diagnosis with
supportive laboratory and imaging features
• There is a broad differential for transverse
myelitis – it is a descriptive term rather than
etiology

210
 Pain Neurology
Victor C Wang, MD, PhD
Division Chief, Pain Neurology
Brigham and Women’s Hospital

Disclosures
No disclosures

211
Pain
Most common symptom of disease

Must recognize disease and treat the disease

MI presenting as chest pain
Gout/arthritis presenting as joint pain
Metastases presenting with various pain

Etiology of pain
Acute pain
Trauma
Disease

Chronic pain
Central nervous system
Peripheral nervous system
Disease

212
Sensory pathways
Transmission of pain – nociception
Different fibers
Aδ fibers – small myelinated
Pain and temperature
C fibers – small unmyelinated
Slow pain and temperature

Cell bodies in the dorsal root ganglion

Dorsal horn
Brain interpretation of pain

Terms to describe pain

Allodynia
Abnormal perception of pain from normal stimulus

Hyperalgesia
Abnormal pain response from a normally painful
stimulus

Hypoalgesia
Decreased sensitivity to painful stimuli

Analgesia
Reduced perception of pain stimulus

Paresthesia
Spontaneous abnormal sensations
Neurologic conditions with
pain
Low back pain Trigeminal neuralgia

Headache and Migraine Postherpetic neuralgia

Diabetic neuropathy Parkinson’s Disease

Carpal tunnel syndrome Thalamic pain syndrome

Ulnar neuropathy

CRPS

Neuropathic pain and

Headache
20 million people in US with peripheral
neuropathy

Migraine is 8th highest cause of disability in the

USA and 3rd leading cause under the age of 50

Covered in other lectures in this series

214
Low back pain
Leading cause of disability in the world

Lifetime incidence of low back pain 60-70% in

industrialized countries

Prevalence increases with age and peaks

between 35 and 55

Common Sources of Low

Back Pain
Structural
Myofascial Emotional Factors
Soft Tissues, ligaments Stress, somatization
Neurogenic Functional Changes
Nerve roots
Poor posture,
Joints deconditioning
Facet joints, SI Joints
Spinal Stenosis,
Spondylolisthesis, Tumor
Evaluating Back and/or Leg Pain
Symptoms exacerbated by
standing
Standing in erect position
leads to extension of the
spine which worsens stenosis
of the canal and foramina.
Loading facet joints in
extension and rotation is a
sign of facet arthropathy

Neurogenic Claudication
Cardinal symptom of Spinal
Stenosis
Progressive onset of radicular
pain, numbness and weakness
initiated by walking
Symptoms relieved by sitting, not
standing alone.
Classic scenario is a patient who is
able to walk with out rest in the
supermarket pushing a cart, but is
unable to stand in the parking lot
Lumbar radiculopathy

Approach to Chronic Pain

Multidisciplinary
Physician Evaluation
Complete History Physical Exam
Appropriate Imaging
Therapeutic Plan

Psychological assessment if indicated

Maintain Function
Continue rehabilitation program

217
Conservative management
Physical therapy

Heat/cold

Massage/chiropractic

Yoga

Acupuncture

Medication therapy
Anti-inflammatories
Tylenol
NSAIDs

Muscle relaxants

Anticonvulsants
Gabapentin
Therapeutic Blocks
When patient fails conservative management

Local anesthetic and corticosteroid injections for treatment of

the lumbar spine was based on the efficacy of these injections
to control inflammation

Corticosteroids relieve pain related to inflammation

Facilitate recovery in nerve compression injury

CRPS
Pain condition that affects a limb usually after
injury

Type 1
Without confirmed nerve injury

Type 2
Known nerve injury

219
CRPS
Diagnosed by history, signs and symptoms

Symptoms
Continuous burning pain
Hyperesthesia
Temperature changes
Nail and hair growth changes
Abnormal sweating pattern
Tremor

CRPS
Treatment
Physical therapy
Continued use of affected limb
Psychotherapy
Medication therapy
Botox
Sympathetic nerve blocks
Spinal cord stimulation
Trigeminal neuralgia
Episodes of severe shooting facial pain
Can last seconds to minutes
In the distribution of the trigeminal nerve

Triggers
Light touch
Chewing
Toothbrush
Talking

Trigeminal Neuralgia
Treatments
Medications
Anticonvulsants
Carbamazepine
Oxcarbazepine
Lamotrigine
Phenytoin
Microvascular decompression
Gamma knife
Radiofrequency lesioning

221
Post-herpetic neuralgia
Peripheral nerve damage after herpes zoster
attack

Pain that persists after shingles rash resolves

Burning sharp pain
Hyperesthesia or allodynia
Frequency increases with age

Postherpetic neuralgia
Treatment
Topical
Lidocaine
Capsaicin
Systemic
Gabapentin, pregabalin, tricyclic antidepressants
Parkinson’s Disease
Significant overlap of co-morbid pain

Neurodegenerative disorder

40-60% of patients with chronic pain

MSK
Dystonic
Radicular
Central neuropathic

Depression

Psychiatric comorbidities of
chronic pain
Must address other underlying issues

Pain can cause depression and vice-versa

Psychotherapy
Cognitive behavioral therapy
Biofeedback

223
Thalamic pain syndrome
Thalamic stroke or lesion
Dejerine-Roussy Syndrome
Sensory loss, allodynia and/or burning/freezing
sensations over the opposite side of body

Imaging for lesion

Thalamic pain syndrome

Treatment
Manage risk factors for stroke including hypertension,
smoking, diabetes and cholesterol
Tricyclics or SSRIs
Anticonvulsants
Topicals
Deep-brain stimulation
Opioids

224
Opioids in chronic pain
Controversial current medical and political
environment

Minimal evidence for long term benefit

Strong evidence for harm and death

Addiction
Sedation
Nausea
Constipation
Tolerance
Respiratory depression

225
Opioid risks

CDC guidelines 2016

Long term opioid use begins with treatment of
acute pain
For acute pain: only if severe. Less than 3 days
should suffice and more than 7 days is rarely needed

Only use opioids if expected benefit for BOTH

pain and function outweighs risk
Identify risks for misuse
Combine therapy with non-opioids
Establish realistic goals, exit strategy, opioid
agreement
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Risk factors:
History of OD
Substance use disorder
psychiatric disease
Concurrent benzodiazepine use
Sleep apnea
Renal or hepatic insufficiency

Avoid increasing dosage to greater than 90

MME/day

Frequent re-evaluation

Review patient’s history of controlled substance

prescriptions with state drug monitoring programs

Urine drug testing at least annually for prescribed

medication and illicit substances

227
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pain Neurology
Find and treat the etiology of the pain

Symptomatic management

Conservative strategies

Interventions

228
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

EPILEPSY
TRACEY A. MILLIGAN, MD, MS, FAAN
EPILEPTOLOGIST

DISTINGUISHED CLINICIAN
VICE CHAIR FOR EDUCATION
DEPARTMENT OF NEUROLOGY
DISTINGUISHED CLINICIAN, BRIGHAM HEALTH
ASSISTANT PROFESSOR OF NEUROLOGY
HARVARD MEDICAL SCHOOL

No disclosures

229
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epilepsy is Common: 1 in 26
Diagnosis US Prevalence US New Cases/yr
Migraine 28 million
Alzheimer’s Dementia 5.4 million 454,000
Stroke 4.4 million 700,000
Epilepsy 3.4 million 300,000 / 200,000

Parkinson’s disease 500,000 50,000

Multiple sclerosis 400,000 10,000

https://www.cdc.gov/epilepsy/d
ata/index.html

Learning Objectives

Review the critical components of

epilepsy diagnosis
Understand the treatment options
available for epilepsy
Remember the common co‐
morbidities and safety issues

230
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

231
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Conceptual Definition of Epilepsy

Epilepsia, 46(4):470-472, 2005

Blackwell Publishing, Inc. © 2005 International League Against Epilepsy

Epileptic Seizures and Epilepsy: Definitions Proposed By the International

League Against Epilepsy (ILAE) and the International Bureau for Epilepsy
(IBE).

Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr.

Epilepsy is a disorder of the brain characterized by an enduring predisposition

to generate epileptic seizures, and by the neurobiologic, cognitive,
psychological, and social consequences of this condition. The definition of
epilepsy requires the occurrence of at least one epileptic seizure.

232
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ILAE OFFICIAL
REPORT

Epilepsy is a disease of the brain defined by any of the following conditions

1. A least two unprovoked (or reflex) seizures occurring >24 h apart

2. One unprovoked (or reflex) seizure and a probability of further seizures similar to
the general recurrence risk (at least 60%) after two unprovoked seizures, occurring
over the next 10 years

3. Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but
are now past the applicable age or those who have remained seizure-free for the last 10 years, with no
seizure medicines for the last 5 years.

ILAE OFFICIAL
REPORT

Epilepsy is a disease of the brain defined by any of the following conditions

1. A least two unprovoked (or reflex) seizures occurring >24 h apart

2. One unprovoked (or reflex) seizure and a probability of further seizures similar to
the general recurrence risk (at least 60%) after two unprovoked seizures, occurring
over the next 10 years

3. Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but
are now past the applicable age or those who have remained seizure-free for the last 10 years, with no
seizure medicines for the last 5 years. Can Dx and Tx for Epilepsy after
ONE seizure

233
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Classification System
• Designed to provide greater diagnostic specificity
for treatment and research
• Change in terminology used to describe seizure
type and to describe etiology

Instruction manual for the ILAE 2017 operational classification of seizure types

Epilepsia
8 MAR 2017 DOI: 10.1111/epi.13671
http://onlinelibrary.wiley.com/doi/10.1111/epi.13671/full#epi13671‐fig‐0002
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ILAE classification of the epilepsies: Position paper of the ILAE Commission for
Classification and Terminology

Epilepsia
8 MAR 2017 DOI: 10.1111/epi.13709
http://onlinelibrary.wiley.com/doi/10.1111/epi.13709/full#epi13709‐fig‐0001

Case 1: Status Epilepticus

• 36 y.o. man with a PMH of a penetrating head
injury 10 years previously resulting in behavioral
and cognitive deficits
• While having dinner with his mother he has a “fit”
and has 2 seizures later that night
• He does not receive treatment and 3 months later
has a severe seizure
• He receives treatment, but he continues to have
seizures and dies 2 days later
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1860 ‐ Phineas Gage

Status epilepticus

• 30 minutes of either:
• Continuous seizure activity
• Repetitive seizures without recovery in
between
Epilepsy Foundation of America –
JAMA 1993

• 5 minutes or more of continuous clinical

and/or electrographic seizure activity or
recurrent seizure activity without recovery
between seizures

Brophy, Gretchen M., et al. "Guidelines for the

evaluation and management of status
epilepticus." Neurocritical care 17.1 (2012): 3‐23.

236
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

How do you treat Status

Epilepticus?

Use algorithm

Lowenstein, DH, Alldredge, BK Status Epilepticus

N Engl J Med 1998 338: 970-976
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Status Epilepticus Pearls

• A seizure lasting 5 minutes is a medical emergency
• Treat while looking for cause
• Faster treatment is more effective treatment
• 1st line benzodiazepine
• 2nd line fosphenytoin

238
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2: Epilepsy in the Elderly

A 75 year old woman is brought to the physician for
episodes of confusion. She has weekly episodes of
feeling unwell and staring into space for 30‐60
seconds followed by mild confusion. She has a
history of hypertension, tobacco use and was
recently diagnosed with lung cancer. Her
examination is normal. Which of the following is the
most likely diagnosis?
A. Generalized seizure disorder
B. Focal motor seizure
C. Dementia
D. Psychogenic non‐epileptic seizure
E. Absence seizure

Classification System: 2 Seizure Categories

Focal Generalized
originate at some point
originate within within, and rapidly
networks limited to engaging, bilaterally
one hemisphere distributed networks (can
include cortical and
(may be discretely subcortical structures,
localized or more but not necessarily
widely distributed) include the entire cortex)

239
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Which of the following are true?

A. A normal EEG excludes the diagnosis of epilepsy
B. The EEG will show generalized seizure activity
C. Focal slowing on the EEG helps to localize the
anatomic origin of the seizures
D. A normal MRI excludes seizures as a diagnosis

EEG

• Assess for epileptiform discharges (30%,

increases to 80‐90% with 3 EEGs)
• Help diagnose presence, type, and location
of epilepsy
• Negative EEG does not rule out epilepsy
• Sleep deprived EEG more sensitive
(increase yield by 30%)
• EEG after spell or seizure is more sensitive
(51% vs 30%)
• Extended monitoring: video EEG or
ambulatory EEG
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Imaging
• After 1st seizure MRI is indicated
• Yield of about 10% leading to diagnosis of brain
tumor, stroke, cystircercosis or other structural
lesions
• May help determine risk of seizure recurrence

Late-onset epilepsy
Common Causes

Cerebrovascular disease >50%

Neurodegenerative disease 10‐20%

Intracerebral tumors 10‐30%

Traumatic brain injury 20%

Brodie et al, Lancet Neurol 2009; 8: 1019–30

241
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Age and Etiology of Epilepsy

When etiology is known:
Older Adults (>60 years)

Adapted from Hauser WA. Epilepsia. 1992;33(suppl 4):S6‐S14.

AED Treatment
• Treat after a single seizure and significant risk of
recurrence
• Treat after diagnosis of epilepsy
• Use single AED (will control seizures in 2/3 of patients)
• Increase dose to effectiveness or toxicity before
beginning a second agent
• Drug levels can establish compliance
• Trough levels can influence dosing
• Newer AEDs are preferred (just as efficacious and fewer
side effects)

242
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Many Antiepileptic Drugs (AEDs)

Older Medications Newer Medications
(1st Generation) (2nd Generation)
Trade
Generic Name FDA Approval
Trade Name
Generic Name Year Introduced
Name
Felbamate 1993 Felbatol®

Bromides 1857 — Gabapentin 1993 Neurontin®

Phenobarbital 1912 Luminal® Lamotrigine 1994 Lamictal®

Topiramate 1996 Topamax®

Phenytoin Sodium 1956 Dilantin®
Tiagabine 1997 Gabitril®
Ethosuximide 1960 Zarontin®
Levetiracetam 1999 Keppra®
Diazepam 1963 Valium®
Oxcarbazepine 2000 Trileptal®
Carbamazepine 1968 Tegretol® Zonisamide 2000 Zonegran®

Lorazepam 1977 Ativan® Pregabalin 2005 Lyrica®

Lacosamide 2008 Vimpat®

Valproic acid (VPA) 1978 Depakene®
Rufinamide 2008 Banzel®

Divalproex sodium 1983 Depakote® Potiga®

Ezogabine 2011

Carbamazepine 1986 Epitol®

Clobazam 2011 Onfi®

Diazepam 1997 Diastat®

Perampanel 2012 Fycompa®
Carbamazepine 1997 Carbatrol®

Eslicarbazepine 2014 Aptiom®

Phenytoin Sodium 1998 Phenytek®
Brivaracetam 2016 Briviact®

Many Antiepileptic Drugs (AEDs)

Older Medications Newer Medications
(1st Generation) (2nd Generation)

Trade
Generic Name Generic Name FDA Approval
Name

Gabapentin 1993 Neurontin®

Phenobarbital

Lamotrigine 1994 Lamictal®

Phenytoin Sodium
Topiramate 1996 Topamax®

Carbamazepine Levetiracetam 1999 Keppra®

Oxcarbazepine 2000 Trileptal®

Divalproex sodium
Zonisamide 2000 Zonegran®

Pregabalin 2005 Lyrica®

Carbamazepine

Lacosamide 2008 Vimpat®

243
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Which AED is best for an older

adult?
• A. Carbamazepine
• B. Gabapentin
• C. Lamotrigine

Figure 4.

A. J. Rowan et al. Neurology 2005;64:1868-1873

©2005 by Lippincott Williams & Wilkins

244
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epilepsy in the Elderly‐ Pearls

• Epilepsy most commonly occurs in the elderly

• New onset epilepsy is focal epilepsy
• EEG and MRI may be normal
• Monotherapy – low dose lamotrigine, levetiracetam,
gabapentin
• Avoid carbamazepine and oxcarbazepine
• Newer AEDs have less side effects and fewer drug‐drug
interactions
• Have a high index of suspicion for episodes of altered
awareness, confusion, falls, loss of consciousness

Case 3 – First Seizure?

• Emily is brought to the ED after a witnessed GTC
• She was with a friend at a coffee shop the morning
after a concert
• At the concert, she drank ETOH
• She did not sleep that night
• Her friend noticed jerking movements and then Emily
had a GTC
• Emily feels tired and sore and doesn’t remember
anything
• Her examination is normal
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Seizure

Syncope (convulsive)

Psychiatric disturbance (psychogenic non‐epileptic

seizure, panic attack)

Paroxysmal Migraine

Behavioral Cerebral ischemia (TIA)

Event Movement disorder

Sleep disorder

Metabolic disturbance

Self‐Reported Symptoms
Less Frequent More Frequent

Syncope PNES Epilepsy

After: I feel drained or sleepy
I want to know what happens when I have blacked out
My attacks come on without any warning
During: I have no idea what is happening around me
After: I feel very upset
After: I feel very confused
In: I feel lightheaded, like I might pass out
After: my muscles ache
My attacks make me feel very low or empty
My attacks come over me
When I feel an attack coming on I try to fight it
In: sounds are distorted
In: my vision goes dim or dark
In: I feel hot or cold
After: I feel relieved
In: I am conscious but I can’t react to things
In: my mouth goes very dry
My attacks are associated with emotional stress
I am aware of a trigger for my attacks
During: my heart pounds and I feel shaky and sweaty
During: I feel very frightened
During: I can see or hear the people around me
My head spins in my attacks
During: I do not recognize my friends or family
In: everything seems to move away from me

Reuber, M et al. 2016. Neurology

246
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HISTORY and Examination

• Risk factors for epilepsy: family history, TBI, other
brain injuries, birth trauma, febrile seizures
• Full neurologic and general physical examination:
focal neurologic signs, cognitive or developmental
disorder, unrecognized medical disease

Listen for:
Trouble describing aura

Description of aura that is suggestive of an epilepsy aura

• Hallucinations, illusions
• Deja‐vu
• Automatisms
• Rising abdominal sensation
Unresponsiveness and lost time

Epileptic cry

Cyanosis, tonic‐clonic, foaming at the mouth, bleeding from the mouth

Post‐ictal breathing and agitation

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1. Was it really a seizure?

(open ended questions, eye‐witness, pre‐ & post‐ictal clues)

2. Is it a provoked seizure?
(alcohol or drugs, etc.)

Key 3. Is it the first seizure?

Questions (myoclonus, prior auras, altered awareness, photosensitive)

Guiding 4. Localization/Type of seizure

the
History 5. Cause of seizure

6. Epilepsy syndrome?

Epilepsy Syndromes
• Defined typical characteristics in addition to seizure
type
• Age, location, EEG, treatment, prognosis
• Examples include: Childhood absence epilepsy
(CAE), juvenile myoclonic epilepsy (JME), and
benign rolandic epilepsy (BRE)

248
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• Spectrum of action (broad vs.

narrow)
• Parenteral
Anti‐Epileptic administration/loading options
• Pharmacokinetics and drug
Drug (AED) interactions
• Inducers: carbamazepine,
Considerations phenytoin, phenobarbital
• Inhibitors: valproate,
felbamate
• Protein bound: valproate,
phenytoin

• Concomitant disease
• Birth control

Broad Spectrum – use when you don’t • Likely adverse effects

know the type or cause of seizure – • Efficacy
levetiracetam, lamotrigine, valproate, • Cost
topiramate, zonisamide

Idiosyncratic: usually systemic/allergic

• Rashes

AEDs:
• Organ toxicity

Dose‐related: usually CNS

Adverse • Dizziness, drowsiness, ataxia

• Cognitive slowing, depression (may also be

Effects idiosyncratic)

Chronic: drug‐induced diseases

• Osteoporosis
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DO NOT START:
Carbamazepine
351% Oxcarbazepine
Phenytoin
increased risk
Lamotrigine
(Eslicarbazepine)

Bone Health
Increased risk of fracture in
Decrease in bone density people with epilepsy
• Phenytoin
• Primidone
• Phenobarbital
• Carbamazepine
• Valproic acid

Significant bone loss in men too

Supplement with vitamin D and more frequent evaluation of bone
mineral density
Neurology 2003; 61: S2‐17; Adnress DL et al,
Arch Neurol, 2002
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Women With Epilepsy

In women of childbearing age
• Periodically readdress AED therapy and birth
control; be aware of drug‐drug interactions
between AEDs and oral contraceptives
In women considering pregnancy
• Preconception counseling
• Folic acid 1 mg daily, early prenatal care
• Contact epilepsy specialist and/or high‐risk
obstetrician, if appropriate
All women (and men)
• Bone health

Teratogenic Risk
Profiles of Antiepleptic
Drugs
Carbamazepine Phenytoin
Lamotrigine
Phenobarbital Valproic acid
Levetiracetam Oxcarbazepine
* Topiramate*

Increasing Risk
Slide courtesy of Page
* = neurodevelopmental outcomes are not yet known Pennell
Pennell PB. Neurotherapeutics 2016.

251
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Driving
• Epilepsy may account for 0.02% to 0.04%
of reported car crashes
• Required seizure‐free intervals vary
greatly among jurisdictions (typically 3 to
12 months)
• Mandatory physician reporting: CA,
OR, PA, DE, NV, NJ
• State driver licensing laws available at
http://www.epilepsyfoundation.org
• Discuss driving with patient and
document in medical record

Start with possibility it was not a

seizure
Look for provoking causes

50% of patients with 1st seizure

1st Seizure have epilepsy

Pearls Family hx, neuro exam, MRI, EEG

are key for prognosis
Start AED in some cases

Counsel regarding safety and no

driving

252
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 4 – DDx and Discontinuing

AED
• A 64 year old woman comes for evaluation of
whether or not she should continue phenytoin.
• She has a history of a seizure 20 years ago and has
been taking phenytoin since that time.
• She has gingival hyperplasia requiring dental scaling
3 times a year. She has osteoporosis.
• What is the risk versus benefit of continuing to
prescribe phenytoin?

• No seizure for >5 years

• Favorable factors
Discontinuing • control on one drug
at low dose
AEDs • no unsuccessful
attempts at
withdrawal
• Normal neurologic
exam, EEG, “benign
syndrome”
• Consider risks/benefits
(e.g. driving, pregnancy,
job issues)
• Always taper

253
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

AED Withdrawal Pearls

• Consider after 5 years of seizure freedom
• Cause of epilepsy matters
• Select low risk patients
• Always taper
• EEG prior to taper
• Recommend no driving for 3 months
• Epilepsypredictiontools.info
Lamberink HJ et al. Lancet Neurology 2017;
16(7):523

Case 5 – Modern Treatment for

Refractory Epilepsy
• Matt is a 36 year old man uncontrolled seizures and
his MRI shows mesial temporal sclerosis.
• Which of the following is the most effective
treatment?
• A. Resection of the anterior temporal lobe
• B. Marijuana
• C. Ketogenic diet
• D. Vagus nerve stimulator
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Surgery for TLE

Wiebe, Blume, Girvin, Eliasziw. A Randomized Controlled Trials of Surgery for Temporal Lobe Epilepsy; NEJM, 2001

Treatment Options in Epilepsy

• Antiepileptic drugs (AEDs)
• 1st generation
• 2nd generation
• Extended release
• Devices
• Vagus nerve stimulation (VNS®)
• Responsive neurostimulation (RNS)
• Epilepsy surgery
• Alternative therapies

255
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Intractable=Pharmacoresistant
Epilepsy=Drug Resistant Epilepsy
• Epilepsy unresponsive to medical management:
• 30%
• Morbidity and mortality:
• Falls, drowning, co‐morbid conditions
• Sudden unexpected death in epilepsy (SUDEP)–
• SUDEP (1/500‐1/1000 per year)
• 27 X that in the general population and the cause of
death in 2‐18% of patients, but less than half of epilepsy
related deaths
• Patients randomized to placebo – 10X more likely to
have SUDEP

55

Epilepsy, Depression and Death

• More than 1 of every 3 people with epilepsy have depression
• 3‐4X risk of suicide
• newly diagnosed (5X), hx psychiatric illness (29X)
• Prior suicide attempt ‐> 5X risk of subsequent epilepsy
• Substance abuse, psychosis, bipolar disorder, schizophrenia,
depression independently associated with new‐onset epilepsy

Leestma et al. Ann Neurol 1989;26(2):195-203 ;Fricker,

1998;Walczak et al. Neurology 2001;56(4):519-525;
Christensen J, Vestergaard M, Mortensen PB, et al.
Martin et al Epilepsia 2014; Fazel S et al. 2013. Lancet;
Epilepsy and risk of suicide: a population‐based
382:1646-54
case‐control study. Lancet Neurol 2007; 6:693‐698.

256
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

After failure of 2 AEDs

consider surgery and refer
to Epilepsy Monitoring Unit

Refractory Other treatment options:

ketogenic diet, VNS, RNS,
Epilepsy epilepsy brain surgery
Pearls
Surgery is worth the risk
given high risk of seizures
(e.g., SUDEP)

Epilepsy is a common disease with different

causes and manifestations

Other disorders can mimic seizures, including

convulsive syncope and psychogenic seizures

History is key to accurate diagnosis

Summary
of Key Diagnostic studies for all patients: MRI, EEG

Points
There are many therapeutic options

Education and safety issues are important

considerations

257
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Seizures as a
Symptom of
Systemic Disease
TRACEY A. MILLIGAN, MD, MS, FAAN
EPILEPTOLOGIST

DISTINGUISHED CLINICIAN
VICE CHAIR FOR EDUCATION
DEPARTMENT OF NEUROLOGY
DISTINGUISHED CLINICIAN, BRIGHAM HEALTH
ASSISTANT PROFESSOR OF NEUROLOGY
HARVARD MEDICAL SCHOOL

No disclosures
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions
• Seizure: the clinical manifestation of an abnormal
and excessive excitation of a population of cortical
neurons

• Epilepsy: a tendency toward recurrent seizures

unprovoked by systemic or neurologic insults

• Acute symptomatic seizure—seizure resulting

directly from a systemic or neurologic insult

Instruction manual for the ILAE 2017 operational classification of seizure types

Epilepsia
8 MAR 2017 DOI: 10.1111/epi.13671
http://onlinelibrary.wiley.com/doi/10.1111/epi.13671/full#epi13671-fig-0002

259
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Symptomatic Seizures
• Close temporal relationship to acute brain injury
or
• Simultaneously due to metabolic, toxic, infections,
inflammatory process
• Clinically and on EEG look like epileptic seizures
(typically GTC)
• Different pathogenesis, therapy, prognosis

Symptomatic Seizures
• Metabolic (hyponatremia, hypoglycemia, hyperthyroidism,
nonketotic hyperglycemia, hypocalcemia, hypomagnesemia,
renal failure, porphyria)
• Within 24 hours

• Medications (benzodiazepine withdrawal, barbiturate

withdrawal,phenothiazines, bupropion, tramadol)

• Substance abuse (alcohol withdrawal, cocaine, amphetamine,

phencyclidine, methylenedioxymethamphetatime [“ecstasy”])

• Acute neurologic insults

• Within 1 week
• Eclampsia 6
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Eclampsia
• GTC in setting of preeclampsia (HTN, proteinuria)
and absence of other neurologic conditions
• Etiology: disease of placenta; endothelial damage,
vasospasm, vasogenic edema
• Second most common cause of maternal death in
US (4-5 cases per 10,1000 live births in developed
countries)
• Third trimester and postpartum
• Magnesium 2g IV rapidly

Cause of Seizure
• 1/3 of the time is initial presentation of epilepsy
• Vascular – 3% of strokes present with a seizure
• Infection – meningitis (17%); febrile seizure 6m – 5y (5%)
• Neoplasm – primary or metastatic (20-40%)
• Drugs – prescribed and nonprescribed
• Inflammatory/Idiopathic - vasculitis
• Congenital – malformations may present with adult seizures
• Autoimmune – SLE (11%)
• Trauma – 2-17% (depending on severity)
• Endocrine/Metabolic – hyponatremia, hypoglycemia

261
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Organ Dysfunction
Cardiac
focal seizures from cardioembolic stroke generalized
tonic-clonic or nonconvulsive or myoclonic seizures
from global cerebral ischemia after cardiac arrest

Renal
Common in acute uremia
7-10 days after onset of renal failure
Typically bilateral tonic-clonic, but can be focal
Uncommon in chronic renal insufficiency
Treat by correcting metabolic abnormalities and
blood pressure if hypertensive encephalopathy
Increased risk with penicillin

Hepatic
Uncommon in acute hepatic encephalopathy and
chronic liver disease
Check for hypoglycemia as a cause
Acute intermittent porphyria – frequently associated
with seizures and epilepsy

• Alcohol dependence:
10.2% among excessive
drinkers (>8 drinks per
week in 30 days) and
10.5% among binge
drinkers (>4 drinks per
occasion
• 50% will experience
symptoms of
alcohol withdrawal
upon reduced
alcohol intake
• 2 million episodes of
ETOH withdrawal per year
in US
• 5-10% of
patients have a
seizure
• 8% of all patients
Alcohol Withdrawal admitted to the hospital
• 16-31% of patients in ICU
Seizures • Up to 31% of trauma
patients

Uusaro A, Parviainen I, Tenhunen JJ, et al. The proportion of intensive care unit admissions related to
alcohol use: a prospective cohort study. Acta Anaesthesiol Scand. 2005;49:1236-1240
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Precipitants of Seizure Pathophysiology

Epileptic seizure aggravated by ETOH Sleep deprivation, missed AEDs, more

rapid metabolism of AEDs, neuronal
dysfunction

Post-traumatic epilepsy (head trauma Neuronal dysfunction, micro and other

from ETOH falls) hemorrhages

Stroke Increased risk of stroke (AF, HTN)

Hypoglycemia Nutritional, insulin regulation, liver

dysfunction

Infection Increased risk of meningitis

Hyponatremia Volume depletion or Beer potomania

Concomitant drug use disorders Benzodiazepine and others

The Alcohol Withdrawal Syndrome

Victor, M. & Adams, R.D. Res Publ Assn Nerv Ment Dis 32, 526-573 (1953).
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alcohol Withdrawal Seizures

Typically occur after years of drinking and
multiple episodes of withdrawal.
Onset 12-48 after last drink
Generalized tonic-clonic
Multiple, within 6 hours
Post-ictal drowsiness < 1 hour

Victor and Brausch; Epilepsia 1967; 1-20

Antiepileptic Drugs and ETOH

w/d
• Phenytoin does not work
• Inpatient treatment
• Benzodiazepines dosed by CIWA
• With status epilepticus: Propofol can open Cl channels in
absence of GABA and may also antagonize glutamate

• Outpatient treatment
• Carbamazepine and valproic acid can help treat alcohol
withdrawal
• Gabapentin
• Lamotrigine, topiramate, memantine better than placebo and
not different from diazepam
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Drug Induced Seizures

• Primary mechanism – drug directly leads to seizure

• Secondary mechanism – drug leads to decreased

substrate required by the brain (e.g., oxygen,
glucose, sodium)

Other Drugs
• Amphetamines (especially IV)
• Cocaine
• MDMA Ecstasy
• Gamma-Hydroxybutyric Acid GHB
• (Marijuana)
• Sedative withdrawal (ETOH, benzodiazepines,
barbiturates, diphenhydramine)

265
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Antibiotics
• Unsubstituted penicillins
• 4th generation
cephalosporins
(cefepime)
• Imipenem
• Ciprofloxacin
• In combination with
renal dysfunction, brain
lesions and epilepsy
• Isoniazid (pyridoxine
deficiency – treat with
B6 and benzodiazepine)

Bupropion
• Incidence is correlated with dose
o Incidence is 0.4% at doses of 300-450mg/day
but increases by 100 fold in doses > 600 mg/day
o Sustained release formulation has lower
incidence due to lower peak plasma
concentrations
o By comparison
-0.1% with SSRIs
- 0.4-2 % with TCAs
• Anorexia and bulimia further increase the risk
(a randomized trial in which bupropion was
given to 55 nondepressed presents induced a
GTC in 4 patients – 7 percent).

Davidson J J Clin Psyciatry 1989

20 yo with severe depression,
self-mutilation, psychosis

Clozapine
• Seizures more common during initiation and high doses
• Study of 283 patients - 60% had EEG abnormalities
• 15% with “spikes” of some kind.
• 2-3% have risk for new onset seizures, particularly at
higher doses
• EEG with focal and generalized slowing and focal or
generalized spikes
• In patients with epileptiform EEGs, level >500 mg/L,
myoclonic jerks: lower dose or add AED (valproate,
lamotrigine) to lower risk of seizure
Varma et al 2001; Gunther et al 1993

267
Rheumatic Disease
• SLE: CNS involvement in 50% of patients
• Headache, mild cognitive deficits, psychosis, seizure,
stroke
• Seizures are more common with antiphospholipid
antibodies
• Sjogren syndrome: less common (1-8% CNS
involvement)
• Vasculitis

Case
• 56 y.o. man with DM2, HTN, CAD, h/o frontal lobe
strokes
• one week of flashing lights, left hemifield blurry vision,
and headache.
• He describes bright flashing lights in his left visual field
that waxes and wanes x1 week. Symptoms were
episodic lasting 3-10 minutes. He also notes associated
blurry vision on his left side. Two days ago, he noted
new onset of right frontotemporal headache. He
reports food is a trigger for headaches and visual
phenomenon. He presented to his ophthalmologist
who diagnosed him with an ocular migraine.

268
Provoked Seizure?
• BP (154-173)/(82-91)
• Medications: None
• Labs: Electrolytes, renal and liver function tests all
normal
• Glucose: 321
• Hemoglobin A1C: 13
• MRI: old strokes in B frontal lobes

Nonketotic Hyperosmolar
Hyperglycemia
• High glucose level leads to seizures
• Treat with IVF and insulin
• May get worse with phenytoin
• Leads to focal seizures

269
Glucose
• Seizures occur in 25% of people with DM
• More common in hyperglycemia (25%) than
hypoglycemia (7%)
• Nonketotic hyperosmolar seizures: focal, including
epilepsia partialis continua (EPC)

Hypertension
• Increased risk of stroke
• Posterior reversible encephalopathy syndrome
(PRES)
• Altered mental state, vision changes, headache,
weakness, nausea
• Up to 84% will have seizures
• Neuroimaging shows vasogenic edema (most commonly
in posterior cerebrum)

270
 Sodium
• Hyponatremia
• Symptoms relate to rate
of change rather than
absolute value
Electrolyte • Hypernatremia

Abnormalitie • Seizure may occur during

rehydration

s Calcium
• Hypocalcemia
• Focal seizures in 20% of
patients, accompanied by
altered mental status and
tetany
• Hypercalcemia
• Infrequently causes
seizures
Magnesium
• Hypomagnesemim (< 0.8
mEq/L)
• Multifocal and generalized
seizures

Metabolic Causes of Seizures

• Hyponatremia: volume depletion, CHF, cirrhosis,
diarrhea, increased ADH, adrenal insufficiency,
hypothyroidism, excessive water, pregnancy, recent
surgery, thiazide diuretics, SSRIs, carbamazepine,
oxcarbazepine, TCAs, sorbitol
• Hypernatremia: excessive water loss, poor water
intake, diarrhea, diabetes insipidus,
hypoparathyroidism
Metabolic Causes of Seizures
• Hypomagnesemia: diarrhea, malabsorption, drugs
(loop and thiazide diuretics, cyclosporine's ,
aminoglycosides), alcoholism, poor nutrition
• Hypocalcemia: parathyroid dysfunction
• Hypercalcemia: malignancy, thiazide diuretics,
lithium, excessive vitamin D, hyperparathyroidism

Case

• 31 yo man with a recent diagnosis of acute myeloid

leukemia
• Admitted for chemotherapy
• Some RLE weakness earlier in the day
• Fell to floor convulsing
Head CT Stat

Neurologic Causes of
Secondary Seizures
• Infection: HSV encephalitis, meningitis,
encephalitis, abscess
• Acute stroke: hemorrhagic, ischemic, venous sinus
thrombosis
• Traumatic brain injury
• Brain tumors
• Increased risk of developing epilepsy, but no
method of decreasing risk through use of
medication

273
Treatment
• Metabolic – correct abnormality
• Drugs – discontinue
• Toxin – remove toxin, benzodiazepines
• Eclampsia – delivery, blood pressure management,
Mg
• Neurologic injury – antiepileptic drug temporarily

Key Summary Points

• There are many provoking factors for seizures
• Investigation through history, examination,
laboratory tests and neuroimaging will often reveal
the cause of the seizure
• Treatment is based on the underlying etiology

274
 Visual Disturbances
Sashank Prasad, MD
Associate Professor of Neurology
Harvard Medical School
Brigham and Women’s Hospital

Disclosures

• Reports no commercial interest

275
 8:00 AM Ross, Betsy
9:00 AM Bonaparte, Napoleon
10:00 AM Roosevelt, Eleanor
11:00 AM Edison, Thomas
1:00 PM Franklin, Benjamin
2:00 PM Earhart, Amelia

A 32-year-old woman
8:00 AM
9:00 AM
Ross, Betsy
Bonaparte, Napoleon
presents with a “smudge” in
10:00 AM
11:00 AM
Roosevelt, Eleanor
Edison, Thomas the right eye that has
1:00 PM Franklin, Benjamin
2:00 PM Earhart, Amelia progressed for 3 days, and
retro-orbital pain that is worse
with eye movements
Optic neuritis: symptoms

normal optic neuritis

“washed out”
“smudge”
• Clinical features
• Pain with eye movements
• Vision nadir at 1 week

Optic neuritis: acuity

Refractive
error

Pinhole
correction

Acuity loss
Optic neuritis: color vision

Ishihara color plates

Optic neuritis: visual fields

Finger counting Automated field

278
Optic neuritis: afferent pupillary defect

Optic neuritis: optic nerve appearance

Mild
swelling

1/3 have mild swelling

normal optic nerve head

279
Optic neuritis: treatment

IV steroids hasten recover

(but do not improve final outcome)

Optic neuritis: risk of MS

72%

25%

280
 A 61-year-old man with
8:00 AM Ross, Betsy
9:00 AM
10:00 AM
Bonaparte, Napoleon
Roosevelt, Eleanor
hypertension presents with
11:00 AM
1:00 PM
Edison, Thomas
Franklin, Benjamin
sudden loss of vision in the
2:00 PM Earhart, Amelia
right eye that he noticed upon
awakening. It has remained
stable all day. There is no
pain.

Ischemic optic neuropathy: nonarteritic

Small cup Disc swelling

Acute painless vision loss (no progression)

Older adults, vascular risk factors
Disc edema
Typically stable deficit, minimal improvement
‘Altitudinal’ field cut
Ischemic optic neuropathy: arteritic
• Clinical features
• Age >60
• Systemic symptoms
(scalp tenderness, myalgias,
jaw claudication, fevers)
pale • Exam
swelling
• Pale disc swelling
Cotton wool • Co-existing retinal ischemia
spots (cotton wool spots)
• Enlarged temporal artery

Ischemic optic neuropathy: arteritic

• Clinical features
• Age >60
• Systemic symptoms
(scalp tenderness, myalgias,
jaw claudication, fevers)
• Exam
• Pale disc swelling
• Co-existing retinal ischemia
(cotton wool spots)
• Enlarged temporal artery
• Diagnosis
• ESR, CRP
• Fluoroscein angiography
• Temporal artery biopsy
• Treatment
• Prompt steroids, hydration
• Prevent contralateral eye
involvement
 8:00 AM Ross, Betsy
A 40-year-old woman who is
9:00 AM
10:00 AM
Bonaparte, Napoleon
Roosevelt, Eleanor
50 lbs over her ideal body
Edison, Thomas
11:00 AM
1:00 PM Franklin, Benjamin weight presents with brief
2:00 PM Earhart, Amelia
episodes of blurred vision in
both eyes. She has
headaches and hears her
pulse. She has gained 15 lbs
over the past 3 months.

Papilledema

Splinter
hemorrhages

retinal vessels
obscured

Evaluate for intracranial mass,

hydrocephalus, DSVT, infection

283
Pseudotumor cerebri
• Increased ICP of unknown etiology
• Clinical features
• Transient visual obscuration (TVO’s)
• Pulsatile tinnitus
• Visual field constriction progressing to central visual loss
• 6th nerve palsy may be only focal (“false-localizing”) sign
• Risk factors
• Obesity, recent weight gain, pregnancy
• Management
• Weight loss!
• Acetazolamide
• Shunting or optic nerve sheath fenestration
• Serial exams and automated visual fields to detect progression

8:00 AM Ross, Betsy

9:00 AM Bonaparte, Napoleon A 43-year-old man has
10:00 AM Roosevelt, Eleanor
11:00 AM
1:00 PM
Edison, Thomas
Franklin, Benjamin
noticed trouble seeing to the
2:00 PM Earhart, Amelia right. He is not sure when the
problem began. He believes
the problem is with the right
eye, but has not specifically
checked each eye separately.
Visual Fields: monocular or central?

Visual Fields: monocular or central?

My right eye is blurry

285
Visual Fields: monocular or central?

Visual Fields: monocular or central?

286
Visual Fields: central

Left eye Right eye

R L
Right superior quadrant field deficit
Left temporal lobe tumor

Visual Fields: central

Left eye Right eye

R L
Right homonymous hemianopia
Left occipital stroke

287
 8:00 AM Ross, Betsy
9:00 AM Bonaparte, Napoleon
10:00 AM
11:00 AM
Roosevelt, Eleanor
Edison, Thomas
A 63-year-old man with
1:00 PM
2:00 PM
Franklin, Benjamin
Earhart, Amelia diabetes presents with double
vision and aching pain behind
the right eye. The double
vision disappears if he closes
either eye.

Double vision

• Monocular
• Present when covering 1 eye
• Ocular cause
• Binocular
• Resolves when covering 1 eye
• Ocular misalignment

288
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ocular ductions
Lateral Medial
Rectus Rectus

Superior Inferior
Rectus Oblique

Primary actions of Inferior Superior

the extra-ocular muscles Rectus Oblique

Double vision

289
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Double vision

Treatment with patch,

prisms,
or eye muscle surgery

8:00 AM Ross, Betsy

9:00 AM Bonaparte, Napoleon
10:00 AM Roosevelt, Eleanor
11:00 AM
1:00 PM
Edison, Thomas
Franklin, Benjamin
A 32-year-old woman presents
Earhart, Amelia
2:00 PM
with double vision. She has
also noticed the left eyelid is
drooping and the left pupil is
larger.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Third nerve palsy: pupil-involving

poor
pupillary
constriction
32 y/o woman with headache and
double vision

Third nerve palsy: pupil-involving

PComm Aneurysm

291
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Third nerve palsy: pupil-sparing

55 y/o man with HTN, DM and double vision

Third nerve palsy: pupil-sparing

55 y/o man with HTN, DM and double vision

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Third nerve palsy: pupil-sparing

55 y/o man with HTN, DM and double vision

Full resolution in 3 months

Third nerve palsy: evaluation

Complete deficits?
- ptosis
- eye fully down-and-out?

Incomplete Complete

Pupil-involved Pupil-spared

CT/MRI close
with angiography observation

293
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Outline

• Optic neuritis
• Ischemic optic neuropathy
• Pseudotumor cerebri
• Visual fields
• Double vision
• Third nerve palsy
Thank you!

294
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

EYE MOVEMENT, LID, AND PUPIL ABNORMALITIES

Robert M. Mallery, MD
Division of Neuro-Ophthalmology
Brigham and Women’s Hospital

Disclosures
• Reports no commercial interest
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Outline

• Ocular Motor Neuropathies

• Gaze Disorders

• Nystagmus

• Disorders of Pupil

• Disorders of the Eyelid

Action of the ocular motor nerves

• Third cranial nerve

SO
(oculomotor)
SR
• Superior rectus muscle
(elevation, internal rotation)
• Inferior rectus (depression, III MR
external rotation) IV
• Medial rectus (adduction) VI IR
• Inferior oblique (external rotation,
elevation) IO
LR
• Fourth cranial nerve
Schematic of right orbit.
(trochlear)
• Superior oblique (internal rotation,
depression)
• Sixth cranial nerve
(abducens)
• Lateral rectus (abduction)

Images from Liu et al. Neuro-Ophthalmology.

296
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Third nerve palsy

• Course
• Originates in the dorsal
midbrain
• Passes in close proximity to
the PCA and P. Com. artery
as it passes toward the
cavernous sinus.
• Branches into superior and
inferior divisions in the
anterior cavernous sinus
• Causes
• Vasculopathic/diabetic
• Compressive
(aneurysm, mass)
• GCA
• Trauma (skull base
fractures)
• Schwannoma

Images from Liu et al. Neuro-Ophthalmology.

The Rule of the Pupil

• Compression of CN 3 by an aneurysm
typically leads to pupil involvement.

• But…when the pupil is unaffected and

the other muscles are only partially
involved, the CN 3 palsy could
progress to involve the pupil. Vascular
imaging with MRA or CTA is needed to
evaluate for aneurysm.

• A complete pupil-sparing CN 3 palsy

does not require urgent neuroimaging

Images from Liu et al. Neuro-Ophthalmology.

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Fourth nerve palsy

• Originates in the dorsal
lower midbrain
• Decussates (crosses)
posteriorly
• Smallest ocular motor
nerve, susceptible to Anterior
trauma Left CN 4 Palsy
• Causes of CN 4 palsy
• Congenital
• Trauma Worse in
• Ischemic/vasculopathic right gaze
• Compression by mass
• GCA
• Schwannoma

Worse with
Images from Liu et al. Neuro-Ophthalmology. left head tilt

Sixth nerve palsy

• Course
• Originates in the dorsal pons
• Lateral gaze initiated in the
PPRF
• Interneurons link the CN 6
nucleus with contralateral CN
3 medial rectus subnucleus
• Traverses over the clivus and
skull base to enter the
cavernous sinus at Dorello’s
canal
• Passes into the orbit at the
superior orbital fissure

• Causes
• Vasculopathic/diabetic
• Intracranial hypertension
• Compression (cavernous
sinus aneurysm, meningioma)
• Petrous apex disease
• GCA
• Schwannoma
Video from Leigh and Zee. The Neurology of Eye Movements.
Diagram from Liu et al. Neuro-Ophthalmology.

298
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Horizontal gaze palsy

• Impairment of conjugate
gaze
• Causes
• Frontal lobe lesion
(contralateral gaze palsy)
• Brainstem lesion (ipsilateral
gaze palsy)

Left gaze palsy

Video from Leigh and Zee. The Neurology of Eye Movements.
Diagram from Liu et al. Neuro-Ophthalmology.

Internuclear ophthalmoplegia
• Lesion of MLF between the CN 6 nucleus and
contralateral CN 3 nucleus
• Impaired adduction on the side of the INO
• Common causes:
• Demyelination (women, young)
• Stroke (older, vascular risk factors)

Video from Leigh and Zee. The Neurology of Eye Movements. Left INO
Diagram from Liu et al. Neuro-Ophthalmology.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dorsal Midbrain Syndrome

• Lesion affecting the tectum
(dorsal midbrain)
• Hydrocephalus
• Mass
• Stroke

• Features
• Impaired upward gaze
• Convergence-retraction
saccades
• Light-near dissociation of the
pupils
• Eyelid retraction

Vertical gaze palsy

Convergence retraction saccades
Video from Leigh and Zee. The Neurology of Eye Movements.

Nystagmus and Nystagmoid Eye Movements

• Nystagmus

• An involuntary, rhythmic eye movement in which a slow

drift of the eyes prevents steady fixation

• Saccadic intrusion
• An abnormal eye movement in which an inappropriate
saccadic (fast) movement interrupts fixation

300
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nystagmus: Wave Forms

• Constant velocity drift:
• Vestibular disease: peripheral or central
• Lesions of the cerebellum

Forms of
Jerk • Decreasing velocity waveform:
• Gaze-evoked nystagmus
Nystagmus

• Increasing velocity waveform:

• Congenital nystagmus (horizontal)
• Cerebellar disease (vertical)

• Pendular nystagmus: often congenital

From Leigh and Zee. The Neurology of Eye Movements.

Congenital nystagmus
• Conjugate, horizontal (even in upgaze)

• Large amplitude, low frequency pendular

nystagmus at onset
• Converts to higher frequency jerk or mixed
nystagmus some time before 1 year.
• Damps with convergence or eyelid closure

• Accentuated by attempts at fixation

• Presence of a null point

• No oscillopsia (Foveation periods)

301
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

2 mo. infant with congenital nystagmus

Video courtesy of Dr. Grant Liu.

Classification of congenital nystagmus

• Congenital motor nystagmus
• Dysfunction of ocular motor systems involved with
visual fixation
• Usually sporadic but may be AD, AR, or X-linked

• Congenital sensory nystagmus

• ‘Mis-wiring’ due to visual deprivation
• Optic nerve hypoplasia/atrophy
• Ocular albinism

• Retinal dystrophies
• Congenital cataracts

302
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Workup of congenital nystagmus

• Afferent visual function

• Slit lamp exam

• Fundus exam

• MRI/VEP/ERG for
patients with congenital
sensory nystagmus

Acquired forms of nystagmus

• Vestibular nystagmus

• Peripheral

• Central

• Acquired pendular nystagmus

• See-saw nystagmus

• Periodic alternating nystagmus (PAN)

303
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral vestibular nystagmus

• Jerk, with linear slow
phase (“saw-tooth”)
• Trajectory obeys the
geometry of the
affected semicircular
canals
• Suppressed by visual
Courtesy of David Zee
fixation Arrows indicate the direction of the slow
phase if an individual canal is stimulated

If multiple canals are stimulated the slow

phase direction is a vector sum

Posterior canal BPPV

Arrows
indicate the
direction of
the slow
phase if an
individual
canal is
stimulated

If multiple
canals are
stimulated the
slow phase
direction is a
vector sum

Courtesy of David Zee

304
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Posterior canal BPPV

From Leigh and Zee. The Neurology of Eye Movements, 4th Ed.

Right labyrinthitis
Arrows
indicate the
direction of
the slow
phase if an
v individual
canal is
stimulated

If multiple
canals are
stimulated the
slow phase
direction is a
vector sum

Courtesy of David Zee

305
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Central Vestibular Nystagmus

• Pure torsional

• Vertical nystagmus in primary gaze

• Downbeat – localized to cervicomedullary junction and the

cerebellar flocculus (including from medication effects)

• Upbeat – less localizing to the brainstem and cerebellum

• Direction changes in different gaze positions

• Gaze-evoked nystagmus (often metabolic or toxic)

Pure torsional nystagmus

• Usually indicates a central vestibular disorder
• Patients often have an ocular tilt reaction
• Nystagmus beats toward the opposite shoulder in a
medullary lesion and toward the ipsilateral shoulder
in midbrain lesions

306
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Torsional nystagmus

Etiology of downbeat nystagmus

• Degenerations affecting the vestibulocerebellum
(cervicomedullary junction or flocculus)
• Lesions near the craniocervical junction
• Craniocervical anomalies
• Brainstem or cerebellar infarction
• Multiple sclerosis (MS)
• Tumor

• Toxic/metabolic
• Anticonvulsants
• Lithium
• Alcohol
• Wernicke’s encephalopathy
• Hypomagnesemia
• Amiodarone
• Opioids
• B12 or thiamine deficiency
• Toluene abuse

307
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Downbeat nystagmus

From Leigh and Zee. The Neurology of Eye Movements.

Saccadic intrusions

• Square-wave jerks

• Macrosaccadic oscillations

• Ocular flutter

• Opsoclonus

308
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Square-wave jerks
• Pairs of small horizontal saccades (<2 deg) that take
the eye away from the target and then return it within
200 ms

Macrosaccadic oscillations
• Hypermetric saccades around the fixation point that wax and
wane, with an intersaccadic interval of about 200 ms
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ocular flutter
• Intermittent bursts of conjugate horizontal saccades
without an intersaccadic interval

Opsoclonus
• Combined multidirecitonal horizontal, vertical,
and torsional saccadic oscillations, without an
intersaccadic interval
• Children
• 50% of children with opsoclonus have neuroblastoma
• Parainfectious

• Adults
• Parainfectious
• Drug induced
• Paraneoplastic (anti-Hu, anti-Ri, gynecologic cancers)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Opsoclonus

From the collection of Dr. Frank Walsh. In Leigh and Zee.

The Neurology of Eye Movements, 4th Ed.

Voluntary ‘nystagmus’ (flutter)

• Conjugate, horizontal oscillations

• High frequency (15-25 Hz)

• Unsustained for more that about 30 seconds

• Often precipitated by convergence

• Accompanied by eyelid fluttering

311
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Voluntary ‘nystagmus’

From Leigh and Zee. The Neurology of Eye Movements, 4th Ed.

The Pupil
• Aperture of the optic system
• Diameter varies between 2 and 8-9 mm
• Prevents sudden overexposure of the retina

• Provides depth of focus during near vision

• Iris muscles
• Sphincter muscle
• Surrounds the pupillary margin
• Parasympathetic (muscarinic receptors)

• Dilator
• Thin layer of myoepithelial cells spread across the
iris, with connections to the sphincter
• Sympathetic (primarily alpha-2 adrenergic)

312
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non-neurologic causes of abnormal pupils

• Congenital mal-development

• Iritis

• Trauma (including surgical)

• Iris atrophy Central posterior

synechiae related to iritis.
• Pharmacologic dilation

• Plants: nightshade, jimson weed

• Ipratropium

• Scopolamine

Iris coloboma
Photos from Eyerounds.org (U. Iowa)

Innervation of the Pupil

Parasympathetic

Sympathetic

From Wilhelm et al. 2011

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Innervation of the Pupil

Sympathetic

Horner’s syndrome

From Wilhelm et al. 2011

Innervation of the Pupil

Sympathetic

Horner’s syndrome

From Wilhelm et al. 2011

314
 Innervation of the Pupil

Sympathetic

Horner’s syndrome

From Wilhelm et al. 2011

Innervation of the Pupil

Parasympathetic

Poor reaction to light

From Wilhelm et al. 2011

315
 Innervation of the Pupil

Parasympathetic

Poor reaction to light

From Wilhelm et al. 2011

Innervation of the Pupil

Parasympathetic

Poor reaction to light

From Wilhelm et al. 2011

316
 Neurologic Disorders of the Pupil:
Which pupil is abnormal?

• Anisocoria greater in the dark

The smaller pupil dilates
poorly (Horner’s syndrome)
• Anisocoria greater in the light
The larger pupil constricts
poorly (3rd nerve palsy or
tonic pupil) Horner syndrome Physiologic
anisocoria
• Anisocoria equal in light and
dark physiologic (25% of
normals)

Images from Wilhelm et al. Disorders of the Pupil. Handbook of Clinical Neurology 2011.

Common Causes of Horner’s syndrome

• Internal carotid artery dissection

• Painful, dysgeusia, history of trauma or
neck manipulation
• Stroke (eg. dorsolateral medullary
stroke)
• Double vision (skew deviation), vertigo
(torsional nystagmus)
• Brainstem tumor
• Apical lung tumor
• Smoking history, productive cough Smaller left pupil, mild left upper and lower
• Neuroblastoma eyelid ptosis
• Occurring in infancy
• May have iris heterochromia

• Congenital
• ?Regressed neuroblastoma, birth trauma

• Cluster Headache
• Idiopathic

317
 Tonic pupil
• Injury to the ciliary ganglion
(parasympathetic)
• Initially an irregular dilated pupil
• Over time becomes more
constricted
• Poorly reactive to light
• React better to near with slow re-
dilation (tonic)
• Signs
• Segmental iris constriction 10 s delay
• Loss of pupillary ruff A-B: Irregular and poor reaction to light
• Vermiform movements of iris C-D: Intact near response, slow re-dilation
• Adie’s syndrome when
accompanied by loss of peripheral
deep tendon reflexes

Images from Wilhelm et al. Disorders of the Pupil. Handbook of Clinical Neurology 2011.

Third cranial nerve palsy

• Pupil parasympathetic fibers travel with CN 3 (oculomotor
nerve)
• Dilated pupil due to CN 3 palsy is almost always
accompanied by an ocular motility disturbance
• Ddx:
• Microvascular/diabetic
• Posterior communicating artery aneurysm (Emergency)
• Giant cell arteritis (>50 years-old)
• Midbrain lesion (eg. stroke, demyelination, etc.)
 Eyelid abnormalities
Levator palpebrae
• Ptosis
• Mechanical
• Neurologic (CN3 or
Horner)
• Neuromuscular Orbicularis oculi Superior tarsal
(myasthenia gravis) (Muller’s) muscle
• Myopathic

• Eyelid retraction Tarsal plate

• Thyroid eye disease
Inner eyelid
• Dorsal midbrain
surface
syndrome

• Pseudo-ptosis

Liu et al. Neuro-Ophthalmology

Non-neurologic ptosis

Levator dehiscence (right eye) Dermatochalasis causing

pseudo-ptosis (both eyes)

Kearns Sayre Syndrome

(Chronic Progressive External
Ophthalmoplegia)
Eyerounds.org
 Ocular Myasthenia Gravis
• Fluctuating ptosis

• Diplopia

• Bilateral facial weakness

• May have Cogan lid twitch

Ptosis and lid twitch due to

myasthenia gravis

Video courtesy of Dean Cestari

Neurologic Ptosis
• Third nerve palsy
• Weakness of levator
palpebrae superioris
• Mild to complete upper
eyelid ptosis
• Eye movement abnormality

• Oculosympathetic palsy
(Horner syndrome)
• Weak tarsal muscles
Left CN 3 palsy
• Mild (1-2 mm) upper eyelid
ptosis
• Lower eyelid ptosis
• Impaired pupil dilation

Left Horner syndrome

Images 1 and 2 from Liu et al. Neuro-Ophthalmology
 Eyelid Retraction
• Dorsal Midbrain Syndrome
• Pineal region tumor
• Dorsal midbrain tumor
• Stroke
• Hydrocephalus

• Thyroid Eye Disease Collier sign due to astrocytoma

Eyelid retraction in Grave’s disease

References
• Liu, Volpe, and Galetta. Neuro-ophthlamology: Diagnosis
and Management, 2nd Ed, 2010.
• Leigh RJ and Zee D. The Neurology of Eye Movements,
4th Ed.
• Wilhelm H. Disorders of the Pupil in Handbook of Clinical
Neurology, C. Kennard and R.J. Leigh, Editors. 2011.
• http://novel.utah.edu
• Eyerounds.org: http://webeye.ophth.uiowa.edu/eyeforum/

321
 Parkinsonism
Chizoba Umeh, M.D.
Instructor, Department of Neurology
Brigham and Women’s Hospital

Disclosures
None

322
Objectives
Overview of Parkinson’s disease (PD)
Epidemiology
Pathophysiology
Clinical Diagnosis
Differential diagnosis of Parkinsonism
Treatment of Parkinson’s disease

Case 1: PD, tremor predominant, Hoehn &

Yahr stage 1

58 year old male

onset of right hand intermittent rest tremor
in 2014 followed by development of left hand
rest tremor in January 2017.
associated micrographia, rapid eye movement
sleep behavior disorder.

Exam: decreased facial expression, right hand

rest tremor, cogwheeling rigidity in wrists (R>L),
limb bradykinesia- worse on the right, mild gait
bradykinesia
 James Parkinson, 1817
“Involuntary tremulous motion, with
lessened muscular power, in part not in
action and even when supported; with a
propensity to bend the trunk forward, and
to pass from a walking to a running pace:
the senses and intellect being uninjured.”

An Essay on the Shaking Palsy (1817)

Parkinson Disease: most common cause of

Parkinsonism

Stacy, M. and J. Jankovic, Differential diagnosis of Parkinson's disease and the parkinsonism plus syndromes. Neurol Clin, 1992. 10(2): p. 341-59.

324
Epidemiology of PD in the U.S.
Prevalence: Up to 1.0 million individuals

Incidence per year: ~60,000 new cases per year

Mean age of onset: 62 years

Onset before age 50: 4% of cases

Gender risk difference: Men 1.5 times more likely to

develop PD than women.

http://www.pdf.org/en/parkinson_statistics

Parkinson’s disease: pathophysiology

Loss of dopamine producing
neurons in Substantia Nigra
Dysfunction of the
dopaminergic pathway from
the substantia nigra to the
striatum.
Increased (inhibitory)
output of the basal ganglia to
the thalamus.
Clinical manifestations: tremor,
rigidity, bradykinesia, postural
instability.

Source: The 2010 Nobel Prize in Physiology or Medicine - Illustrated Information

325
Parkinson’s Disease: Pathology

Normal: S. Nigra (pigment) Parkinson’s: S. Nigra (decreased pigment)

Source: http://neuropathology-web.org/

PD Pathology: Lewy Body

Lewy Body: abnormal
aggregates of misfolded
protein (alpha synuclein).
Eosinophilic cytoplasmic
inclusion
dense core surrounded by
a halo of radiating alpha
synuclein fibrils.

Source: https://depts.washington.edu/adrcweb

326
Case 2: tremor predominant, Hoehn and
Yahr stage 3, PD diagnosis
58 year old woman
onset of left hand rest tremor in 2012–2013
Subsequent development of right hand rest tremor, gait
bradykinesia, rigidity
Exam: bilateral upper extremities resting tremor, marked
cogwheel rigidity upper extremities, limb/gait bradykinesia,
retropulsion

UK Brain Bank Criteria: (bradykinesia, rest tremor, rigidity,

postural instability)

PD Clinical Diagnosis: UK Brain Bank Criteria

Parkinson Disease, clinical

diagnosis
Step 1
Diagnosis of parkinsonian
syndrome
Step 2
Exclude other Parkinsonism
Step 3
Supportive criteria for IPD

Jankovic, J., Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry, 2008. 79(4): p. 368-76

327
Step1: Diagnosis of Parkinsonian syndrome

• Bradykinesia plus
• At least one of the following:
– Muscular rigidity
– 4-6 Hz rest tremor
– Postural instability not from
other causes
• NOTE
– 20-25% of patients with
Parkinson’s disease do NOT
have a rest tremor
• PD Clinical features
mnemonic: “TRAP”

Source: http://humanphysiology.academy/Neurosciences%202015/Chapter%205/CL.5p%20Parkinson.html

Bradykinesia
Bradykinesia –poverty of movement
limbs, trunk, gait

Loss of facial expression (hypomimia)

decreased blinking

‘Decay’ or decrement – finger-tap/heel-tap

328
Rigidity
Resistance to passive movement
Reinforcement – ‘froment’s maneuver’ can enhance rigidity

‘cogwheel’ quality

decreased arm swing, “frozen shoulder”

Tremor
Involuntary rhythmic alternating movement
At rest
‘Pill rolling’ quality
Increase with stress, anxiety
Typically may start unilaterally – upper limb
4 – 6 hertz
First symptom in 75%
~ 20-25 % never develop rest tremor

329
Postural instability
Retropulsion Assess pull test (2 steps
or less normal)
Inability to maintain
equilibrium Limited specificity in older
patients
Inability to adjust to quick
changes in position

Other features
Decreased Sialorrhea (drooling)
blinking/reduced facial Dysphagia
expression (hypomimia) Freezing of gait
Softer voice (hypophonia)
Micrographia

http://www.parkinsonsclinic.ca/parkinsonsdisease.html

330
Case 3: PD, Akinetic rigid, H&Y 2

65 year old woman

2015- onset of decreased right hand dexterity, micrographia,

R>L arm rigidity and gait bradykinesia.

Exam: asymmetric cogwheel rigidity bilateral wrists (R>L),

decreased arm swing bilaterally, limb and gait bradykinesia,
negative retropulsion

Diagnosis: Parkinson’s disease, Hoehn and Yahr stage 2

Hoehn and Yahr Stage

Source: www,parkinson.org

331
PD STAGES

LATE STAGE
EARLY STAGE
PRE-CLINICAL Bilateral symptoms
Unilateral symptoms
STAGE Dyskinesia
Masked face
REM Behavior Disorder Motor fluctuations (On-off)
Slowness
Loss of smell Dysphagia
Rigidity (stiffness)
Constipation Memory decline, dementia
Rest tremor
Low blood pressure Hallucinations
Shuffling gait
Freezing of gait, falls.

Classification of advanced stages of Parkinson’s disease: translation into stratified treatments. Rejko Krüger et al. J Neural Transm
(Vienna) 2017; 124(8): 1015–1027.

Tremor Predominant vs. Akinetic Rigid PD

Baumann CR(1), Held U, Valko PO, Wienecke M, Waldvogel D. Body side and predominant motor features at the onset of Parkinson's disease are
linked to motor and nonmotor progression. Mov Disord. 2014 Feb;29(2):207-13

332
Case 4: Young onset PD

44 year old man

February 2014: onset of left leg bradykinesia, gait and balance

difficulty.

Exam: reduced facial expression, left wrist cogwheeling

rigidity, limb and gait bradykinesia

Young onset vs. older onset PD

Wagner ML(1), Fedak MN, Sage JI, Mark MH. Complications of disease and therapy: a comparison of younger and older patients
with Parkinson's disease. Ann Clin Lab Sci. 1996 Sep-Oct;26(5):389-95

333
Step 2: exclude other Parkinsonism

Stacy, M. and J. Jankovic, Differential diagnosis of Parkinson's disease and the parkinsonism plus syndromes. Neurol Clin, 1992. 10(2): p. 341-59.

Other causes of parkinsonism

Essential tremor-Parkinsonism
Drug induced Parkinsonism
Vascular Parkinsonism
Parkinson’s plus syndromes
Progressive Supranuclear Palsy
Corticobasal syndrome
Psychogenic Parkinsonism

Source: http://clinicalgate.com/parkinsonism/
Case 5: Essential Tremor-Parkinsonism (ET-PD)

79 year old woman

2002: onset of mild bilateral hand action and resting tremor.
2013: increased severity of the bilateral action and resting hand
tremors and onset of gait bradykinesia.
2015: tremors began impacting daily activities (eating, handwriting)
Exam:
Essential Tremor signs: moderate postural and kinetic hand tremors
Parkinsonism signs: hypomimia, moderate resting tremors bilateral
upper extremities, mild cogwheel rigidity bilateral wrists, moderate
limb and gait bradykinesia

Essential Tremor-Parkinsonism (ET-PD)

Minen MT(1), Louis ED. Emergence of Parkinson's disease in essential tremor: a study of the clinical
correlates in 53 patients. Mov Disord. 2008 Aug 15;23(11):1602-5

335
Essential Tremor-Parkinsonism (ET-PD)

Minen MT(1), Louis ED. Emergence of Parkinson's disease in essential tremor: a study of the clinical
correlates in 53 patients. Mov Disord. 2008 Aug 15;23(11):1602-5

Case 6: Drug induced Parkinsonism

72 year old woman

history of bipolar disorder: treatment- lithium, haloperidol,

lurasidone

2014: onset of gait bradykinesia, stooped posture, mild postural

instability

Exam:
marked cogwheel rigidity bilateral upper extremities, decreased
facial expression, moderate gait bradykinesia.

336
Drug-Induced Parkinsonism

Alvarez MV(1), Evidente VG. Understanding drug-induced parkinsonism: separating pearls from oy-sters. Neurology. 2008 Feb 19;70(8):e32-4.

Drug-induced Parkinsonism

Shin HW(1), Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012 Mar;8(1):15-21.

337
Drug-induced Parkinsonism: imaging
Pathophysiology:
postsynaptic dopaminergic
receptor blockade
presynaptic dopaminergic
neurons intact

http://interactive.snm.org/docs/JNMT_CE_Article_Dec_2012.pdf

Case 7: Vascular Parkinsonism

55 year old man

Strokes in 1999 with residual left-sided weakness and
muscle rigidity
MRI Brain 2011: old hemorrhage in the left basal ganglia
and right internal capsule
2014: reported onset of RUE resting tremor.
Exam:
Residual stroke signs: left hemiparesis, spasticity left arm
Parkinsonism: right hand rest tremor, marked cogwheel
rigidity right arm, limb and gait bradykinesia.
Vascular Parkinsonism

Korczyn AD. Vascular parkinsonism--characteristics, pathogenesis and treatment. Nat Rev Neurol 2015;11:319-326

Vascular Parkinsonism: imaging

T2-weighted image shows a section of the brain of a 63-year-old

male with lower body parkinsonism. Disruption of the
periventricular and deep white matter (white and black arrows,
respectively) is seen.

Korczyn AD. Vascular parkinsonism--characteristics, pathogenesis and treatment. Nat Rev Neurol 2015;11:319-326
Case 8: Progressive Supranuclear Palsy (PSP)
82 year old woman
onset of gait bradykinesia (2008) and balance difficulty with falls(2011)
Exam:
Vertical supranuclear gaze palsy with limited vertical eye movements
and slowed vertical saccades
Parkinsonism with severe limb bradykinesia bilateral hands, mild
cogwheel rigidity right hand, severe gait bradykinesia and postural
instability
+ applause sign: tendency to continue clapping in response to
instructions to clap three times

PSP: Clinical features

Bradykinesia and rigidity, usually symmetrical in onset

Postural instability, early frequent falls
Vertical supranuclear palsy
impaired voluntary downward/upward gaze
gaze paresis corrects with passive oculocephalic
maneuver
Ocular findings: slowed vertical saccades, "square-wave
jerks"
“Applause” sign
Neck > limb rigidity, pseudobulbar palsy
Minimal levodopa response
Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear
palsy: a clinical cohort study. Neurology. 2003 Mar 25;60(6):910-6.

340
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ocular findings in PSP

Armstrong RA(1). Visual signs and symptoms of progressive supranuclear palsy. Clin Exp Optom. 2011 Mar;94(2):150-60.

Applause sign in PSP

Dubois B(1), Slachevsky A, Pillon B, Beato R, Villalponda JM, Litvan I. "Applause sign" helps to discriminate PSP from FTD and PD. Neurology.
2005 Jun 28;64(12):2132-3.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PSP: imaging

(A) Sagittal T1-MRI through the brainstem: Volume loss in the midbrain with
relative preservation of the pons- “hummingbird sign”. (B) Axial T1-weighted
imaging, dorsal midbrain is markedly reduced in volume: “mickey mouse sign”.

http://brain.oxfordjournals.org/content/130/3/816

Case 9: Corticobasal syndrome (CBS)

60 year old man
onset of apraxia (difficulty putting on tie) in
2010, with associated development of
parkinsonism (limb bradykinesia, left hand rest
tremor, left arm rigidity, gait bradykinesia)
micrographia, expressive aphasia, left hand alien
limb phenomenon
Exam:
Parkinsonism: left hand resting tremor, left arm
rigidity, limb and gait bradykinesia
Cognitive exam: impaired attention, expressive
aphasia
Cortical signs: limb-kinetic and ideomotor
apraxia (L>R arm)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CBS: diagnosis

Boeve B. Corticobasal degeneration: the syndrome and the disease. In: Litvan I, editor. , ed. Atypical Parkinsonian Disorders: Clinical and Research
Aspects. Totowa, NJ: Humana Press; 2005: 309–334

CBS: diagnosis

Boeve B. Corticobasal degeneration: the syndrome and the disease. In: Litvan I, editor. , ed. Atypical Parkinsonian Disorders: Clinical and Research
Aspects. Totowa, NJ: Humana Press; 2005: 309–334

343
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CBS: imaging

Boeve B. Corticobasal degeneration: the syndrome and the disease. In: Litvan I, editor. , ed. Atypical Parkinsonian Disorders: Clinical and Research
Aspects. Totowa, NJ: Humana Press; 2005: 309–334

Case 10: Psychogenic Parkinsonism

31 year old woman
Onset of bilateral hand tremors at age 8, later developed head tremor at
age 12, leg tremors at age 14, vocal tremor at age 20.
PMH: anxiety, depression
Exam:
Mixed tremor with postural, action and resting hand tremors bilaterally
with features of variability and distractibility of the tremor.
Pseudo-akinesia on finger taps with reduced frequency without
decrement in amplitude
Diagnostics:
MRI brain (April 2008): negative for stroke, mass, bleed, abnormal
enhancement.
Dopamine transporter scan negative

344
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical features of Psychogenic PD

Hallett M(1), Weiner WJ, Kompoliti K. Psychogenic movement disorders. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S155-7.

UK Brain Bank Criteria: Step 3

Supportive prospective positive criteria

Three or more required for clinical diagnosis of PD in
combination with Step 1
Unilateral onset
Rest tremor
Progressive symptoms
Persistent asymmetry
Excellent response to levodopa
Severe levodopa-induced dyskinesias
Levodopa response for 5 years or more
Clinical course of 10 years or more

Jankovic, J., Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry, 2008. 79(4): p. 368-76

345
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3 revisited: PD treatment

HPI: 65 year old woman

2015: onset of decreased right hand dexterity, micrographia,

R>L arm rigidity, gait bradykinesia.

Exam: asymmetric cogwheel rigidity (R>L), asymmetric

decreased arm swing b/l, limb/gait bradykinesia

Treatment: Carbidopa/levodopa 25/100 mg IR, 1.5 tablets t.i.d.

PD: treatment
MAO-B Inhibitors Anticholinergics
Azilect (rasagiline) Artane (trihexyphenidyl)
Eldepryl (selegiline) Cogentin (Benztropine)
Dopamine Agonists
COMT-Inhibitors
Requip (ropinirole) IR and ER
Mirapex (pramipexole) IR and ER Comtan (entacapone)
Neupro Patch (rotigotine) Tolcapone (tasmar)
Levodopa Amantadine
Sinemet (carbidopa/levodopa) IR and ER Symmetrel
Stalevo (carbidopa/levodopa/entacapone)
Parcopa (sublingual)
Rytary (carbidopa/levodopa extended
release)

346
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Exercise improves physical function in PD

Goodwin et al., Movement Disorders 23(5): 631-640

Treatment pearls

Timing of initial therapy varies

Stage of disease
Age of onset
Impact of symptoms on ADLs and quality of life
Tremor predominant vs akinetic rigid phenotype
Drug side effect profile
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary
Parkinson’s disease: increasing in frequency
PD: clinical diagnosis
Determine if patient has Parkinsonism
Rule out other causes of parkinsonism
Identify prospective supportive criteria
Treatment options
C/L, DAs, MAO-I, COMT-I, Amantadine, Anti-cholinergics
Exercise
Newer treatments in pipeline

Q&A
Question. Which of the following represents the most likely pathological finding
associated with Parkinson’s disease?

A. basophilic globose-shaped neurofibrillary tangles

B. amyloid plaques consisting of beta-amyloid protein fragments and neurofibrillary tangles
C. accumulation of α-synuclein in neuronal perikarya
D. tau-positive inclusions with associated neuron loss and gliosis

Answer: C. accumulation of α-synuclein in neuronal perikarya

“Abnormal aggregation of α-synuclein within neuronal perikarya (Lewy bodies)
and neurites (Lewy neurites) are defining neuropathological hallmarks of
Parkinson’s Disease”

Reference:
Miners JS, Renfrew R, Swirski M, Love S. Accumulation of α-synuclein in dementia with Lewy
bodies is associated with decline in the α-synuclein-degrading enzymes kallikrein-6 and
calpain-1. Acta Neuropathologica Communications. 2014;2:164. doi:10.1186/s40478-014-0164-0.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271448/

348
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tremor

Albert Hung, MD, PhD

Assistant Professor of Neurology, Harvard Medical School

Brigham and Women’s Hospital
Massachusetts General Hospital

Disclosures

• Funding support provided by the

Parkinson’s Foundation, Michael J. Fox
Foundation, and NIH

• No financial relationships relevant to the

content of this presentation

349
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Overview

• Definition and types of tremor

• Rest tremor
• Isolated action tremors
• Tremors combined with other
neurological symptoms
• Functional tremor

Tremor

• Definition: Involuntary, rhythmic, oscillatory

movement of a body part

• Most common form of involuntary movement

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Classification of Tremors
(Axis 1: Clinical features)

• History
• Tremor characteristics
• Associated signs (isolated vs. combined)
• Additional laboratory tests

Bhatia et al., Mov Disord 2018

Historical Features

• Age of onset
• Temporal onset and evolution
• Past medical history
• Family history
• Alcohol and drug sensitivity

351
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tremor Characteristics

• Activation • Body distribution

– Rest tremor – Focal
– Action tremor – Segmental
• Kinetic tremor – Hemitremor
– Simple kinetic tremor – Generalized
– Intention tremor
– Task-specific tremor
• Postural tremor • Frequency
• Isometric tremor

Classification of Tremors
(Axis 2: Etiology)

• Genetic
• Acquired
• Idiopathic
– Familial
– Sporadic

Bhatia et al., Mov Disord 2018

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rest Tremor

• Present when affected body part is fully supported vs.

gravity
– May reappear with brief latency as limb assumes a new
position (“re-emergent tremor”)

• Most commonly caused by Parkinson’s disease or other

Parkinsonian syndromes

• Can be drug-induced (dopamine antagonists)

Parkinsonian Tremor

353
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Essential Tremor
• Most common movement disorder: estimated prevalence
up to 5% of population

• Incidence increases with age (but can affect young

individuals)

• Familial (autosomal dominant): ~ 50% with positive

family history

• Most often bilateral upper extremity postural/kinetic

tremor; can also affect legs, head/neck, voice

• May be responsive to alcohol

Essential Tremor

354
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Essential Tremor

Essential Tremor

Archimedes spiral

355
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment of Essential Tremor

• First-line agents
– Propranolol: 10-320 mg/d
– Primidone: 25-750 mg/d

• Second-line agents
– Topiramate: 25-300 mg/d
– Gabapentin: 100-1800 mg/d
– Benzodiazepines (e.g. clonazepam: 0.5-4 mg/d)

• Likely not efficacious: zonisamide, levetiracetam,

pregabalin
• Surgical options
– Deep brain stimulation (Vim nucleus of thalamus)
– Focused ultrasound therapy

Parkinsonian tremor vs. Essential tremor

PD ET

Tremor type Typically rest Postural/kinetic

Tremor onset Asymmetric Bilateral

Head/neck involvement Typically absent May be present

Other signs? Present Absent

Response to alcohol? Not beneficial Beneficial

356
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DaT Scan: Role in Diagnosis?

• Dopamine transporter imaging

– [123I] ioflupane binds to dopamine
transporters on healthy dopamine-
producing cells

• Differentiates neurodegenerative
Parkinsonism from:
– Essential tremor
– Drug-induced Parkinsonism
– Vascular Parkinsonism

• Useful in certain clinical settings,

but not a “gold standard”

Mixed Essential and Parkinsonian Tremor

357
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Essential Tremor & Parkinson’s Disease

• Patients can have both essential tremor and

Parkinson’s disease

• Controversial relationship between ET and PD

• Focus on treating the symptomatic component

• May potentially require combination of

medications

Enhanced Physiologic Tremor

• Low-amplitude, high-frequency action tremor present in all
persons

• Causes
– Stress-induced: anxiety, emotion, exertion, fever
– Drug-induced
• Bronchodilators (β-agonists, theophylline)
• Steroids
• Mood stabilizing agents (lithium, valproic acid)
• Selective serotonin reuptake inhibitors (SSRIs)
• Stimulants (caffeine, methylphenidate, amphetamines, pseudoephedrine)
– Systemic disease
• Thyrotoxicosis
• Hypoglycemia
• Drug/alcohol withdrawal

358
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Enhanced Physiologic Tremor

Orthostatic Tremor

• Limited to legs/trunk, exclusively with standing

• Relieved by sitting or walking

• Typically fast, ~14-16 Hz tremor

• May be relieved by clonazepam or gabapentin

359
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Orthostatic Tremor

Cerebellar Tremor

• Typically disabling, low frequency (3-4 Hz) intention,

simple kinetic, or postural tremor

• Associated with other cerebellar signs (dysmetria, ataxia,

or nystagmus)

• Head titubation may be present

• Due to pathology in cerebellum or cerebellar pathways

• Brain imaging indicated

• Refractory to pharmacotherapy

360
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cerebellar Tremor

Cerebellar Tremor

361
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rubral Tremor
(Holmes tremor)

• Irregular coarse tremor (slow frequency),

generally unilateral

• Usually rest, postural, and kinetic components

• Lesions in midbrain tegmentum, superior

cerebellar peduncle, posterior thalamus

Rubral Tremor
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rubral Tremor

Dystonic Tremor

• Dystonia: Syndrome of sustained muscle contractions,

frequently causing twisting and repetitive movements or
abnormal postures

• Dystonia and tremor can be simultaneously present in

the same body part, or in different body parts

• Typically position- or task-specific

• Often jerky and irregular

• May respond to anticholinergic medications or

botulinum toxin injection

363
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dystonic Tremor

Functional Tremor

364
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Functional Movement Disorders:

Clinical Clues
• Abrupt onset • Entrainment of the movement
to frequency of repetitive
• History of precipitating event movement

• Inconsistent movements • Association with false

weakness, sensory loss, or pain
• Incongruous movements that
do not fit reconized patterns • Responsiveness to placebo or
suggestion
• Spontaneous remission
• Unresponsive to drugs for
• Decreased movement with organic movement disorders
distraction

• Increased movement during

observation or examination

Summary
• Tremor is a common neurological condition seen in clinical practice
• Clinical classification – especially rest vs. action tremor – is
important in formulating a differential diagnosis
• Parkinson’s disease and other Parkinsonian syndromes are the most
common cause of rest tremor
• Isolated tremor syndromes include essential tremor, enhanced
physiologic tremor, and orthostatic tremor
• Tremor can occur in combination with other neurological findings
including cerebellar signs and dystonia
• It is important to exclude reversible causes (e.g. drug-induced) and
recognize functional disorders
• Pharmacologic and surgical options may be available for
symptomatic treatment
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hypokinetic Movement Disorders

(other than Parkinson’s disease)

E Miyawaki, MD
Brigham and Women’s Hospital
Harvard Medical School

Neurology for Non-Neurologists 2016

Disclosures
• Reports no commercial interest

366
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Typical Parkinson’s Disease

Atypical Parkinsonism

In the Emergency Department

“Fixed” hand Can’t speak well

Arch Neurol 2011;68(5):567-572, fig. 1

367
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute/Subacute Parkinsonisms
• Toxic Parkinsonism (iatrogenic)
• Even the atypical antipsychotics, except
clozapine
• Neuroleptic Malignant Syndrome (NMS)
• Withdrawal from Parkinsonian medications
• Serotonin Syndrome (Note: MDMA)
• Metabolic conditions
– Can be a predominant manifestation of acquired
hepatolenticular degeneration
• Inflammatory (infectious and paraneoplastic)
– e.g., HIV, anti-Ma2 encephalitis

NMS v. Serotonin Syndrome

Confused (>90%) Confused (50%)

Rigid (>90%) Rigid (50%)

Febrile (>90%) Febrile (50%)

Myoclonus is rare Myoclonus (50%)

High CPK, WBC (>90%) High CPK, WBC (<20%)

Resolution over days Can improve < 24 hrs

Modified from Arch Neurol 2011;68(5):567-572, table 3

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

54 M

with a “fixed, staring gaze”

a lot of falls

Arch Neurol 1964;10:333-359,

fig. 16

369
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Groschel K et al. Neurol 2006;66:950, fig B

T1

Radiology 2008;246:214-221, fig. 2

370
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Immunohistological staining for TAU protein

371
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

History in summary

• Early postural instability

• (Dysarthria)
• Axial rigidity, including the face
• Symmetrical symptoms and signs
• Poor response to antiparkinsonian
medications

Carbidopa/
2011 EBM Review, Mov Disord 2011;26, suppl 3

Levodopa
25/
100

Carbidopa/
Levodopa
25/
250

Also: Controlled-release (CR)

Rapid-onset oral & Infusion formulations (duodenal)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Early “atypical” alerts?

• Too demented, too early
• Too fast (pace of disease)
• Too unsteady
• (Base too wide)
• Too dizzy, orthostatic (-30 mmHg systolic or -15 mmHg diastolic
drop after 2 min of standing)

• Too weird:
– Cortical sensory deficit
– Supranuclear gaze palsy
– Stridor

Courtesy JP Vonsattel, New York

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEJM, 1992

Location of pathological sample: frontal white matter

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Classification of Atypical Parkinsonisms

according to protein aggregates

• Tauopathies • Synucleinopathies
– Progressive – Multiple system atrophy
Supranuclear Palsy – Parkinsonian variant
(PSP) • (MSA-P)
• abnormal tau gene MAPT, – Cerebellar variant
H1 haplotype
• (MSA-C)
– Pure Akinesia (“OPCA,” “SND”
Also: “Shy-Drager,” “PAF”)
– Corticobasal
degeneration – Dementia with Lewy
Bodies or Diffuse Lewy
– Frontotemporal Body Disease
dementia

375
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Atypical v. Typical, Over Time

Early _______ No Early Falls or
Dementia
Symmetrical Asymmetrical, then bilateral

Midline features Persisting asymmetry

Poor response to Convincing initial

levodopa levodopa response
No levodopa-induced Levodopa-induced
dyskinesia dyskinesia

67 M

Avid sportsperson
Drinks wine

376
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1987 AP / Bob Daugherty

1991 AP / Denis Paquin

377
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

40th – 43rd Presidents of the United States

• 1981-1985, Ronald Reagan

• 1985-1989, Ronald Reagan 1987
• 1989-1993, George H. W. Bush 1991
• 1993-1997, William J. Clinton 1993
• 1997-2001, William J. Clinton 1999
• 2001-2005, George W. Bush 2004
• 2005-2009, George W. Bush

1993 research.archives.gov

378
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1999 AP / Ron Edmonds

June 2004 White House Photo by Eric Draper

379
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Braak H et al., 2004

Cell Tissue Res (2004) 318: 121–134 figure 1 B and D

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

chlorpromazine

381
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

chlorpromazine
haloperidol

chlorpromazine
haloperidol

382
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

chlorpromazine
haloperidol

clozapine
risperidone

olanzapine

quetiapine

chlorpromazine
haloperidol

clozapine

risperidone

olanzapine

quetiapine
pimavanserin

383
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary

• The significance of the history

• Typical and Atypical Parkinsonism
• Pathological correlation
–tauopathy v. (alpha) synucleinopathy
• Progression in Parkinsonism
– Neocortical involvement or spread

384
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hyperkinetic Movement Disorders

E Miyawaki, MD
Brigham and Women’s Hospital
Harvard Medical School

Neurology for Non-Neurologists 2016

Disclosures

Reports no commercial interest

385
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dyskinesias

• Akathisia • Myoclonus
• Athetosis • Stereotypy
• Ballism • Tic
• Chorea • Tremor
• Dystonia • Others

70 F
• Non-insulin dependent diabetic
• Admitted for hyperosmolar state
• Previously treated with
metoclopramide
• Developed “tardive dyskinesia”
• But it was unilateral

386
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Left

387
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cortex

STN GPe Striatum

GP interna

Thalamus

Cortex
glutamate

STN GPe Striatum

glutamate

GP interna
GABA

Thalamus

388
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

INHIBIT

INHIBIT
Nambu et al. Neuroscience Research 2002;43:111-117, cited with permission.

Cortex

STN GPe Striatum

GP interna

Thalamus
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cortex

STN GPe Striatum

GP interna

Thalamus

40 M
• fidgets • slowed saccades
• marionette • blinks to break
• parakinesia fixation
• mental status?

390
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Huntington’s Disease
• Chorea + Dementia (+ Dystonia?)
• Eyes in early disease
• Akinetic-rigid features late
• Affective illness a common
presentation (high suicide rates)
• Variable pace of cognitive deficits

43

17
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Courtesy of JP Vonsattel

Features of CAG trinucleotide-repeat

diseases
• N.B.: not Fragile X (CGG), Myotonic Dystrophy
(CTG), Friedreich’s Ataxia (GAA)
• For CAG diseases: autosomal dominant,
midlife onset, young onset/higher repeat
count, anticipation, multiple “systems”
neuronal loss
• Ubiquitin-positive intranuclear inclusions
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEJM, 2014

1912
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Courtesy of D. Bienfang
Brigham and Women’s Hospital
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Wilson’s Disease

• Autosomal • ~40% present with

recessive neurologic disease
• potentially curable • ~40% present with
hepatic disease
• chromosome 13
• Impaired copper
• variable age of elimination
onset • 5-10% with normal
ceruloplasmin

Ceruloplasmin

• Low ceruloplasmin also seen

transiently in: protein-losing
enteropathies, nephrotic syndrome,
liver failure
• Ancillary testing in WD: 24-hour
urinary copper assay (> 100
micrograms/day), liver biopsy (>250
micrograms/g of dry tissue)

395
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment in WD
• trientine
• tetrathiomolybdate
• Chronic d-penicillamine Rx associated
with lupus-like syndrome,
thrombocytopenia, retinal hemorrhage,
Goodpasture’s syndrome, subcutaneous
bleeding
• Given high mortality in hepatic failure:
orthotopic liver transplantation

Oculist.net

396
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lookfordiagnosis.com

Colosimo and Berardelli 2011, fig 3.

397
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1908

398
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1910

(NEJM 2014)

AD AR or sporadic
GCH1 TH, SPR
(DYT 5a) (DYT 5b)

All encoded proteins are involved in

catecholamine synthesis.
GTP cyclohydrolase 1 (GCH1), 14q
Tyrosine hydroxylase (TH), 11p
Sepiapterin reductase (SPR), 2 p

399
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

9F

A problem with handrails;

Purposeless movements of the left
hand

FLAIR
Pediatric Neurology 2002;27(1):65-67

400
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Immune-mediated movement disorders

(with chorea)
Antineuronal Clinical Associations
Antibody/ies Syndrome
Sydenham, ?cross reaction Chorea, dystonia, tics a/w Streptococcus B
with basal ganglia antigen

Antiphospholipid Chorea none

NMDA (NR1 subunit) Chorea, orofacial Teratoma

dyskinesia,
dystonia
Collapsin response- Chorea, Small cell lung,
mediated protein 5 encephalomyelitis thymoma
(CRMP5)

Could be a colleague near you

• Normal?
• Abnormal?
• Can be stimulus-induced
• Can result, evidently, from loss of
intellectual stimulation

401
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Myoclonus

• Positive and • Unstable response

Negative to afferent input
(startle)
• May be normal • Spontaneous
• May be a/w discharges without
pathology at any trigger, in
“myoclonic
level epilepsies”
• May be • Associations with
generalized, ataxia and dystonia
multifocal, or focal

Antipsychotics Antiepileptics Levodopa

Myoclonus
- clozapine, olanzapine,
metoclopramide - valproate,
phenytoin,
MAO inhibitors
Antimicrobials carbamazepine,
phenobarbital,
gabapentin,
- penicillin, primidone
cephalosporins, Bismuth salts Narcotic analgesics
imipenem, quinolones,
acyclovir,
aminoglycosides, Nifedipine,
tetracyclines verapamil - morphine, hydrocodone,
Anesthetics fentanyl, tramadol,
Cholinesterase buprenorphenine,
inhibitors dextropropoxyphene
- etomidate, propofol
Dopamine agonists

Anxiolytics
- levodopa,
amantadine, and
- benzodiazepines, entacapone,
zolpidem, zolpiclone selegiline
Mackay D, Miyawaki E.
Dopamine
Antidepressants Hyperkinetic movement
antagonists
disorders.
- haloperidol, In:
- fluoxetine, sertraline, sulpiride, and Nabel B, ed.
fluvoxamine, paroxetine, chlorpromazine
trazodone, cyclic Scientific American Medicine
antidepressants, Lithium
buspirone (rare)
Amiodarone
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1921

90 F

30-year history, but she died due to

non-neurological disease

403
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Courtesy of JP Vonsattel, New York

Essential Tremor
• ~400/100,000 above the age of 40
• Childhood onset in many
• Family history common, linkages: 2p, 3q
• Can be alcohol responsive
• Bilateral action tremor (though resting
component may occur), head, voice,
“orthostatic”
• Rx: Primidone, beta blockers,
benzodiazepines

404
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DBS lead
in situ

courtesy
J Joseph

Ventrointermediate (VIM) nucleus of

thalamus

• Receives input from other thalamic

nuclei and deep cerebellar nuclei
• Both ablation and chronic, high-
frequency electrical stimulation of
VIM attenuate some tremor types in
the contralateral hemibody
 Restless Legs
• Karl-Axel Ekbom (1945)
• Akathisic, can present as “PLMS”
• Associated with “comfortable
positions”
• Associated with Pregnancy, Anemia,
Uremia, Neuropathy
• Responds to Fe, dopamine agonists,
opiates, others

. . . when being a Bed, they betake themselves to sleep, presently in the Arms
and Legs, Leapings and Contractions of the Tendons, and so great a
Restlessness and Tossings of their Members ensue, that the diseased are no
more able to sleep, than if they were in a Place of the greatest Torture.

1684

406
 Tourette’s
• Onset < 10 y of age • No conclusions
regarding genetics
• Multiple tics – (Tic, ADHD, OCD: variable
phenotypes of one genetic
• Male predilection abnormality?)

• 20% of school-age • Relationship to

kids will develop a histamine
neurotransmission?
transient tic
• Clonidine for Tics +
• 50% with ADHD ADHD
• 50% with OCD • Haloperidol for Tics

Summary
Clinicoanatomic Multiple anatomic sites;
Correlation Diverse phenomenology

Genetics Multiple gene linkages;

More everyday

Syndromes A pathophysiology of
Networks or Pathways

407
 BRIGHAM AND
WOMEN’S HOSPITAL

Stroke Prevention

Steven Feske, M.D.

Chief, Stroke Division
Brigham and Women’s Hospital

May 17, 2018

Disclosures
I have no financial relationships with the developers of any of
the products discussed.

NINDS
• SPOTRIAS
• NeuSTART
• IRIS (and Takeda Pharmaceuticals)
• ATACH II
• POINT
• StrokeNET
• DEFUSE-3
• ARCADIA

Covidien
• SWIFT PRIME
Stroke Prevention Overview
For Everyone
• HTN control
• Hyperlipidemia control
• Diabetes mellitus control
• Diet and exercise
• Smoking cessation

Antiplatelet Agent or Anticoagulant

Surgery
• Left atrial appendage occlusion
• CEA/CAS
• PFO closure
• EC-IC bypass

AHA/ASA Guidelines
Primary Prevention Stroke 2014;45:3754

Secondary Prevention Stroke 2014;45:2160

 HTN
Control

HTN Control
Primary Prevention
1. Patients who have HTN should be treated with drugs to a target BP of
< 140/90 mm Hg (Class I; Level of Evidence A).
2. Successful reduction of BP is more important in reducing stroke risk than the
choice of a specific agent (Class I; Level of Evidence A).
3. Self-measured BP monitoring is recommended to improve BP control (Class I;
Level of Evidence A).

Secondary Prevention
1. Initiation of BP therapy is indicated for previously untreated patients with AIS
or TIA who, after the first several days, have an established BP ≥ 140/90 (Class
I; Level of Evidence B).
2. Targets are the same as for primary prevention (Class IIa; Level of Evidence B).
For patients with a recent lacunar stroke, it might be reasonable to target SBP
< 130 mm Hg (Class IIb; Level of Evidence B).
3. The choice of specific drugs and targets should be individualized (Class IIa;
Level of Evidence B).

410
 AHA Guidelines

BP lowering to a target of < 130 mm Hg may reduce the risk

of several important outcomes including risk of MI, stroke,
heart failure, and major cardiovascular events.

Hypertension 2018;71:e116

National Health and Nutrition Examination Survey

CDC / NCHS, Health United States, 2013, Fig 9

411
 Mortality Trends in US, 1969-2013
Declining rates of heart disease and stroke

Male Female

Ma JAMA 2015;314: 1731

Heart Outcomes Prevention Evaluation Study

HOPE
Effect of Ramipril on the Risk of MI, Stroke, and CV Death

RR = 0.78
95% CI, 0.70 – 0.86
P < 0.001

During 4.5 years of follow-up, ramipril decreased the risk of MI,

stroke, and CV death.
NEJM 2000;342: 145

412
 HOPE Subgroups

Patients with stroke had a lower risk of the clustered endpoint.

Long-Term Effects of Ramipril

on Cardiovascular Events and Diabetes
HOPE/HOPE-TOO

RR = 0.83 RR = 0.79
95% CI, 0.75 – 0.91 95% CI, 0.65 – 0.97
P = 0.0002 P = 0.023

MI, Stroke, and CV Death Stroke

Benefits of ACEI, ramipril, extend to 7.1 years,

regardless of other risk factors or treatments, and
extend to stroke as an endpoint. Circulation 2005;112: 1339
 Lipid
Lowering

Lipid Lowering
Primary Prevention
1. Lifestyle changes and treatment with a statin are recommended for primary
prevention of stroke in patients estimated to have a high 10-year risk for CV
events (see ACC/AHA Guideline on the Treatment of Blood Cholesterol to
Reduce Atherosclerotic Cardiovascular Risk in Adults (Class I; Level of
Evidence A).
2. Niacin may be considered with low HDL or elevated Lp(a), but efficacy for
stroke prevention is not established, niacin increases risk of myopathy (Class
IIb; Level of Evidence B).
3. Fibrates may be considered with elevated TG, but their efficacy for stroke
prevention is not established (Class IIb; Level of Evidence C).
4. Treatment with alternative agents (fibrates, bile salt sequestrants, niacin,
ezetimibe) may be considered in those who cannot tolerate statins, but their
efficacy for stroke prevention is not established (Class IIb; Level of Evidence
C).

414
 Lipid Lowering
Secondary Prevention
1. Statin therapy is recommended in patients with ischemic stroke or TIA
presumed to be of atherosclerotic origin and an LDL-C > 100 mg/dL with or
without evidence of other clinical ASCVD (Class I; Level of Evidence B).
2. Statin therapy is recommended in patients with ischemic stroke or TIA
presumed to be of atherosclerotic origin, LDL-C < 100 mg/dL, and no
evidence for other clinical ASCVD (Class I; Level of Evidence C).
3. Patients with ischemic stroke or TIA and other comorbid ASCVD should be
otherwise managed according to the 2013 ACC/AHA cholesterol guidelines,
which include lifestyle modification, dietary recommendations, and
medication recommendations (Class I; Level of Evidence A).

SPARCL
Stroke Coronary Event

HR = 0.84 (95% CI, 0.71-0.99) HR = 0.58 (95% CI, 0.46-0.73)

P = 0.03 P < 0.001

NEJM 2006;355:549

415
 SPARCL
Proportion of total follow-up time in each % change in LDL-C category

Stroke 2007;38:3198

SPARCL

Stroke 2007;38:3198
 Cardiovascular Benefits of
non-Statin Lipid-Lowering Agents
IMPROVE-IT

HR = 0.936
95% CI, 0.89 – 0.99
P = 0.016

Ezetimibe showed a statistically significant, though questionably

clinically significant additional benefit.
Cannon NEJM 2015;372:2387

Statins: Mechanism of Action

Active
intermediates

Cholesterol

417
The LDL Hypothesis / Statin Uniqueness Hypothesis

Reduction in Rate of Major CV Events (%)

Supports the LDL-hypothesis.

Refutes the statin hypothesis.

Reduction in LDL Cholesterol (mmol/L)

Cannon NEJM 2015;372:2387

PCSK9 Inhibitors: Mechanism of Action

PCSK9-mediated lysosomal PCSK9 inhibition with

degradation of LDL-R recycling of LDL-R

Lambert J Lipid Res 2012;53:2515

 PCSK9 Inhibitors for LDL Lowering

LDL Cholesterol Level (mg/dl)

Weeks

Alirocumab lowered LDL by 62%.

Evolocumab lowered LDL by 50-60%.
Robinson NEJM 2015;372: 1489

PCSK9 Inhibitors for Prevention of CV Events

Recently found to be effective in 2 large trials

FOURIER: evolocumab reduced the rate of death, MI,

stroke, and hospitalization for angina or revascularization
by 15% in patients with elevated cardiovascular risk.

ODYSSEY OUTCOMES: alirocumab reduced the rate of

cardiovascular outcomes and all-cause mortality by 15% in
patients with acute coronary syndromes and elevated lipids
despite maximal statin therapy. Reduced stroke by 24%.

acc.org 2018

419
 Diabetes
Control

Glucose Control
Primary Prevention
1. Control of BP according to AHA/ACC/CDC Advisory targeting < 140/90 mm Hg is
recommended in patients with types 1 and 2 DM (Class I; Level of Evidence A).
2. Treatment of adults with DM with statins, especially those with additional risk
factors, is recommended (Class I; Level of Evidence A).
3. The usefulness of aspirin for primary stroke prevention for patients with DM but
low 10-year-risk of CVD is unclear (Class IIb; Level of Evidence B).
4. Adding a fibrate to a statin in people with DM is not useful for decreasing stroke
risk (Class III; Level of Evidence B).

Secondary Prevention
1. After stroke or TIA, all patients should be screened for DM (Class IIa; Level of
Evidence C).
2. Use of existing ADA guidelines for glycemic control and CV risk factor
management is recommended in patients with stroke or TIA and DM or pre-
DM (Class I; Level of Evidence B).

420
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pioglitazone for Patients with Insulin Resistance

and Recent Stroke or TIA (IRIS)

HR = 0.76
95% CI, 0.62 – 0.93
P = 0.007

After 4.8 years, patients treated with pioglitazone had a lower

rate of stroke or MI and a lower rate of DM.
Patients had a higher rate of weight gain and bone fracture.
Kernan NEJM 2016;374: 1321

Exercise
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Exercise
Primary Prevention
1. Physical activity is recommended because it is associated with a reduction in
the risk of stroke (Class I; Level of Evidence B).
2. Healthy adults should perform at least moderate- to vigorous-intensity
aerobic physical activity at least 40 min/d 3 to 4 d/wk (Class I; Level of
Evidence B).

Secondary Prevention
1. Physical activity…at least 3-4 sessions/wk moderate- to vigorous-intensity
aerobic physical exercise are reasonable…avg of 40 min…moderate: to break a
sweat or noticeably raise HR (brisk walk, exercise bike)…vigorous: such as
jogging (Class IIa; Level of Evidence C).
2. Referral to a comprehensive behaviorally oriented program is reasonable
(Class IIa; Level of Evidence C).
3. If disabled, supervision by a physical therapist or cardiac rehabilitation
professional, at least on initiation of an exercise regimen, may be considered
(Class IIb; Level of Evidence C).

Exercise
From Epidemiological Studies and Controlled Trials
1. Exercise can:
1. Reduce BP
2. Improve lipid metabolism
3. Decrease insulin resistance
4. Reduce weight
5. Improve endothelial function

From Epidemiological Studies

1. At least moderate levels of occupational physical activity are associated with a
10-30% reduction in the risk of stroke and CHD in men and women
2. Aerobic and strength training will improve cardiovascular fitness after stroke

Effectiveness of Interventions
1. Advice alone
2. Intensive face-to-face counseling
3. Comprehensive, behaviorally oriented program

422
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Exercise
From Epidemiological Studies and Controlled Trials
1. Exercise can:
1. Reduce BP
2. Improve lipid metabolism
3. Decrease insulin resistance
4. Reduce weight
5. Improve endothelial function

From Epidemiological Studies

1. At least moderate levels of occupational physical activity are associated with a
10-30% reduction in the risk of stroke and CHD in men and women
2. Aerobic and strength training will improve cardiovascular fitness after stroke

Effectiveness of Interventions
1. Advice alone NO
2. Intensive face-to-face counseling NO
3. Comprehensive, behaviorally oriented program PROBABLY

Walking versus Running for HTN,

Hypercholesterolemia, and DM Risk Reduction
Hazard Ratio

x-Fold increase over recommended levels

Equivalent energy expenditures by moderate (walking) and

vigorous (running) exercise produced similar risk reduction for
HTN, HL, DM, and possibly CHD.
Williams Arterioscler Thromb Vasc Biol 2013;33: 1085

423
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Smoking
Cessation

Smoking Cessation
Primary Prevention
1. Counseling, in combination with drug therapy using nicotine replacement,
bupropion, or varenicline, is recommended for active smokers (Class I; Level of
Evidence A).
2. Abstention from cigarette smoking is recommended for patients who have
never smoked (Class I; Level of Evidence B).
3. Community-wide or statewide bans on smoking in public places are
reasonable for reducing the risk of stroke and MI (Class IIa; Level of Evidence
B).

Secondary Prevention
1. Healthcare providers should strongly advise every patient with stroke or TIA
who has smoked in the past year to quit (Class I; Level of Evidence C).
2. It is reasonable to advise patients after TIA or stroke to avoid environmental
(passive) tobacco smoke (Class IIa; Level of Evidence B).
3. Counseling, nicotine products, and oral smoking cessation medications are
effective in helping smokers to quit (Class I; Level of Evidence A).

424
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

National Health and Nutrition Examination Survey

NIH / NIDA, Monitoring the Future Study
CDC / NCHS, Health United States, 2013, Fig 9

National Health and Nutrition Examination Survey

NIH / NIDA, Monitoring the Future Study
CDC / NCHS, Health United States, 2013, Fig 9

425
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Antiplatelet
Therapy

Antiplatelet Therapy
Primary Prevention
1. Aspirin (81-100 mg qod) can be useful to prevent first stroke in women,
including those with DM, whose risk is high enough for the benefits to
outweigh the risks (Class IIa; Level of Evidence B).
2. Aspirin might be considered for primary prevention in those with CRF with
GFR < 45 cc/min/1.73 mm2 (Class IIb; Level of Evidence C).
3. Cilostazol may be reasonable for primary stroke prevention in patients with
PAD (Class IIb; Level of Evidence B).

Secondary Prevention
1. After noncardioembolic stroke or TIA, an antiplatelet agent rather than oral AC is
recommended (Class I; Level of Evidence A).
2. Aspirin, aspirin + ER dipyridamole (Class I) or clopidogrel (Class IIa) are
recommended after stroke or TIA (Level of Evidence B).
3. Aspirin + clopidogrel might be considered within 24 h of minor stroke or TIA and
continued for 21 days (Class IIb; Level of Evidence B).
4. Combination aspirin + clopidogrel is not recommended for long-term secondary
prevention; it increase hemorrhagic risk (Class III; Level of Evidence A).
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Antithrombotic Trialists’ Collaboration

Aspirin for Primary Prevention

6 trials; 95,000 patients, 660,000 person-years

ATC Lancet 2009;373: 1849

Antithrombotic Trialists’ Collaboration

Aspirin for Secondary Prevention

Primary Prevention Secondary Prevention

• 0.20 v 0.21% per year • 2.08 v 2.54% per year
• ARR = 0.01% per year • ARR = 0.46% per year
• RRR = 5% • RRR = 18%
• p = 0.4 • p = 0.02

ATC Lancet 2009;373: 1849

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dual Antiplatelet Therapy for Long-term Use

MATCH Lancet 2004;364:331
• ASA + clopidogrel v clopidogrel; followed 18 months
• No significant benefit
• Increased rates of life-threatening, major, and minor bleeding

CHARISMA NEJM 2006;354:1706

• ASA + clopidogrel v ASA; followed 28 months
• No significant benefit
• Increase risk of moderate bleeding

PRoFESS NEJM 2008;359:1238

• ASA + ER dipyridamole v clopidogrel; followed 2.5 years
• No significant benefit
• Increased rates of severe hemorrhage, including intracranial

CHANCE
Probability of Stroke-free Survival

POINT has completed enrollment in the US;

12 hr window; 600 mg load; 3 month therapy
NEJM 2013;369:11

428
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Anticoagulant
Therapy

Anticoagulation for Non-Rheumatic Atrial Fibrillation

Study/Year Stroke Rate (% per year) RRR (%)

Warfarin Placebo

AFASAK 1989 2.0 4.2 52

BAATAF 1990 0.4 3.0 84
SPAF 1991 2.3 7.0 67
CAFA 1991 2.6 3.8 32
SPINAF (VA) 1992 0.9 4.3 80
EAFT 1993 3.9 12.3 68

Stroke rates on warfarin down to: 0.4 – 3.9 % per year

429
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pooled analysis of 5 studies* overall results:

RRR = 68%
ARR = 3.1% (4.5% 1.4%)
NNT = 32 (treat 1000 to prevent 31 strokes)

Rate of major hemorrhage 1.0% 1.3%

ICH assoc with higher BP and INR (3.5 -3.7) (small N)

*AFASAK, SPAF, BAATAF, CAFA, SPINAF

Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449

Should we then anticoagulate

all patients with AF?

430
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Should we then anticoagulate

all patients with AF?

The absolute risk of stroke varies 20-fold

among patients with AF according to age
and associated risk factors.

Pooled Analysis: Age Stratification

Patients with ≥ 1 Risk Factor

Age Group Placebo Warfarin

Strokes/yr Strokes/yr
< 65 4.9 1.7
65-75 5.7 1.7
> 75 8.1 1.2

Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449

431
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pooled Analysis: Age Stratification

Patients with No Risk Factors*

Age Group Placebo Warfarin

Strokes/yr Strokes/yr
< 65 1.0 1.0
65-75 4.3 1.1
> 75 3.5 1.7

Benefit was present in men and women.

* No HTN, no DM, no prior stroke or TIA

Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449

CHADS2 Score

Condition Points
C Congestive heart failure 1
H Hypertension (> 140/90 or on medication) 1
A Age ≥75 years 1
D Diabetes mellitus 1
S2 Prior stroke or TIA or thromboembolism 2

432
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CHA2DS2-VASc Score
Condition Points
C Congestive heart failure 1
H Hypertension (> 140/90 or on medication) 1
A Age ≥75 years 2
D Diabetes mellitus 1
S2 Prior stroke or TIA or thromboembolism 2
V Vascular disease (CAD, PAD, aortic plaque) 1
A Age 65-74 years 1
Sc Sex category: female* 1
* If at least 1 other risk factor

Net Clinical Benefit of Warfarin for AF

Net benefit increases with increasing age.

Net benefit increases with increasing CHADS2 score; becoming
significant when ≥ 2.
Singer Ann Intern Med 2009;151:297

433
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Moving the Tipping Point

Eckman et al Circ Cardiovasc Qual Outcomes 2011;4(1):14-21

Alternatives to Warfarin for Anticoagulation for AF

Ischemic ICH Major

Drug Stroke Stroke Bleeding Mortality

Dabigatran 150 mg ↓ ↓ no Δ no Δ (near ↓)

Dabigatran 110 mg no Δ ↓ ↓ no Δ

Rivaroxaban no Δ ↓ no Δ no Δ

Apixaban (ARISTOTLE) no Δ ↓ ↓ ↓

Apixaban (AVERROES) Apixaban superior to ASA without more bleeding

RE-LY NEJM 2009;361: 1139

ROCKET-AF NEJM 2011;365:883
ARISTOTLE NEJM 2011;365:981
AVERROES NEJM 2011;364:806
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Reversal of
anticoagulation
with NOACs.

Idarucizumab binds to and inhibits

dabigatran binding to thrombin.
Dabigatran’s affinity for idarucizumab is
350-fold greater than for thrombin.

Andexanet, a modified, inactive, recombinant factor X

binds factor Xa inhibitors and competitively inhibits their
binding to X. Reverses rivaroxaban, apixaban,
edoxaban, LMWH, fondaparinux.

Warfarin for Stroke of Unknown Cause

WARSS

No benefit of warfarin over aspirin; increase in

minor hemorrhage
Mohr NEJM 2001;345: 1444
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DOACs for ESUS Stroke?

STUDY DESCRIPTION STATUS

NAVIGATE ESUS rivaroxaban v ASA in ESUS Stopped for futility

RESPECT ESUS dabigatran v ASA in ESUS Pending

ARCADIA apixaban v ASA in ESUS Enrolling

with atrial cardiopathy

Other Indications for Anticoagulation – Strong Data/Consensus

Study/Year Description Results

Mechanical Valve --- ---

APAS
Rosove 1992 Retrospective Warfarin > 3.0
Khamashta 1995 Retrospective Warfarin > 3.0
Crowther 2003 RCT INR 2-3 v 3.1-4 High target INR not superior

Cancer-related
LMWH study 2003 CLOT Study Dalteparin superior to coumarin
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stroke Risk after MI Depends on LVEF

“For every
decrease of 5 %
in LVEF, the
risk of stroke
increases
by 18 %.”

Loh NEJM 1997:336;251

WARCEF

Primary Outcome:
Mean Time to first event:
LVEF = 25% ischemic stroke, ICH,
or death

NEJM 2012;366:1859
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

WARCEF

Outcome Warfarin Aspirin HR P-value

Primary outcome 7.47 7.93 0.93 0.40

Ischemic stroke 0.72 1.36 0.52 0.005

Major hemorrhage 1.78 0.87 <0.001

“A reduced risk of ischemic stroke with warfarin

was offset by an increased risk of major
hemorrhage. The choice between warfarin and
aspirin should be individualized.”
NEJM 2012;366:1859

WARCEF: Time-Dependent Outcomes

Homma S. International Stroke Conference, 2012

438
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Surgical
Therapies

Left Atrial Appendage Occlusion

Watchman Device

439
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LAA Occluder versus Warfarin for Atrial Fibrillation

PROTECT AF

Percutaneous LAA occlusion was non-inferior to warfarin.

There was a higher rate of adverse events.
Holmes DR Lancet 2009;374:534

CEA v CAS for Carotid Stenosis

CREST

There was a higher risk of periprocedural stroke with stenting;

a higher risk of MI with CEA. Brott NEJM 2010;363: 11

440
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CEA v CAS for Carotid Stenosis

CREST: Age

Brott NEJM 2010;363: 11

Decreasing Annual Rates of Stroke

Medically Treated Patients with
Asymptomatic Carotid Stenosis

Naylor AR Nat Rev Cardiol 2012;9:116

441
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CEA v CAS for Asymptomatic Carotid Stenosis

CREST 2

Patients: Asymptomatic ≥ 70% carotid stenosis

• CEA versus intensive medical therapy

• CAS versus intensive medical therapy

PFO Device Closure

CLOSURE I 2012
PC Trial 2013
RESPECT 2013
CLOSE 2017
REDUCE 2017

NEJM 2012;366:991
NEJM 2013;368:1083
NEJM 2013;368:1092
NEJM 2017;377:1011
NEJM 2017;377:1033 REDUCE 2017

442
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

EC-IC Bypass

Powers JAMA 2011;306: 1983

COSS

Powers JAMA 2011;306: 1983

443
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stroke Prevention Overview

For Everyone
• HTN control
• Hyperlipidemia control
• Diabetes mellitus control
• Diet and exercise
• Smoking cessation

Antiplatelet Agent or Anticoagulant

Surgery
• Left atrial appendage occlusion
• CEA/CAS
• PFO closure
• EC-IC bypass

444
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Impact of Social
Networks in Stroke
Amar Dhand, MD DPhil
Assistant Professor of Neurology

Research Support

Financial Disclosures: None

445
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

We can quickly create social network maps

N

2
–1

x 100

! "#
x 100
! "# ! "#

Dhand A, Luke DA, Lang CE, Lee JM. Nat Rev Neurol. 2016;12(10):605-612.

Network
Medicine
Risk factor management

Medication adherence

Functional recovery

Barabási A-L. N Engl J Med. 2007;357(4):404-407.

446
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

"She literally looked at me and said, 'I want to be with Carrie,' and closed
her eyes and went to sleep."
- Todd Fisher

From the Cases of

Dr. Marty Samuels
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

‘Voodoo Death’,
Neurocardiac Phenomenon Mechanisms
(Cannon and Samuels)

‘Social Pain’,
Anterior Cingulate Cortex
(Eisenberger and Lieberman)

Dhand et al (2016). Social networks and neurological illness. Nat Rev Neurol.

448
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

75% of Patients Arrive After 3 Hours of

Stroke Symptoms
• 70% of strokes
occur at home

• 80% of stroke
occur in the
presence of others

Tong D, Reeves MJ, Hernandez AF, Mandelzweig et al. Stroke.

et al. Stroke. 2012;43(7):1912-1917. 2006;37(5):1248-1253.

Stroke. 2010.

449
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Social Networks and Risk of Delayed

Hospital Arrival after Acute Stroke

Constrained Unconstrained

450
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

61

8 40

Slow Fast

75% contact a 40% contact a

strongly-tied person strongly-tied person
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Communication of Slow Arriver Networks:

“Blinded By Affection” (Gowers)

1. Selectively disclose symptoms

2. Over-negotiate symptoms

3. Socially confirm watch-and-wait plan

Communication of Fast Arriver

Networks: “An awakening” (Hardy)
Coworkers, who were weak ties in one patient’s network, called 911
without discussion with the patient and said:

“Something is wrong with you. You need to go to the doctor.”

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Communication of Fast Arriver

Networks: “An awakening” (Hardy)
…Susan had an awakening. A friend to whom she confided her history
ridiculed her grave acceptance of her position; and all was over with her
peace of mind.

…and Susan’s staunch, religious adherence to him as her husband in

principle, till her views has been disturbed by enlightenment, was
demanded no more.
- Thomas Hardy, 1886, The Mayor of Casterbridge

Information benefits of an open network

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

In Acute Coronary Syndrome…

“The fastest response times are found in
those who are with a coworker or a
companion who is not a family member
when symptoms begin. Family members
(particularly spouses) often recommend
strategies that increase delay.”

Moser DK, Kimble LP, Alberts MJ, et al.

Circulation. 2006;114(2):168-182.

Quantifiable Social Processes Are Related to

Delayed Hospital Arrival After Stroke.

Slow: Constrained Fast: Unconstrained

454
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Social Networks Shrink After Ischemic

Stroke But Not Myocardial Infarction
Lubben Social Network Scale Score

*p=0.04 controlling for

socio-demographics,
baseline cognitive
function, and depression.
Years Before and After Vascular Event
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Social Networks Get Smaller and Close-Knit

After Stroke
Enrollment 3 months 6 months

We Found that Average Stroke Survivor Loses

One Person in their Network over 6 Months

456
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Network Size At Stroke Onset Is Associated With 3-

And 6-month Patient-Reported Physical Function
Physical Function Score at 6 months

beta=0.74 [0.51,0.97], p<0.001,

controlling for age, stroke
severity, and depression.

Social Network Size at Stroke Onset

Positive Interactions and Larger Networks

Size and Quality of
Social Interactions
Change in network size
20
96
18
101
16 197
117
14
76
12 200
network size

82
10
67
8 176
Negative Interactions and Smaller Networks
103
6
66
4 145
135
2
93
0 71
0 6
73
Time (months)

Positive Quality
Negative Quality

457
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stroke Arrival vs. Stroke Recovery

Network Intervention: Once a week, bring a

friend to therapy session
“Invite Elaine on Friday.”

“Invite Shawn next week.”

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Network Intervention II: Work together to

improve health habits in core network.
Goes to doctor regularly
Rolanda Smokes
Goes to doctor regularly Does not exercise
Smokes Eat unhealthy meals
Does not exercise
“Jonathan, Rolanda, and Eats healthy

you should try to stop

Jonathan
smoking together.”

“Jessica is a positive role

model. Invite her to
rehab appointments.”

Jessica

Goes to doctor regularly

Does not smoke
Goes to doctor regularly Does not exercise
Smokes MJ
You Eats healthy
Exercises regularly
Eats unhealthy meals
1488 networks generated
by online survey

459
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

460
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

www.socialnetneuro.com
@SocialNetNeuro

www.lboartstudio.com

461
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Stroke Treatments

Galen V. Henderson, M.D.

Brigham and Women’s Hospital
Department of Neurology
Director, Neurocritical Care

Assistant Professor of Neurology

Harvard Medical School

Disclosures
• I have no relationships to disclose

462
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Outline
Ischemic Stroke
Epidemiology
Imaging
Thrombolysis
Extended thrombolysis window

Cerebral hemorrhage
•Epidemiology
•Imaging
•Prognosis
•Hypertonic saline
•Protein complex concentrates

Stroke in the US
• 795 000 people experience a new or
recurrent stroke.
– Approximately 610 000 of these are first
attacks, and 185 000 are recurrent
attacks.
• 137 000 stroke deaths annually in the United
States.
• Leading cause of serious, long-term disability
• Third leading cause of death in the U.S.;
second leading cause worldwide
• Second-leading cause of hospital admission
among older adults
Stroke. 2011;42:849-877
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Prevalence of Ischemic Stroke

88%
of all strokes
are ischemic

Ischemic Stroke
88% Intracerebral
Hemorrhage
9%

Subarachnoid
Hemorrhage
3%

American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005.

Risk Factors
•Modifiable •Nonmodifiable
–Hypertension –Age
–Smoking
–Transient Ischemic –Gender
Attacks –Race
–Heart Disease –Prior Stroke
–Diabetes Mellitus –Heredity
–Atrial Fibrillation
–Obesity
–Physical Inactivity

464
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Prevalence of Stroke by Age

14

12
% of population

10 Men
8 Women

6
4
2

0
20–24 25–34 35–44 45–54 55–64 65–74 75+
Age range (years)

AHA. Heart Disease and Stroke Statistics—2004 Update.

Total Number of Elderly by Age

Group: 1900 to 2050
Millions
80

60

40 65 or older

20 85 or older

0
1900 1950 2000 2050
Projected

Note: data for the years 2000 to 2050 are middle-series projections of the population.
Reference population: these data refer to the resident population.
US Census Bureau. Decennial Census Data and Population Projections, 2003.

465
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Transient Ischemic Attacks (TIAs)

Historic Definition
Temporary focal brain or retinal
deficits caused by vascular
disease that resolve within 24
hours

New Definition of TIA

TIA is a brief episode of

neurologic dysfunction caused
by focal brain or retinal ischemia,
with clinical symptoms typically
lasting less than one hour, and
without evidence of acute
infarction
N Engl J Med, Vol. 337, Nov 21, 2002, 1713-1717.
Stroke, Vol 37, 2006, 577-617.
Stroke. 2009;40:2276.

466
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Short-term Prognosis after

Emergency Department Diagnosis of TIA

30.0%
Inclusion criteria: TIA by ED physicians
25.1% Objective: Short-term risk of stroke
25.0% Outcome events after ED diagnosis
Outcome
Measures: Risk of stroke and other
20.0% events during the 90 days
after index TIA

15.0% 12.7%
10.5% Johnston SC. et al. JAMA 2000;
10.0% 284: 2901-2906

5.0% 2.6% 2.6%

0.0%
Total Stroke Recurrent CV event Death
TIA

ABCD2 of TIA
• Patients with TIA score points for each of the following factors:
• Age 60 years (1 point)

• Blood pressure 140/90 mm Hg on first evaluation (1 point)

• Clinical symptoms of focal weakness with the spell (2 points) or

speech impairment without weakness (1point)

• Duration 60 minutes (2 points) or 10 to 59 minutes (1 point)

• Diabetes (1 point)

• 2-day risk of stroke:

• 0% for scores of 0 -1
• 1.3% for 2 -3
• 3, 4.1% for 4-5
• 8.1% for 6-7 Stroke. 2009;40:2276.

467
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Working up TIA

• Neuroimaging evaluation within 24 hours of symptom

onset.
• MRI, including DWI, is the preferred brain
diagnostic imaging modality.

• Noninvasive imaging of the cervicocephalic vessels

should be performed routinely as part of the evaluation

• Noninvasive testing of the intracranial vasculature

reliably excludes the presence of intracranial stenosis

• Should be evaluated as soon as possible after an

event

• ECG/ECHO Stroke. 2009;40:2276

Admit to the Hospital?

• Reasonable to hospitalize patients with TIA if they

present within 72 hours of the event and any of
the following criteria are present:

• ABCD2 score of 3

• ABCD2 score of 0-2 and uncertainty that

diagnostic workup can be completed within 2
days as an outpatient

Stroke. 2009;40:2276.

468
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Original Article
One-Year Risk of Stroke after Transient Ischemic
Attack or Minor Stroke
Pierre Amarenco, M.D., Philippa C. Lavallée, M.D., Julien Labreuche, B.S.T., Gregory
W. Albers, M.D., Natan M. Bornstein, M.D., Patrícia Canhão, M.D., Louis R.
Caplan, M.D., Geoffrey A. Donnan, M.D., José M. Ferro, M.D., Michael G.
Hennerici, M.D., Carlos Molina, M.D., Peter M. Rothwell, M.D., Leila Sissani, B.S.T.,
David Školoudík, M.D., Ph.D., Philippe Gabriel Steg, M.D., Pierre-Jean Touboul, M.D.,
Shinichiro Uchiyama, M.D., Éric Vicaut, M.D., Lawrence K.S. Wong, M.D., for the
TIAregistry.org Investigators

N Engl J Med
Volume 374(16):1533-1542
April 21, 2016

Study Overview

• In this international registry

study of patients who had a
transient ischemic attack or
minor stroke and who were
evaluated on an urgent basis by
stroke specialists, the 1-year risk
of recurrent stroke was 5.1%,
which is lower than the risk
reported in historical cohorts.

469
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cumulative Incidence of the Composite Outcome in the Overall Population.

Amarenco P et al. N Engl J Med 2016;374:1533-1542

Main Investigation Findings

during Evaluation by Stroke
Specialist and Key Urgent
Treatment before Discharge.

Amarenco P et al. N Engl J Med

2016;374:1533-1542

470
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Conclusions

• We observed a lower risk of

cardiovascular events after TIA than
previously reported.

• The ABCD2 score, findings on brain

imaging, and status with respect to
large-artery atherosclerosis helped
stratify the risk of recurrent stroke
within 1 year after a TIA or minor
stroke.

Goals of Emergent Evaluation

•Rule-out stroke mimics
•Differentiate hemorrhage from
ischemia
•Determine etiology / mechanism of
the event
•Confirm vascular etiology
•Provide early prognostic information

471
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Evaluation of Tissue Status:

Noncontrast Head CT
Advantages Disadvantages

• Almost universally •Often normal in

available hyperacute phase

• Rapid •Insensitive to lacunar

and posterior fossa
• High sensitivity for strokes
detection of
hemorrhage (100%
ICH, 90% SAH)

Evaluation of Tissue Status:

Multimodal MRI (including DWI)
Advantages Disadvantages
– More sensitive to –Not universally available
acute ischemia
– More sensitive to –Longer scanning time
posterior fossa
lesions –Patient contraindications
– More sensitive to (e.g. pacemaker)
small vessel, lacunar
lesions
– More sensitive in
differentiating acute
from subacute or
chronic lesions

472
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MRI - Tissue Status: Ischemia

CT

DWI

Evaluation of Vessel Status

1. CT Angiography

2. MR Angiography

3. Ultrasound Techniques

4. Catheter Angiography
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CT Angiography
•Requires injection of intravenous contrast
agent

•New generation helical scanners allow rapid

evaluation of aortic arch, neck, and
intracranial vessels with 1 injection

•80-100% accuracy compared with catheter

angiography

•Disadvantages: iodinated contrast agent,

radiation exposure

CTA: Carotid Stenosis

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CTA: MCA Stenosis

MR Angiography
•Noninvasive means to evaluate neck and
intracranial vessels

•Time of flight technique may overestimate stenoses

•Not reliable in identifying distal or branch

intracranial occlusions

•Sensitivity and specificity 70-100% compared to

catheter angiography

•Power-injector, contrast-enhanced techniques –

increased sensitivity

•Subject to limitations of standard MRI

475
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MR Angiography

Neck MRA: Right Intracranial MRA:

Carotid Stenosis Left ICA Occlusion

Evidence-based guideline: The role of diffusion and

perfusion MRI for the diagnosis of acute ischemic
stroke

• DWI should be considered superior to noncontrast CT scan

for the diagnosis of acute ischemic stroke in patients
presenting within 12 hours of symptom onset (Level A).
• There is insufficient evidence to support or refute the value of PWI in
diagnosing acute ischemic stroke (Level U).
• Baseline DWI volume should be considered useful in
predicting baseline clinical stroke severity and final lesion volume
in anterior-circulation stroke syndromes (Level B).
• Baseline DWI volume may be considered not useful in
predicting baseline NIHSS score in posterior-circulation stroke
syndromes (Level C).
• Baseline DWI volume may be considered useful in predicting
clinical outcome as measured by the NIHSS and Barthel Index
(Level C).
• Baseline PWI volume may be considered useful in predicting
baseline clinical stroke severity (Level C).
NEUROLOGY 2010;75:177-185

476
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

rtPA for Acute Stroke

•Only FDA-approved therapy

•Can reverse effects of stroke
•Only used in about 4-8% of cases
–Time limit: must be administered within 3 hours
of stroke onset
–Rapid identification and treatment

•Utility of rt-PA is limited due to:

– Three hours time window
– Associated with a significant risk of ICH

Overall Benefits and Risks of IV

tPA for Stroke
•Benefit: Neurologically normal at 3 months1
–55% relative increase; 12% absolute
increase
•Robust effect2:
–NNT to cure=7
•Risk of symptomatic ICH: 6.4%1
•Overall benefits in spite of the ICHs
•Risk of ICH can be reduced by closely following
tPA protocol

1. NINDS rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.

2. Ringleb PA et al. Stroke. 2002;33:1437-1441.

477
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NINDS Trial: Stroke Subtypes

Efficacy of rtPA by Stroke Subtype

80 75
% Normal by Barthel Score

70
60
50 49
at 3 Months

50 46
37 rtPA
40 36
Placebo
30
20
10
0
Lacunar Atherothrombotic Cardioembolic

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.

Empirical Characteristics of Litigation Involving Tissue

Plasminogen Activator and Ischemic Stroke
Study objective:
• The use of tissue plasminogen activator (tPA) in potential
stroke victims by emergency physicians is controversial.
One factor that may represent a barrier to use is
medicolegal concerns resulting from adverse outcomes.

Results:
• Thirty-three cases were found involving tPA ischemic
stroke therapy. In 29 (88%) of these cases, patient injury
was claimed to have resulted from failure to treat with
tPA.

• Emergency physicians were the most common physician

defendants. Defendants prevailed in 21 (64%) cases,
and among the 12 with results favorable to the plaintiff,
10 (83%) involved failure to treat and 2 (17%) claimed
injury from treatment with tPA.
Ann Emerg Med. 2008;52:160-164.

478
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

rt-PA Dosing
•0.9 mg/kg (max = 90 mg)

•10% bolus (over 1 minute)

•Remainder as a 1 hour infusion

•Have rt-PA in the Emergency Department

– Do not use the cardiac dose
– Do not exceed the 90 mg maximum dose.
– Do not give aspirin, heparin or warfarin for
24 hours

Eligibility for IV treatment with rt-PA

• Age 18 or older

• Clinical diagnosis of ischemic stroke

causing a measurable neurological
deficit

• Time of symptom onset well

established to be less than 180
minutes before treatment would
begin

479
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Exclusion Criteria
•Stroke or head trauma in 3 mos
•Major surgery within 14 days
•Any history of intracranial hemorrhage
•SBP > 185 mm Hg
•DBP > 110 mm Hg
•Rapidly improving or minor symptoms
•Symptoms suggestive of subarachnoid
hemorrhage
•Glucose < 50 or > 400 mg/dl
•GI hemorrhage within 21 days
•Urinary tract hemorrhage within 21 days

Exclusion Criteria
•Arterial puncture at non-compressible
site past 7 days
•Seizures at the onset of stroke
•Patients taking oral anticoagulants
•Heparin within 48 hours AND an elevated
PTT
•PT >15 / INR >1.7
•Platelet count <100 X 10/L

480
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Ischemic Stroke:

ASA/AAN/ACCP Guidelines
• Pharmacotherapies
– tPA (tissue plasminogen activator) within 3 hours of stroke
onset

– Aspirin for acute stroke (within 48 hours of symptom onset):

160 to 325 mg/day) to reduce stroke mortality and decrease
morbidity; ONLY if no contraindications or if patient will not
be given rtPA1

– Heparin and low molecular weight heparin (LMWH): not

indicated and may increase bleeding complications

– LMWH and heparinoids may be considered for DVT

prophylaxis in at-risk patients1

• Early consultation by neurologist or stroke team critical2

1. Coull BM et al. Stroke. 2002;33:1934-1942.
2. Adams HP et al. Stroke. 2003;34:1056-1083.

Quality Improvement Program and

tPA Use
•Stroke quality improvement program initiated in
Cleveland Clinic Health System in 1999
•Retrospective chart review from 1999 to 2000
conducted
•Findings:
–Intravenous tPA use increased from 1.8% to
18.8%
–Rates of symptomatic intracranial hemorrhage
and protocol deviations decreased (ICH from
15.7% to 6.4%; Deviations from 50% to 19.1%)
Katzan IL et al, on behalf of the Cleveland Clinic Health System Stroke Quality Improvement Team.
Stroke. 2003;34:799-800.

481
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Economic Benefit of Increasing Utilization

of Intravenous Tissue Plasminogen
• A $600 net cost savings is associated with each
tPA-treated patient.

• Currently, an estimated 2% of all ischemic stroke

patients receive tPA.
• If the proportion was increased to 4, 6, 8, 10, 15, or
20%, the realized cost savings would be
approximately $15, 22, 30, 37, 55, and 74 million,
respectively.

• If increases tPA were achieved

• result in an enormous realized savings for America’s
healthcare system.
Stroke. 2005;36:2500

An Advisory Statement from the Stroke Council, American

Heart Association and American Stroke Association
EXPANSION OF THE TIME WINDOW FOR TREATMENT
OF ACUTE ISCHEMIC STROKE WITH INTRAVENOUS
TISSUE PLASMINOGEN ACTIVATOR

Gregory J. del Zoppo, MD, MS, FAHA; Jeffrey L. Saver, MD, FAHA; Edward C.
Jauch, M.D, MS, FAHA; Harold P. Adams, Jr., MD, FAHA
This science advisory reflects a consensus of expert opinion following thorough literature review that consisted of a look
at clinical trials and other evidence related to the management of acute ischemic stroke.

482
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ECASS - 3

DESIGN AND METHODS

• Multicenter, prospective, placebo-controlled RCT
• Usual criteria for rt-PA eligibility within 3 hrs, exclusion criteria
included:
– older than 80 years; baseline NIH Stroke Scale score >25;
on oral anticoagulants; combo of a previous stroke & DM
• rt-PA (n = 418) or placebo (n = 403) given at 3.0 - 4.5 hrs from
stroke symptom onset
• Dose = 0.9 mg/kg (max 90 mg); 10% as initial bolus & remainder
infused over 1 hr.
• Primary outcome: modified Rankin Scale Score 0-1 (minimal or
no disability) at 90 days after Tx.
•

ECASS - 3
RESULTS
Primary Outcome:
• mRS 0-1: rt-PA (52.4%) vs placebo (45.2%)
(OR 1.34, 95% CI = 1.02-1.76; p = 0.04)
Secondary Outcome:
Global Favorable Outcome
(mRS of 0-1, Barthel Index score >95, an NIHSS
score of 0-1& Glascow Outcome Score of 1)
• ECASS – 3 = OR 1.28, 95% CI = 1.00-1.65) vs
NINDS pool pts (enrolled 0-3hrs) = OR1.9, 95% CI
1.2-2.9
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ECASS - 3
RESULTS
• Symptomatic ICH (ECASS-3 definition) occurred in
rt-PA n = 10 (2.4%) vs placebo n = 1 (0.2%)
(OR 9.85, 95% CI 1.26-77.32, p = 0.008)
• Symptomatic ICH (NINDS study definition) occurred in
rt-PA n = 33 (7.9%) vs placebo n = 14 (3.5%)
(OR 2.38, 95% CI = 1.25-4.52, p = 0.006)

• Increased incidence of symptomatic ICH is consistent

with the experience with rt-PA in other clinical trials with
rt-PA

• Mortality in the two treatment groups did not differ

significantly, although it was nominally higher among the
subjects treated with placebo (7.7% vs. 8.4%, p=0.68)

Recommendations

• rt-PA should be administered to eligible pts within 3.0-4.5

hours after stroke (Class I Recommendation, LOE B)

• Eligibility criteria in this time period are similar to those for

persons treated at earlier time periods with the following
additional exclusion criteria:
– Age > 80 years; Oral anticoagulant use with INR ≤ 1.7*; baseline NIH
Stroke Scale score > 25; a history of stroke and diabetes (*For the 3.0 –
4.5 hr window all pts receiving oral anticoagulant are excluded whatever
their INR).

• The efficacy of IV rt-PA within 3.0 – 4.5 hours after stroke

in pts with these exclusion criteria is not well-established &
requires further study. (Class IIb Recommendation, LOE C)

484
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

In patients with acute ischemic stroke:

• < 3 hours for IV r-tPA (Grade 1A)

• 3 < 4.5 hours we suggest IV r-tPA over

no IV r-tPA (Grade 2C)

• Cannot be initiated < 4.5 h of symptom

onset, we recommend against IV r-tPA
(Grade 1B)

CHEST. 2012;141(2_suppl):1S-1S. doi: 10.1378/chest.1412S1

PHANTOM-S: The Pre-Hospital Acute Neurological Therapy and

Optimization of Medical Care in Stroke Patients - Study "PHANTOM-S"

Lancet Neurol. 2012 May;11(5):397-404. doi:

10.1016/S1474-4422(12)70057-1. Epub 2012 Apr 11.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meta-analysis Shows a Strong Correlation Between

Revascularization and Good Patient Outcomes
70%

60% 58.1%

50%
% of Patients

41.6%
40%

30% 24.8%

20% 14.4% 13.7% 12.5%

10%

0%
Good Outcome 90-Day Mortality SICH *
(mRS 0-2)

Revascularized Non-revascularized
*Differences in sICH were not statistically significant between the
revascularized and non-revascularized groups
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome:
a meta-analysis. Stroke. 2007 Mar;38(3):967-73.

35-40% of Ischemic Strokes are Considered

“Large Vessel”
• This subset of ischemic stroke comprises blockages in the:
– Internal Carotid Artery (ICA)
– Middle Cerebral Artery (MCA)
– Vertebral / Basilar Artery

• Patient prognosis with these types of stroke is poor

Vessel Mortality Rate

ICA 53%1
MCA 27%2
Basilar Artery 89-90%3
1. Jansen O, et al.
2. Furlan A et al. PROACT II Trial
3. Brückmann H et al.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Trial Summary
mRS 0-2
Imaging Required TICI 2b/3
to Confirm Device(s) Used in Revascularization
Trial Intervention Control Odds Ratio
Occlusion Prior to Intervention Arm Rate in the
Randomization? Intervention Arm Arm Arm (95% CI)

IA Lytic (138), Merci 38% ICA

0.02
Retriever® (95), EKOS 44% M1 40.8% 38.7%
IMS III No (-0.06 to
(22), Penumbra (54), 44% M2 (N=415) (N=214)
0.09)
Solitaire FR (5) 23% multi M2
24% pen 21% pen 26% pen
Merci Retriever®,
(n=34) (n=34) (n=34)
MR RESCUE No EKOS, IA Lytic, NS
27% nonp 17% nonp 10% nonp
Penumbra
(n=30) (n=30) (n=20)

97% Stent
33% 19% 2.16
MR CLEAN Yes Retrievers, 2% other 58.7% (N=196)
(N=233) (N=267) (1.39-3.38)
Mechanical

72.4% 53.0% 29.3% 1.8

ESCAPE Yes 86% Stent Retriever
(n=156) (n=164) (n=147) (1.4-2.4)
88.0% 60.2% 35.5% 2.75
SWIFT PRIME Yes 100% Stent Retriever
(n=83) (n=98) (n=93) (1.53,4.95)
86.2% 71% 40% 4.2
EXTEND-IA Yes 100% Stent Retriever
(n=29) (n=35) (n=35) (1.3-13)

Goal of Ischemic Stroke Treatment

Before Intervention

After Successful Intervention

487
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ASA Treatment Guidelines: Ischemic Stroke Not

Eligible for Thrombolytic Therapy

BP Level
Treatment
(mm Hg)
SBP <220
OR No treatment unless end-organ involvement
DBP <120
SBP >220
OR Nicardipine or labetalol to 10% -15% ↓ in BP
DBP <121-140

DBP >140 Nitroprusside to 10% -15% ↓ in BP

ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.
Adams HP, et al. Stroke. 2007;38:1655-1711.

ASA Treatment Guidelines: Ischemic Stroke

Eligible for Thrombolytic Therapy

BP Level (mm Hg) Treatment

Pretreatment Labetalol (may repeat once), nitropaste, or
SBP >185 or nicardipine
DBP >110 If BP not reduced and maintained,
do not administer rt-PA
During and after
rt-PA
SBP 180-230
OR Labetalol
DBP 105-120
SBP >230
Nicardipine or labetalol
OR
If BP not controlled, consider nitroprusside
DBP 121-140

rt-PA = recombinant tissue plasminogen activator.

Adams HP, et al. Stroke. 2007;38:1655-1711.

488
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Primary objective of the CHANCE trial

• To assess the efficacy of a 3-month regimen of

clopidogrel-aspirin (300 mg load followed by
75 mg/day) vs. aspirin alone on reducing the 3-
month risk of new stroke (ischemic or
hemorrhagic) when initiated within 24 hours of
symptom onset in patients with high-risk TIA
or minor stroke.

International Stroke Conference 2013

CHANCE trial
• Age ≥ 40 years;

• Either:
Non-disabling ischemic
stroke(NIHSS≤3), or
TIA with moderate-to-high risk of
stroke recurrence (ABCD2 score ≥ 4).

• Study drug can be given within 24 h of

symptom onset.
International Stroke Conference 2013

489
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CHANCE Trial Summary

• TIA and minor ischemic stroke are a treatable
emergency

• Clopidogrel with a 300 mg load plus aspirin reduces

subsequent stroke risk compared to aspirin alone.

• Clopidogrel-aspirin is safe in this setting with no

increase in bleeding.

• Even more aggressive interventions after acute TIA and

minor stroke may be indicated but require clinical
trials.

International Stroke Conference 2013

Original Article
Hemicraniectomy in Older Patients with Extensive
Middle-Cerebral-Artery Stroke
Eric Jüttler, M.D., Ph.D., Andreas Unterberg, M.D., Ph.D., Johannes Woitzik, M.D.,
Ph.D., Julian Bösel, M.D., Hemasse Amiri, M.D., Oliver W. Sakowitz, M.D., Ph.D.,
Matthias Gondan, Ph.D., Petra Schiller, Ph.D., Ronald Limprecht, Steffen Luntz, M.D.,
Hauke Schneider, M.D., Ph.D., Thomas Pinzer, M.D., Ph.D., Carsten Hobohm, M.D.,
Jürgen Meixensberger, M.D., Ph.D., Werner Hacke, M.D., Ph.D., for the DESTINY II
Investigators

N Engl J Med
Volume 370(12):1091-1100
March 20, 2014
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Study Overview
• In patients older than 60 years of
age with extensive middle-cerebral-
artery strokes, early
hemicraniectomy improved survival
as compared with treatment in the
ICU alone.

• The majority of survivors had

substantial disability and required
assistance with most bodily needs.

Functional Outcome after Hemicraniectomy and after Conservative Treatment Alone

According to the Modified Rankin Score.

Jüttler E et al. N Engl J Med 2014;370:1091-1100

491
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Kaplan–Meier Estimates of Survival in the Hemicraniectomy and Control Groups.

Jüttler E et al. N Engl J Med 2014;370:1091-1100

Causes of Death.

Jüttler E et al. N Engl J Med 2014;370:1091-1100

492
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

2nd Decompression

493
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Significance of cerebral
hemorrhage
• ICH represents 10 – 15% of all strokes

• Twice as common as subarachnoid hemorrhage and just as

deadly

• Only 20% live independently at 6 months

• Incidence: 67,000 in US each year (worldwide incidence: 10–20

cases per 100,000 population)

• 30 day mortality rate 35-52%, half of deaths occur in the first 2

days

• Mortality rate unchanged over the last 20 years

American Heart Association. Heart Disease and Stroke Statistics–2005 Update;

Qureshi AI et al. N Engl J Med. 2001;344:1450-1460.
Broderick JP et al. Stroke. 1999;30:905-915; Broderick JP et al. N Engl J Med. 1992;326:733-736.
Broderick JP, et al. Stroke. 2007;38:1-23.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Intracerebral Hemorrhage Subtypes

• Primary • Subarachnoid
– Hematomas – Aneurysmal
– Microbleeds – Non-aneurysmal

• Secondary • Subdural hematoma

– Tumors
– Vascular • Epidural hematoma
malformation
– Aneurysms
– Coagulopathy
– Trauma
– Ischemic stroke with
trans.
– Drug use

Most Common Sites of ICH

50% deep
35% lobar
10% cerebellum
6% brainstem

Qureshi AI et al. N Engl J Med. 2001;344:1450-1460.

Broderick JP, et al. Stroke. 2007;38:1-23.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ICH Volume
Powerful Determinant of 30-day Outcome

Full Recovery 2
Condition3 at 30 days
4
(Oxford
5
Handicap
6
Scale)
Dead

Condition at 30 days (Oxford Handicap Scale)

Good recovery with volume > 30 mL does not occur

Broderick JP et al. Stroke. 1993;24:987-993.

Early Hemorrhage Growth in

Patients with ICH
• 103 patients scanned < 3
hours of onset
• 38% experienced significant
hematoma growth (> 33%
increase in volume)
– 26% within 1 hour of baseline
scan
– 12% between 1- and 20-hour
scan
• ICH growth was associated
with clinical deterioration on
NIHSS
• In patients with putaminal ICH,
hematoma growth (> 33%)
occurs early (shown)

NIHSS, National Institutes of Health Stroke Scale.

Brott T et al. Stroke. 1997;28:1-5.

496
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

28 mL

43 mL

Image courtesy T. Brott, MD.

Contrast within the hematoma

Goldstein, J. N. et al. Neurology 2007;68:889-894

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The ICH Score Components

ICH Score
Component Points
GCS score
3–4 2
5–12 1
13–15 0
ICH volume, cm3
30 1
<30 0
IVH
Yes 1
No 0
Infratentorial origin of
ICH
Yes 1
No 0
Age, y
80 1
<80 0
Total ICH Score 0–6

The ICH Score and 30-day mortality

Hemphill, J. C. et al. Stroke 2001;32:891-897

498
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

FUNC score prediction tool

Rost, N. S. et al. Stroke 2008;39:2304-2309

AHA Treatment Guidelines for ICH

BP level
Treatment to Consider
(mm Hg)
Aggressive reduction of blood
SBP > 220 mmHg pressure with continuous intravenous
infusion
Monitoring ICP and reducing blood
SBP > 150 - 220 mmHg and
pressure using intermittent or
evidence or suspicion of
continuous intravenous medications
elevated ICP
to keep CPP > 60-80 mm Hg

SBP > 150 - 220 mmHg and no Modest reduction of blood pressure to
evidence or suspicion or 140 mmHg is safe using intermittent
elevated ICP or continuous intravenous

AHA = American Heart Association; ICH = intracerebral hemorrhage; SBP = systolic blood pressure; CPP = cerebral perfusion
pressure; ICP = intracranial pressure

Broderick JP, et al. Stroke. 2007;38:1-23 and Stroke, 2015;46:2032-2060.

499
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Original Article
Rapid Blood-Pressure Lowering in Patients with
Acute Intracerebral Hemorrhage
Craig S. Anderson, M.D., Ph.D., Emma Heeley, Ph.D., Yining Huang, M.D., Jiguang
Wang, M.D., Christian Stapf, M.D., Candice Delcourt, M.D., Richard Lindley, M.D.,
Thompson Robinson, M.D., Pablo Lavados, M.D., M.P.H., Bruce Neal, M.D., Ph.D.,
Jun Hata, M.D., Ph.D., Hisatomi Arima, M.D., Ph.D., Mark Parsons, M.D., Ph.D.,
Yuechun Li, M.D., Jinchao Wang, M.D., Stephane Heritier, Ph.D., Qiang Li, B.Sc.,
Mark Woodward, Ph.D., R. John Simes, M.D., Ph.D., Stephen M. Davis, M.D., John
Chalmers, M.D., Ph.D., for the INTERACT2 Investigators

N Engl J Med
Volume 368(25):2355-2365
June 20, 2013

Study Overview

• In this trial involving patients with

intracerebral hemorrhage, intensive BP
lowering (target systolic BP <140 mm
Hg) did not significantly reduce the rate
of the primary outcome of death or
major disability but did significantly
improve overall functional outcomes.

500
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Effect of Early Intensive Blood-Pressure–Lowering Treatment on the Primary Outcome,

According to Prespecified Subgroups.

Anderson CS et al. N Engl J Med 2013;368:2355-2365

Conclusions

• In patients with intracerebral hemorrhage,

intensive lowering of blood pressure did not
result in a significant reduction in the rate of
the primary outcome of death or severe
disability.

• An ordinal analysis of modified Rankin scores

indicated improved functional outcomes with
intensive lowering of blood pressure.

501
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Signs of Elevated ICP

Combination of signs
• Depressed level of consciousness
• Reflex hypertension, with or
without bradycardia
• Headache
• Vomiting
• Papilledema
• Cranial nerve palsies

Osmolality of IV fluids
Fluid Osmolality (mOsm/kg)
5% Dextrose 252
Lactated ringers 250-260
Plasma 285
5% Albumin 290
Normal Saline 0.9% 308
25% Albumin 310
6% Hetastarch 310
2% Normal Saline 682
3% Normal Saline 1025
25% Mannitol 1375
7.5% Normal Saline 2400
23.4% Normal Saline 8008

502
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Early seizures after ICH

• Clinically apparent seizures
– 4% in 1st 24 hours; 8% in 1st month
– Predictors: lobar location, small ICH
volume
– No convincing effect on outcome

• Electrographic seizures
– 28-31% by continuous EEG over ~ 72 hours
– Predictors; hematoma enlargement on 24-
hr CT
– Periodic discharges associated with poor
outcome
Passero et al, Epilepsia, 2002
Kilpatrick et, Arch Neurolgoy 1990
Vespa et al, Neurology, 2003
Franke et al, JNNP, 1992
Classen et al, Neurology, 2007
Stroke 2010;41;2108-2129

Treatment of Warfarin
Associated ICH

Aguilar et al Mayo Clin Proc. 2007;82:82-92

503
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thrombotics and Anticoagulation

Anticoagulant Agent Dose
INR >6 → 50 IU/kg
Kcentra INR >4 → 35 IU/kg
INR < 4 → 25 IU/kg

Warfarin + Vitamin K 10mg IV over 10min

INR >4 → 50 IU/kg

or Profilnine SD
INR < 4 → 25 IU/kg

or FFP 2-6 units

fibrinogen > 150 → 2 vials

RiaSTAP fibrinogen < 150 → 2+2 vials
TPA
fibrinogen < 150 → 20+20 units
or Cryoprecipitate fibrinogen > 150 → 20 units

Heparin Protamine 1mg/100 heparin units over the last 4 h

If <8h → 1mg/mg of enoxiparin

Enoxaparin (Lovenox) Protamine If > 8h → 0.5mg/mg of enoxiparin

Aspirin Platelets 6 pack

ddAVP 0.3 µg/kg over 30 min

Plavix
Platelets 6 pack

5g IV x1
Dabigatran (Thrombin) Idarucizumab Under study:
Check TT FEIBA 100 units/kg

Rivazoxaban, Apixaban, Kcentra 35 IU/kg

Edoxaban, (factor Xa)

Check Xa and PT Andexanet Under study:

Uremia ddAVP 0.3 µg/kg over 30 min

Fondaparinux Factor VIIa 90 µg/kg

ddAVP 0.3 µg/kg over 30 min

Argatroban
Cryoprecipitate 10 units

Surgical Therapies for ICH

• Surgical evacuation
– Large (>3 cm) cerebellar
hemorrhages
– Large lobular hemorrhages
– Substantial mass effect
– Rapidly deteriorating condition

.
O’Connell KA, et al. JAMA. 2006;295:293-298.

504
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

STICH Trial: Surgery for ICH?

• 1033 enrolled
• Eligible if clinical
equipoise
• Enrollment within 72
hours of onset
– Early surgery
– No early surgery
• No effect on mortality
• No effect of outcome Early No Early
Surgery Surgery

Dead or Disabled
63% 64%
Good Outcome
26% 24%

Mendelow DA, et al, Lancet 2005;365;387

ICH: DVT Prophylaxis

• DVT prophylaxis
–Heparin 5000 U SC q12H started
on day 2 is safe and reduces
DVT/PE
–STANDARD: Start low dose
subcutaneous heparin on day 2
–OPTION: Enoxaparin 40 mg qd

Boeer A, et al, J Neurology Neurosurg Psychiatry 1991;54:466

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary
Ischemic Stroke
Epidemiology
Imaging
Thrombolysis
Extended thrombolysis window

Cerebral hemorrhage
•Epidemiology
•Imaging
•Prognosis
•Subclinical seizures
•Hypertonic saline
•Protein complex concentrates

• All who drink of this treatment recover

within a short time, except in those
who do not.

Therefore, it fails only in incurable

cases
-Galen
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thank you for your Attention

Question 1
Factors that are important in the
evaluation of a TIA:
A. Age
B. Blood pressure
C. Clinical features of event
D. Cerebral/cervical vessel imaging
E. All of these above

507
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Answer to Question 1
Factors that are important in the
evaluation of a TIA:
A. Age
B. Blood pressure
C. Clinical features of event
D. Cerebral/cervical vessel imaging
E. All of these above

Question 2
A 84 yo presents with a right
hemiparesis and aphasia at 3.5 hours
after onset, all items would exclude
the patient from getting IV r-TPA,
except?
A. Age
B. Patient taking anticoagulation for afib
C. Patient just chewed an ASA at home
D. NIHSS > 25
E. None of these above

508
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Answer to Question 2
A 84 yo presents with a right
hemiparesis and aphasia at 3.5 hours
after onset, what would exclude the
patient from getting IV r-TPA, except?
A. Age
B. Patient taking anticoagulation for afib
C. Patient just chewed an ASA at home
D. NIHSS > 25
E. None of these above

Question 3
In the reversal of warfarin related
cerebral hemorrhage, the most rapid
treatment would be:
A. IV vitamin K
B. Fresh frozen plasma
C. Protein complex concentrates (PCC)
D. A and B
E. A and C

509
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Answer to Question 3
• In the reversal of warfarin related
cerebral hemorrhage, the most rapid
treatment would be:
A. IV vitamin K
B. Fresh frozen plasma
C. Protein complex concentrates (PCC)
D. A and B
E. A and C
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Primary Brain Tumors

Lakshmi Nayak, M.D.

Director, Center for CNS Lymphoma
Center For Neuro-Oncology
Dana-Farber/Brigham and Women’s Cancer Center

Division of Cancer Neurology, Department of Neurology

Brigham and Women’s Hospital

Assistant Professor Neurology

Harvard Medical School

Disclosures:
Consulting- Bristol Myers Squibb

511
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Preview

• Epidemiology

• Clinical Presentation
– Including diagnosis and work up

• Management
– General overview of treatment
– Specific treatment for more common subtypes

Preview

• Epidemiology

• Clinical Presentation
– Including diagnosis and work up

• Management
– General overview of treatment
– Specific treatment for more common subtypes
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

How Common is “Brain Cancer”?

Site Estimated New Cases Estimated
Deaths
Breast 249,260 40,490
Lung 224,390 158,080
Prostate 180,890 26,120
Colon 95,270 49,190
Non Hodgkin Lymphoma 72,580 20,150
Melanoma 76,360 10,130
Brain / nervous system 23,770 16,050

American Cancer Society (2016). Cancer Facts and Figures 2016.

Epidemiology

• Brain tumors can be broadly classified as:

– Primary (ie. arising from cells within the brain)
– Secondary (ie. arising from systemic tumors
metastasizing to the brain)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology

• Primary brain & CNS tumors

– various histologic types
– account for ~2% of all cancers
– incidence rate of 27.86 per 100,000

• In children and adolescents (0-19y), they are the

most common neoplasm

Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62

Primary Brain Tumor Histologies

– Diffuse astrocytic and oligodendroglial – Tumors of the pineal region
tumors – Embryonal Tumors
• Astrocytoma, IDH mutant, IDH wild • Medulloblastoma
type, NOS – Tumors of cranial & paraspinal nerves
• Glioblastoma, IDH wildtype, IDH • Schwannoma
mutant, NOS
• Neurofibroma
• Oligodendroglioma, IDH mutant &
1p/19q codeleted, NOS – Meningiomas
– Other astrocytic tumors – Mesenchymal tumors
• Pilocytic astrocytoma, PXA , SEGA • Solitary fibrous tumor
– Ependymal tumors • Hemangioblastoma
– Choroid plexus tumors – Lymphomas
– Neuronal Tumors – Germ cell tumors
• Ganglioglioma • Germinoma
• Gangliocytoma • Teratoma
• Central neurocytoma – Tumors of the sellar region
• Craniopharyngioma

Louis DN, et al. The 2016 WHO Classification of Tumors of the Central Nervous System.
Acta Neuropathol 2016; 131:803

514
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology

• The most common subtype of primary brain and CNS

tumors is meningioma accounting for 36%, majority
of which are non-malignant.

• 34% of all primary brain and CNS tumors are

malignant, of which the most common tumor is
glioblastoma.

Incidence Increases with Age

Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62

515
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Survival Declines with Age

Age 5-Year Survival 5-Year Survival

for GBM for Meningioma
0-19 17.7% ──
20-44 17.9% 87.9%
45-54 6.5% 76.6%
55-64 4.1% 68.7%
65-74 2.1% 55.5%
75+ 0.9% 48.2%
Quinn T. Ostrom et al. Neuro Oncol 2015;17:iv1-iv62

Risk Factors

• The majority of brain tumors are sporadic

• Hereditary genetic syndromes <5%
• Ionizing radiation
– increase incidence of GBM, gliosarcoma &
meningioma
• No definitive link between cell phones and gliomas

516
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Genetic Syndromes

Syndrome Gene/Protein Classic Brain Tumors

NF1 NF1/Neurofibromin Optic nerve gliomas

NF2 NF2/Merlin CN 8 schwannomas,

meningiomas
Von Hippel Lindeau VHL Hemangioblastomas

Li-Fraumeni TP53 Gliomas

Turcot’s APC, others Medulloblastomas

Basal cell nevus (Gorlin’s) PTCH Medulloblastomas

Preview

• Epidemiology

• Clinical Presentation
– Including diagnosis and work up

• Management
– General overview of treatment
– Specific treatment for more common subtypes
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Presentation

• Patients with primary brain tumors can present with a

variety of clinical symptoms and neurologic signs.

• These manifestations are not specific for individual tumor

subtypes or even brain tumors in general, and symptoms
can easily be mistaken for a number of other neurologic
conditions.

• In general, symptoms and signs are influenced by the

underlying tumor’s location, size, and growth rate.

Clinical Presentation

• CNS tumors cause neurologic symptoms and signs by

invasion, compression, CSF obstruction and herniation.

• Invasion and compression typically lead to focal

symptoms, allowing clinical localization of the underlying
tumor.

• Whereas CSF obstruction and herniation cause more

generalized and non-localizing or even false localizing
symptoms and signs.

518
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Signs and Symptoms that Might

Suggest a Brain Tumor
• Generalized symptoms due to increased ICP or
involvement of multiple areas
– Headaches
– Nausea/vomiting
– Depressed level of consciousness
– Neurocognitive dysfunction

– A new onset headache in an adult with no prior history of

headaches or change in the quality, severity, or location of a
pre-existing headache should be evaluated with detailed
neurologic examination and brain imaging.

Signs and Symptoms that Might

Suggest a Brain Tumor
• Focal symptoms due to local brain invasion or
compression of adjacent structures
– Depend on the location of the lesion
– Lateralizing motor or sensory symptoms / aphasia / visual
field deficit / ataxia
– Seizures

519
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Presentation

• Typically, there is gradual development of symptoms -

unlike the sudden onset seen in stroke; although acute
symptoms can develop in the setting of a seizure or
intratumoral hemorrhage.

• As hemorrhage can be common in certain brain tumors,

it is important to obtain a 1-2 month follow up MRI in a
patient presenting with new unexplained hemorrhage.

Clinical Presentation

• Seizures are common in brain tumor patients and can

occur at initial presentation or anytime over the
subsequent course of the disease.

• New onset or increasing frequency or severity of

seizures can be a sign of underlying tumor
progression and should prompt re-evaluation.

• The overall incidence of seizures varies with

underlying tumor type and location
– more common in slow growing, low grade tumors

520
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

If you suspect a brain tumor …

• MRI with and without gadolinium

• Avoid corticosteroids (in case of CNS lymphoma)
• Radiographic appearance can often provide guidance
on possible pathology
• Imaging cannot substitute pathology
• LP rarely helpful (few exceptions)
• Do not need to do CAP CT if suspect primary brain
tumor (exception: extent of disease evaluation for
primary CNS lymphoma)

Diagnosis and Work Up

• Radiographic appearance varies depending on the type
of brain tumor
• High grade gliomas are irregular with heterogeneous
contrast enhancement and evidence of invasive disease.
• Low grade gliomas usually exhibit no or minimal contrast
enhancement and no edema.
• Primary CNS lymphomas are often multiple,
periventricular, irregular and homogenously enhancing
lesions
• Meningiomas are dural-based homogenously enhancing
lesions with a relative lack of peritumoral edema.

521
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MRI: Glioblastoma

T1 T2 T1
pre-gadolinium post-gadolinium

MRI: Low-Grade Glioma

T1 post-gadolinium FLAIR

522
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MRI: Meningioma

A B

T1 post-gadolinium T2

MRI: Primary CNS Lymphoma

T1 T1 post-gadolinium FLAIR DWI

523
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis and Work Up

• Tissue examination by surgical resection or biopsy is

required to make the histopathologic diagnosis.

• Additional work up depends on the tumor-type.

• For the majority of primary brain and CNS tumors, like

gliomas and meningiomas, evaluation of the entire
neuroaxis and CSF is not necessary unless indicated.
– Exceptions: tumors with a tendency to drop metastases or
leptomeningeal seeding, eg. medulloblastoma, ependymoma,
PCNSL

Diagnosis and Work Up

• Extent of disease evaluation and systemic staging for

PCNSL
– Body PET/CT
– Ophthalmologic evaluation
– Bone marrow biopsy
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Preview

• Epidemiology

• Clinical Presentation
– Including diagnosis and work up

• Management
– General overview of treatment
– Specific treatment for more common subtypes

Principles of Treatment

• Surgery
• Radiation
• Chemotherapy
• Experimental approaches (targeted agents,
immunotherapy, vaccines)
• Supportive Treatment
– Anti-Epileptic Drugs (AEDs)
– Corticosteroids
– Anticoagulants

525
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Treatment – Role of Surgery

• Surgery is a modality of diagnosis as well as treatment in

the majority of CNS tumors.

• It may help with mechanical decompression & relief from

acute symptoms
– Improvement of focal neurologic deficits
– Relief from herniation and raised intracranial pressure (ICP)

Principles of Treatment – Role of Surgery

• Maximal surgical resection is recommended for the

majority of the primary brain tumors
– Exception: highly chemosensitive tumors - PCNSL &
Germ Cell Tumors (GCTs)

• Complete or gross total resection may be the only

treatment required in tumors such as pituitary
adenomas, pilocytic astrocytomas & grade 1
meningiomas.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Treatment – Role of Surgery

• Functional MRI pre-operatively and intraoperative

cortical mapping may be utilized if the tumor is close to a
functionally important location.

• Intraoperative MRI, robotic equipment and endoscopic

surgery may be employed to improve neurosurgical
approach.

Principles of Treatment – Role of Surgery

• Placement of VP shunt or EVD for hydrocephalus and

raised ICP

• Spinal surgery is indicated in patients with:

– spinal cord lesions
– spinal instability from vertebral metastases or
– cord compression from epidural disease or pathologic
fractures.

527
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Treatment – Role of Radiation

• Radiation is one of the most important treatment
modalities for the majority of brain tumors

• Ionizing RT can be delivered to the tumor in several

ways:
– 3D Conformal field RT
– Intensity modulated RT (IMRT)
– Stereotactic RT
– Interstitial brachytherapy
– WBRT and craniospinal RT (CSRT)

Principles of Treatment –
Role of Chemotherapy
• Chemotherapy alone is seldom the treatment of choice
in the majority of primary CNS tumors.

• Traditionally, some of the challenges with chemotherapy

have been inability of some agents to cross the blood
brain barrier, intrinsic resistance & heterogeneity of
tumors like gliomas.

• Specific types of chemotherapy discussed with individual

tumor subtype.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SupportiveTreatment –
Seizures and Anti-Epileptic Drugs
• AEDs are currently not recommended for prophylaxis
except in the peri-operative period.
– There is currently an on-going randomized trial investigating the
prophylactic use of lacosamide in patients with high-grade
gliomas without seizures at initial presentation.

• Non-enzyme inducing AEDs, such as levetiracitam,

lacosamide, lamotrigine, valproate are preferred in brain
tumor patients as there is limited interaction with
chemotherapy & they are less toxic.

SupportiveTreatment -
Vasogenic edema & Corticosteroids

• Corticosteroids help alleviating symptoms from

peritumoral edema or raised ICP.

• Symptomatic improvement may begin within minutes-

hours with peak effect in 24-72 hrs.

• Dexamethasone is preferred due to lack of

mineralocorticoid activity and long t1/2
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SupportiveTreatment -
Vasogenic edema & Corticosteroids
• Indications of corticosteroids:
– symptomatic edema or herniation
– cord compression
– peri-operatively
– Exception: suspected and undiagnosed lymphoma
due to lympholytic effects causing tumor necrosis
which may preclude definitive diagnosis

SupportiveTreatment -
Vasogenic edema & Corticosteroids
• They have several long term side effects, including,
– immunosuppression,
– HTN,
– DM,
– adrenal insufficiency,
– GI side effects,
– psychiatric symptoms etc.

• It is important to use PJP prophylaxis in all patients who

are on corticosteroids for >4 weeks.

530
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SupportiveTreatment - Venous
Thromoboembolism & Anticoagulation
• There is a very high risk of thromboembolism in pts with
brain tumors.
– 30% glioma pts are affected
– The risk is high during the post-operative period, but
persists throughout the course of disease.
– Risk factors:
• high grade gliomas,
• large tumor >5cm,
• biopsy or incomplete resection,
• leg paralysis, immobility,
• older age,
• anti-VEGF therapy.

SupportiveTreatment - Venous
Thromoboembolism & Anticoagulation
• LMWH is preferred over warfarin.

• IVC filters are used only in patients with contraindication

to anticoagulation.

• Presence of brain tumor does not exclude

anticoagulation as long as there is no acute intratumoral
or intracranial hemorrhage.

531
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SupportiveTreatment - Venous
Thromoboembolism & Anticoagulation
• The use of bevacizumab, anti-VEGF agent (for recurrent
GBM) increases the risk of venous thromboembolism.

• Bevacizumab may increase the risk of intracranial

hemorrhage.

• Concurrent use of bevacizumab & anticoagulation may

lead to a marginally higher risk.
– This is generally thought to be acceptable weighing the risk-
benefit ratio.

Preview

• Epidemiology

• Clinical Presentation
– Including diagnosis and work up

• Management
– General overview of treatment
– Specific treatment for more common subtypes
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Specific Subtypes

• High grade gliomas

• Low grade glioma
• Pilocytic astrocytoma
• Medullobastoma
• Meningioma
• Vestibular schwannoma
• PCNSL

High grade gliomas

• A 56 y/o RHM with no significant PMH presented to the

ED with progressively worsening mental status over 2-3
days. On the day of admission, he was noted by his wife
to have word finding difficulty. Upon further questioning,
he had developed new onset dull headaches for 4-6
weeks and mild confusion. Brain MRI revealed a large
left frontal contrast enhancing lesion with surrounding T2
changes and midline shift. He was started on
dexamethasone upon which his symptoms improved and
he underwent surgical resection of the lesion, pathology
of which was c/w GBM. He presented to neuro-oncology
multidisciplinary clinic for next steps in management.

533
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

High Grade Gliomas (HGG) : Background

• Most common primary malignant brain

tumor in adults
• In the U.S. ,10-12,000 people are
diagnosed with glioblastoma
annually
• Classification of HGG is based on
histopathological characteristics
• WHO Grade III (anaplastic
gliomas)
• WHO Grade IV (Glioblastoma,
GBM) Pseudopalisading necrosis and
vascular proliferation in GBM
• Glioblastoma 70% of HGG

HGG : Prognosis
• Overall survival is poor
• Median survival with GBM is 15-20 months
• Median survival with anaplastic gliomas is 2-5
years

• Recurrence is nearly universal

• Median overall survival after first recurrence is
estimated around 8 months
• Median overall survival after bevacizumab failure
in glioblastoma was 4.2 months
Walbert, T. & Mikkelsen, T. (2011).. Expert Rev Neurotherapeutics, 11, 509-18.
Iwamoto, FM. et. al. (2009). Neurology, 73, 1200-1206.

534
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

High grade Gliomas

• Prognostic factors include:

– Age
– Performance status
– Extent of surgical resection
– MGMT methylation
– IDH1 mutation
– 1p/19q codeletion

HGG : Treatment

• Treatment of high grade gliomas involves surgery

followed by chemoradiation

• Maximal surgical resection is recommended as the initial

therapy
– Longer survival is noted in pts with greater extent of
resection

535
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HGG : Treatment
• Fractionated RT to the involved field is the next step.
Dose of 60 Gy is recommended for GBM delivered in 30-
33 fractions of 1.8 to 2 Gy.

• All high grade gliomas are treated to a total dose of 54 to

60 Gy.

• Side effects:
– Fatigue, alopecia, scalp irritation, nausea, headache
– Cerebral edema
– Seizures
– Radiation necrosis
– Neurocognitive decline

HGG : Treatment

• Temozolomide, an alkylating chemotherapeutic agent is

a part of standard treatment

• Mild side effects:

– fatigue,
– nausea/vomiting,
– constipation,
– myelosuppression

536
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Standard of Care for Newly Diagnosed GBM

Standard of care for newly diagnosed glioblastoma is

maximal safe resection, combination of radiation and
concurrent temozolomide followed by adjuvant temozolomide

Concomitant TMZ
+ RT Adjuvant TMZ
TMZ 75 mg/m2 PO daily for 6 weeks,
then 150-200 mg/m2 PO on Days 1-5 every 28
days for 6 cycles

Focal RT daily — 30 x 200 cGy;

Total dose: 60 Gy
0 6 10 14 18 22 26 30 Weeks

Stupp R et al. N Engl J Med 2005;352:987-96.

Temozolomide Given Concurrently With

Radiation Plus Adjuvantly in Newly
Diagnosed GBM
Median survival 14.6 months vs.
12.1 months

Stupp R et al. N Engl J Med 2005;352:987-96.

Stupp R, et al. Lancet Oncol. 2009;10(5):459-466.

537
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Role of MGMT methylation

• O6-Methylguanine
Methyltransferase (MGMT)
methylation status is prognostic
and predictive for response to
TMZ
• Retrospective analysis of
prospectively treated patients
within EORTC/NCIC phase III trial
• Benefit of TMZ mainly in tumors
with methylated MGMT promoter
Hegi et al. N Engl J Med 2005: 352(10); 997-1003.

Role of Tumor Treating Fields

• Antimitotic treatment that selectively

disrupts the division of cells by
delivering low-intensity,
intermediate-frequency (200 kHz)
alternating electric fields via
transducer arrays applied to the
shaved scalp

Stupp et al. JAMA. 2015;314(23):2535-2543.

538
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

EF-14: Tumor Treating Fields

Phase III trial in newly diagnosed

GBM randomizing patients
postradiation to TTFields + TMZ
versus TMZ alone

20.5 mo • Wear 18 hours/day

• Continue TTF even after first
progression for 24 months
15.6 mo • Shaved head
• Battery pack (6 lbs 2.7 lb)
• FDA approval as a device

Stupp et al. JAMA. 2015;314(23):2535-2543.

Role of Bevacizumab

• Bevacizumab : monoclonal antibody targeting

vascular endothelial growth factor and angiogenesis
• FDA approved for recurrent GBM
• Side effects:
– HTN
– DVT/PE
– Bleeding, CNS hemorrhage
– Arterial thromboembolism
– Delayed/impaired would healing
– Proteinuria
– GI perforation

539
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Phase 3 Bevacizumab Trials in Newly-

Diagnosed GBM
AVAglio RTOG 0825
Outcomes (Chinot, NEJM 2014) (Gilbert, NEJM 2014)

Bev/RT/TMZ RT/TMZ Bev/RT/TMZ RT/TMZ

Median PFS 10.6 mo 6.2 mo 10.7 mo 7.3 mo
Median OS 16.8 mo 16.7 mo 15.7 mo 16.1 mo
Health-related Improved over Worse over
quality of life time time
Neuro-cognitive Worse over
Not tested
function time

No overall survival benefit

Chinot et al. N Engl J Med. 2014 Feb 20;370(8):709-22.
Gilbert et al. N Engl J Med. 2014 Feb 20;370(8):699-708

Phase 3 Bevacizumab Trial in

Recurrent GBM
RANDOMIZE

Bev + Lomustine
GBM at first
recurrence
(n=437) Lomustine

EORTC 26101
Outcomes
Bev/Lomustine Lomustine Hazard Ratios
HR 0.49 (0.39-0.61)
Median PFS 4.17 mo 1.54 mo
P=<0.0001
HR 0.95 (0.74-1.21)
Median OS 9.10 mo 8.64 mo
P=0.650

540
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

FDA-Approved Treatments in
Malignant Glioma
• June 14, 1996: Carmustine wafer for recurrent GBM

• January 12, 1999: Temozolomide for anaplastic astrocytoma

• February 25, 2003: Carmustine wafer for newly diagnosed GBM

• March 15, 2005: Temozolomide for newly diagnosed GBM

• May 5, 2009: Bevacizumab for recurrent GBM (accelerated approval)

• April 15, 2011: Tumor Treatment Fields (Optune) for recurrent GBM

• October 5, 2015: Tumor Treatment Fields (Optune) for newly

diagnosed GBM

• December 5, 2017: Full approval - Bevacizumab for recurrent GBM

SOC for Anaplastic Gliomas

• Not established / evolving

• Anaplastic gliomas: no difference sequential

treatment (RT then chemo versus chemo then RT)
(NOA-04)

• Anaplastic oligodendroglioma (1p/19q codeleted):

adding PCV to RT extends survival for 1p/19q
codeleted tumors but not for 1p/19q nondeleted
tumors (RTOG 9402, EORTC 26951)
RTOG 9402 (Cairncross, et al. J Clin Oncol 2006;24:2707-2714)
EORTC 26951 (Van den Bent, et al. J Clin Oncol 2006 24:2715-2722)
NOA-04 (Wick et al. J Clin Oncol 2009;27:5874-5880)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CATNON (EORTC / Alliance)

Van den Bent et al. ASCO 2016

CATNON:
Phase 3 trial in 1p/19q nondeleted AG

No
adjuvant Adjuvant
TMZ TMZ
Outcome (N=372) (N=373) P-Value
Median 41.1 mo NR 0.03
OS
Median 19.9 mo 42.8 mo <0.0001
PFS

• Role for adjuvant TMZ after RT

• RTOG 9402 and EORTC 26951 previously demonstrated no benefit to adding PCV
to RT in 1p/19q nondeleted AO/AOA
• Concurrent TMZ requires further follow up, efficacy boundary has not been met

542
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Low Grade Gliomas

• A 29 y/o woman presented to the ED with new onset

seizures. Brain MRI revealed a non-enhancing lesion in
the right frontal lobe. She underwent surgical resection
of the lesion, pathology of which was c/w grade II
astrocytoma with IDH1 mutation. She presents to the
neurooncology clinic for the next steps in management.

Low Grade Gliomas

• These tumors are commonly seen in young adults and

are associated with a relatively longer survival compared
to high grade gliomas.

• Treatment of low grade gliomas includes surgical

resection, radiation and chemotherapy.

• Debulking or maximal surgical resection is preferred in

LGG to lower the possibility of sampling error leading to
diagnostic accuracy – as often there may be foci of high
grade tumor in a low grade background.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Low Grade Gliomas

• Given the longer survival in this pt population, the

consideration of toxicity and hence the timing of
intervention makes management of these patients
challenging.

• Moreover, these are rare tumors, and definitive

treatment recommendations from multiple clinical trials
are lacking

Low Grade Gliomas

• The timing of surgery and also chemotherapy and

radiation & its sequence is controversial; ie. regarding
early resection & treatment vs observation & delayed
intervention.

• So far there is no evidence that indicates early

intervention improves outcomes over observation.

544
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Low Grade Gliomas

• 75-90% of all low grade gliomas have mutations in

isocitrate dehydrogenase (IDH) –confers a favorable
prognosis.

• Oligodendroglioma with 1p/19q loss of heterozygosity

portends favorable prognosis.

Low Grade Gliomas

• Other prognostic factors for survival to identify low risk

and high risk pts are :
– age >40y,
– astrocytoma histology,
– larger tumor size >6 cm,
– tumor crossing the midline, and
– neurologic deficit prior to surgery.
 Low Grade Gliomas

• Long term f/u results of a phase III trial (RTOG 9802) of

RT alone vs RT and PCV in high risk LGG pts, showed
improved survival in pts that received PCV and RT.

Buckner J et al. N Eng J Med 2016; 374: 1344-55

Low Grade Gliomas

• Observation with long term surveillance imaging after

surgery is reasonable in pts with low risk low grade
gliomas

• Eventually, the majority of low grade gliomas can

transform to higher grade gliomas.

546
 Pilocytic astrocytoma

• This is a grade 1 tumor occurring in children and

commonly located in the posterior fossa. It has a
favorable prognosis.

• Complete surgical resection is the treatment of choice.

• RT is reserved for incomplete resection or recurrent

tumors.

Medulloblastoma

• It is the most common PNET, located in the cerebellum &

commonly seen in children.

• Complete surgical resection is the 1st step

• Treatment of standard risk medulloblastoma – CSRT to 23.4

Gy and boost 55 Gy to posterior fossa, with chemotherapy

• Treatment of high risk M - CSRT to 36 Gy and boost 55 Gy to

posterior fossa, with chemotherapy

• CT- platinum, etoposide, cyclophosphamide, nitrosoureas,

vincristine.

547
 Meningioma

• Most common primary CNS

tumor (36.1% of all PBT)
• F:M ratio 2:1
• Arise from arachnoid cap
cells in dura
• Risk factors
– Radiation
– Hereditary syndromes (NF2)
– ?hormones

Meningioma : Grading & Prognosis

WHO Grade Proportion Relapse Rate Median Survival

I (Benign) 90% 7-20% Usual life expectancy

II (Atypical) 5-7% 40% 10-12 years

III (Malignant) < 3% 50-80% 2-3 years

548
 Meningioma Management

• Observation
– Can be considered for small, asymptomatic benign
meningiomas

• Surgical resection
– If complete resection is achieved for grade 1 and 2
meningiomas, no further therapy is indicated.

Meningioma Management
• Incomplete resection increases the rate of recurrence.

• RT is indicated in
– inoperable tumors,
– partially resected grade 2 tumors
– Grade 3 tumors
– Recurrent tumors

• Chemotherapy has not proven to be beneficial so far in

meningiomas, but several novel agents are being
investigated.

549
 Vestibular schwannoma
• Peripheral nerve sheath tumor
• If small and asymptomatic, observation will suffice.

• Surgery and RT are treatment options.

• SRS can be employed in smaller tumors <2cm, and

fractionated RT is preferable in larger tumors.

• Bevacizumab treatment has demonstrated hearing

improvement and tumor shrinkage in progressive
vestibular schwannomas in NF2 patients.

PCNSL
• A 62 y/o RHM presented with left facial weakness for a
week which was progressively worsening. Subsequently
he developed left arm weakness. His family reported that
he had been quite withdrawn and less talkative over the
last few weeks. MRI brain revealed contrast enhancing
lesions in the corpus callosum and right frontoparietal
region. He underwent brain biopsy which confirmed
DLBCL. CSF studies, ophthalmologic exam, bone
marrow biopsy and body PET/CT were unremarkable.
Diagnosis of PCNSL was made.
 PCNSL
• Role of surgery in PCNSL at this time is limited to
stereotactic biopsy for histopathologic diagnosis.

• Treatment for PCNSL involves induction and

consolidation phases

PCNSL
• Induction treatment is the initial treatment employed to
induce a remission, including a radiographic response.

• HD-MTX–based chemotherapy is considered the first-

line treatment for newly diagnosed primary CNS
lymphoma and typically used for induction.
– Addition of rituximab and high-dose cytarabine has been shown
to improve response rates

• Despite a complete radiographic response after initial

treatment, a high rate of recurrence exists.
 PCNSL
• Consolidation
– Whole brain radiation
– High dose chemotherapy
– Thiotepa based high-dose chemotherapy followed by autologous
stem cell rescue

• The goal of consolidation is to reduce recurrence rates

and improve overall survival rates.

Thank You

552
 Neurological Aspects of Systemic
Cancer
Eudocia Quant Lee, MD, MPH
Division of Cancer Neurology,
Department of Neurology,
Brigham and Women’s Hospital

Center for Neuro-Oncology

Dana Farber/Brigham and Women’s Cancer Center

Assistant Professor of Neurology,

Harvard Medical School

Disclosures
• Contributor to www.uptodate.com
• Consulting for Genentech/Roche

• Off label use of agents will be discussed

553
 Importance
• Increase in incidence of cancer
• Patients with cancer living longer
• Patients may develop neurologic disorders
due to nervous system relapse or toxicity from
treatments
• Neurologic complications may limit potential
therapies

http://www.cancer.org/research/cancerfactsstatistics/

Overview
• Nervous system metastases
– Brain metastases
– Metastatic epidural spinal cord compression
• Cognitive impairment in cancer patients
• Chemotherapy induced peripheral neuropathy

554
32M with malignant melanoma presents
with right motor seizure with secondary
generalization

Hemorrhagic brain metastases from melanoma

Nervous System Metastases

 Brain Metastases

Leptomeningeal
Metastases
Metastatic Epidural
Spinal Cord Compression

Images modified from: www.thelancet.com

Intracranial Dural Metastases

Brain Metastases

Neoplastic Plexopathy

Leptomeningeal
Metastases
Metastatic Epidural
Spinal Cord Compression

Intramedullary Spinal
Cord Metastases

Images modified from: www.thelancet.com

556
Intracranial Dural Metastases
Brain Metastases

Neoplastic Plexopathy

Leptomeningeal
Metastases
Metastatic Epidural
Spinal Cord Compression

Intramedullary Spinal
Cord Metastases

Images modified from: www.thelancet.com

BM Epidemiology
• Most common intracranial tumor
• Estimated incidence of 100,000 to 300,000 patients
in the US each year
• Incidence is increasing
• Most common primary cancers: lung, breast, kidney,
colorectal cancer, melanoma
• Risk of brain mets varies by stage and tumor type

Sperduto et al. J Clin Oncol 2012; 30(4): 419.

Nayak et al. Curr Oncol Rep. 2012;14(1): 48.

557
 BM Presentation
• Highly variable
• Headaches 40-50%
• Focal neurologic deficits 20-40%
• Cognitive dysfunction 30-35%
• Seizures 10-20%
• Tumor hemorrhage 5-10%
• Asymptomatic (incidental finding on imaging)

Wen and Loeffler. 2013. UpToDate. Retrieved from http://www.uptodate.com/home/index.html.

BM Diagnosis
• Brain MRI with and without contrast
– Grey-white junction
– Cerebral hemispheres > cerebellum
– Punctate, nodular, ring-enhancing
– Hemorrhage
– Extent of peritumoral edema varies
• Advanced systemic disease with multiple
enhancing CNS lesions

Mills SJ, et al. Cancer Imaging 2012; 12: 245-252.

558
 Prognosis: Diagnosis Specific Graded
Prognosis Assessment

3.0

Breast cancer
NSCLC
SCLC
GI cancers (colorectal)
Renal cell carcinoma
Melanoma
Other

Sperduto et al. J Clin Oncol 2012; 30(4): 419.

Treatment / Management
• Individualized according to patient, number of brain
mets, extent of systemic disease, functional status,
etc.

• Surgery
• Radiation (WBRT, SRS)
• Chemotherapy
• Medical Management / Supportive Care
– Corticosteroids
• For adults with brain tumors who have not experienced a
seizure, routine prophylactic use of AEDs is not
recommended
• In patients with brain tumors who have not had a seizure,
tapering and discontinuing anticonvulsants after the first
postoperative week is appropriate, particularly in those
patients who are medically stable and who are experiencing
anticonvulsant-related side effects

Glantz et al. Neurology 2000; 54: 1886.

Anticonvulsants
Enzyme Inducers Non Enzyme Inducers
• Phenytoin • Levetiracetam
• Carbamazepine • Lacosamide
• Phenobarbital • Topiramate
• Oxcarbazepine • Lamotrigine
• Zonisamide
Enzyme Inhibitor • Gabapentin
• Valproic acid • Tiagabine
• Pregabalin

560
 Non-EIAED

EIAED

Cloughesy TF, et al. J Clin Oncol. 2006;24:3651

Vasogenic Cerebral Edema

• Disruption of blood-brain barrier,
allowing protein rich fluid to
collect in extracellular space
• Can be seen on brain MRI or
head CT
• Does not always require
intervention
• Avoid steroids (if possible) for
undiagnosed lymphoma
 Mainstay of Treatment
Steroid Dose equivalent to Biologic half-life, Mineralocorticoid
20 mg cortisone, mg hours activity (cortisol = 1)
Dexamethasone 0.75 36-54 < 0.2
Hydrocortisone or 20 8-12 1
cortisol
Prednisone 5 12-36 0.8
Methylprednisolone 4 12-36 0.5

• Steroids decrease vascular permeability

• Dexamethasone: less potential for fluid retention, lower risk
of infection, less cognitive impairment compared to some
other steroids

Galicich et al. J Lancet. 1961;81:46.

Batchelor and DeAngelis. Neurosurg Clin N Am. 1996;7(3):435
Pruitt. Current Treatment Options in Neurology. 2011;13:413–426

Dexamethasone
• Symptomatic improvement within 24-72 hours
Side Effects Possible Management
Insomnia Avoid late night doses
Weight gain Diet modification
High blood sugars Blood sugar management
Stomach ulcers Prevention with omeprazole, etc.
Weakness of proximal muscles Exercise, PT
Opportunistic infections Prevention with antibiotics, etc.
Steroid withdrawal syndrome Taper more slowly
(adrenal insufficiency,
arthralgias)
Galicich et al. J Lancet. 1961;81:46.
Batchelor and DeAngelis. Neurosurg Clin N Am. 1996;7(3):435
Pruitt. Current Treatment Options in Neurology. 2011;13:413–426

562
58 W with chronic lower back pain
p/w leg weakness
• 7/2: Presents to the ED with acute on chronic back pain, mild
bilateral EHL weakness, no sensory or bladder/bowel
symptoms. No cancer history. LS spine MRI without contrast
showed degenerative disc disease.

• 7/14: Returns to ED with progressive weakness and now

sensory loss from hips below and urinary incontinence. Not
able to walk x 4 days. Entire spine MRI obtained.

T4 T10

Paraspinal mass T2 to T9 with significant circumferential epidural component

Obliteration of the thecal sac with abnormal cord signal T4-T5
Extension into left neural foramina T2-T6 and right neural foramina T2-T7
Open biopsy: Pathology c/w B-Cell Non-Hodgkin Lymphoma
 Metastatic Epidural Spinal Cord
Compression (MESCC)

Importance
• Oncologic emergency
• Potentially irreversible loss of neurologic
function
• Common neurological complication in patients
with cancer

564
 Epidemiology
• Frequency estimated to be 5% of cancer patients
• 20% of cases are the initial manifestation of
malignancy
• Common underlying cancers: prostate, breast, lung
• Highest incidence rates among multiple myeloma,
Hodgkin / non-Hodgkin lymphomas, prostate cancer

Schiff et al. Neurology. 1997;49(2):452.

Cole and Patchell. Lancet Neuro 2008; 7:459.
Mak, et al. Int J Radiat Oncol Biol Phys 2011; 80(3): 824.

Pathophysiology

• Epidural space lies

between bone and
dura
• Direct cord
compression
• 85-90% due to metastatic tumor in the vertebral
bones
• 10-15% due to growth of a paravertebral tumor
directly into the spinal canal through foramina

Cole and Patchell. Lancet Neuro 2008; 7:459.

565
 Localization Within Spine
• Thoracic spine60%
• Lumbosacral spine 30%
• Cervical spine 10%
• Multiple sites 10-35%
• Lung and breast cancer often involves thoracic
spine
• Renal, prostate, GI tumors often involve
lumbosacral spine

Cole and Patchell. Lancet Neuro 2008; 7:459.

Clinical Features
• Pain most common presenting symptom (95% of
patients) – worse with lying down, awakening at
night, radicular pain worse with Valsalva
• Neurologic deficits and sphincter disturbance
develop after pain
• Weakness 78% - UMN or LMN
• Numbness 51%
• Urinary symptoms 57%
• 30% of patients with weakness become paraplegic
within a week

Cole and Patchell. Lancet Neuro 2008; 7:459.

566
 Diagnosis
• Spine MRI with contrast is imaging of choice
– Scan the spine from the level of dysfunction
upwards
• For patients unable to undergo MRI, CT
myelography
• Plain films and PET scans not sufficiently
sensitive or specific

Cole and Patchell. Lancet Neuro 2008; 7:459.

Immediate Management
• Send your patient to the ED
• Dexamethasone
– Optimal dose unknown (Cochrane meta-analysis)
– 100 mg IV + 4 mg QID = 10 mg IV+ 4 mg QID
(Vecht et al. Neurology 1989;39:125)
– Low dose steroids (16 mg/day) may be considered
for patients with pain but minimal neurologic
dysfunction
• Pain management

Cole and Patchell. Lancet Neuro 2008; 7:459.

George, et al. Cochrane Database Syst Rev 2008.

567
 Definitive Treatment
• Radiation therapy (30 Gy in 10 fractions)
• Do not perform laminectomy
• Circumferential decompressive surgery in select
population only
– Paraplegic < 48 hours, life expectancy > 3 months, single
level epidural cord compression, not lymphoma
(radiosensitive tumors), not primary spine tumor
– Immediate decompression
– Direct mechanical stabilization for unstable spines

Cole and Patchell. Lancet Neuro 2008; 7:459.

www.uptodate.com

Prognosis
• MESCC usually occurs in setting of widespread cancer
• Predictors of ambulatory outcome with RT
– Better pretreatment motor function
– Motor deficits develop more slowly (longer than 2 weeks
vs. less than 1 week)
– Beginning treatment < 12 hours after loss of ambulation in
nonambulatory patients
– Radiosensitive tumors (multiple myeloma, germ cell
tumors, lymphomas, small-cell carcinomas)

Cole and Patchell. Lancet Neuro 2008; 7:459.

www.uptodate.com
58 M with lung cancer who reports
memory loss
• History of brain metastases – treated with whole
brain radiation (WBRT)
• Several months after WBRT, patient reports
misplacing keys, forgetting appointments, difficulty
with multi-tasking
• Repeat brain MRI with contrast shows no changes,
no new metastases

Contributors to Neurocognitive Impairment

• Baseline neurocognitive impairment from CNS lesion

• CNS progression
• Radiation
• Chemotherapy
• Fatigue
• Depression
• Medications (e.g., AEDs)
• Medical problems (e.g., endocrine dysfunction, metabolic
disturbances)

Shih et al. Cancer Treatment and Research Volume 150, 2009, pp 23-41.
 “Chemo Brain”
• Neurocognitive complaints
– Poor working memory
– Impaired attention
– Poor concentration
– Decreased processing speed
– Poor executive function
• Best studied in breast cancer patients: 20–40% of breast
cancer patients develop cognitive deficits following cancer
therapy
• Some imaging studies show structural and functional changes
in the hippocampus

Neurocognitive Function and WBRT

• Association between CNS radiation and
neurocognitive impairment in children is known
• Biphasic pattern to radiation induced neurocognitive
impairment
– Many patients have neurocognitive dysfunction at baseline
– Subacute transient decline with peak at 4 months
– Late delayed irreversible months to years after WBRT
• ? Relationship to uncontrolled BM
 Minimizing neurocognitive decline
from WBRT?
RTOG 0614: phase III RCT

RANDOMIZE
Brain mets
Memantine 20 mg daily
undergoing
WBRT
37.5 Gy Placebo daily
(N = 554)

Baseline 4w 8w 12w 16w 20w 24w 52w

Brown PD, et al. Neuro-Oncology 15(10):1429–1437, 2013

Minimizing neurocognitive decline

from WBRT?
RTOG 0614: phase III RCT
RANDOMIZE

Brain mets
Memantine 20 mg daily
undergoing
WBRT
37.5 Gy Placebo daily
(N = 554)

Baseline 4w 8w 12w 16w 20w 24w 52w

• No difference in OS (6 months) or PFS (5 months) between arms

• Poorer than expected survival lead to poor protocol compliance
• 149 patients analyzable at 24 weeks (Only 35% statistical power)

Brown PD, et al. Neuro-Oncology 15(10):1429–1437, 2013

 RTOG 0614: Outcomes
• Primary endpoint: Reduced the decline in HVLT-R DR by 0.9
(P=.059) at 24 weeks
• 17% reduced relative risk of
cognitive decline (p=.01)
• Delayed time to cognitive
decline (p=.01)
• Reduced the rate of decline
in cognitive, executive, and
global function as well as
processing speed (p<.01)

Brown PD, et al. Neuro-Oncology 15(10):1429–1437, 2013.

How about patients who are

already cognitively limited?
• Single arm studies suggest potential improvement:
– Methylphenidate 10 mg BID may improves cognition,
mood, and ADL function in patients with malignant glioma1
– Donepezil 5 mg/d for 6 weeks, then 10 mg/d for 18 weeks
in post-radiation patients with primary brain tumor may
improve attention, mood, and verbal memory2
• No control group!

1. Meyers, et al. J Clin Oncol.1998;16(7):2522–7.

2. Shaw, et al. J Clin Oncol. 2006;24(9):1415–20.

572
 Donepezil for Radiation Related
Cognitive Changes
Primary or

RANDOMIZE
metatastic Donepezil 5-10 mg daily
brain tumor
> 6 months
since Placebo daily
completing
brain
irradiation Baseline 12w 24w

1. Cumulative cognitive score (HVLT-R, Rey-Osterreith Complex Figure,

TMT, Digit Spain, COWA, Grooved Pegboard)
2. Fatigue
3. Mood
4. QOL

Rapp, et al. J Clin Oncol 31, 2013 (suppl; abstr 2006). Presented at ASCO 2013.

Donepezil for Radiation Related

Cognitive Changes
Primary or
RANDOMIZE

metatastic Donepezil 5-10 mg daily

brain tumor
> 6 months
since Placebo daily
completing
brain
irradiation Baseline 12w 24w

• Cumulative cognitive score improved in both arms (p <0.01) but not

statistically difference between groups (p=0.57)
• “Benefit of donepezil relative to placebo was greater for those with worse
baseline scores.”

Rapp, et al. J Clin Oncol 31, 2013 (suppl; abstr 2006). Presented at ASCO 2013.

573
 Treatment of Cognitive Impairment
• Psychostimulants unclear benefit
• Memantine prophylaxis while undergoing WBRT
• Donepezil unclear benefit, perhaps the most
cognitively impaired patients may benefit
• VP shunt for normal pressure hydrocephalus
• Cognitive and behavioral rehabilitation?

50 RH M with colon cancer who

develops paresthesias in his hands
and feet
• March – Diagnosed with colon cancer and initiates treatment
on FOLFOX (5-FU, leuocovorin, oxaliplatin)
• Soon thereafter, notes symmetric parethesias in feet resulting
in gait instability. Progresses to involve hands and difficulty
with buttons.
• Examination reveals distal sensory loss, loss of reflexes in legs,
and changes in proprioception.

Oxaliplatin induced peripheral neuropathy

 Chemotherapy Induced
Peripheral Neuropathy (CIPN)

Causes of Neuropathy in Cancer

Patients
• Leptomeningeal metastases (cranial
neuropathies and radiculopathies)
• Plexopathy by tumor invasion or radiation
• Paraneoplastic syndrome (sensory
neuronopathy in SCLC, sensorimotor
neuropathy in Waldenstrom’s)
• Chemotherapy-induced peripheral neuropathy
Drug Sensory Sensory Neuropathic Motor Autonomic Acute Coasting
impairment, impairment, pain/painful impairment impairment symptoms
superficial * deep ** paresthesias

cisplatin ++ +++ ++ - + - +++

carboplatin + ++ - - -/+ - ++

oxaliplatin ++ +++ + - -/+ +++ ++

paclitaxel ++ ++ + ++ -/+ ++ -/+

docetaxel ++ + + + -/+ + -/+

vincristine ++ + ++ ++ +++ - +

ixabepilone +++ + -/+ + - - -

bortezomib +++ + +++ + -/+ - -

thalidomide ++ + + + - - -

lenalidomide + -/+ - - - - -

- = absent; -/+ = uncertain; + = rare; ++ = common; +++ = very frequent

* = touch, temperature, pain sensation; ** = vibration, position sensation

Cavaletti and Marmiroli. Chapter 15 in Neurologic Complications of Cancer Therapy. Wen, Schiff, Lee (eds.)

Common Clinical Features

• Sensory symptoms >> motor impairment
• Sensory loss or paresthesias
• Worse in lower extremities
• Pain can be a late and chronic manifestation
• Loss of reflexes
• Muscle cramps (taxanes)

576
 Diagnosis
• Clinical grounds
• ? EMG/NCS
• ? Skin biopsy (small fiber neuropathy)
• Look for alternative causes: diabetes, vitamin
B12 deficiency, etc.

CIPN Prevention/Treatment
• Treatment modification (chemotherapy dose reduction or
cessation)
• Number of agents have been tested for prevention/treatment
of CIPN including TCAs, vitamin E, acetyl-L-carnitine,
glutamine, glutathione, vitamin B6, omega-3 fatty acids,
magnesium, calcium, alpha lipoic acid
– Most have failed to demonstrate efficacy
– Randomized, double-blind, placebo-controlled, crossover, phase III of
gabapentin for symptomatic CIPN failed to show efficacy1
– Randomized, double-blind, study of Acetyl-L-carnitine for the
prevention of taxane-induced neuropathy in women undergoing
adjuvant breast cancer therapy showed no efficacy at 12 weeks,
worsened CIPN at 24 weeks2
1. Rao et al. Cancer. 2007;110(9):2110
2. Hershman, et al. J Clin Oncol 2013;31(20):2627-33.
 Randomized, double-blind, placebo-
controlled study of duloxetine in CIPN
(CALGB/ALLIANCE)
Taxane or

RANDOMIZE
platinum-related Duloxetine* Placebo
painful
chemotherapy
induced Placebo Duloxetine*
peripheral
neuropathy,
average pain 5 wk 8 wk 12 wk

score >4/10 for * Duloxetine 30 mg/day x 1 week, then

3+ months 60 mg/day x 4 additional weeks

• Individuals receiving duloxetine as their initial 5-week treatment reported

a mean decrease in average pain of 1.06 (95% CI, 0.72-1.40) vs 0.34 (95%
CI, 0.01-0.66) among those who received placebo (P=.003; effect size,
0.513).

Smith, et al. JAMA. 2013;309(13):1359-1367

Summary
• Neurological complications are common in
cancer patients with a significant impact on
quality of life
• Low threshold for CNS imaging in cancer
patients with neurologic symptoms
• Treatments for chemotherapy induced
peripheral neuropathy are limited and
management may include chemotherapy dose
reduction

578
 Encephalitis

Jennifer L. Lyons, MD
Chief, Division of Neurological Infections and Inflammatory Diseases
Brigham and Women’s Hospital Department of Neurology

Assistant Professor of Neurology

Harvard Medical School

Disclosures
• None
International Encephalitis Consortium:
Defining encephalitis

Encephalitis =

Inflammation of the brain parenchyma

+
Neurologic dysfunction

Venkatesan, et al CID 2013

International Encephalitis Consortium:

Clinical definition of encephalitis
Acute Encephalitis =
≥24H of altered level of consciousness,
personality change, or lethargy
+ ≥3 of:
• Fever ≥38°C within 72H of presentation
• Seizure not attributable to epilepsy
• CSF pleocytosis
• Imaging consistent with encephalitis
• EEG consistent with encephalitis
Venkatesan, et al CID 2013
 Encephalitis Epidemiology
• 3.5 – 7.4 cases/100,000 person-years worldwide
(non-outbreak situations)
• More common in children than adults
• Most common etiology: UNKNOWN
• When etiology identified, most commonly is
infectious and usually viral
• In North America, Europe, Australia, HSV is most
commonly identified virus
• > 100 pathogens are known to cause infectious
encephalitis

Granerod Neurology 2010, Kramer Crit Care Clinics 2013

Granerod, et al Neurology 2010

581
 Etiologies of Encephalitis
• Infectious
• Viral (eg HSV, rabies, EV, HIV, arboviruses, influenza,
HHV6*)
• Bacterial (eg Listeria)
• Parasitic (eg Naegleria fowleri, Taenia solium)
• Immune mediated
• Para/post-infectious (eg ADEM, AHLE, influenza)
• Onconeuronal antibody-mediated (eg anti-Hu)
• Neuronal cell surface antibody-mediated (eg anti-
NMDAR)

*BMT population

Encephalitis Workup:
Initial LP tests
• If CT required prior to LP, do not delay antibiotics
• Collect 20cc spinal fluid if possible; freeze extra
• Send for cells/differential, glucose, total protein,
gram stain and bacterial culture, oligoclonal
bands
• Send HSV PCR, VZV PCR, and serologies if
available
• Consider sending cytology/flow cytometry
• Additional tests initially depend on index of
suspicion or local epidemiology

582
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Herpes Simplex Virus Encephalitis

• Incidence is ~3 cases/1,000,000 population
• M:F ratio is basically 1:1
• Bimodal age distribution of <20 and >50 (peak
between 60-64 years)
• No immune compromise required
• 90% of HSVE is due to HSV-1 in immune
competence

Steiner Current Opinion in Neurology 2011

Herpes Simplex Virus Encephalitis

• Fever is the most common symptom at
presentation
• 90% will have headache
• Personality changes, confusion, and
disorientation seen about 75% of cases
• Patients usually present with symptom duration
of <1 week
• Diagnosis by HSV PCR on CSF
• Treat with 10mg/kg acyclovir TID for no less than
14-21 days

Steiner Current Opinion in Neurology 2011

583
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sensitivity of HSV PCR on therapy*

* Majority with vidarabine, 3 with acyclovir

Lakeman The Journal of Infectious Diseases 1995

Herpes Simplex Virus Encephalitis

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rabies Encephalitis
• Basically uniformly fatal encephalitis typically
1-3 months after inoculation
• > 50,000 deaths yearly worldwide, mostly in
Asia and Africa
• Dogs transmit > 99% of human infections
• Around 1-3/year in the US, transmitted by
bats, skunks, raccoons, or traveling abroad
• Human-to-human transmission is very rare

Rabies Encephalitis
• Diagnosis is by RNA detection in clinical
sample (brain, skin, saliva, urine)
• Vaccine preventable (animals and humans)
• PEP strategies
• Immediate wound care plus
• 1 dose rabies immune globulin
• 4 doses vaccination over 14 days
• No reproducibly effective treatments

585
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rabies Encephalitis

Mukerji S. Viruses (Chap 66) Merritt’s Neurology, 13th ed. 2016

Arbovirus Encephalitis
• Viruses carried by arthropod vectors (mosquitoes or ticks)
• Most belong to Flavivirus, Alphavirus, Bunyavirus genera
• Flaviviruses: WNV, JEV, SLEV, TBEV, POWV, MVEV, Kunjin, Zika
• Alphaviruses: EEE, WEE, VEE, CHIKV*
• Bunyaviruses: LACV, CEV, Jamestown Canyon
• Epidemiology varies; JEV alone causes 30,000 deaths annually
• Diagnosis generally by IgM in CSF or evidence of seroconversion
(beware of positive IgG as most arboviral infections are
asymptomatic)
• No treatments available; corticosteroids/IVIg empiric
• Prevention
• Vector control
• Vaccination

* CHIKV more commonly causes a febrile arthritis

586
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Powassan Virus Encephalitis

Piantadosi Clin Infect Dis 2016

Eastern Equine Virus Encephalitis

Mukerji S. Viruses (Chap 66) Merritt’s Neurology, 13th ed. 2016

587
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Disseminated
Encephalomyelitis (ADEM)
• Acute, monophasic multifocal autoimmune
demyelination usually in context of preceding illness or
vaccination
• Very rare (<1/100,000 children; adult incidence
unknown)
• Pediatric diagnostic criteria:
• Polyfocal demyelinating event plus
• Encephalopathy not attributable to fever
• Abnormal MRI brain acutely (with characteristic findings)
• No new lesions/events beyond 3 months
• Treatment is typically with plasma exchange and/or
corticosteroids

ADEM

Typical findings:
• Multiple large predominately white matter plaques
• Deep structures may be involved
• Variable enhancement, uncommon T1 hypointensity
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Onconeuronal antibody mediated

• Autoantibodies that react with intracellular neuronal
antigens (Hu, Yo, Ma/Ta, Ri, CRMP5)*
• Generally produced in response to an underlying tumor
• Subacute limbic, rhombencephalic, cerebellar
presentations
• Typically occur in older individuals
• Pathophysiology of encephalitis unknown; T cells thought
responsible and not antibodies
• Diagnosis by clinical syndrome and antibody detection in
serum and/or CSF (MRI often normal)
• Treated with strong immune suppression and tumor
eradication typical but outcomes are generally poor

*GAD-65 and amphiphysin are directed at intracellular antigens but unusually paraneoplastic

Neuronal cell surface antibody

mediated
• Antibodies directed toward neuronal cell surface
markers, variably within the context of a primary
tumor (NMDAR, VGKC spectrum, GlyR, mGluR5, AMPA)
• Typically a subacute, limbic presentation
• Age is widely varied
• Antibodies are thought pathogenic
• Diagnosis by clinical syndrome and detection of
antibodies in CSF and/or serum (MRI may be normal)
• Typically responsive to/cured by immune modulation
• Remove tumors when present
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Outcomes in encephalitis
• Mortality overall is 5-10%
• Survivors frequently suffer significant
morbidity (eg ~60% of HSVE survivors suffer
neurologic sequelae)
• Better outcomes tend to be in younger
patients with less fulminant disease

Venkatesan CIDR 2013, Whitely NEJM 1992, Thakur Neurology 2013

590
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meningitis

Jennifer Lyons, MD
Chief, Division of Neurological Infections and Inflammatory Diseases
Brigham and Women’s Hospital Department of Neurology

Assistant Professor of Neurology

Harvard Medical School

Disclosures
• None
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meningeal anatomy

Leptomeninges Pachymeninges
(arachnoid mater (dura mater)
and pia mater)

Pia mater Dura mater

Skull
Scalp

Arachnoid mater

Categorizing Meningitis
• By location
– Pachymeningitis
– Leptomeningitis
• By symptom duration
– Acute (hours to days)
– Subacute (weeks)
– Chronic (months to years)
• By CSF profile
– Mononuclear
– Polymorphonuclear
– Other (malignant, eosinophilic, mixed)
• By etiology
– Bacterial
– Viral
– Fungal
– Mycobacterial
– Immune-mediated
– Chemical
– Malignant (“carcinomatous”)

592
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Leptomeningitis
Leptomeningitis =
Inflammatory
reaction of the
pia mater,
arachnoid mater,
involving CSF in
the subarachnoid
space, providing
means of
measurement

Meningitis presentation
• Classic triad (Many will not have all 3)
– Fever (60-85%)
– Headache (60-85%)
– Neck stiffness (70-80%)
• Additionally
– Altered mental status (85-90%)
• Less common
– Focal neurologic deficit (30-40%)
– Seizure (10-20%)
– Coma (10-20%)

Weisfelt The Lancet Neurology 2006

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meningitis evaluation
• History
– Duration of symptoms
– Immune status
– Exposures/bites
• Physical exam
– Vital signs
– Rashes
– Level of consciousness
– Papilledema
– Focal deficits (especially brainstem/cerebellar)
• Blood Cultures ( antibiotic initiation)
• Lumbar puncture with CT rule

Meningitis:
LP studies
• CBC with differential
• Total protein
• Glucose (simultaneous fingerstick)
• Gram stain and bacterial culture
• HSV PCR
• Pneumococcal antigen if available
• Lactate if recent surgical intervention
• Other tests depending on history/exposures/time of
year

594
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CSF profiles in meningitis

Diagnosis Opening WBC Count WBC Glucose Total Protein
Pressure (cells/uL) Differential (mg/dL) (mg/dL)
(cm H2O)
Normal <20 <5 N/A 50 – 100 (≥2/3 15 – 60 (lab
(corrected serum) dependent)
for RBC)
Bacterial Very high; Very high; Strong <40% serum; Very high;
Meningitis often >30 often >1K neutrophilic often very low often >500
predominance
Viral/aseptic Usually High; teens Strong Usually normal Normal to high
Meningitis normal to hundreds mononuclear
predominance*

Fungal/TB High to very Variably Neutrophilic or Low to very High to very

Meningitis high high; teens mononuclear or low high
to hundreds mixed
to thousands
*Early on can be neutrophilic

Neutrophilic meningitis
– Acute bacterial
– Autoimmune
– Chemical
– Very early viral infections
– Fungal
– Tuberculosis (typically early)
– Seizure/stroke

595
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology of acute bacterial

meningitis (ABM) in adults
• 2.6-6 cases/100,000 per year; up to 10X higher in
developing countries
• Etiology:
– Developed countries: S. pneumoniae >> N. meningitidis > GBS ≥
H. influenzae > L. monocytogenes
– Meningitis belt: N. meningitidis
• Vaccine-preventable strains of pneumococcus account for
some 40% of US pneumococcal cases, and these have a
higher fatality rate
• Vaccine-preventable strains of meningococcus account for
some 60% of US meningococcal cases (prior to Men B
vaccine)
Thigpen NEJM 2011, Weisfelt The Lancet Neurology 2006

ABM Epidemiology in the US

L. monocytogenes
Group B Strepotococcus
H. influenzae
N. meningitidis

S. pneumoniae

Thigpen NEJM 2011

596
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

N. meningitidis epicenter

• Over 800,000
cases between
Highest endemicity
1996-2010, with
10% mortality “Meningitis Belt”
(WHO)
• Serogroups A,
W135 prevail
• These
serogroups are
vaccine
preventable

Acute Bacterial Meningitis:

Initial Management
• Outcomes depend largely on time to definitive
therapy, so antimicrobials should be instituted once
suspicion is raised, but blood cultures at least are
ideally drawn prior to initiation
• Antibiotics choices vary by region in terms of
susceptibility
• Dexamethasone initiation improves outcomes when
started at or before the first dose of antibiotics, but
likely only in developed countries

Brouwer Cochrane Reviews 2013

597
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Bacterial Meningitis:

Initial Management

Tunkel Clinical Infectious Diseases 2004

Acute Meningitis
Initial Management*
*Also
consider
acyclovir
to cover
HSV!

Cho Neurologic Clinics 2010

598
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Bacterial Meningitis:

Follow up
• Narrow antibiotics once organism identified
• Continue dexamethasone for 4 days if S. pneumoniae;
discontinue if not
• Antibiotics duration depends on etiology but for S.
pneumoniae is typically 14 days
• Search for source/spread of infection
• Monitor for and manage complications

Acute Bacterial Meningitis:

Complications
• Systemic
– Sepsis
– Cardiorespiratory failure
– Disseminated intravascular coagulation
– Adrenal failure (meningococcus)
• Neurologic
– Seizure
– Cerebral edema and hydrocephalus
– Arteriopathy
– Venus sinus thrombosis
– Arterial or venous infarct
– Cranial neuropathy

599
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute Bacterial Meningitis:

Outcomes in adults
• Overall mortality most recently is about 16% (US)
• 9% for ages 18-34
• 23% for ≥ 65
• Neurologic sequelae are common (29-72%) and
include:
• Hearing loss
• Cranial nerve palsies
• Cognitive deficits
• Aphasia
• Ataxia
• Focal paresis
Thigpen NEJM 2011, Weisfelt The Lancet Neurology 2011

Lymphocytic meningitis
– Viral:
• Enterovirus (most common)
• Herpesviruses (mostly HSV and VZV)
• Arboviruses (depend on locale and season)
• HIV
• Other
– Fungal:
• Cryptococcus
• Aspergillus Esp if immune compromised
• Candida
• Dimorphic fungi (depend on locale/exposure/travel)
– Mycobacterial
– Other
• Syphilis
• Lyme
• Malignancy
• Autoimmune disease
• HaNDL
• Seizure

600
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lymphocytic meningitis
Diagnosis and management
– Viral:
• CSF studies
– Viral RNA/DNA (enteroviruses, herpesviruses, HIV)
– Immune globulins (arboviruses, VZV)
• Serologies demonstrating acute infection (arboviruses)
• Management overall is supportive
– Fungal:
• CSF studies
– Antigen detection (Cryptococcus, Histoplasma, Aspergillus)
– Antibody detection (dimorphic fungi)
• Serologies (dimorphic fungi)
• Management with antifungal medications, ICP control, +/- steroids
– Mycobacterial:
• CSF studies
– Mycobacterial culture
– AFB stain
– Nucleic acid amplification
• Management with anti-tuberculous therapy, ICP control, and steroids
– Other:
• Syphilis: VDRL in CSF; manage with IV penicillin
• Lyme: CSF antibodies, PCR; manage with ceftriaxone

Conclusion
– There are many forms of meningitis
– Presenting symptoms can be nonspecific and/or
can overlap with encephalitis
– Acute bacterial meningitis is a life-threatening
emergency whose outcome depends on rapid
diagnosis and management initiation
– Complications and sequelae of bacterial
meningitis are common
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV Neurology in Primary

Care
Nagagopal Venna, MD, MRCP
Dept of Neurology, MGH
2016

Disclosure
• None

602
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV Neurology
• HIV infection transformed from fatal to
chronic, manageable disease by highly
active combination ART (cART) introduced
in 1996
• Severe, life-threatening neurological
complications decreased
• Several milder neurological disorders still
prevalent: peripheral neuropathy , mild
cognitive impairment

Changes after HAART

• OIs: cryptococcal meningitis, toxoplasmosis
encephalitis now rare
• Cerebral lymphoma due to Epstein-Barr viral
infection decreased dramatically
• Severe dementia of HIV encephalitis rare
• A few patients continue to present with severe
neurological disorders of dementia, OIs such as
meningitis, cerebral toxoplasmosis due to
advanced AIDS, typically in recent immigrants

603
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Changes in HIV Neurology

• Progressive multifocal leukoencephalopathy
(PML) due to JCV decreased to lesser degree

• Mild cognitive impairment is prevalent

• New forms encephalitis have emerged: rare

cerebral immune reconstitution inflammatory
syndrome (IRIS); HIV CNS escape encephalitis

Neurological Syndromes in HIV

• Peripheral neuropathies
• Encephalitis
• Focal brain lesions

604
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV Neuropathies
• Distal sensory neuropathy (DSN)
• Guillian-Barre syndrome
• Chronic inflammatory demyelinating
polyneuropathy (CIDP)
• Mononeuropathy multiplex
• Brachial neuritis
• Lumbosacral radiculitis

Distal Sensory Neuropathy

• Common neurological complication of HIV
• Occurs in 30% of patients
• Incidence did not decrease despite cART
though current forms less severe
• Pre-cART era risk factors:
CD4 < 200
• viral load; >10,000
• older age
• NRTIs ddI, ddc, d4T(stavudine)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DSPN in cART Era

• Not correlated with viremia level
• Not correlated current CD4 counts
• Risk factors:
Current cART
Past NRTI treatment
CD4 nadir <350

• Neuropathic pain: higher with higher CD4 counts

DSN-Pathology

• Length-dependent axonal degeneration

• Small unmyelinated, large myelinated
fibers are affected
• Inflammatory component:
macrophage/lymphocyte infiltration of
axons, dorsal root ganglia
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DSN- Pathogenesis
• HIV sparse in nerves
• Para-infectious: inflammatory mediators:
alpha TNF, gamma interferon, IL-6
• HIV gp120: toxic to axons, Schwann cells,
DRGs
• ART drugs : nerve mitochondrial toxicity
• Alcohol
• Concurrent neurotoxic drugs: dapsone,
vincristine, cisplatin, INH, ethambutol,
thalidomide
• Metabolic: diabetes, malnutrition

DSN: Clinical Features

• Common stocking-glove pattern neuropathy
• Tingling, numbness, burning, electrical
sensations, rarely, itch
• Pain leading reason to seek help
• Allodynia: non-painful stimuli of standing,
touching , pressure painful
• Gait: antalgic, walking on toes
• Weakness: not a feature; red flag for different
mechanism of neuropathy

607
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DSN: Clinical Signs

• Decreased sensation to touch, pin, cold, vibration in
distal stocking distribution
• Severe cases: impaired joint sense
• Allodynia: elicited by touch, pressure; useful sign of
neuropathic pain
• DTRs :ankle reflexes decreased first
• Muscle strength normal
• Clinical diagnosis is sufficient
• EMG rarely needed; weakness: demyelinating
neuropathies, asymmetric signs (mononeuropathy
multiplex)

Treatment
• Removal of neurotoxic drugs when
possible: rare now in cART era
• Cofactor management: alcohol, diabetes
control, d/c non-HIV drugs when feasible
• No definite neuroprotective agents with
lasting effect in recovery
• Treatment of neuropathic pain

608
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropathic Pain
• Treatment symptomatic; remains unsatisfactory
• Gabapentin widely used: no RCT. Safety, lack of
interactions with HIV drugs; typical dosing: 600-1200
mgs tid
• Duloxetine: extrapolated from diabetic neuropathy;
suited for patients with depression
• Opiates in severe neuropathic pain-short term
• Amitryptiline, mexelitine, pregabalin, topical lidocaine,
capsaicin, acupuncture ineffective in clinical trials, but
used in clinical practice
• Lamotrigine in pain of toxic neuropathies 100mgs
bid, common dose, slowly titrated up

Acute Demyelinating
Neuropathies
• HIV is recognized rare cause of GBS
• Clinical, electrical similarity to non-HIV
• CSF: mononuclear pleocytosis in GBS
• Primary, early stages of infection
• Rarely, with IRIS after initiating cART
• Good response to IVIg

609
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Chronic Inflammatory
Demyelinating Polyneuropathies
• HIV is a trigger for this syndrome
• Can occur in early, intermediate stages
• Clue: limb weakness leading symptom
• NCV/EMG critical for diagnosis: prolonged
conduction velocities
• Good response to IVIg or steroids

HIV Encephalitis
• Unique pathological syndrome
• Rapidly progressive dementia as
presentation of AIDS still occurs
• Mild cognitive impairment prevalent
• Rarely: Parkinsonism; acute mania

610
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV Dementia
• Advanced immunodeficiency: CD4 <200
• Can be presenting symptom of HIV
• Subacute dementia over weeks to months
• Main symptoms: apathy, slowed thinking,
memory impairment, occupational, social
and personal care decline
• May lead to akinetic mutism
• Gait instability is chief accompaniment
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV Dementia
• MRI: confluent white matter hyper-intensities in
cerebral hemispheres, cerebral atrophy
• CSF: normal or slight increase in lymphocytes
• CSF HIV load: present, often higher than serum

HIV-Dementia
• Interstitial encephalitis: neurons not infected
• HIV in microglial nodules
• Basal ganglia, white matter
• Pathogenesis: indirect, chronic
neuroinflammation, driven by HIV activation of
macrophages-microglia
• Dementia reversible
• cART effective irrespective of BBB penetration
• Key is control viremia, restoring CD4
• Improvement can be dramatic over 6 months
•

612
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Mild Cognitive Impairment of HIV

• Prevalent in cART era

• Despite suppressed viremia, restored CD4
• Chronic, stable in many
• Progress to severe cognitive decline in some
• Mechanism: chronic inflammation in brain, prior
HIV encephalitis, effects of medications

Mild Cognitive Impairment

• Increasing understanding of risk factors
• Older age of HIV patients
• Glucose intolerance, hyperlipidemia,
hypertension
• No specific treatments at present
• Treat cofactors: depression, B12
deficiency, alcoholism, drug abuse
• Clinical trials: boosting ART; treatment of
metabolic syndrome

613
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuro-IRIS
• Immune reconstitution with cART
• Rapid decline of viremia
• Steep increase of CD4 T cells
• Increased ability to produce tissue
inflammatory injury
• Against OIs in brain: PML, cryptococcal
meningitis
• Against HIV , brain autoantigens

IRIS Encephalitis
• Increasingly recognized syndrome
• Acute form 4-6 weeks after cART
• Headache, confusion, seizures, multifocal
sensory motor disturbances similar to ADEM
• MRI: multifocal white matter hyperintensities
• CSF: lymphocytic pleocytosis
• Exclude OIs and metabolic-toxic factors
• Improve naturally in many
• Severe cases: steroids can help
• Relapsing-remitting , chronic forms up to 2
yrs of cART- steroid-repsonsive 26/90
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CNS Escape of HIV

• Rare dementia in cART treated patients
• Subacute dementia: HIV undetectable
serum ; good CD4
• CSF HIV load is high
• No other cause found
• Reversible by modified cART based on
genotype -CSF penetration

616
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Focal Brain Lesions

• Used to be the most common cerebral
syndromes in HIV , now uncommon
• Principal causes toxoplasmosis & PML
• Primary CNS lymphoma rare, still occurs
• PML not decreased as much other Ois

PML
• Advanced AIDS , CD4<50; presenting feature
• Post-cART: even with higher CD4
• May emerge after initiating cART, due to IRIS
• Subacute, progressive, focal deficits
• MRI: lesions restricted to white matter, no
mass effect ; no enhancement
• CSF JCV by PCR. sensitive/specific in AIDS;
less in patients on cART
• 90% mortality pre-cART era
• 70% patients survive indefinitely with cART
•

617
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Potential Advances in PML

• Early clinical trials
• Monoclonal antibody PD-1 inhibitor
pembrolizumab
• IL- 2 infusions

618
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Conclusion
• HIV neurology burden markedly less
thanks to cART and preventive care
• New syndromes continue to emerge from
dynamic interactions among HIV, rapidly
changing treatment regimens, immune
reconstitution and CNS escape of HIV
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PERIPHERAL
NEUROPATHIES
Mohammad Kian Salajegheh, MD
Department of Neurology
Division of Neuromuscular Disease
Brigham and Women’s Hospital
Boston, MA

Disclosures
• None

620
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Neuropathies
• Important to establish pattern/type
– Presentation at onset and progression
– Sensory modalities affected and DTR on exam
– Pes cavus, hammertoes (chronic)
– NCS/EMG (demyelinating vs. axonal)

Routine NCS evaluates large fibers but NOT

small fibers (pain and temperature) so will be
normal in small fiber neuropathies
“Cold nerves are slow,” so be wary of limb
temperature if NCS noted as “demyelinating”

Peripheral Neuropathies
• Diagnostic workup
– Blood tests
– Nerve biopsy
– Nerve imaging
– Genetic testing

• Management
– Treat the underlying cause if found
– Physical and occupational therapy
– Foot hygiene and precautions

621
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Neuropathies
• Neuropathic pain medication (similar)
– Oral
• Gabapentin 300 to 1200 mg TID
• Pregabalin 50 to 200 mg TID
• Duloxetine 30 to 120 mg QD
• Amitriptyline or nortriptyline 10 to 100 mg QD

– Topical (if limited to feet)

• Lidocaine 2.5% + Prilocaine 2.5% cream QID
• Lidoderm 5% patch up to 3 patches daily for 12 hrs
• Capsaicin 0.025% to 0.075% cream QID

Peripheral Neuropathy Patterns

622
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Neuropathy Patterns

• Length-dependent axonal sensory > motor
neuropathy (LD-PN)

• Non length-dependent axonal neuropathy

with motor > or = to sensory (NLD-PN)

• Multiple mononeuropathies (MM)

• Ganglionopathy (sensory neuronopathy)

Length-dependent axonal sensory > motor

polyneuropathy (LD-PN)
• Most common form
• Symmetric
• Distal > proximal “length-dependent”
• Sensory > motor
• Small fiber (pain, temperature, autonomic) >
large fiber (vibration, proprioception, DTR)

• EMG: axonal sensorimotor polyneuropathy

• Biopsy: rarely needed

623
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Length-dependent axonal sensory > motor

polyneuropathy
• Laboratory testing
– Routine
• FBS, HgbA1c
• B12 (MMA if low normal)
• SPEP and immunofixation
• Lyme (endemic areas)
– Special circumstances
• Inflammatory and autoimmune (ANA, RF, SSA, SSB)
• Infections (HIV, leprosy, hepatitis panel)
• Toxin history including drugs and alcohol
• Nutritional (thiamine)

Length-dependent axonal sensory > motor

polyneuropathy
• Laboratory testing
– Routine
• FBS, HgbA1c
• B12 (MMA if low normal)
• SPEP and immunofixation
• Lyme (endemic areas)

Idiopathic (cryptogenic) > 1/3 of cases

despite thorough workup
“cryptogenic sensory polyneuropathy”
CSPN

624
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non length-dependent neuropathies with

motor ≥ sensory (NLD-PN)
• Non length-dependent -/+ cranial nerves
• Sensory (large fiber) and motor -/+
autonomic
• Reduced reflexes

• EMG: demyelinating neuropathy in some or

diffuse axonal (motor ≥ sensory)

• LP and nerve biopsy may be needed

Non length-dependent neuropathies with

motor ≥ sensory
• Etiology
– Autoimmune neuropathies
• GBS, CIDP
– Paraproteinemia neuropathies
– Some drugs (amiodarone)
– Some toxins (high-dose arsenic, lead)

– Inherited neuropathies (Charcot-Marie-Tooth)

625
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple mononeuropathies (MM)

• Individual nerves -/+ cranial

• Stepwise cumulative may lead to “confluent
polyneuropathy”
• Usually painful if infarcts (vasculitis)

• EMG confirms multiple mononeuropathies

• Biopsy most useful
– Vasculitis
– Cell infiltration (lymphoma)
– Infectious agent (leprosy)

Multiple mononeuropathies

• Etiology
– Vasculitis (lupus, PAN, Churg-Strauss)
– Infiltration (lymphoma) or paraneoplastic
– Infection (Lyme, leprosy, HSV, HIV)
– Granulomatous (sarcoid)

– Some autoimmune neuropathies

– Hereditary neuropathy with liability to pressure
palsies (HNPP)

626
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ganglionopathy (sensory neuronopathy)

• Non length-dependent diffuse or asymmetric

• All sensory modalities -/+ autonomic (no
motor)
• Prominent sensory ataxia

• EMG: diffuse loss of sensory responses

• Nerve biopsy rarely needed

Ganglionopathy (sensory neuronopathy)

• Etiology
– Sjogren’s syndrome
– Drugs (B6 toxicity, thalidomide)
– Paraneoplastic (anti-Hu)
– Autoimmune (anti-ganglionic AChR Ab)
– Infectious (HIV)

627
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Autoimmune and Inflammatory

Neuropathies

Guillain-Barré syndrome (GBS)

• Most common cause of acute generalized
weakness

• Not a single disease but several syndromes

of acute autoimmune polyneuropathies
– Acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) most common
– Axonal motor and/or sensory,…
• 2/3 report infection or immunization in prior
days to weeks

628
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Guillain-Barré syndrome (GBS)

• Presentation
– Numbness and tingling ascending from feet to
arms and even face
• Large fiber (vibration, proprioception) > small fiber
– Weakness
• Mostly ascending from legs to arms, trunk and neck
• Facial weakness, ptosis and ophthalmoparesis
possible
– Hyporeflexia or areflexia
– Autonomic instability (labile BP, arrythmias)
– Respiratory failure (check FVC per shift)

Guillain-Barré syndrome (GBS)

• Diagnostic workup
– CSF: albumino-cytological disassociation
• 1/3 to 1/2 may be normal in first week
• Lymphocytes > 50/mm3 test for Lyme, HIV, CMV,
sarcoidosis
– Electrodiagnostic reporting an acquired
demyelinating polyneuropathy
• May be normal or minor abnormalities in first week

– MRI with contrast showing root enhancement

– Anti-ganglioside Abs

629
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Guillain-Barré syndrome (GBS)

• Treatment
– Patient with major deficit within 7-10 days of
symptom onset (<2 weeks)
– Intravenous immunoglobulin (IVIG)
• Mostly replaced PLEX as treatment of choice
• As effective as PLEX and no benefit for IVIG after
PLEX
• 2 g/kg body weight spread over 2-5 days

– Plasma exchange (PLEX)

• 200–250 mL/kg of patient body weight over 10–14
days

Chronic Inflammatory
Demyelinating PN (CIDP)
• Chronic with relapsing or progressive
course

• Presentation
– Symmetric proximal AND distal limb weakness
– Almost always with areflexia or hyporeflexia.
– Cranial nerve involvement less frequent and
mild
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CIDP
• Diagnostic workup
– CSF: albumino-cytological disassociation
• If elevated lymphocytes look for Lyme, HIV,
infiltration, sarcoidosis
– Electrodiagnostic reporting an acquired
demyelinating polyneuropathy

– MRI with contrast showing root enlargement

and enhancement
– Nerve biopsy rarely required

CIDP
• Treatment
– Randomized control trials shown efficacy for
corticosteroids, PLEX and IVIG
• IVIG given monthly with dose and interval adjusted
based on response
• Prednisone 1-1.5 mg/kg (up to 100 mg) daily, then
switched to alternate-day after 3-4 weeks and
slowly tapered after response
• Response to PLEX is fast but transient and needs
to be repeated periodically

– Second line agents can be used if resistant to

therapy or dependent on prednisone

631
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CIDP
• Treatment
– Second line agents (less evidence):
• Azathioprine: 50 mg/d and gradually increase to 2 to
3 mg/kg/d
• Mycophenolate mofetil: 1 g bid and gradually
increase to 1.5 g p.o. b.i.d.
• Methotrexate: 7.5 mg/week and slowly increase to
25 mg/wk
• Cyclosporine: up to 4 to 6 mg/kg per day with
adjustment for trough levels (150 and 200 mg/dL)
• Rituximab: 750 mg/m2 (up to 1 g) IV repeated in 2
weeks and repeated every 6 to 12 months
• Cyclophosphamide if not responsive

Vasculitic Neuropathy
• Vasculitis
– Primary
• Polyarteritis nodosa (PAN) – most common
• Churg-Strauss syndrome (CSS)
• Granulomatosis with angiitis (GAN)
– Secondary to a systemic disorder (ex.
connective tissue diseases)

• Presentation
– Most common MM (may become confluent)
– Less common generalized neuropathy
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Vasculitic Neuropathy
• Diagnostic workup
– EMG: MM pattern or asymmetric axonal PN
– Blood tests:
• ESR, CRP, complement levels
• ANCA, ANA, RF
• HIV, HCV and HBV

– Nerve biopsy
• Transmural inflammation
• Vessel wall necrosis

Amato A and Russell J 2008

Vasculitic Neuropathy
• Treatment
– Mainstay is combination corticosteroids and
cyclophosphamide
• Cyclophosphamide replaced with azathioprine or
methotrexate after improvement (mycophenolate
mofetil also used)

– Rituximab shown to induce remission in

“ANCA-associated” vasculitis

– Hepatitis B- or C-related vasculitis require

antiviral therapy

633
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sarcoid Neuropathy
• Multisystem granulomatous disorder (~5%
nervous system involvement)

• Presentation
– CNS (granulomas)
– Neuropathy
• Relapsing/remitting or progressive
• MM, LD-PN or NLD-PN -/+ cranial nerves
• Polyradiculopathy

Sarcoid Neuropathy
• Diagnostic Workup
– Hilar adenopathy on chest imaging
– MRI spinal root enhancement
– CSF
• Elevated protein and lymphocytes

– EMG based on pattern

– Nerve biopsy
• Noncaseating granulomas

Amato A and Russell J, 2008

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sarcoid Neuropathy
• Treatment
– Usually respond to high-dose prednisone
– Other immunosuppressive agents can be used if
not responsive

Paraproteinemia & Neuropathy

• Paraproteinemia
– MGUS
– Multiple myeloma (mostly IgG or IgA)
– Waldenström macroglobulinemia (IgM)
– Osteosclerotic myeloma (IgG or IgA)
– POEMS (IgG or IgA-lambda; VEGF elevated)
P polyneuropathy
O organomegaly (liver, spleen, lymphatic system)
E endocrinopathy (diabetes, hypothyroid, fertility)
M monoclonal gammopathy
S skin change (edema, clubbing, hyperpigmentation)
– Primary AL amyloidosis (light chain deposits)

635
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Paraproteinemia & Neuropathy

• Presentation
– LD-PN axonal (small fiber in amyloidosis)
– NLD-PN demyelinating (CIDP-like)
• IgM with 50% anti-MAG in DADS (Distal acquired
demyelinating symmetric polyneuropathy)
• Diagnostic workup (after finding M spike)
– EMG to determine pattern and biopsy site
– Fat pad or nerve biopsy for amyloidosis
– CBC, serum calcium and renal function
– Skeletal survey
– Bone marrow biopsy

Paraproteinemia & Neuropathy

• Treatment
– Identify and treat malignancy
– CIDP-like (mostly IgG or IgA MGUS) similar to
CIDP immunomodulatory therapy
– DADS (IgM MGUS -/+ anti-MAG) relatively
refractory to immunomodulating therapiy
– Axonal (IgM, IgG, or IgA MGUS) typically not
responsive to immunotherapy.

– Amyloidosis
• Chemotherapy (ex. melphalan, prednisone)
• Autologous stem cell transplantation

636
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Endocrine Neuropathies

Diabetic Neuropathy
• Risk correlated with duration of DM and
control of hyperglycemia
• Presentation
– Most common form LD-PN -/+ autonomic
– Other
• Lumbosacral radiculoplexus polyneuropathy
• Radiculopathy (thoracic)
• Cranial neuropathy

• Treatment
– Optimize control of blood sugar with
medication and dietary measures

637
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pre-Diabetes & Neuropathy

• Relationship between pre-diabetes and PN
under debate
TEST PRE-DM DM
FBS (mg/dL) 100-125 (IFG) ≥126
2Hr GTT (mg/dL) 140-199 (IGT) ≥ 200
HgbA1c (%) 5.7%-6.4% ≥ 6.5%

– 40-50% in patients with PN c/w 15% without

– Some suggest relationship with “metabolic
syndrome” and dyslipidemia not glucose

Pre-Diabetes & Neuropathy

• Presentation (most common)
– Small fiber LD-PN (pain and temperature)
– Normal NCS

• Important to consider as dietary and life-

style modifications may reverse
neuropathy

638
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Infectious Neuropathies

Leprosy (Hansen Disease)

• Caused Mycobacterium leprae
– Most common worldwide cause of neuropathy
• Presentation based on immune response
– Tuberculoid leprosy (TT; intact immunity)
• Well-defined hypopigmented skin lesions with
erythematous borders
• Loss of sensation at center of skin lesions
• Mostly in cooler regions
• Neuropathy mononeuropathy or MM
• Thickened nerves

Amato A and Russell J, 2008

639
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Leprosy (Hansen Disease)

– Lepromatous leprosy (LL; impaired immunity)
• Confluent distal symmetrical rash and anesthesia
• “Leonine Facies”
– Loss of eyebrows and eyelashes
– Exaggeration natural folds
• Slowly progressive LD-PN
• CN involvement (particular CN 7)

– Borderline leprosy (BB) between TT and LL

Salgado CG et al. N Engl J Med 2012

Leprosy (Hansen Disease)

• Diagnostic Workup
– EMG based on neuropathy type

– Biopsy
• Skin with red bacilli (Fite stain)
• Nerve (if no skin lesions)
– Tuberculoid
» Granulomas -/+ caseation may or may not be present
» Bacilli usually not seen
– Lepromatous
» Large number of bacilli in clusters
» Minimal granuloma formation

http://wwwnc.cdc.gov/eid/article/19/1/12-0864-
f1.htm Trindale MAB et al. Braz J Infect Dis 2008

640
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Leprosy (Hansen Disease)

• Treatment with multiple drugs (WHO)
– Tuberculoid
• Dapsone and rifampin 6 mo
– Lepromatous
• Dapsone, rifampin and clofazimine 1-2 years (or until
skin smear is zero)

Lyme Neuropathy
• Due to Borrelia burgdorferi in N. America
– Spirochete transmitted by ticks
– ~24 hr tick attachment needed

• Presentation (3 stages)
– Stage 1 (Early localized; days to weeks)
• Erythematous circular lesion
• Expands with central clearing
• Resolves spontaneously weeks

Bull’s eye lesion

[http://en.wikipedia.org/wiki/Lyme_disease

641
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lyme Neuropathy
• Presentation (cont…)
– Stage 2 (Early disseminated; weeks to months)
• Dissemination in the body with systemic involvement
(cardiac, joints, CNS,…)
• Neuropathy
– Cranial neuropathy (in particular CN 7 with 50% bilateral)
– Polyradiculoneuropathy and GBS mimic
– Multiple mononeuropathies and asymmetric PN

– Stage 3 (late stage; months to years)

• Develop into LD-PN

Lyme Neuropathy
• Diagnostic Workup
– ELISA for Lyme antibodies with western blot
confirmation if equivocal or positive
– CSF with lymphocytic pleocytosis, elevated
protein and positive Lyme Ab
– EMG based on neuropathy type
• Treatment (adults)
– Isolated CN7: doxycycline 100 mg bid for 2
weeks (can use amoxicillin 500 tid)
– Other neurologic involvement: ceftriaxone 2 g
IV daily for 2 to 4 weeks
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Toxic Neuropathies

Toxic Neuropathies
• Various agents
– Alcohol
– Medications
• Dapsone, ethambutol, isoniazide, fluoroquinolones
• Metronidazole, nitrofurantoin, anti-retrovirals
• Chloroquine, hydroxychloroquine, amiodarone
• Phenytoin, disulfiram
– Chemotherapy agents
– Industrial toxins
• Acrylamide, Carbon Disulfide, toluene
– Heavy metals
• Lead, arsenic, mercury, thallium

643
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alcohol Neuropathy
• Neuropathy in approximately half of the
alcoholics

• Dose-depndent
– 15 ml/kg total lifetime dose
– 100 ml alcohol (3L beer and 300 ml spirits) per
day for 3 years

• Neuropathy
– Usually LD-PN

Pyridoxine (B6) Toxicity

• Usually high daily doses (>50-100 mg)
• Causes as severe ganglionopathy

• Presentation
– Pure sensory with ataxia
– No motor involvement
• EMG with diffuse loss of sensory
responses

• Treatment is to discontinue B6

644
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Arsenic Neuropathy
• Presentation
– Immediate GI symptoms of abdominal pain,
nausea, vomiting and diarrhea
– Neuropathy 5-10 days after ingestion
• DL-PN low toxicity
• High toxicity can mimic GBS
– Other:
• Skin

Skin pigmentation hands Mee’s lines

https://yourhealthofima.wordpress.com/20
12/06/02/arsenicosis-a-global-problem/ http://stanfordmedicine25.stanford.edu/the25/hand.html

Arsenic Neuropathy
• Diagnostic workup
– Arsenic levels in urine, hair and nails (clears
from blood quickly)
– Anemia and pancytopenia
• RBC stippling

Basophilic stippling
• Treatment
– British anti-Lewisite unclear benefit

https://www.studyblue.com/notes/note/n/pathoma-5-microcytic-anemia/deck/13327369

645
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lead Neuropathy
• Rare but seen in
– Children ingesting lead-based paints
– Industrial workers exposed to lead products
• Presentation
– Predominantly motor (sensory preserved)
• Wrist and finger extension and foot dorsiflexion
– Other
• Bluish line of the gums
• Metaphyseal dense
bands on X-Ray

http://www.medicaljournals.se/acta/content/?doi
=10.2340/00015555-1201&html=1 Burton’s line in “plumbism”

Lead Neuropathy
• Diagnostic workup
– EMG mainly reduced motor responses
– Measurement of lead in 24 hr urine
– Anemia with RBC stippling

• Treatment
– Chelation therapy with “British anti-Lewisite”
and penicillamine variably effective
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Mercury Neuropathy
• Presentation
– Organic (methyl ethyl mercury)
• Paresthesia hands and feet that may involve face
and tongue (mainly sensory like ganglionopathy)

– Inorganic (industrial salts)

• Mainly GI symptoms and nephrotic syndrome
• May cause LD-PN

Mercury Neuropathy
• Diagnostic workup
– EMG mainly with loss of sensory responses
– 24 urine measurement and with fractionation
for organic and inorganic components

• Treatment
– Effect of penicillamine chelation unclear

647
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thank You!

648
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MUSCLE AND
NEUROMUSCULAR
JUNCTION DISORDERS
Mohammad Kian Salajegheh, MD
Department of Neurology
Division of Neuromuscular Disease
Brigham and Women’s Hospital
Boston, MA

Disclosures
• None
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Nervous System

• Sensory
– Roots (dorsal)
– Dorsal sensory ganglion
– Nerve (sensory fiber)
– Sensory receptor
• Motor
– Motor neuron (anterior horn)
– Roots (ventral)
– Nerve (motor fiber)
– Neuromuscular junction
– Muscle

Peripheral Nervous System

• Sensory
– Roots (dorsal)
– Dorsal sensory ganglion
– Nerve (sensory fiber)
– Sensory receptor
• Motor
– Motor neuron (anterior horn)
– Roots (ventral)
– Nerve (motor fiber)
– Neuromuscular junction
– Muscle
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Nervous System

• Sensory
– Roots (dorsal)
– Dorsal sensory ganglion
– Nerve (sensory fiber)
– Sensory receptor
• Motor
– Motor neuron (anterior horn)
– Roots (ventral)
– Nerve (motor fiber)
– Neuromuscular junction
– Muscle

Motor
• Motor neuron disease
• Motor fibers
• Neuromuscular Junction
– Fluctuating and fatigable muscle weakness
– Ocular and bulbar symptoms common
– Rarely have atrophy

– Disorders
• Myasthenia gravis
• LEMS
• Drugs and toxins
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Motor
• Motor neuron disease
• Motor fibers
• Neuromuscular Junction
• Muscle (myopathies)
– Proximal > distal
• Inflammatory myopathies
• Endocrine (thyrotoxicosis)
• Toxic (Statins)
• Limb-girdle muscular dystrophy and
dystrophinopathies

Motor
• Motor neuron disease
• Motor fibers
• Neuromuscular Junction
• Muscle (myopathies)
– Proximal > distal
– Distal > or = proximal
• Myotonic dystrophy type 1 (myotonia on exam and EMG)
• Some muscular dystrophies
• Inclusion body myositis (IBM; most common inflammatory of
the elderly)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Motor
• Motor neuron disease
• Motor fibers
• Neuromuscular Junction
• Muscle (myopathies)
– Proximal > distal
– Distal > = proximal
– Diffuse
• ICU myopathy
• Channelopathies (periodic paralysis)

NEUROMUSCULAR
JUNCTION DISORDERS

653
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NMJ Introduction
• Interface between motor nerve and muscle fiber
(transducer)

Electrical current
(nerve)

Chemical signal
(synaptic cleft) 3

2
Electrical current
(muscle)

NMJ Structure
Pre-Synaptic Membrane:
- Complex process with
>1000 proteins involved

- ACh synthesized and

packaged into vesicles

-Voltage-gated calcium
channel

- SNARE proteins involved

in vesicle binding, fusion
and release
Amato A and Russell J 2008

654
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NMJ Structure
Post-Synaptic
Membrane:

AChR:
- Transmembrane channel
consisting of 5 subunits

MuSK:
- AChR clustering

Amato A and Russell J 2008

NMJ Disorder
• Acquired or hereditary defects
• Alterations in structure or function of the NMJ
– Presynaptic
• Defective synthesis or packaging of ACh into vesicles
• Reduced release of ACh vesicles
– Reduced entry of calcium
– Reduced docking and fusion
– Synaptic
• Reduced or dysfunctional AChE
– Postsynaptic
• Reduced number or reactivity of AChR

655
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Myasthenia Gravis (MG)

Myasthenia Gravis (MG)

• Age of onset bimodal
– Early: 3rd and 4th decade (W>M ~7:3)
– Late: women and men 8th decade (W=M)

• Present with “fatigable” and “fluctuating”

weakness
• Exacerbating factors
– Exercise & warm weather
– Systemic infections and disease
– Anxiety & emotional stress
– Pregnancy

656
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Clinical Features
• Variable weakness pattern
– Muscles innervated by cranial nerves
• Ptosis (asymmetric) and ophthalmoparesis
• Weak eye closure or whistling (facial)
• Voice changes
– Hypophonic (vocal cord or respiratory muscles)
– Dysarthric (labial, glossal or buccal)
– Nasal quality (palatal)
Combination of CN
• Swallowing motor abnormalities
– Nasal regurgitation (palatal)
– Food stuck in cheek or behind teeth (tongue or buccal)
– Aspiration
• Difficulty with sniffing, coughing and nose-blowing

MG-Clinical Features
– Limb weakness
• Mostly proximal symmetric (“limb-girdle” pattern)
• Other forms described (distal, focal or multifocal)
– Head drop
– Respiratory insufficiency

• Uncommon
– Bowel and bladder involvement
– Autonomic symptoms (pupils, dry mouth,…)

657
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Clinical Features
• Exam
– Weakness in muscles noted
– Provocative maneuvers
• Sustained up gaze
• Eccentric gaze (may cause pseudo-nystagmus)
• Sustained arm abduction

– Normal reflexes and sensory exam

MG-Associated Disease
• Thymic hyperplasia & thymoma
• Autoimmune diseases
– Pernicious anemia
– Rheumatoid arthritis, Sjogren syndrome, SLE
– Addison disease, hyper- and hypo- thyroidism

• Neuromuscular disease
– CIDP
– Myositis

658
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Workup
• NCS/EMG
– Slow (3 Hz) RNS
– SFEMG

• Edrophonium (Tensilon) test

• Need to see objective improvement (ptosis, EOM)
• Use under close cardiac monitoring (bradycardia)

• CT or MRI of the chest (thymoma)

• PFT and swallow evaluation

MG-Workup
• Serology
– Acetylcholine receptor Ab
• Binding: main Ab measured and highly specific
• Modulating: in 5% with negative binding Ab
• Blocking: not used for screening

– Muscle-specific kinase (MuSK) Ab

• In 40% MG with negative AChR Ab

– Anti-striated muscle (striational) antibodies

• Limited use (suspicion for thymoma in <40 yrs)

659
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Treatment
• AChE inhibitors (pyridostigmine)
– Symptomatic therapy
• Only medication if isolated oculomotor symptoms
• Reducing symptoms while treating with prednisone
– Dosing
• 30-60 mg every 6-8 hours up to 600 mg/day
• 30 min before meals improves swallowing

– Side effects (cholinergic)

• Nausea, vomiting, abdominal cramping and diarrhea
• Increased oral and bronchial secretions
• Bradycardia

MG-Treatment
• Prednisone
– Slow approach
• Start at 20 mg/day
• Increase by 10 mg/day every 4 weeks to 1 mg/kg
daily or return to baseline and continue for 4 weeks
• Slow taper key

• If symptoms recur
– Exclude infection, drugs or electrolyte imbalance
– Stop taper and return to previous dose or add 10 mg
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Treatment
• Prednisone (continued)
– Alternate approaches
• Start high-dose prednisone (1mg/kg/day)
– Risk of worsening symptoms
– Usually started after IVIG or PLEX in inpatients

• Second immunomodulatory agents

• Steroid resistant
• “Steroid sparing” therapy if can not
• Can be considered early if severe and generalized
MG, diabetes mellitus or significant osteopenia

– All have side effects that need to be considered

MG-Treatment
• Azathioprine
– Most frequently used second-line agent
– Start at 50 mg/d with gradual increase to 2–3
mg/kg/d over 1–2 months
– Delayed onset of action of 6 months or more

• Cyclosporine
– Start 2-3 mg/kg/d in two divided doses and
gradually increase to maximum 6.0 mg/kg/d
– Adjust for trough <150-200 ng/mL and stable Cr
– Onset of effect 2–3 months (peak at 7 months)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Treatment
• Mycophenolate mofetil
– Beneficial effect in small open-label trials
– Two controlled trials of prednisone plus placebo
or mycophenolate no added benefit

• Methotrexate
– Not shown to be definitively beneficial
– Initiate orally 7.5 mg/week and slowly increase
– Concomitantly treat with folate

MG-Treatment
• Other agents for refractory MG
– Rituximab
• Shown to be beneficial in refractory cases
• Multi-center placebo controlled trial underway

– Cyclophosphamide
• Few reports describing the use of cyclophosphamide
• Significant side effects and need to be administered
by someone experienced with its use

– Drugs being studied

• Eculizumab
• Belimumab
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Treatment
• IVIG and PLEX
– Usually for myasthenic crisis
– Bolster patient strength in anticipation of
thymectomy

– Chronic therapy
• Usually expensive and time consuming
• PLEX for MuSK patients
• IVIG for MG patients with worsening weakness
• Patients refractory to or intolerant of other therapies

MG-Treatment
• IVIG
– 2 gr/kg IV spread over 2-5 days
– Repeat infusions monthly for at least 3 months
– Adjust to smallest dose at longest intervals

• PLEX
– Usually need central venous access
– Effect lasts less than 6-8 weeks

663
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Treatment
• Thymectomy
– Recommended in thymoma
– Role in the absence of thymoma unclear
• Final results of trial (MGTX) to be published
• Less response in patients with MuSK Abs

Myasthenic Crisis
• New onset or exacerbation of MG
– Respiratory compromise
– Severe bulbar (difficulty swallowing)

– Admission to ICU
• Close monitoring of breathing
– Intubation with FVC <15 mL/kg
– Avoid AChE inhibitors to minimize secretions
• IVIG or PLEX
• Followed by
– 0.8 mg/kg/day IV methylpredinsolone (until taking PO)
– 1 mg/kg/day PO prednisone

664
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MG-Pregnancy
• High risk pregnancy
– Mother with MG exacerbation or difficult birth
– Treatment
• Control MG before pregnancy
• Pyridostigmine and prednisone
• IVIG can be used for exacerbation

• Neonatal MG
– 10% of infants in first 3 days of life
– Monitor for symptoms
– Temporary with mean duration 18–20 days

Lambert-Eaton Myasthenic
Syndrome (LEMS)

665
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LEMS
• Second most common NMJDO (presynaptic)

• Paraneoplastic in approximately 2/3 of cases

– Malignancies
• Small cell carcinoma (~ 90%)
• Lymphoproliferative disorders
• Breast and ovarian
• Pancreas

– Majority older than 40 years

LEMS
• Non-paraneoplastic (approximately 1/3)
– More common in younger females
– Other autoimmune diseases possible

• Paraneoplastic and non-paraneoplastic

clinically and electrophysiologically similar
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LEMS-Clinical Features
• Weakness and easy fatigability
– Proximal lower > upper extremity
– Cranial muscle weakness and ventilatory issues
not as common or severe as MG but possible

• Autonomic symptoms common

– Blurred vision
– Decreased sweating
– Impotence

LEMS-Clinical Features
• Reduced DTR (may improve with contraction)
• Muscle atrophy in advanced stages of LEMS

• Sensory neuronopathy and cerebellar ataxia

possible due to other paraneoplastic
antibodies (anti-Hu)

667
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LEMS-Workup
• Electrodiagnostic
– Reduced CMAP amplitudes with abnormal
facilitation after exercise or on rapid RNS

• Serology
– Anti-voltage gated calcium channels (VGCC)

• Screen for malignancy with serial evaluations

LEMS-Treatment
• Treatment of underlying tumor

• AChE inhibitors (pyridostigmine) response

variable and often modest
• 3,4-diaminopyridine (3,4-DAP) improves
strength usually 10-20 mg 3 times per day
(max 80 mg/day)

• Immunosuppressive therapy
• IVIG and PLEX may improve strength

668
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Other NMJDO

Botulism
• Caused by clostridium botulinum
– Classic or food borne (mainly contaminated
canned foods)
– Infant botulism (most common form in US by
enteric spore inoculation (sp. honey and 6 mo
and <1 year old)
– Wound botulism (IV drug users, trauma)
– Iatrogenic (botulinum toxin injection)

669
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Botulism
• Typical acute onset with progression 12-36
hours
– Dysphagia, dysarthria, diplopia and xerostomia
– First upper then lower extremity weakness
– Shortness of breath

– Ptosis and facial paralysis

– Diminished gag reflex and tongue weakness
– Autonomic dysfunction
• Poor pupillary response to light
• Lack of vasomotor response to postural changes
• Ileus and urinary retention

Botulism-Workup
• Workup
– Rapid RNS with abnormal facilitation
– Analyze for toxin and culture for organism

• Treatment
– Antitoxin
• Equine-derived for adults if < 24 hours of onset
• Human botulinum immune globulin for infant botulism
– Wound debridement and antibiotics (after above)
– Intensive care with mechanical ventilation
– Supportive care (long-term)

670
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Medications
• Drugs that may unmask or exacerbate MG
– Aminoglycosides, erythromycin
– Corticosteroids
– Magnesium (parenteral)
– Neuromuscular blocking agents
– Iodine contrast agents

• Drugs that may cause MG

– D-Penicillamine
– Resolves within 2–6 months of drug withdrawal

Toxins
• Organophosphate compounds
– Chemical weapons
– Insecticide
• Accidental
• Homicide or Suicide
• Envenomation
– ω-Conotoxin - Conus marine snails
– β-bungarotoxin - Multibanded krait
– Crotoxin - Brazilian rattlesnake
– α-latrotoxin - Black and brown widow spider
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MUSCLE DISORDERS

Inflammatory Myopathies (IM)

672
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Inflammatory Myopathies (IM)

• Dermatomyositis (DM)
– Skin
– Muscle
• Polymyositis (PM) and immune necrotizing
myopathy (INM)
– Muscle
• Inclusion body myositis (IBM)
– Muscle

• Other subtypes
– Granulomatous myositis
– “Overlap syndromes” – in association with defined CTD
– Infections (viral, fungal, bacterial and parasites)

DM-Skin Manifestations
Heliotrope rash with Gottron papules
periorbital edema (erythematous rash)
Periungual
telangiectasia

“V” sign (erythematous sun

sensitive macular rash)
Amato A and Russell J 2008
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IM – Clinical Features
• DM
– Skin
– Muscle: proximal
Responsive to
– Other tissue immunomodulating
therapies
• PM and INM
– Muscle: proximal
– Other tissue

NOT responsive to
• Inclusion body myositis immunomodulating
– Muscle: proximal and distal therapies

IM-Diagnostic Evaluation
• Laboratory Studies
– CK
• DM – usually high (may be normal)
• PM – almost always high
• IBM – normal or modest increase
– ANA
• If abnormal, prompt testing for dsDNA, RNP, SSA, SSB
– Anti-Jo-1 and Anti-SRP antibodies in INM

– HTLV1 and HIV

• PM or IBM phenotypes

– Malignancy evaluation (sp. in DM, PM and INM)

674
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IM-Diagnostic Evaluation
• Radiological Studies
– Malignancy evaluation
• Chest/Abdomen/Pelvic CT
• Mammogram
• ?Bone scan

– Sarcoidosis
• Chest CT

– MRI muscle
• Inflammation
• Fibrotic tissue replacement

IM-Diagnostic Evaluation
• Pulmonary function tests (PFT)
– DM and PM patients with possible ILD
– FVC sitting and lying (10% drop significant)

• Modified barium swallow

– Should ask about effects of dysphagia
• Weight loss
• Eating slower
• Coughing or choking with food
• Changing what is eaten (consistency)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IM-Diagnostic Evaluation
• Electrodiagnostic studies (EMG)
– Needle EMG (irritable myopathy)
• Determining involved muscles (for biopsy)
• Differentiating myositis from MND or steroid myopathy

• Muscle Biopsy (most helpful test)

– Best if muscle is ~ 4/5 on MRC scale
– Can use EMG, ultrasound or MRI for choosing muscle

PM-Pathology
119th ENMC international workshop (2004) requires endomysial CD8+ T cell
infiltrates invading non-necrotic muscle fibers for definite PM diagnosis

Amato A and Russell J 2008

676
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DM-Pathology
Perifascicular atrophy with small degenerating and regenerating fibers

Courtesy SA Greenberg, MD

DM-Pathology
Perivascular inflammation

Courtesy SA Greenberg, MD

677
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

INM-Pathology
Necrotizing myositis with scattered necrotic fibers but rare, if any,
inflammatory cells except in fibers undergoing phagocytosis

Amato A and Russell J 2008

IM - Treatment
• Glucocorticosteroid (prednisone)
– Start at 1.0-1.5 mg/kg/day (max 100mg)
– Switch to alternate day after 3-4 weeks
– Continue until normal for 1-2 months
– Slow taper key
• Second-line agents
– Used if refractory to or dependent on steroids
• Methotrexate second line unless patient has ILD
• Mycophenolate mofetil
• Azathioprine
• IVIG
• Rituximab
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IBM-Clinical Features
• Most common inflammatory myopathy in
individuals over the age of 50

• Slowly progressive and asymmetric muscle

weakness and atrophy.
– Quadriceps femoris (sp. with strong hip flexors)
– Biceps and triceps (sp with strong deltoid)
– Tibialis anterior
– Wrist and finger flexors (FDP)

• Dysphagia common (65%)

IBM-FDP Weakness

Asymmetric
finger flexor
weakness

Amato A and Russell J 2008

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IBM-Pathology Features

Red rimmed vacuoles (GTC stain)

Endomysial CD8+ T cell infiltrates invading non-

Endomysial inflammation necrotic muscle fibers for definite PM diagnosis

IBM-Pathology Features
“Amyloid” deposits

Inclusion body Congo red staining visualized

(H&E staining) through a Texas-red filter

Rimmed
vacuoles

Crystal violet staining

Engel et al Neurology 2006

680
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

IBM-Treatment
• Not promising
– Accepted to be refractory to corticosteroids
– Placebo controlled trials
• IVIG +/- prednisone 3 months – no benefit
• Beta-interferon 6 months – no benefit
• Methotrexate 48 weeks – no benefit
• Oxandrolone 12 weeks – no benefit

– Uncontrolled trials
• Azathioprine
• Anti-thymocyte globulin x 6 months
• Alemtuzumab (Campath)

Toxic Myopathies

681
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Toxic Myopathies
• Cholesterol lowering agents
• Chloroquine, hydroxychloroquine,
amiodarone
• Colchicine, vincristine
• Cyclosporine, tacrolimus
• Zidovudine
• Steroid myopathy
– High dose and long term use
– Normal CK and needle EMG
– Improve with reducing dose

Toxic Myopathies
• Clinical findings
– Use of offending agent (may be years)
– Myalgia and proximal weakness
– Some with concomitant neuropathy

• CK mildly-moderately elevated
– Unless rhabdomyolysis
• Electrophysiology
– NCS: normal (unless neuropathy or generalized
myopathy)
– EMG: irritable myopathy
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Toxic Myopathies
Necrotic myofiber:
• Pale cytoplasm
• Loss of striations

Myophagocytosis:
Myofiber invaded by macrophages

Amato A and Russell J 2008

Toxic Myopathies
• Treatment
– Discontinuation of offending agent
– Supportive care and rehabilitation

– Some may require immunotherapy

683
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Statin Myopathy
• Incidence
– Various reviews:
• Myalgias 9-20%
• Weakness or CK elevation 0.1-1%
• Increased risk with concomitant myotoxic agents or renal
or liver dysfunction

• Some trigger an immune mechanism (INM)

– Weakness progresses or does not improve after
stopping Statin (wait few months)
– Elevated anti-HMG-Co A reductase in blood
– Require aggressive immunotherapy

Critical Illness Myopathy

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Critical Illness Myopathy

• Acute quadriplegic myopathy (AQM)
• Differentiate from
– Critical illness neuropathy (CIN)
– Prolonged neuromuscular blockade

• Setting of
– High-dose corticosteroids
– Non-depolarizing neuromuscular blockade
– Sepsis
– Multiorgan failure
– Recent organ transplantation (likely due to
combination of above factors)

Critical Illness Myopathy

• Clinical findings
– Severe generalized muscle weakness
– Sometimes noticed by inability to wean patient
from ventilator
• EMG with irritable myopathy
• CK normal or moderately elevated

• Treatment
– Supportive over several months
– Stop CS or non-depolarizing NM blockers
– PT & OT to prevent contractures and rehabilitation
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hereditary Myopathies

Muscle Channelopathies
• Autosomal dominant (most) disorders of
muscle membrane ion-channels
– Sodium
– Calcium
– Potassium
– Chloride
• Present with (one or both features)
– Myotonia (muscle stiffness and inability to
relax after contraction)
– Periodic paralysis (attacks of focal to
generalized weakness)

686
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Muscle Channelopathies
• Diagnosis
– Potassium levels during attack (may be normal)
– Genetic testing available
• Based on presentation
• Findings on electrophysiologic testing
• Muscle biopsy not usually required
• Treatment
– Medication
• Myotonia: antiepileptics or antiarrythmics (mexiletine)
• Periodic paralysis: acetazolamide or
dichlrophenamide
– Target environmental factors and triggers

Muscular Dystrophies
• Inheritance
– Autosomal dominant
• Myotonic dystrophy type 1 and 2
• Limb-girdle muscular dystrophies (type 1)
• Facioscapulohumeral muscular dystrophy (FSHD)
– Autosomal recessive
• Limb-girdle muscular dystrophies (type 2)
– X-linked
• Duchenne and Becker muscular dystrophies

687
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Muscular Dystrophies
• Clinical presentation
– Proximal and/or distal weakness and muscle
atrophy
– Cardiomyopathy or cardiac conduction defects
– Dysphagia and dyspnea
– Other systemic issues (early cataracts)

• Diagnosis
– CK usually elevated (not in all of them)
– Muscle biopsy
– Genetic testing

Muscular Dystrophies
• Treatment
– High-dose prednisone in Duchenne
– Supportive care for other issues
– Physical therapy and bracing

688
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Motor Neuron Diseases

Nazem Atassi, MD, MMSc

Neurological Clinical Research Institute (NCRI)
Massachusetts General Hospital
Harvard Medical School

Disclosures

• No Related Disclosures

689
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Upper and Lower Motor Neurons

Upper Motor Neurons Lower Motor Neurons

Picture Credit: www.doctorexclusive.com

Motor Neuron Diseases by Anatomy

1- Diseases of the Upper Motor Neurons

• Hereditary Spastic Paraparesis (HSP)
• Primary Lateral Sclerosis (PLS)

2- Diseases of Both Upper and Lower Motor Neurons

• Amyotrophic Lateral Sclerosis (familial and sporadic)

3- Diseases of the Lower Motor Neurons

• Polio & Polio-like enteroviruses
• West Nile Virus
• Kennedy’s Disease (Spinobulbar Muscular Atrophy; SBMA)
• Spinomuscular Atrophy (SMA)
• Progressive Muscular Atrophy (PMA)

690
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Motor Neuron Diseases by Etiology

1- Infectious
• Polio
• Polio-like enteroviruses
• West Nile Virus

2- Inherited Neurodegenerative
• Kennedy’s Disease (Spinobulbar Muscular Atrophy; SBMA)
• Spinomuscular Atrophy (SMA)
• Hereditary Spastic Paraparesis (HSP)
• Familial Amyotrophic Lateral Sclerosis (fALS)

3- Sporadic Neurodegenerative
• Primary Lateral Sclerosis (PLS)
• Progressive Muscular Atrophy (PMA)
• Sporadic Amyotrophic Lateral Sclerosis (sALS)

1- Infectious Motor Neuron Diseases

• Polio

• West Nile Virus

691
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Polio
• Enterovirus with fecal-oral and oral-oral transmission
• Polio remains endemic in countries outside the US
• Incubation period is 5-30 days
• Acute illness: GI upset, headache, mild fever
• 1% get paralytic polio (poliomyelitis)
– follows fever by 5-7 days
– Asymmetric flaccid weakness and decreased reflexes (LMN)
– +/- Respiratory involvement; +/- Bulbar involvement

• Diagnosis:
– Clinical, CSF pleocytosis/elevated protein
– Polio virus from stool or oral swab, Ab in blood or CSF
• Treatment: Supportive; vaccine prevents infection
• Prognosis: Variable

West Nile Virus (WNV)

• Mosquito-borne RNA virus
• 1% of infections cause neurologic dz
• Encephalitis, Meningitis, +/- Acute Flaccid Paralysis (AFP)
• Weakness is asymmetric, can involve respiratory muscles

• Diagnosis: Clinical, CSF pleocytosis/protein elevation, WNV

from blood or CSF
• Treatment: Supportive
• Prognosis: 30% Strength recovery

2003, Sampathkumar P; 2005, Saad et al; 2002, Ark Dept Health. CDC Website

692
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

2- Inherited Motor Neuron Diseases

• Spinobulbar Muscular Atrophy (SBMA)
Also known as “Kennedy’s Disease”
– Androgen receptor mutation, X-linked

• Spinomuscular Atrophy (SMA)

– Rare disease, but most common inherited infantile weakness (AR)

• Hereditary Spastic Paraparesis (HSP)

– Heterogeneous group of disorders with insidious onset (most AD)

• Familial ALS (fALS)

– Closely resembles sporadic ALS (most AD)

Kennedy’s Disease
(Spinobulbar Muscular Atrophy; SBMA)
• X-Linked - Affects men
– CAG repeat in the androgen receptor
• Slowly progressive disease of LMN (Limbs/Face)
• Onset 20-40 yo
• Also causes an axonal sensory polyneuropathy
• Gynecomastia, +/- infertility, +/- chin fasciculations

• Diagnosis: FHx, Exam, EMG, Gene test

• Treatment: Symptomatic management
• Prognosis: Weakness progresses over years to
decades

Picture Credit: http://neuromuscular.wustl.edu/pics/people/patients/bsmasmileb.jpg;

http://img.medscape.com/pi/emed/ckb/neurology/1134815-1172604-439.jpg

693
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Spinomuscular Atrophy (SMA)

– Autosomal Recessive mutation in SMN1 gene
– Lower motor neurons
– Four “types” defined clinically by time of onset
• Type I: Onset <6 mo (early infancy)
• Type II: Onset 6-18 mo (late infancy)
• Type III: Onset >18 mo (juvenile)
• Type IV: Adult onset

– Diagnosis: Clinical, Gene Testing, EMG

– Treatment: nusinersen (Antisense oligonucleotide)
– Prognosis: Depends on type and severity
• Types I and II – Significantly improved with new Rx
• Types III and IV - Variable

Picture Credit: http://radiopaedia.org/images/530297

Hereditary Spastic Paraparesis (HSP)

– Heterogeneous group of genetic mutations, most are AD
– Slowly progressive upper motor neuron dysfunction of the legs
– Avg age of onset 24 y/o
– Clinically Uncomplicated or Complicated
• Uncomplicated: leg spasticity and weakness +/- bladder spasticity
• Complicated: +/- MR, cataracts, ataxia, epilepsy

– Diagnosis:
• Clinical history, exam, family history, genetic testing
• Rule out other diseases:
– MRI brain, cervical, and thoracic spine +/- lumbar spine
– Labs & EMG
– Treatment: Supportive
– Prognosis: Slowly progressive, variably disabling
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Familial ALS (fALS)

• 5-10% of ALS is familial
• Usually AD inheritance
• Many causative genes have been described
• SOD1 is the first described mutation
• C9Orf72 hexanucleotide repeat expansion is most common
• Some mutations remain unknown
• Overall, clinically indistinguishable from sALS
– Some fALS mutations cause early onset with rapid progression

• Diagnosis, Treatment, and Prognosis are otherwise the

same as sALS
– Some gene testing is available clinically

3- Sporadic Motor Neuron Diseases

• Sporadic ALS (UMN + LMN)

– Most common adult-onset motor neuron disease

• Primary Lateral Sclerosis (UMN)*

– Probably 5% of MND
– Diagnosed after 4 years

• Progressive Muscular Atrophy (LMN)*

– Probably 5% of MND
– Typically limb onset
– Diagnosed after 4 years

* Some consider PLS and PMA as ALS variants with better prognosis

695
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ALS Overview

Amyotrophic Lateral Sclerosis (ALS)

• Amyotrophy – describes clinical muscle atrophy

• Lateral Sclerosis – describes the gross

pathology finding of sclerosis (scarring) of the
lateral corticospinal tracts in the spinal cord.
Picture Credits: www.mdconsult.com; Bradley: Neurology in Clinical Practice, 5th ed ; 2000 – M&N - Goetz (review)

696
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Amyotrophic Lateral Sclerosis (ALS)

• Progressive upper and lower motor neuron disease

• Asymmetric weakness with regional spread
• Usually spares EOM and sphincters

• Average survival after symptom onset is 3-5 years (Variable)

• Pathophysiology not well understood

• No known cure
• Two FDA-approved medications: riluzole (PO) & ederavone (IV)
• Active area of genetic, pathological, and clinical research

2000 – Arch Neuro - Traynor, et al; 2006 – EJN - Zoccolella

ALS Epidemiology

• Incidence ~2-4/100,000
• Prevalence ~5/100,000

• Male predominant
• Average age of onset is 55 y.o.
– Onset before 30 years of age is uncommon

• No reliable risk factors identified

2011 – JNNP – Huisman, et al.; 2001 – JNS - Worms, et al.

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hypotheses of ALS Pathophysiology

Mitochondrial Oxidative Damage
Dysfunction

Glutamate
RNA Translation Excitotoxicity
Dysregulation Motor
Neuron

Axonal Transport
Breakdown
Inflammation-
(Protein Aggregation)
mediated damage

Loss of Neuromuscular
Junction Viability

Clinical Features of ALS

UMN
LMN
Bulbar
Non-motor

698
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

UMN Symptoms and Signs

UMN Symptoms

Weakness, Stiffness, Slow Movements, Imbalance,

Slurred Speech, Increased Gag, Excessive Yawning

UMN Signs
Hyper-reflexia, Clonus, Babinski Sign, Hoffman’s sign,
Increased Jaw Jerk, Spastic Tone, Slow RAM,
Dysarthria: Strangled/Spastic speech

LMN Symptoms and Signs

LMN Symptoms
Weakness, Muscle Thinning, Muscle Cramps, Muscle
Twitches, Slurred Speech, Nasal Regurgitation

LMN Signs
Weakness, Atrophy, Fasciculations, Depressed
Reflexes, Flaccid Muscle Tone, and
Dysarthria: Nasal speech

699
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Bulbar Symptoms

• Can occur in isolation or with limb symptoms

• If isolated it is called Progressive Bulbar Palsy
• Hypoglossal nerve typically affected first (tongue)
– Dysphagia (often liquid before solid)
– Dysarthria
– Sialorrhea (drooling)
– Nasal Regurgitation (LMN)
– Aspiration

– Exam: Tongue Atrophy, Weakness, and Fasciculations

Picture Credit: http://www.sharinginhealth.ca/conditions_and_diseases/als.html
Photo by Dr Ian Grant, Dalhousie University Faculty of Medicine, Division of Neurology

Non-Motor Manifestations
• Weight Loss
• Fatigue
• Sleep difficulty
• Shortness of breath
• Pseudobulbar Affect (PBA)
• Pain is common (Immobility, Cramps, Spasticity, HA)
• Depression affects roughly 5-10%
• Cognitive changes resembling FTD affect 5%
– Behavioral changes, mood changes, executive function
changes, and language problems

2009 – Neurology – Miller, et al; 2011 – Neurology – Weis, et al; 2008 – EMM – Guo, et al.

700
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ALS Symptom Onset

• Fatigue, weight loss and fasciculations often precede weakness

• Onset of weakness
– 1/3 bulbar, 1/3 arms, 1/3 legs
– Limbs: begins asymmetrically
– Bulbar: CN XII typically first involved

• Patients commonly present to clinic when symptoms limit daily

function
– Delay between symptom onset and diagnosis averages 12 months

2009 – OJRD – Wijesekera and Leigh (review)

ALS Diagnosis: Ruling Out Dz Mimics

• Few diseases mimic true ALS – widespread dysfunction of

UMN & LMN

• Early presentations may be regional with UMN or LMN signs

1. EMG: r/o autoimmune neuropathies (MMN), polyradic

2. MRI’s: r/o CNS demyelination, mass lesion, vascular lesion in brain
and/or spine
3. Labs: depends upon specifics

701
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ALS Diagnosis: Ruling Out Dz Mimics

• Potential labs based on clinical presentation

– Autoimmune neuropathies (eg. MMN) – GM1 Ab panel, SPEP/IFE

– MG – Anti-AChR Ab, MUSK Ab
– Autoimmune disease – ANA and subpanel (SSA/B, anti-DNA)
– Infectious disease –WNV, Polio, RPR (syphilis)
– Endocrine function – TSH and PTH
– Myopathy (IBM) – CK
– Myeloneuropathy - Vitamin B12, VLCFA (ALD/AMN), Copper and Zinc,
HIV, Heavy metals
– Genetic tests (SBMA, HSP, SMA)

ALS Treatments

• Riluzole (1994)
– RCT: Increases trach-free survival by 2-3
months. (Class I)
– AE: Nausea, Asthenia, LFT increases
– Monitor LFT’s monthly for 3 months, then
every 3 months

• Radicava (2017)
– RCT: slow disease progression by 30%
– Daily IV infusion two weeks On / Off
– Relatively safe

2007 – Cochrane Database – Miller, et al; 2009 – Neurology – Miller, et al. Akimoto M et al; Lancet
Neurology 2017

702
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Multidisciplinary care
– Improves QOL (Class II)
– Improves survival (Class II)
– More appropriate use of Resources (Level II)

• Referral to an ALS Multidisciplinary clinic should be

strongly considered (Level B rec)

2003 - JNNP – Traynor, et al. ; 2005 – Neurology – Van den berg, et al.; 2006 – JNNP – Chio, et al.;
2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Respiratory Care
– Follow PFTs regularly
• FVC or MIP (Class C)
– Non-Invasive ventilation
• Ideal time to initiate is not known
• FVC <50% or MIP <-60 is commonly used as threshold
– Cough assist and suction machines can help (Class III)
– Tracheostomy discussed as option

2009 – Neurology – Miller, et al.

703
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Respiratory Care
– Follow PFTs regularly
• FVC or MIP (Class C)
– Non-Invasive ventilation
• Ideal time to initiate is not known
• FVC <50% or MIP <-60 is commonly used as threshold
– Cough assist and suction machines can help (Class III)
– Tracheostomy discussed as option
• Weight Maintenance
– Weight loss correlates with shorter survival
– High calorie recipes and shakes
– Gastrostomy tube
• Stabilizes weight (Class II) and may prolong survival (Class II; Class B rec)
• No evidence about ideal timing
2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Fall Prevention and Mobility (Class U)

– Physical therapists can help address
– Moderate exercise and ROM
– Ankle-Foot Orthotics (AFOs), Canes, Walkers
– Home Safety Evaluation

2009 – Neurology – Miller, et al.

704
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Fall Prevention and Mobility (Class U)

– Physical therapists can help address
– Moderate exercise and ROM
– Ankle-Foot Orthotics (AFOs), Canes, Walkers
– Home Safety Evaluation

• Communication (Class U)
– Speech therapists can help address
– Augmented communication devices
• Dedicated devices
• Tablets

2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Spasticity
– Baclofen, tizanidine, dronabinol are used by some (Class U)
– Botulinum toxin is often avoided due to risk of worsening
weakness (no evidence)

2009 – Neurology – Miller, et al.

705
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Spasticity
– Baclofen, tizanidine, dronabinol are used by some (Class U)
– Botulinum toxin is often avoided due to risk of worsening
weakness (no evidence)
• Cramps
– Quinine was widely used, but FDA now prohibits
– Mexiletine is used by some physicians (Class U)

2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Spasticity
– Baclofen, tizanidine, dronabinol are used by some (Class U)
– Botulinum toxin is often avoided due to risk of worsening
weakness (no evidence)
• Cramps
– Quinine was widely used, but FDA now prohibits
– Mexiletine is used by some physicians (Class U)
• Cognitive Impairment
– Consider screening for cognitive changes (Level B rec)
– No evidence supports a given treatment

2009 – Neurology – Miller, et al.

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Pseudobulbar Affect
– Dextromethorphan/quinidine (Class I)

2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Psuedobulbar Affect
– Dextromethorphan/quinidine (Class I)
• Sialorrhea (~50% of patients)
– TCAs, glycopyrrholate (70% report improvement) (Class III)
– Botulinum toxin B is equally effective (Class I)

2009 – Neurology – Miller, et al.

707
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multidisciplinary Treatment of ALS

• Psuedobulbar Affect
– Dextromethorphan/quinidine (Class I)
• Sialorrhea (~50% of patients)
– TCAs, glycopyrrholate (70% report improvement) (Class III)
– Botulinum toxin B is equally effective (Class I)
• Pain
– PT for ROM
– TCAs, gabapentin/pregabalin, NSAIDs (Class U)

2009 – Neurology – Miller, et al.

Multidisciplinary Treatment of ALS

• Psuedobulbar Affect
– Dextromethorphan/quinidine (Class I)
• Sialorrhea (~50% of patients)
– TCAs, glycopyrrholate (70% report improvement) (Class III)
– Botulinum toxin B is equally effective (Class I)
• Pain
– PT for ROM
– TCAs, gabapentin/pregabalin, NSAIDs (Class U)
• Depression
– SSRIs and SNRIs (Class U)

2009 – Neurology – Miller, et al.

708
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thank you
Nazem Atassi MD MMSc

709
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple Sclerosis: An Overview

James Stankiewicz, M.D.

Partners MS Center
Brigham and Women’s Hospital
Harvard Medical School

Disclosures
I have received consulting fees within the past year from:
Biogen Idec, Genzyme, Celgene, Bayer, EMD Serono

710
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple Sclerosis: An Overview

• I. Epidemiology
– Vitamin D
– Epstein-Barr virus
– Genetics
– Smoking
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment

Epidemiology
• Another 1st degree FM 20% (40x pop risk)
• 25% of identical twins have MS
• 400,000 cases in US, 2.5 million worldwide
• Prevalence varies by latitude (1/1000 Boston)
• Most typical age 18-50
• Roughly 2:1 F:M
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology

Epidemiology: Vitamin D

712
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology: Vitamin D
HSPH website

A positive vitamin D trial

• All patients on IFN-beta 1b (n=66)
• Two groups: vit D3 20000 IU/week or no D
• Average vit D 25OH 54 110nmol/L after 1
year
• T1 enhancing lesions (p<0.05)
• EDSS (trend)
• timed tandem walk (trend)

Soilu-Hänninen M, Aivo J, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to
interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:565-571.

713
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sunlight and MS
• Sun exposure obtained
by questionnaire, vit D
levels checked
• summer sun
exposure led to brain
• Including vitamin D
levels did not change
associations

Zivadinov R, Treu C et al.. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J
Neurol Neurosurg Psychiatry. 2013 Feb 5.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology: EBV

715
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology: Genetics

Of the 931 case subjects in these families, 531

(57.0%) carried at least one copy of HLA-
DRB1*1501.

IL2RA, IL7RA “heritable risk factors”

Multiple Sclerosis: An Overview

• I. Epidemiology
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment

716
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathophysiology

Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?
Ann Neurol. 2009;65:239-248.

Pathophysiology: Inflammation
• Macrophage, microglia, or B cell react to myelin
present it on surface peripheral T cells activated,
express adhesion molecule cross BBB spread
inflammatory cytokines (TNF-a, IFN-gamma)
• CNS bystanders activated (epitope spreading)
• CNS cells activated include: monocytes, microglia,
dendritic cells, NK cells, B and T cells
• Microglia can release damaging NO, free radicals,
proteases
• Dysfunctional regulatory T cell pathway also likely to
contribute.

717
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathophysiology

Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?
Ann Neurol. 2009;65:239-248.

Pathophysiology: Axonal damage

• Number of transected axons: 11,236/mm3 of
tissue in active lesions (1/mm3 in controls)

Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998 Jan
29;338(5):278-85.

718
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple Sclerosis: An Overview

• I. Epidemiology
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment

719
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Out with the old…

Polman CH, Reingold SC, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005;58:840-846.

New diagnostic criteria

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

New diagnostic criteria

721
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

723
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple Sclerosis: An Overview

• I. Epidemiology
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment

MS: MRI progression

Subclinical Relapsing-Remitting Secondary Progressive
Increasing Disability/Deterioration

Time
Cognitive dysfunction
Accumulated MRI lesion burden Acute (new and Gd+) MRI activity
Level of disability
T1 BH lesion load Brain volume

Noseworthy JH, et al. N Engl J Med. 2000;343:938-952; Weinshenker BG, et al. Brain. 1989;112:133-146;
Trapp BD, et al. Curr Opin Neurol. 1999;12:295-302.

724
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

725
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Typical MRI

Neema M, Stankiewicz J, Arora A, Guss ZD, Bakshi R.MRI in multiple sclerosis: what's
inside the toolbox?Neurotherapeutics. 2007 Oct;4(4):602-17.

T1 gad enhancement

Neema M, Stankiewicz J, Arora A, Guss ZD, Bakshi R.MRI in multiple sclerosis: what's
inside the toolbox?Neurotherapeutics. 2007 Oct;4(4):602-17.

726
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Multiple Sclerosis: An Overview

• I. Epidemiology
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment

Treatment: acute
• IVMP 1g IV 3-5 days is standard
• Oral prednisone (1250mg) may be equivalent
to IV
• Consider PEX for severe relapse with poor
steroid recovery
• Another possibility: Cytoxan induction

727
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dalfampridine (Ampyra)
• Study 1 (Lancet): 35% responded to
medication, walk time improved 25%
• Study 2 (Neurology): 37% responded, walk
time improved 24%

Injectables
Medicine Admin Freq Mechanism Side effects
Glatiramer SC daily Th1->Th2 Localized site rxn
acetate shift IV injection: vasodilation
(Copaxone)
IFN Beta-1a IM weekly Th1 Th2 Flu-like sx
(Avonex) shift LFT abnl
IFN Beta-1a SC Three times thyroid abnl
(Rebif) weekly fatigue

IFN Beta-1b SC Every other

(Betaseron/Ext day
avia)

728
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Orals

Medication Dosing Approval Mechanism Tolerability Safety

Diarrhea, nausea, hair
Teriflunomide QD 9/2012 Decreases white blood cells loss Potential fetal toxicity

rare liver function abnormalities

Decreases white blood cells First dose heart slowing
Fingolimod QD 9/2010 in circulation Well tolerated macular edema
No significant adverse events in
Dimethyl Enhances NRF2 free radical Stomach upset, flushing trial
Fumarate BID 4/2013 scavenge pathway? first month Fumaderm: 4 PML

Orals: Efficacy

Efficacy*
Clinical MRI
Relapse Rate New or larger T2 New Gad Disability
Aubagio (Teriflunomide) 31% 70% 80% 30%
Gilenya (Fingolimod) 54% 74% 81% 37%
Tecfidera (Dimethyl Fumarate) 53% 85% 90% 38%

729
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tysabri MOA
• Prevents WBC from crossing into the brain

Natalizumab Efficacy vs. Placebo

68% ↓ Relapse rate

92% ↓ Gd Enhancement

730
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy
in a patient treated with natalizumab. N Engl J Med. 2005 Jul 28;353(4):375-81.

PML and our drugs

• Natalizumab
• Fingolimod
• Dimethyl fumarate
• Rituximab (ocrelizumab)

731
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ocrelizumab (Ocrevus)
• 46-percent and 47-percent reduction in the ARR compared
with interferon beta-1a over the two-year period in OPERA I
and OPERA II, respectively (p<0.0001 both).
• A 43-percent and 37-percent risk reduction in CDP sustained
for 12 weeks compared with interferon beta-1a in OPERA I
and OPERA II, respectively (p<0.5 both)
• A 94-percent and 95-percent reduction in the total number of
T1 gadolinium-enhancing lesions compared with interferon
beta-1a in OPERA I and OPERA II, respectively (p<0.01 both)
• A 77-percent and 83-percent reduction in the total number of
new and/or enlarging hyperintense T2 lesions compared with
interferon beta-1a in OPERA I and OPERA II, respectively
(p<0.01 both)

732
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ocrelizumab for PPMS

• Significantly reduced the risk of progression of
clinical disability sustained for at least 12
weeks by 24 percent compared with placebo,
as measured by the EDSS (p=0.0321).
• Ocrelizumab reduced the rate of whole brain
volume loss over 120 weeks by 17.5 percent
compared to placebo (p=0.0206).

Multiple Sclerosis: An Overview

• I. Epidemiology
– Vitamin D
– Epstein-Barr virus
– Genetics
– Smoking
• II. Pathophysiology
• III. MS diagnostic criteria
• IV. Prognosis
• V. Treatment
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Autoimmune Neurology

Henri Vaitkevicius, MD
May 15, 2018

Disclosures
• No relevant disclosures

734
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Objectives
• Case driven presentation about neuro-
immunology
• Approach to diagnosis of fulminant autoimmune
CNS disease
-encephalopathy workup
-inflammation screen
-therapy risk assessment
-therapeutic options
• Therapy focused organization of
neuroimmunologic disease
• Introduction to iatrogenic immunity

Effective interventional Neurology

735
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case #1: Toxic metabolic …

• 52 year old lawyer
• 5 weeks ago: difficulties at work
• 3 weeks ago: headaches, paranoia
• 1 week ago: sleepy and withdrawn
• Family brought in after she was found
urinating in the corner of the room.

Exam
• Disinhibited
• Diffuse myoclonus
• MRI normal

736
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Workup:
This is likely “not” neurologic ….
Screening labs
CBC with differential* Toxicology screen
Electrolytes, glucose* Urinalysis and culture
BUN/Cr* Blood culture
Liver function tests* Serologies for syphilis
Ammonia SPEP with immunofixation,
B12 vitamin serum-free light chains
Coagulation panel* Blood flow cytometry
Thyroid function Beta 2 microglobulin
Cortisol

Workup:
EEG is not just for seizures ….

EEG finding Diagnosis

Extreme delta brush Anti-NMDA receptor encephalitis
Periodic synchronous bi- or triphasic CJD
sharp wave complexes (PSWC)
Periodic temporal discharges HSV encephalitis
Diffuse slowing with triphasic waves Metabolic encephalopathy

737
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Workup:
Encephalopathy and EEG

Courtesy of Dr. Jay Pathmanathan

EEG delta brush

738
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Labs
12
• Basics: 4.5
34
220

• CSF:
-Pr: 50, Glu: 60, WBC: 3, RBC: 12
• Anti-TPO: 864
• 14-3-3 negative
• Imaging normal

Walter Russell Brain

(Lord Brain)
• Steroid responsive encephalopathy
• 49 year old man with thyroid disease
• 1966

J Med Biogr. 2009 Feb;17(1):30-4.

739
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment
• Steroids with slow taper
• Improved and went back to work in 4 weeks
• Recurred 12 months later after steroids were
tapered to prednisone 10mg QD

Therapy:
Steroids
Relative potency
• Genomic Steroid
Glucose Immune Salt
t1/2
hours
• Non-genomic
Hydrocortisone 20 1 1 1.5
-cytokines
Prednisone 5 4 0.8 1
-Leukocyte adhesion
Methylprednisolone 4 5 0.5 3

Dexamethasone 0.75 30 0 3.5

Fludrocortisone 0 15 150 4

Note: Methylpred 1gm = Dex?

Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis, Facts and Comparisons, Inc.:122-128, 1997

740
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Therapy:
Steroids
Relative potency
• Genomic Steroid
Glucose Immune Salt
t1/2
hours
• Non-genomic
Hydrocortisone 20 1 1 1.5
-cytokines
Prednisone 5 4 0.8 1
-Leukocyte adhesion
Methylprednisolone 4 5 0.5 3

Dexamethasone 0.75 30 0 3.5

Fludrocortisone 0 15 150 4

Note: Methylpred 1gm = Dex 190mg = Prednisone 1.3g m

Adrenal Cortical Steroids. In Drug Facts and Comparisons. 5th ed. St. Louis, Facts and Comparisons, Inc.:122-128, 1997

Case #2: Beyond steroids, surface antigen

• 30 year old visiting Florida

-1 week: headaches, back pain, confusion
Flu?
-2 days: psychosis, paranoia
Stress? Psychiatry?
-Presented with ”convulsions”
-Autonomic instability
Seizures? EEE in the area?

741
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical exam

Ann Neurol 2009;66:11–18

Movement Disorders Vol. 23, No. 9, 2008, pp. 1256–1261

Workup:
Clinical “slam dunks”
Classic syndromes Possible diagnosis
Paraneoplastic (including anti-NMDA
Limbic encephalopathy receptor antibodies), HSV, HHV6,
syphilis
Faciobrachial dystonic seizures Anti-LGI1 antibodies
Motor cerebellar syndrome (subacute
cerebellar degeneration) Paraneoplastic, parainfectious
Opsoclonus-myoclonus
Optic neuritis, myelitis NMO, MS
Miller-Fisher syndrome Anti-GQ1b antibodies
Anti-GAD, anti-GABAa,
Stiff-person syndrome
anti-amphiphysin antibodies
Morvan’s syndrome (neuromyotonia, limbic
encephalitis/encephalopathy, and autonomic Anti-Caspr2 antibodies
dysfunction)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Workup:
Standard inflammation screen

Markers of inflammation and/or autoimmunity

ESR* Myositis-specific antibodies
CRP* Complement levels
ANA* Cryoglobulins
Anti-dsDNA* IgG4 level
Extractable nuclear antigens (ENA) – anti-Ro/La * Anti-TPO antibodies
ANCA* ACE
RF, ACPA (anti-citrullinated peptide antibodies) HLA-B51
Antiphospholipid antibodies Anti-NMO antibodies
Paraneoplastic antibodies

Workup:
We always image …
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Labs
10.7
• Basics: 9.0
33.1
213

• CSF:
-Pr: 26, Glu: 53, WBC: 69 (94% L), RBC: 13, no bands
• ESR 78; CRP:1.3

• Young woman with subacute psychosis,

seizures, coma and inflammatory CSF …
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• Young woman with subacute psychosis,

seizures, coma and inflammatory CSF …

= ovarian US

745
Causes of death …
• NMDA Ab test -> 2 weeks
• Medical complications
-Autonomic instability
-Airway complications
-Pulmonary embolus
-Medication side effects

Treatment
• Risks/benefits
• Oophorectomy
• Solumedrol 1gm QD x 5 days
• IVIG 2g/kg over 5 days

746
 Outcome
• Back to baseline

Immunoglobulins
• Direct interactions
-Fc/Fab (autoantibodies)
**lots/brands
-TCR/HLA/CD5
-Passive immunization
• Compliment
-↓ C1q, C4
• Cytokine modulation
-↓ TNFα, IL-1β
• Expression modulation
-↓ ICAM-1 lymph,↑FcγRIIB
• IgG downregulation

J Neuroimmunol. 2011 Feb;231(1-2):61-9. doi: 10.1016/j.jneuroim.2010.09.015

N Engl J Med 2012;367:2015-25

747
 IVIG use
• IgG1,2,3,4 (1000 donors) • Systemic reactions(<15%)
• 2g/kg divided over 2-5 days -rate dependent
-IBW • No cases of Hep B/C, HIV, CJD
• IgA? • Side effects
• Colloid -Headache 48%
• Cost ($100/g) -Meningismus 11% fever
-Renal failure 6.7%
-Embolism
-Anemia

Transfusion Medicine, 2010, 20, 403–408

Plasma exchange

• Offending factors
-Immunoglobulins
-Proliferation factors
-TNF/compliment
• Effectiveness
-Vascular space
-↓40-60% after 2 sessions
• Short Term
• Rebound? - feedback

J Neuroimmunol. 2011 Feb;231(1-2):61-9. doi: 10.1016/j.jneuroim.2010.09.015

 Complications
• Infections (33.7%) • Large catheter
• Hypotension (18.8%) -13.5 Fr (16cm/19.5cm/24cm)
• Bleeding • Flow problems
-Catheter rotation
• Hypocalcemia -Reversal of flow

Case #3: getting fancy …

• 53 y.o. man with cough, memory problems
and ”functional” gait disorder
-4 months of fevers, sweats and weight loss
-Inflammatory CSF
-ACE normal and B2-microglobulin high

749
What is inflammatory CSF?
CSF study Result
Glucose normal
Protein elevated
WBCs 5-100
IgG index >0.66 (laboratory dependent)

Oligoclonal bands >1 (laboratory dependent)

Paraneoplastic antibodies positive

HSV1/HSV2 PCR negative
VZV PCR, IgM and IgG negative

Next-generation sequencing of
negative
microbial DNA
Cytology normal
Flow cytometry normal
β2 microglobulin normal
IgH gene rearrangement absent

Case #3: getting fancy …

• 53 y.o. man with cough, memory problems
and ”functional” gait disorder
-4 months of fevers, sweats and weight loss
-Inflammatory CSF
-ACE normal and B2-microglobulin high
-Biopsy
Risk assessment
Infection screens Other labs
Hepatitis B screening (HBsAg, anti-HBs, anti-HBc)* CBC*
Hepatitis C screening (anti-HCV)* BUN/Cr*
HIV antibodies*, PCR; T cell CD4 count LFTs*
TB testing (PPD/IGRA)* hCG
JC virus antibodies Vitamin D
Strongyloides stercoralis, serology Bone densitometry
Trypanosoma cruzi, serology TMPT genotype
CXR
Ophthalmologic evaluation
Immunoglobulin levels (IgM, IgG, IgA)
*Obtain in all patients
IGRA, interferon-gamma-release assay; PPD, purified protein derivative; TMPT, 5-thiopurine-
methyltransferase

JC virus index

ANN NEUROL 2014;76:802–812

751
 Outcome
• Started on steroids
• Back to baseline
• Maintained on Infliximab

Acute Toolbox
-Steroids
-Dex
-Solumedrol
-Cyclophosphamide
-Methotrexate
-IVIG
-Plasma Exchange
-Biologicals
Rituximab
IL-6
-Tociluzimab
TNF-α
-infliximab (Remicade)
-etanercept (Enbrel)
-certolizumab (Cimzia)
-golimumab (Simponi)
-adalimumab (Humira)

752
 More practical way to diagnose
• Diagnosis driven intervention
• Use existing tools
• Do we have to name the disease?
• Address pathophysiology of rare diseases

Disease vs. Mechanism

• Disease based
Neurologic
AIDP, CIDP
Vasculitis
MG
MS
Limbic encephalitis
ADEM
Rheumatologic
Lupus nephritis
Wegner’s
RA
Sarcoid

753
 Disease vs. Mechanism
• Disease based • Mechanism based
Neurologic T cell
AIDP, CIDP MS, ADEM
Vasculitis CIDP
MG Vasculitis
MS B cell
Limbic encephalitis Paraneoplastic
ADEM AIDP, CIDP
Rheumatologic MG
Lupus nephritis Granulomatous
Wegner’s Vasculitis
RA Sarcoid
Sarcoid

Immune system
• Innate
• Adaptive
-T-cell
Tc (CD8) - intracellular
Th (CD4) - soluble
1-proinflammatory
2-humoral modulation
-B-cell (humoral)
Bradley's Neurology in Clinical Practice, Robert B. Daroff MD, Gerald M Fenichel MD, Joseph
Jankovic MD, John C Mazziotta MD PhD Chapter 41
 Paraneoplasia
• Target Antigen
-Intracellular vs. extracellular
• Where is malignancy?

Semin Neurol. 2011 Apr;31(2):144-57 European Journal of Neurology 2010

Paraneoplasia
• Target Antigen
-Intracellular vs. extracellular
• Where is malignancy?

NMDA Teratoma
AMPAR Thymus, lung
VGKC (Lgl1 and CASPR2) Lung, thymus, thyroid
CV2 (CRMP) Lung, thymus
GAD-65 Thymus
Amphiphysin Breast, lung
GABA Lung
Hu (ANNA1) Lung
Ri (ANNA2) Lung, breast
PCA-2 Lung
Ma Testicular, Lung
α3-AChR Breast, prostate, lung

Semin Neurol. 2011 Apr;31(2):144-57 European Journal of Neurology 2010

755
 Most important diagnostic studies …
Diagnostics Finding Potential diagnosis
CT chest and abdomen/pelvis Mass Malignancy
Malignancy,
Whole body FDG-PET/CT Areas of FDG-avidity
inflammation
Anti-NMDA receptor
Transvaginal US Ovarian mass
encephalitis
Branch retinal artery occlusions,
hyperfluorescence of the vessel Susac syndrome
wall

Sarcoidosis, Behçet
Dilated funduscopic examination
Uveitis disease, GPA, other
and fluorescein angiography
rheumatologic conditions

Intraocular-central
Vitreous opacities, sub-retinal
nervous system
pigment epithelial infiltrates
lymphoma
Labial salivary gland biopsy Focal lymphocytic sialadenitis Sjögren syndrome
Temporal artery biopsy Granulomatous inflammation Giant cell arteritis

New Mechanisms: checkpoints

T=0

T = 5 wks

FLAIR T1 Post FLAIR T1 Post

756
 Here to stay
• 40 year old with rapidly progressive and therapy
unresponsive DLBCL
• Received CD19 targeted CARTs

30 days

Iatrogenic autoimmunity 101

• T cell understanding of self

-CTLA-4:CD80/86 (central)
+ Abatacept, belatacept
- Ipilimumab, tremelimumab
-PD1:PDL1 (peripheral)
-PD1 nivolumab, pembrozilumab, BGB-A317
-L1 avelumab, durvalumab

Nature Reviews Clinical Oncology 13, 473–486 (2016)

757
 Iatrogenic autoimmunity 101

• Chimeric T-cells
-Target
-Co-stimulation
activation
expansion
memory/persistence

Nature Reviews Clinical Oncology 13, 473–486 (2016)

Iatrogenic autoimmunity 101

• Understanding Industry
-Kite (10B)/Gilead CD19/20/30/33 Heme
BCMA Myeloma
NKG2D AML/MM
Folate R Ovary
CAIX RCC
-Juno (10B)/Celgene CD44 Ovary
CEA Breast/colorectal
-Bluebird EGP-2/40 Multiple
-Novartis Erb-B2 Prostate/breast
FBP Ovarian
GD2 Neuroblastoma
GD3 Melanoma
Her2 Glioma/medulloblastoma
IL-13R Glioma

Nature Reviews Clinical Oncology 13, 473–486 (2016)

758
 Neurologic progression
Rapid Classic Prolonged
<5 days Starts day 4-14 Day 7-21 days
Headache Tremor Tremor
Somnolence Rigors Asterixis
Death Encephalopathy/agitation Delirium
Disorientation
Paraphasic errors Symptoms Frequency
Mutism CRS 94%
Abulia Headache 47%
Poor fluency Encephalopathy 20-35%
Tremor 29%
Aphasia 18%
Agitation 9%

N Engl J Med 2017;377:2531-44

Blood. 2014;124(2):188-195.

Why is it neurologist’s problem?

• 22 yo with ALL on experimental infusion
HA and Sleepy
Coma
Brain death

T=0

759
 Why is it neurologist’s problem?
• 22 yo with ALL on experimental infusion
HA and Sleepy
Coma
Brain death

T=0 T = 4h

Why is it neurologist’s problem?

• 22 yo with ALL on experimental infusion
HA and Sleepy
Coma
Brain death

T=0 T = 4h T = 24h

760
 Systemic toxicity
• Cytokine storms (0-48 hours)
-Distribu[ve shock (warm, ↑HR, ↓BP,)
-Leaky vessels

Basics of grading
Grade Symptoms
1 Fever, nausea
2 O2 or low pressors
3 O2 > 40% or high pressors
4 About to die
5 Dead

Neurological toxicity

• CTCAE 4.03

Basics of grading
Grade Symptoms
1 Mild
2 Severe
3 About to loose airway
4 About to die
5 Dead
Mechanism based CNS Disorders
Granulomatous Autoinflammatory
Path T-cell mediated B-cell mediated NOS Iatrogenic
disorders disorders
Checkpoint
Multiple sclerosis SLE Sarcoidosis Behçet's disease Susac disease
inhibitors
Antiphospholipid Transverse
ADEM Giant cell arteritis CAR-T
syndrome myelitis NOS
NMO (anti-AQP4, anti- Granulomatosis with
PACNS (PCNSV)
MOG antibodies) polyangiitis
Aβ-related angiitis Miller-Fisher syndrome
Disorders

IgG4-RD Bickerstaff encephalitis

Sjögren's syndrome SREAT
Antibodies against cell-
Antibodies against surface synaptic
intracellular antigens: receptors (NMDA, LGl1,
Hu, Ma2, GAD, CV2, Ri, CASPR2, DPPX, AMPA,
Yo, Amphiphysin, GAD GABA, mGluR5, D2
receptor)
CLIPPERS Antiphospholipids
ADEM: Acute Disseminated Encephalomyelitis; PACNS: Primary Angiitis of the Central Nervous System; SLE: Systemic Lupus Erythematosus;
NMO: Neuromyelitis optica; SREAT: Steroid responsive encephalopathy associated with autoimmune thyroiditis; GCA: Giant Cell Arteritis;
CLIPPERS: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

Mechanism Based Treatments

Granulomatous Autoinflammatory
Path T-cell mediated B-cell mediated NOS Iatrogenic
disorders disorders
Checkpoint
Multiple sclerosis SLE Sarcoidosis Behçet's disease Susac disease
inhibitors
Antiphospholipid Transverse
ADEM Giant cell arteritis CAR-T
syndrome myelitis NOS
NMO (anti-AQP4, anti- Granulomatosis with
PACNS (PCNSV)
MOG antibodies) polyangiitis
Aβ-related angiitis Miller-Fisher syndrome
Disorders

IgG4-RD Bickerstaff encephalitis

Sjögren's syndrome SREAT
Antibodies against cell-
Antibodies against surface synaptic
intracellular antigens: receptors (NMDA, LGl1,
Hu, Ma2, GAD, CV2, Ri, CASPR2, DPPX, AMPA,
Yo, Amphiphysin, GAD GABA, mGluR5, D2
receptor)
CLIPPERS Antiphospholipids
Anti-IL-6R
Steroids Steroids Steroids Steroids Steroids
(tocilizumab),
TNF-alpha inhibitors anti-IL6
Cyclophospha
Cyclophosphamide Plasma exchange (GCA does not TNF-alpha inhibitors (siltuximab)
mide
Treatments

respond)
Anti-CD20
Anti-CD20 targeting Anti-CD20 targeting Steroids
IVIG targeting
therapies therapies
therapies
Anti-CD20 targeting
Natalizumab Cyclophosphamide ATG
therapies
Anti-C5 (eculizumab) Anti-IL-6R (tocilizumab
Anti-IL-6R (tocilizumab)
ADEM: Acute Disseminated Encephalomyelitis; PACNS: Primary Angiitis of the Central Nervous System; SLE: Systemic Lupus Erythematosus;
NMO: Neuromyelitis optica; SREAT: Steroid responsive encephalopathy associated with autoimmune thyroiditis; GCA: Giant Cell Arteritis;
CLIPPERS: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

762
New approach ..
• Goal
-Identify disease mechanism
-Initiate early treatment
-Do not focus on pending Ab
• Rare diseases
-May become more common

Thank You

Special thanks to Dr. Ivana Vodopivec, Dr. Daniel

Rubin and Dr. Ayush Batra who where instrumental in
making this lecture

763
First pass screen for encephalopathy

Screening labs
CBC with differential* Toxicology screen
Electrolytes, glucose* Urinalysis and culture
BUN/Cr* Blood culture
Liver function tests* Serologies for syphilis
Ammonia SPEP with immunofixation,
B12 vitamin serum-free light chains
Coagulation panel* Blood flow cytometry
Thyroid function Beta 2 microglobulin
Cortisol

First pass inflammation screen

Markers of inflammation and/or autoimmunity

ESR* Myositis-specific antibodies
CRP* Complement levels
ANA* Cryoglobulins
Anti-dsDNA* IgG4 level
Extractable nuclear antigens (ENA) – anti-Ro/La * Anti-TPO antibodies
ANCA* ACE
RF, ACPA (anti-citrullinated peptide antibodies) HLA-B51
Antiphospholipid antibodies Anti-NMO antibodies
Paraneoplastic antibodies

764
Clinical “slam dunks”

Classic syndromes Possible diagnosis

Paraneoplastic (including anti-NMDA
Limbic encephalopathy receptor antibodies), HSV, HHV6,
syphilis
Faciobrachial dystonic seizures Anti-LGI1 antibodies
Motor cerebellar syndrome (subacute
cerebellar degeneration) Paraneoplastic, parainfectious
Opsoclonus-myoclonus
Optic neuritis, myelitis NMO, MS
Miller-Fisher syndrome Anti-GQ1b antibodies
Anti-GAD, anti-GABAa,
Stiff-person syndrome
anti-amphiphysin antibodies
Morvan’s syndrome (neuromyotonia, limbic
encephalitis/encephalopathy, and autonomic Anti-Caspr2 antibodies
dysfunction)

Imaging and EEG

Imaging Value
MRI/MRA with contrast May fit a pattern for diagnosis
FDG PET Brain Functional image
(inflammation/seizure)
CT/CTA Vascular mimicker/vasculitis
Conventional angiogram Vascular mimicker/vasculitis

EEG finding Diagnosis

Extreme delta brush Anti-NMDA receptor encephalitis
Periodic synchronous bi- or triphasic CJD
sharp wave complexes (PSWC)
Periodic temporal discharges HSV encephalitis
Diffuse slowing with triphasic waves Metabolic encephalopathy

765
What is inflammatory CSF?
CSF study Result
Glucose normal
Protein elevated
WBCs 5-100
IgG index >0.66 (laboratory dependent)

Oligoclonal bands >1 (laboratory dependent)

Paraneoplastic antibodies positive

HSV1/HSV2 PCR negative
VZV PCR, IgM and IgG negative

Next-generation sequencing of
negative
microbial DNA
Cytology normal
Flow cytometry normal
β2 microglobulin normal
IgH gene rearrangement absent

How to look for malignancy

Diagnostics Finding Potential diagnosis
CT chest and abdomen/pelvis Mass Malignancy
Malignancy,
Whole body FDG-PET/CT Areas of FDG-avidity
inflammation
Anti-NMDA receptor
Transvaginal US Ovarian mass
encephalitis
Branch retinal artery occlusions,
hyperfluorescence of the vessel Susac syndrome
wall

Sarcoidosis, Behçet
Dilated funduscopic examination
Uveitis disease, GPA, other
and fluorescein angiography
rheumatologic conditions

Intraocular-central
Vitreous opacities, sub-retinal
nervous system
pigment epithelial infiltrates
lymphoma
Labial salivary gland biopsy Focal lymphocytic sialadenitis Sjögren syndrome
Temporal artery biopsy Granulomatous inflammation Giant cell arteritis
 Mechanism Based Treatments
Granulomatous Autoinflammatory
Path T-cell mediated B-cell mediated NOS Iatrogenic
disorders disorders
Checkpoint
Multiple sclerosis SLE Sarcoidosis Behçet's disease Susac disease
inhibitors
Antiphospholipid Transverse
ADEM Giant cell arteritis CAR-T
syndrome myelitis NOS
NMO (anti-AQP4, anti- Granulomatosis with
PACNS (PCNSV)
MOG antibodies) polyangiitis
Aβ-related angiitis Miller-Fisher syndrome
Disorders

IgG4-RD Bickerstaff encephalitis

Sjögren's syndrome SREAT
Antibodies against cell-
Antibodies against surface synaptic
intracellular antigens: receptors (NMDA, LGl1,
Hu, Ma2, GAD, CV2, Ri, CASPR2, DPPX, AMPA,
Yo, Amphiphysin, GAD GABA, mGluR5, D2
receptor)
CLIPPERS Antiphospholipids
Anti-IL-6R
Steroids Steroids Steroids Steroids Steroids
(tocilizumab),
TNF-alpha inhibitors anti-IL6
Cyclophospha
Cyclophosphamide Plasma exchange (GCA does not TNF-alpha inhibitors (siltuximab)
mide
Treatments

respond)
Anti-CD20
Anti-CD20 targeting Anti-CD20 targeting Steroids
IVIG targeting
therapies therapies
therapies
Anti-CD20 targeting
Natalizumab Cyclophosphamide ATG
therapies
Anti-C5 (eculizumab) Anti-IL-6R tocilizumab
Anti-IL-6R (tocilizumab)
ADEM: Acute Disseminated Encephalomyelitis; PACNS: Primary Angiitis of the Central Nervous System; SLE: Systemic Lupus Erythematosus;
NMO: Neuromyelitis optica; SREAT: Steroid responsive encephalopathy associated with autoimmune thyroiditis; GCA: Giant Cell Arteritis;
CLIPPERS: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

Risk assessment
Infection screens Other labs
Hepatitis B screening (HBsAg, anti-HBs, anti-HBc)* CBC*
Hepatitis C screening (anti-HCV)* BUN/Cr*
HIV antibodies*, PCR; T cell CD4 count LFTs*
TB testing (PPD/IGRA)* hCG
JC virus antibodies Vitamin D
Strongyloides stercoralis, serology Bone densitometry
Trypanosoma cruzi, serology TMPT genotype
CXR
Ophthalmologic evaluation
Immunoglobulin levels (IgM, IgG, IgA)
*Obtain in all patients
IGRA, interferon-gamma-release assay; PPD, purified protein derivative; TMPT, 5-thiopurine-
methyltransferase

767
 Therapy summaries 1
Immunotherapy
Monitoring
(Mechanisms of Dosing Major Risks Prophylaxis
Parameters
Action)
Hyperglycemia,
PPPI,
psychiatric events, Lipid profile
Glucocorticoids Methylprednisolone 1g IV QD for 3-5 Vitamin D +
infections, adrenal Ophthalmologic
(genomic effects, non- days calcium ±
suppression, evaluation
genomic effects: leukocyte Prednisone start 1mg/kg/day (60-80 bisphosphonates
osteoporosis, Bone
adhesion and cytokine mg QD) and alternatives
osteonecrosis, densitometry Q12
modulation) Dexamethasone 1-40mg Q6H TMP/SMX/atovaq
myopathy, glaucoma, months
uone/dapsone
cataracts
Intravenous Hypersensitivity
immunoglobulin reactions,
VS during infusion
(auto-antibodies, passive thromboembolic
Acetaminophen BUN/Cr within 10
immunization, 2g/kg over 3-5 days events, renal failure,
Diphenhydramine d after initiation
complement down aseptic meningitis,
of IVIg treatment
regulation, cytokine hemolytic anemia,
modulation) neutropenia
IV access
Plasma exchange complications;
1-1.5 plasma volumes, typically 5
(removal of pathogenic hypocalcemia, Calcium CBC, electrolytes,
exchanges allowing for vascular
antibodies from vascular hypotension, carbonate, fluids, Ig levels,
compartment equilibration between
compartment, cytokine arrhythmia, albumin, FFP coagulation panel
treatments (QOD)
modulation) coagulopathy;
medication removal

Therapy summaries 2
Immunotherapy
Monitoring
(Mechanisms of Dosing Major Risks Prophylaxis
Parameters
Action)
Aggressive IVF CBC w/ diff on day
Cytopenias,
Mesna 7, 10, 14, 27-28
Partners MS: 800mg/m2 IV Q4 weeks infections,
Cyclophosphamide Antiemetics after IV, Q2 wks
x6 hemorrhagic cystitis,
(DNA alkylation, Th1 TMP/SMX/atovaq while on PO
EULAR: 15mg/kg IV Q2 weeks x 3 malignancies
suppressor and Th2 uone/dapsone BUN/Cr Q2 wks
SLE NIH: 0.5-1g/m2 Q4 weeks x 6 (particularly bladder
enhancer) Fertility UA Q3-6 mos
EURO lupus: 500mg IV Q2 weeks x 6 cancer), gonadal
preservation (continue after
toxicity
measures discontinuation)
HBV reactivation VS ± telemetry
Hypersensitivity
prophylaxis during infusion
Anti-CD20 antibodies reactions,
Rituximab 1000mg Q2 weeks x 2 Acetaminophen CBC w/ diff Q2-4
(B-cell and plasmablast hypogammaglobuline
Rituximab 375 mg/m2 Qweek x 4 Diphenhydramine mos, CD19/20
depletion) mia, CVID, infections,
Methylprednisolo counts
PML
ne IgG/IgM levels
Hypersensitivity
Treat latent TB
reactions,
HBV reactivation
TNF-alpha inhibitors hepatotoxicity, CNS VS during infusion
prophylaxis
(inhibition of macrophage Infliximab IV 3-10mg/kg Q2 weeks and PNS CBC w/ diff Q≥6
Consider
activation via decrease in Adalimumab SC 40mg Q2 weeks demyelination, mos
TMP/SMX/atovaq
TNFR1/2 stimulation) including optic LFTs Q≥6 mos
uone/dapsone
neuritis, TB
Acetaminophen
reactivation
 Therapy summaries 3
Immunotherapy
Monitoring
(Mechanisms of Dosing Major Risks Prophylaxis
Parameters
Action)
TMPT genotype
Hepatotoxicity, pre-treatment
Azathioprine
Start 1 mg/kg/d (50-100 mg QD), leukopenia and other Q1-2 wk while
(DNA intercalation,
then increase by 50 mg/w to 2-3 cytopenias, None adjusting dose,
inhibition of purine
mg/kg/d infections, GI toxicity then Q4-12 wks:
synthesis)
(nausea, diarrhea) CBC w/ diff
LFTs
CXR pre-
Nausea, diarrhea,
PO: start 7.5 mg Qweek, then treatment
mucositis,
Methotrexate increase to 15-25 mg Qweek Folic acid QD or CBC w/ diff Q2-4
cytopenias,
(inhibition of thymidylate SC: start 7.5 mg Qweek, then folinic acid QW wks for first 12
hepatotoxicity,
and purine synthesis) increase to 10-25 mg Qweek Sun protection wks, then Q8-12
(hypersensitivity
" wks
pneumonitis)
LFTs Q8 wks
Nausea, diarrhea,
abd pain, Q1-2 wk for first
hepatotoxicity, 12 wks, then Q6-
Mycophenolate mofetil Start 250 or 500 mg BID, then
cytopenias, HTN, 8 wks:
(inhibition of guanosine increase by 500 mg/d every 1-2 Sun protection
nephrotoxicity, CBC w/ diff
synthesis) weeks to 1000-1500 mg BID
cough, dyspnea, BUN/Cr
infections, HA, LFTs
tremor

Therapy summaries 4
Immunotherapy
Monitoring
(Mechanisms of Dosing Major Risks Prophylaxis
Parameters
Action)
Cr, CBC, LDH up to
Eculizumab Eculizumab 400-1200mg Hypersensitivity Acetaminophen
12wks after last
(anti-C5 antibody) IV Q2 weeks reactions, HTN, anemia Diphenhydramine
treatment
Hypersensitivity
reactions, GI perforation,
Tocilizumab Tocilizumab 8mg/kg IV hepatotoxicity, Acetaminophen
CBC, LFTs Q4 weeks
(anti-IL-6R antibody) Q4 weeks neutropenia, Diphenhydramine
thrombocytopenia, TB
reactivation
VS during infusion
CBC, LFTs Q6 mos,
Natalizumab
PML, hypersensitivity Acetaminophen anti-JCV antibodies in
(anti-α4-integrin 300mg IV Q4 weeks
reactions Diphenhydramine seronegative patients
antibody)
Q6 mos
 Cyclophosphamide
• TH1 suppressor
• TH2 enhancer
• Suppression of IL 12
• Alkylating agent->apoptosis
• phosphoramide mustard
-Aldehyde dehydrogenase
-hematopoietic cells, hepatocytes, GI
• Liquid tumors

Lancet 2005; 365: 1647–56

How to use cyclophosphamide

Complications Thoughts
• Hemorrhagic cystitis • Pulse dose
• Infertility • Total exposure
-100% > 30y • Urgency of treatment
-50% >20y • Hydration
-15% <20y • Bladder clearance
• Leukemia • Expectations/consent
• Nausea • Prophylaxis (TMP/SMX ss QD)
• Alopecia • P450 inducers
• Infection • Succinylcholine

Ann Rheum Dis 2010;69:61–64.

770
 Data from Lupus nephritis
• Cyclophosphamide better than steroids
-0.5-1g/m2 Q1m x 6 ->2 year quarterly
Cyclophosphamide better than Azathioprine +
steroids
- 750mg/m2 x6m
• Oral cyclophosphamide
-60-80mg/d x 8 weeks
• Eurolupus:
cyclophosphamide 500mg Q2wks x 6 as good as
0.5mg/m2 IV pulses

Ann Rheum Dis 2010;69:61–64.

Protocol basics
• Pulse induction protocol
-Antiemetic Q4-6h
-Cyclophosphamide 600 mg/m2 day: 1,2,4,6, 8
-Cyclophosphamide 500-1500mg/m2
-Solumedrol 1gm on day 2, 3, 4, 5, 6, 7, 8
• Pulse
• Mesna (1:1) 0h, 4h, 8h
• Life time dose 80-100g
 Case #X: 62 Year Old Man
• 3 week course of progressive ataxia
• 2 weeks of diplopia
• On exam “dancing eyes and dancing feet”

Body PET
Mediastinal mass

Rituximab
• Human/murine (CD20)
• Mechanism:
-CD27 memory B cell
-Decrease TNF-alpha
• Watch out
-Hepatitis
-Antihypertensives
-JC virus
-live vaccines
-CVID

J Neuroimmunol. 2006 Nov;180(1-2):63-70. Epub 2006 Aug 14.

 Rituximab: use
• 1000 mg infusion Q2 weeks x 2 over 4-5h
-alternative dose 375mg/m2
-Antihistamines/tylenol/steroids
-flow for CD20
• 6 months?

Arch Neurol, 62(10), 1641-2

Neurology, 64(7), 1270-2

Case 4: 52 Year Old Woman

• 1 week of difficulties with bladder control and

hiccups
• Woke up with painful loss of vision OS

774
 Spine MRI

Brain MRI

775
 Are there limits?

Autologous Hematopoietic Stem Cell

Transplant

Neurology® 2015;84:981–988
Ann Hematol (2015) 94:1149–1157
JAMA. 2015;313(3):275-284

776
Case #2: Beyond steroids …
• 27 year old who cannot walk
• 2 weeks: numbness of lower extremities
• 1 week: weakness
• Presented with paraplegia and urinary
incontinence

Labs
12.7
• Basics: 19.8
37
427

• CSF:
-Pr: 28, Glu: 97, WBC: 14 (87% L), RBC: 11, no bands
-Polyclonal: 20% B cells, CD4>CD8
• ESR 22; CRP:3.9
Workup: Imaging

T2 T1 T2

STIR T1 post T1 post

Course
• Extensive workup … .
• No response to steroids
• Clinically worse with steroid taper
• Now quadriplegic

778
Not Therapy:

Now what ???

• Did not respond to IVIG
• Cyclophosphamide induction
• Azathioprine maintenance
• Transition to Rituximab

779
 Now what ???
• Did not respond to IVIG
• Cyclophosphamide induction
• Azathioprine maintenance
• Transition to Rituximab

• Symptom free and independent

Now what ???

• Did not respond to IVIG Oncology
• Cyclophosphamide induction
• Azathioprine maintanence Rheumatology

• Transition to Rituximab

• Symptom free and independent

Extreme delta brush

Schmitt S E et al. Neurology 2012;79:1094-1100

Case #4: Sit at the table …

• 29 year old woman

• 2 days of nausea, vomiting and hiccups.
• 1 week of gait problems and encephalopathy
• Coma
• Mother died from breast CA
-routine screening was concerning
-Body PET was just performed
• MRI not possible, CT OK

782
12/4/2014
 Data
• CSF:
-Pr: 30, Glu: 66, WBC: 49, RBC: 3, 3 bands
-Flow and cytology negative

12/4/2014

12/11/2014

784
 PE vs. IVIG vs. PE+IVIG (383)
PE: 5x (50 mL/kg) IVIG: 5x (0.4 g/kg) PE + IVIG

Patients 121 130 128

∆ 4wks 0.9 0.8 1.1*
vented 28 29 21
T to D/C 63 53 51
T to work 290 371 281
Deaths 5 6 8

• Disability (2-48 wks)

-0: normal
-1: able to run
-2: 5m walk
-3: 5m walk with assist
-4: unable to stand
-5: ventilator
-6: death
Lancet 1997; 349: 225–30

PE in MG population
IVIG
PE

Artif Organs. 2001 Dec;25(12):967-73.

785
 Clues in CSF?

CSF Constituents Differential diagnosis

Immunoglobulin generating CNS focused autoimmune diseases (MS,
ADEM, neurosarcoidosis, Behҫet disease, SLE, Sjögren syndrome,
paraneoplastic or autoimmune disorders caused by antineuronal
Oligoclonal bands > 1
antibodies)
CNS infections (neurosyphilis, neuroborreliosis, HIV encephalitis)
Lymphoma
IgG index = [CSF IgG / CSF
albumin] / [serum IgG / serum
Immunoglobulin targeting antigens withing CNS
albumin] >0.66 (laboratory-
dependent value)
Autoantibodies May have increased sensitivity

53 y.o. man with cough, memory

problems and ”functional” gait
disorder
-4 months of fevers, sweats and weight loss
-s/p gastric sleeve surgery and low Zn
-Inflammatory CSF
-Despite ACE being normal and B2-microglobulin being
FDG avid
high biopsy demonstrates non-caseating granulomas
Non enhancing nodes and cord
T2 changes

786
 PE number of exchanges needed?
• Demographics (556)
-Mild -walk (45/46)
Low/high Mild Mod Severe
*Age: 40 1y full 60%/77% 48%/64% 57%/53%
* 0 vs. 2 Vent. days 37%/15% 43%/34%
-Mod. –stand (149/155) t to D/C 18 / 13 26 / 21 50 / 44
*Age: 46 ↓ SBP 17%/ 9% 27%/44% 26%/46%
* 2 vs. 4
-Severe -Vent. (81/80)
*Age: 50
* 4 vs. 6
Annals of Neurology; 41(3); 1997
Am J Kidney Dis. 2008 Dec;52(6):1180-96.

Case #5: Uncharted waters …

• 57 year old woman
• Word finding difficulties

787
6 months later …

9 months later …
PD-L1 et al

But ….

789
 GBM
Before After Rx

T1 Post

FLAIR

790
 Evaluation of Cognitive
Impairment
Kirk R. Daffner, M.D.

J. David and Virginia Wimberly Professor of Neurology

Harvard Medical School

Chief, Division of Cognitive and Behavioral Neurology

Brigham and Women’s Hospital

Disclosures
• None

791
 Evaluation of Cognitive Impairment

•Barriers to Completing a Cognitive Assessment

•Reasons Clinicians Should Evaluate Cognitive Status
•Conditions with Salient Cognitive Deficits
•Approach to Assessing Age-related Cognitive Impairment
•Mental Status Screening Instruments: Pros / Cons
•Algorithm for Assessment

Barriers to Completing a Cognitive Assessment

•Patient Resistance

•Time Constraints and Poor Reimbursement

•Perceived Low Return on Investment

792
 Reasons for Evaluating Cognitive Status

•Medicare Mandate – Patient Protection and Affordable

HealthCare Act (Obama Care)

•Implications for medication compliance

•Implications of patient safety and independence

•Critical Component of the diagnosis of a range of common

illnesses/ syndromes

Cognitive Impairment – salient feature of many

common disorders

•Neurodegenerative diseases
•Cerebrovascular disease / stroke(s)
•Toxic-Metabolic Encephalopathy
•Traumatic Brain Injury
•Endocrine Deficiencies (e.g., Thyroid)
•Vitamin Deficiencies (e.g., B12)
•Organ Dysfunction (Liver, Kidney, Lung, Heart)
•Alcohol / Drug Abuse
•Sleep Disorders
•Mood Disorders (e.g., depression, anxiety)

793
 Dementia – Definition

Dementia is a progressive (but not necessarily

irreversible) decline in cognitive or
behavioral functioning that interferes with
daily living activities that are appropriate
for a patient’s age and background, and is
not simply due to a delirium, confusional
state, or related alteration in sensorium.

DSM-5
Major Neurocognitive Disorder
1. Evidence of significant cognitive decline from a previous level of performance in one
or more cognitive domains (complex attention, executive function, learning and
memory, language, perceptual -motor, or social cognition) based on :

a. Concern of the individual, a knowledgeable informant, or the clinician that there

has been a significant decline in cognitive function; and
b. A substantial impairment in cognitive performance, preferably documented by
standardized neuropsychological testing or, in its absence, another quantified
clinical assessment.

2. The cognitive deficits interfere with independence in everyday activities.

3. The cognitive deficits do not occur exclusively in the context of a delirium.
4. The cognitive deficits are not better explained by another mental disorder (e.g., major
depressive disorder, schizophrenia).

794
 DSM-5
Criteria for Major Neurocognitive Disorder
Specify presumed etiology (e.g., AD, FTLD, DLB, VaD, etc.)

Specify with or without behavioral disturbance (e.g, psychotic

symptoms, mood disturbance, agitation, apathy, or other sxs)

Specify current severity

a. Mild: Difficulties with IADLs (e.g., housework, managing

money)
b. Moderate: Difficulties with basic ADLs (e.g., feeding, dressing)
c. Severe: Fully dependent

Alzheimer’s Disease

Normal Aging
Cognitive
function Presymptomatic

Preclinical
(MCI)

Clinical Dementia
Mild
Moderate
Severe

Years

(Courtesy of R. Sperling, MD)

795
 Mild Cognitive Impairment

• Cognitive complaints, preferably corroborated by an

informant
• Objective cognitive impairment (memory, executive fx,
language, visuospatial fx)
• Normal general cognitive function
• Intact activities of daily living
• Not demented

Davis, Rockwood Int. J. Geriatr. Psychiatry 2004; Markesbery et al Arch. Neurol. 2006;
Petersen et al Arch. Neurol. 2006; Petersen et al Neurology 2001; Petersen 2011

Mild Cognitive Impairment

• Amnestic MCI (a-MCI)
• Non-amnestic MCI
• Multidomain MCI
• 12-15% per year progress to dx of dementia vs. 1-2% of
matched healthy older adults
• Predictors of conversion from MCI to dementia
– Greater hippocampal atrophy
– Temporoparietal hypometabolism on PET
– Low CSF Aβ
– ApoE4 allele
– Positive amyloid PET imaging
– Multidomain > Single domain

796
 DSM-5
Minor Neurocognitive Disorder
1. Evidence of modest cognitive decline from a previous level of performance in one
or more cognitive domains (complex attention, executive function, learning and
memory, language, perceptual -motor, or social cognition)

2. The cognitive deficits do not interfere with capacity for independence in everyday
activities (i.e., complex IADLs are preserved, but greater effort, compensatory
strategies, or accommodation may be required).

3. The cognitive deficits do not occur exclusively in the context of a delirium.

4. The cognitive deficits are not better explained by another mental disorder (e.g.,
major depressive disorder, schizophrenia).

Age and age-related diseases are the biggest risk

factors for cognitive impairment
 http://iucar.iu.edu/geninfo/demo/growth.html

Causes of
Dementia

Neuro- Inflammatory/ Vascular Metabolic/ Neoplastic/

degenerative Infectious Toxins Structural

798
Neuro- Inflammatory/ Vascular Metabolic/ Neoplastic/
degenerative Infectious toxins Structural
Alzheimer Disease Multiple sclerosis Vascular Hypothyroid Tumor (depends on
Frontotemporal Dementia Vitamin B12 location)
Syphilis
Dementia
Lyme Thiamine deficiency
Dementia with Lewy Hypoxic/ Paraneoplastic
(Wernicke-
bodies HIV ischemic injury limbic encephalitis
Korsakoff)
Corticobasal Creutzfeldt-Jakob disease
degeneration Post-CABG Niacin deficiency Acute and chronic
Primary CNS vasculitis
Progressive (pellagra) sequelae of brain
supranuclear palsy Vasculitis secondary to radiation
CADASIL
Huntington Disease other autoimmune Vitamin E
diseases deficiency
Multisystem atrophy CAA Chemotherapy
Argyrophilic brain Sarcoid
Uremia/dialysis
disease Chronic meningitis dementia Lymphomatoid
Wilson disease granulomatosis
Viral encephalitis
Hallevorden-Spatz Addison/Cushing
disease Whipple disease
TBI
Mitochondrial diseases Systemic lupus Chronic hepatic
erythematosus encephalography
Kuf disease NPH
Metachromatic Sjögren syndrome Heavy metals
leukodystrophy
Adrenoleukodystrophy Alcohol

What’s Normal Cognitive Aging

•Functions that are Relatively Well-Preserved:
•Established Verbal Skills
•Semantic Knowledge
•Recall of Previously Learned Information

•Functions that Commonly Decline

•Speed of Mental Processing
•Rapid Retrieval of Information (e.g., proper names)
•Executive Function (working memory capacity, mental flexibility,
inhibitory activity)
•Visual Perceptual Abilities

•Normal Cognitive Aging does not significantly interfere with

maintaining an independent, productive life.

799
 Screening for Cognitive Impairment

•History
•Subjective cognitive complaints
•Informant observations
•Premorbid status
•Changes in mental state, functional status,
mood
•Medical conditions
•Family hx

Informant Surveys
•Functional Changes
•Neuropsychiatric Change

800
 Neuropsychiatric Inventory Questionnaire
• Delusions
• Hallucinations
• Agitation or aggression
• Depression or dysphoria
• Anxiety
• Elation or euphoria
• Apathy or indifference
• Disinhibition
• Irritability or lability
• Motor disturbance
• Nighttime behaviors
• Appetite and eating
*Yes/No
If yes: Severity (1-3) Distress (1-5)

Mental Status Examination

EXECUTIVE FUNCTIONS
(Frontal Networks)
Emotional Processing
Praxis
Paralinguistic/Prosody
Finger Recognition;
Calculations
Directed Spatial
Reading/Writing Attention

Language Functions/
Semantic Knowledge Complex Perceptual
Functions

M O
E R
[Limbic System]
M Y
COMPLEX ATTENTION
(Frontal Networks)
MOOD VIGILANCE MOTIVATION

WAKEFULNESS - AROUSAL

[Brainstem RAS - Thalamus]

801
Salient Memory Salient Attention/ Language
Impairment Executive Fx/Slowed Impairment
Processing Speed

Disruption of Disruption of Disruption of Left

Temporolimbic System Frontal/Subcortical hemisphere

Frontotemporal Dementia Primary Progressive

Alzheimer Disease
DLB/PDD Aphasia (agrammatic,
Hypoxic/ ischemic injury
Cerebrovascular Disease semantic, logpenic)
Wernicke-Korsakoff Syndrome
Hypothyroid Focal injury (e.g., stroke,
Limbic Encephalitis
Vitamin B12 tumor)
Multiple sclerosis
TBI
Syphilis/HIV
NPH

ASSESSING MEMORY IS KEY

• Establish that the patient can pay attention to the task
– e.g., months of the year forward/reverse; digit span; serial 7s
• Give new information for the patient to encode
– e.g., 3-5 words
• Test that the information was successfully encoded
– have the patient repeat back what he/she learned
• Test if the patient can retrieve the information after a delay (e.g., at
5 minutes)
• For information not retrieved, give clues or multiple choices
– If able to recognize the learned material, the problem is at the level of activation and
retrieval of successfully stored information
– If unable to recognize, the problem is at the level of memory storage

802
 Screening Tests for Cognitive Impairment:
Issues and Challenges
•Time needed to Administer and Score
•Personnel/ Space to collect the information
•Test Cut Off Values
•Sensitivity
•Specificity
•Prior Probability varies considerably across different patient populations
•Easy (Brief) Tests – “Ceiling Effects”
•Not sensitive to patients with mild impairment; especially those with
higher levels of education and cognitive reserve
•Hard (Longer) Tests – may misidentify patients as impaired who are at
baseline
•Baseline vs. Follow-up Data
•Determine if a patient is declining over time

Mental Status Screening Instruments

•Mini Mental State Exam (MMSE)
•Extended- Mini Mental State Exam (MMX)
•Adden Brooke’s Cognitive Exam (ACE)
•Montreal Cognitive Assessment (MoCA)
•ADAS- Cog
•Mattis Dementia Rating Scale (MDRS)
•CERAD Battery
•Seven- Minute Test
•Mini Cognitive Assessment Instrument (Mini-Cog)
•Short Test of Mental State (STA)
•Cambridge Cognitive Exam (CAMCOG)
•Blessed Information-Memory-Concentration (IMC)
•Abbreviated Mental Test (AMT)
•Clock Drawing Test (CDT)
•General Practitioner Assessment of Cognition (GPCOG)
•Memory Impairment Screen ( MIS)
•Short Portable Mental Status Questionnaire (SPMSQ)
•Computerized testing

803
Mini-Cog
 Nasreddine, J Am Geriatr Soc, 2005

Duration Cut Off Scores

Age and Education
MMSE 7-10’ 24-26 Huge Data-Set
Adjusted Norms
0/3 words
Misclassification rate
Mini Cog 2-3’ 1-2/3 words and Very Quick
~equal to MMSE
Abn CDT
More sensitive than
MoCA 10-15’ 24-26
MMSE for MCI

805
 Cognitive Assessment
Context: Age, Education, Baseline Capacity

Normal

Abnormal

Uncertain/Ambiguous

Cognitive Assessment
Context: Age, Education, Baseline Capacity

Education
Educate aboutabout
how to
Promotion
promote healthyofcognitive
Normal
Successful
aging Cognitive
Aging

806
 Promoting Healthy Cognitive Aging

• Intellectual stimulation
• Exercise
• Social interactions
• Diet/Nutrition
• Exposure to potentially toxic substances (e.g., alcohol; smoking)
• Prevent or Treat Medical Conditions that affect brain function
– HTN
– Metabolic Syndrome (obesity, diabetes)
– Sleep disorders
– Endocrinological changes (e.g., DM)
– Mood disorders

Daffner, 2010; Tsao et al 2008; Swan & Lessov-Schlaggar 2007

Cognitive Assessment
Context: Age, Education, Baseline Capacity

• Informant observations
Gather more • Ensure F/U Assessment
Uncertain/Ambiguous Ensure F/U Assessment
• Consider Referral to Cognitive
information
Neurology/Neuropsychology

807
 Cognitive Assessment
Context: Age, Education, Baseline Capacity

Salient Memory
Impairment AD Pattern
Insidiously Progressive
Abnormal
Memory Relatively
Spared Non-AD Pattern
Insidiously Progressive

Cognitive Assessment
Context: Age, Education, Baseline Capacity

ADL’s Relatively
Amnestic MCI
Spared
AD Pattern
Decreased ADL’s
/ Functional Dementia AD
Status
 Cognitive Assessment
Context: Age, Education, Baseline Capacity

Non-Amnestic
ADL’s ~ Spared
MCI
Non-AD
Pattern
Decreased ADL’s
Dementia (Non-
/ Functional
AD)
Status

Cognitive Assessment
Context: Age, Education, Baseline Capacity

Amnestic MCI

Dementia AD • Assess capacity for

independence;
Access capacitymeds,
for $, safety,
POA
independence; Meds,
$, safety, any
• Find/treat POA potential treatable
Non-Amnestic MCI contributing conditions

Dementia (Non-
AD)

809
 Prevent or Treat Conditions that
Reduce Cognitive Capacity

Find and Treat All Concurrent Illnesses

and Medical or Psychiatric Problems
• Concurrent Problems include
– Cerebrovascular disease (strokes)
– Mood disorders (e.g., depression)
– Sleep disorders
– Endocrine abnormalities
– Pain
– Cardiac, pulmonary, renal abnormalities
– Infection (e.g., UTI, bronchitis)
• Side-effects from medications (e.g. anti-cholinergic)

810
 Key Laboratory Studies
STANDARD – 2016
• Blood work (e.g. TFT’s, LFT’s, Lytes, BUN, Cr, Glu, Ca,
B12, CBC, RPR)
• Consider ESR, U/A, EKG, CXR
• Other lab studies – guided by history (e.g. HIV)
• Neuroimaging
• Key purpose is to identify potential (treatable) contributions to
cognitive decline

NOT STANDARD
• CSF Proteins
– Aβ42
– Tau (total; phosphorylated)
• Genetic Testing

Formichi et al J. Cell Physiol 2006; de Leon et al Ann. N.Y. Acad. Sci. 2007; Clarfield Arch. Intern. Med. 2003

Late Life Depression

• Mental State Changes
– Diminished attention; slowed processing speed and output, limited
motivation
– Memory problems usually at the level of encoding/retrieval, not storage
(relatively preserved recognition after delay)
– Complaints of not knowing answers, rather than offering incorrect ones
– No aphasia, but word retrieval may be slow

• Late life depression often is a symptom of a neurodegenerative

disease (AD) or of cerebrovascular disease

• Treat the depression which often results in clinical improvement

of mood (and cognition)

• Follow closely over time

811
 Cognitive Assessment
Context: Age, Education, Baseline Capacity

Normal • Educate about promotion of

healthy cognitive aging

Amnestic MCI

AD Pattern

Dementia (AD)
• Find
Assess
andcapacity
treat anyfor
Access capacity
independence; for
meds,
Abnormal
potential
Decreased
independence;
treatable
ADL’s
Meds, / $, $, safety,
conditions thatStatus
• Functional
Find Safety
/treat may be
potentially treatable
contributing
contributing conditions
Non-Amnestic MCI

Non-AD Pattern

Dementia (Non-AD)

• Informant observations
• Ensure F/U Assessment
Uncertain/Ambiguous
• Consider Referral to Cognitive
Neuro/Neuropsychology

Evaluation of Cognitive Impairment

•Barriers to Completing a Cognitive Assessment

•Reasons Clinicians Should Evaluate Cognitive Status
•Conditions with Salient Cognitive Deficits
•Approach to Assessing Age-related Cognitive Impairment
•Mental Status Screening Instruments: Pros / Cons
•Algorithm for Assessment

812
 Abnormal Performance on a Cognitive Screen
• Consider abnormal performance as a neurological sign
• Represents the starting point of an evaluation
• Need to establish a diagnosis
– History (e.g., onset, pace)
– Major risk factors (e.g., CVD, medical conditions, FH)
– Pattern of Cognitive Deficits
• Is Memory (storage of new information) the most salient impairment?
• Attention/executive functions, Language, Visuospatial
– In patients who do not have the typical pattern of cognitive deficits or
the slow insidious course of AD, consider referral to a specialist
 Early Diagnosis and Treatment of
Alzheimer’s Disease

Reisa Sperling, M.D.

Center for Alzheimer Research and Treatment
Brigham and Women’s Hospital
Massachusetts General Hospital
Harvard Medical School

Disclosures and Funding

Research Grants: Eli Lilly, Janssen

Advisory Role: Roche, Lundbeck, Merck, Pfizer,

General Electric, Insightec, AC Immune, Eisai

Spouse Advisory Role: Lundbeck, Piramal

Healthcare, Siemens, Novartis
 Alzheimer’s Disease

• Typically manifests clinically

with insidious progression of memory loss and
executive dysfunction
• Eventually affects language, visuospatial,
behavior
• Accounts for 60-70% of all late-life dementia
• Prevalence increases exponentially by decade

Good News / Bad News

BAD NEWS FIRST
• 1 out of every 9 individuals over 65 has AD!
• 5.8 million AD patients currently in U.S.,
increasing exponentially over the next 3 decades
• Cost estimates - > $$ 277 billion/year
• Multiple recent drug trials failed to show benefit
GOOD NEWS
• Multiple new mechanisms starting clinical trials
• Long preclinical phase of AD to intervene!
 Risk Factors for AD
• Age
• Genetics/Family History
– Apolipoprotein E ε4
• Cerebrovascular risk factors
– Diabetes/Insulin resistance (may be independent
risk)
• Head trauma
• Low education
– ? Less cognitive reserve – unable to hide
pathology

Genetic risk for AD

Risk genes
• Autosomal dominant AD
– Presenillin-1, Presenillin-2, APP mutations
• Trisomy 21 – APP
• Apolipoprotein E ε4

Protective Genes
• Apolipoprotein E ε2
• APP β-secretase mutation (Icelandic DeCode)
 Alzheimer’s Disease
Normal Aging
Cognitive
function Preclinical
Prodromal
(MCI due to AD)

Clinical Dementia
Mild
Moderate
Severe

Age/Time
 PIB-PET Amyloid Imaging

Normal
Aging

2.0
DVR = 1.0
Alzheimer’s
Disease

L
R Keith Johnson MGH

CSF Biomarkers of Alzheimer’s disease:

Low Aβ 1−42 and high tau

Hansson Lancet Neurology 2006

 Amyloid and Tau PET Imaging

Aβ
(PiB)

Tau
(T807)

CN CN AD Dementia

Sperling, Mormino, Johnson Neuron 2014

Hypothetical Interaction of Amyloid and Tau

in Preclinical AD

Age MTL Tau

Accumulation
?

Synaptic Dysfunction
Amyloid-β Neocortical Tau Glial Activation Cognitive Decline
Accumulation Accumulation Neuronal Loss

Age
Genetics

Sperling, Mormino, Johnson Neuron 2014

 Treatment of Alzheimer’s Disease

Cognitive Disease-
Function Modifying
Therapy

Symptomatic
Therapy

Natural
History of AD

Years

Pharmacologic Treatment of AD
Overview
• Symptomatic treatment
– Cholinesterase inhibitors
– Memantine
• Attempts at prevention/disease modification
– Epidemiological approaches
– Aimed at amyloid pathology
• Immunotherapy
• Secretase inhibitors
• Biomarker acceleration of early therapeutic
intervention
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cholinesterase Inhibitor
Development

1993 1997 2000 2001

tacrine donepezil rivastigmine galantamine
(Cognex®) (Aricept®) (Exelon®) (Reminyl®
Razadyne ®)

Donepezil: ADAS-Cog*
–3 †
Mean Change from Baseline

†
†
–2 *
Clinical
–1 Improvement
‡
0 ¥
†
1
Clinical
2 10 mg/d (n=157) Decline
5 mg/d (n=154)
3 Placebo (n=162)
4
Baseline 6 12 18 Endpoint 30
Weeks on Therapy
Placebo
Washout

*Alzheimer’s Disease Assessment Scale–Cognitive Subscale. †P<0.0001; ‡P<0.0007; ¥P<0.0012.

Rogers SL, et al. Neurology. 1998;50:136-145.
28
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Long-term Treatment - Galantamine

Double-blind Open-extension Improvement
–4
–3
–2
–1
0 *
1
2
3
4
5
6
7
0 3 6 9 12 Deterioration
Months
Placebo/galantamine 24 mg
Galantamine 24 mg/galantamine
Historical
24 mg placebo group
* p < 0.05 vs placebo/galantamine Reprinted with permission from
(not statistically different from Raskind MA et al. Neurology. 2000;54:2261-
baseline). 2268.

Glutamate Modulation
• NMDA antagonists
– Memantine
– ?symptomatic effects vs. neuroprotection
– Currently approved for treatment of moderate
to severe AD
– Mixed results in mild AD trials

822
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Memantine + Donepezil in Moderate to Severe AD

Cognition—Severe Impairment Battery
4 P<.001 †P<.001

Improvement
3
Baseline in SIB Score
Mean Change From

2
1
0

Deterioration
-1
-2 Memantine+Donepezil
-3 Placebo+Donepezil
-4
0 4 8 12 18 24End Point
n= 198 192 190 185 181 171 198
n= 197 194 180 169 164 153 196
*OC analysis. †LOCF analysis. Treatment Week
Adapted from Tariot P, et al. JAMA. 2004;291:317-324.
Data on file, Forest Laboratories, Inc.

Potential Disease Modifying Agents

• Aimed at underlying pathology
• May or may not have much symptomatic
improvement
• Primarily amyloid based approaches
– Decrease production of toxic form of amyloid
– Decrease amyloid aggregation
– Increase amyloid clearance
• Tau therapies coming…

823
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Decreasing Production of A-β

• Gamma secretase inhibitors
– Relationship to Presenilin1
– Notch related toxicity
– Ibuprofen like NSAIDs – Flurizan
– Multiple trials halted due to toxicity – Gamma secretase
modulators coming
• Beta secretase inhibitors (BACE)
– Encouraging evidence of biological activity reducing
production of Aβ1-42
– ? Peripheral myelin toxicity and retinal toxicity in animals
– Some early trials halted with toxicity or lack of efficacy,
several agents continuing
• Augmenting alpha secretase
– AF102B, ?Estrogen, ?Statins

824
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Increase clearance of Aβ
• Active immunization with Aβ- “Vaccine”
– Clearance of plaques, behavioral benefits in mice
– Large Phase II trial with injected A-beta 1-42
stopped secondary to inflammatory complications
– Alternative vaccines -shortened peptides in Phase
II/III – difficulty with immunogenicity?
• Passive immunization: antibody
– IVIG – Phase III - Negative
– Monoclonal antibodies – Phase III – Negative in
moderate AD - ? Response in mild subgroups

Removing the toxic form of Aβ?

• Mixed evidence from clinical trials thus far
– Bapineuzumab - ? Some biomarker effects in mild
subgroup but no clinical signal
– Solanezumab - ? Modest clinical effect in mild
subgroup, but no clear biomarker evidence
– Crenezumab - ? Modest clinical effect in mild
subgroup, but no clear biomarker data
– Gantenerumab - ? Evidence of Aβ reduction at high
doses in Phase 1, recent MCI trial stopped
– Aducanamab - Evidence of both Aβ reduction and
clinical stablization with dose response, BUT very
small sample size – Phase 1

825
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Bapineuzumab: PIB PET Cortical Average SUVr

Heterozygotes
Homozygotes
3 Noncarrier
Baseline PiB PET GCA SUVr

2.5

1.5

1.35

8/123 (6.5%) Below threshold 22/61 (36.1%)

1 for inclusion

APOE ε4 carriers Non-carriers

302 Study N=123 301 Study N=61
Mean SUVr of all carrier PiB PET patients: 2.07 Mean SUVr of all non-carrier PiB PET patients: 1.72
Mean SUVr of carrier analysis population: 2.14 Mean SUVr of non-carrier analysis population: 2.05
Salloway
25 S, Sperling R et al NEJM 2014

Spectrum of Amyloid Related Imaging Abnormalities

Multi-focal Micro-
gray and hemorrhages
white matter (ARIA-H)
edema
(ARIA-E)

Sulcal Subtle lepto-

effusion Meningeal
(ARIA-E) involvement
(ARIA-E)

Sperling et al. Alz Dementia 2011

826
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Need for earlier intervention

• Twelve Phase III trial failures at stage of AD
dementia over the past decade!
• Intervention prior to dementia (and stage of
irreversible brain cell loss) may have better
chance of changing clinical course of the disease
• Delaying dementia by 5 years would reduce
projected Medicare costs by nearly 50%
• Think about what happens in cancer, stroke,
diabetes, osteoporosis, HIV…. if we wait to treat
until after symptoms are clearly manifest?

The Continuum of Alzheimer’s Disease

“Normal” Aging
Cognitive
function Preclinical

MCI
(Prodromal AD)

Dementia

Years

827
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Preclinical Alzheimer’s disease?

1/3 of CN with elevated Aβ accumulation

CN CN AD
Αβ− Αβ+ Αβ+ Harvard Aging Brain Sudy
29
Sperling, Mormino, Johnson Neuron 2014

Preclinical Alzheimer’s Disease?

Prevalence
of PiB+ve PET
60
in HC

50

Prevalence of plaques
Prevalence (%)

40 in HC
(Davies, 1988, n=110)
(Braak, 1996, n=551)
30 (Sugihara, 1995, n=123)
~15 yrs
20 Prevalence
of AD
(Tobias, 2008)
10

0
30 40 50 60 70 80 90 100

+ Age (years)

Rowe C et al Neurobiology of Aging 2010

828
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stage 0
No biomarker Staging Framework for
abnormalities
Preclinical Alzheimer’s disease
Stage 1
Asymptomatic amyloidosis
-High PET amyloid retention
-Low CSF Aβ1-42
NIA-AA Preclinical Workgroup
Stage 2
Amyloidosis + Neurodegeneration
-Neuronal dysfunction on FDG-PET/fMRI
-High CSF tau/p-tau
-Cortical thinning/Hippocampal atrophy on sMRI

Stage 3
Amyloidosis + Neurodegeneration + Subtle Cognitive Decline
-Evidence of subtle change from baseline level of cognition
MCI Dementia
-Poor performance on more challenging cognitive tests due to AD
-Does not yet meet criteria for MCI

SNAP
Suspected non-Alzheimer
pathology
- Neurodegeneration
markers without evident Sperling, Mormino, Johnson Neuron 2014
amyloidosis Adapted from Sperling 2011, Jack 2012

Targeting the appropriate stage of AD

Aβ accumulation Cognitive impairment

Sperling, Jack, Aisen Science Trans Med 2011

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

“Secondary Prevention” AD Trials

• Dominantly Inherited Alzheimer Network (DIAN)
– PS-1, PS-2, APP – Solanezumab, Gantanerumab, BACEi
• Alzheimer Prevention Initiative (API)
– PS-1 Colombian kindred – Crenezumab
– APOE 4/4 – Active Vaccine, BACE TOMMorrow Trial
– TOMM40- Pioglitazone
• Anti-Amyloid Treatment in Asymptomatic AD (A4)
– A4 – Amyloid + normal 65-85yo– Solanezumab
– “A3” – getting closer to primary prevention

Encouraging history from other fields

• Cholesterol Wars in Cardiology
• Good vs. bad cholesterol
• Secondary prevention trials in familial
hypercholesterolemia and in post-MI
• Reduction of cholesterol estimated to have reduced
cardiac morbidity and mortality by 28%
• Amyloid does not have to be “the” cause of AD,
merely “a” critical factor to impact the disease
• Ultimately will likely need combination therapy
in patients with symptomatic AD to fully prevent
cognitive decline
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Delirium and Confusion

Joshua P. Klein, M.D., Ph.D.

Departments of Neurology and Radiology
Brigham and Women’s Hospital
Harvard Medical School

Disclosures

None
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

Acute confusional syndrome should be

treated as a medical emergency.

There are many etiologies.

Diagnosis is made by careful history taking,

physical exam, and ancillary tests.

Definitions

The confusional syndrome

1. Acute alteration of arousal and comportment,

with characteristically fluctuating severity

2. Disorder of attention and perception that

interfere with speed, clarity, and coherence of
thought, memory formation, and capacity for
performing tasks

Adams and Victor’s Principles of Neurology

832
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

The confusional syndrome

Three subtypes

1. Acute confusional state

2. Delirium

3. Beclouded dementia

Adams and Victor’s Principles of Neurology

Definitions

Acute confusional state: reduction in

alertness and psychomotor activity

Delirium: overactivity, sleeplessness,

tremulousness, and hallucinations

Beclouded dementia: confusional state in

patient with underlying cerebral disease

833
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

Acute confusion (psychomotor underactivity)

I. Associated with medical/surgical disease

Neurologically non-focal, CSF clear
1. Metabolic disorders
2. Infectious disorders
3. Congestive heart failure
4. Post-operative and post-traumatic states
5. Primary psychiatric conditions

Definitions

Acute confusion (psychomotor underactivity)

II. Associated with drug intoxication

Neurologically non-focal, CSF clear
1. Medication exposure: sedatives, opiates,
barbiturates, corticosteroids, anticholinergics,
anticonvulsants, antihistamines, and
dopaminergic and serotonergic medications
2. Toxin exposure: mercury, arsenic, solvents,
organophosphates

834
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

Acute confusion (psychomotor underactivity)

III. Associated with diseases of the CNS

Neurologically focal and/or CSF abnormal
1. Vascular: stroke, SDH, vasculitis, PRES
2. Tumor: intra-axial, extra-axial
3. Infection: meningitis, encephalitis, abscess
4. Demyelination
5. Hydrocephalus

Definitions

Delirium (psychomotor overactivity)

I. Associated with medical/surgical disease

Neurologically non-focal, CSF clear
1. Pneumonia and other infections
2. Bacteremia
3. Thyrotoxicosis
4. Post-operative and post-traumatic states
5. Primary psychiatric conditions

835
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

Delirium (psychomotor overactivity)

II. Associated with abstinence states,

intoxications, or post-convulsive states
Neurologically non-focal, CSF clear
1. Withdrawal from ethanol and sedatives
2. Intoxication with anticholinergics, cocaine,
hallucinogens, phenylcyclidine

Definitions

Delirium (psychomotor overactivity)

III. Associated with diseases of the CNS

Neurologically focal and/or CSF abnormal
1. Vascular
2. Tumor
3. Trauma/contusion
4. Meningitis/encephalitis

836
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definitions

Beclouded dementia

I. Underlying brain disease (dementing or

otherwise) in combination with:
1. Fever/infection
2. Drug reactions
3. Trauma
4. Heart failure

Pathophysiology

Abnormalities are metabolic and sub-cellular,

not revealed by conventional (structural)
brain imaging.

Loss of integrated activity of association

cortices may be reflected by slowing, loss of
organization, and abnormal non-epileptic
waveforms on EEG.

837
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathophysiology

Abnormalities are metabolic and sub-cellular,

not revealed by conventional (structural)
brain imaging.

History: Symptoms, pace, review of systems,

identification of non-neurologic disease,
medication changes, and drug use.

Physical exam: Localizing signs.

Neuroanatomy (alteration of arousal)

JNEN 2013;72:505

838
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathophysiology

Physical exam: Localizing signs

1. Meningismus
2. Vascular bruits, murmurs, JVP elevation
3. Peripheral emboli
4. Evidence of trauma
5. Jaundice, ascites, asterixis
6. Dysautonomia: fever, tachycardia, hypoxemia,
diaphoresis, hypercarbia, pupil asymmetry,
Cheyne-Stokes/Kussmaul respiratory pattern

Pathophysiology

Physical exam: Localizing signs

1. Dysexecutive / “frontal”
2. Visual field abnormality
3. Dysphasia (versus confused speech)
4. Neglect
5. Hemiparesis / extrapyramidal
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathophysiology

Laboratory studies
1. Glucose and electrolytes
2. CBC
3. BUN/Cr
4. Liver function and ammonia
5. Thyroid function
6. Infections (urinalysis, cultures)
7. ECG, cardiac enzymes, CXR, KUB
8. LP
9. CT/MRI
10. EEG

Pathophysiology

“Confusion plus” syndromes

1. HSV encephalitis: fever, dysphasia, seizures
2. Wernicke: ataxia, oculomotor paresis
3. Limbic encephalitis: seizures, behavior change
4. CJD: progressive, seizures, myoclonus
5. NPH: ataxia, incontinence
6. PML: immunosuppression
7. PRES: hypertension, exposure to chemotherapeutics
8. Status epilepticus: especially non-convulsive
9. Serotonin syndrome, NMS, med exposures
10. Acute hepatic encephalopathy: elevated NH3
11. Pontine (and extrapontine) myelinolysis: hypo-Na

840
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HSV encephalitis

Wernicke encephalopathy

Edlow et al. JNEN 2013;72:505

841
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIV encephalitis

AIDS Pt Care STDS 2012;26:383

CJD

842
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Paraneoplastic limbic encephalitis

Intracranial hemorrhage / TBI

843
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ischemic stroke and TGA

PRES
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Reversible cerebral vasoconstriction

syndrome (RCVS)

Status epilepticus

845
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acute hepatic encephalopathy

Neurohospitalist 2013;3:125

Pontine myelinolysis

846
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Conclusion

The acute confusional state is a medical

emergency

Psychomotor slowing or overactivity, with or

without underlying brain disease

Rapid clinical and laboratory evaluation can

identify treatable and reversible causes of this
syndrome

847
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry
John F. Sullivan, MD
Neuropsychiatrist, Brigham and Women's Hospital
Instructor, Harvard Medical School

Disclosures

• None

848
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry for the

Non-Neurologist
This presentation includes mentions of
off-label use of medications.

“Research has afforded irrefutable proof that

mental activity is bound up with the function
of the brain ... But every attempt to deduce
from these facts a localization of mental
processes, every endeavour to think of ideas
as stored up in nerve cells and of excitations
as travelling along nerve-fibres, has
completely miscarried.”
–Sigmund Freud, 1915, "The Unconscious"

849
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Neuropsychiatry
• Care of patients with psychiatric symptoms that are attributable to
neurological disorders

• E.g. Psychosis of dementia or epilepsy, depression of Parkinson's

disease, post-stroke depression

• Care of patients with significant psychiatric and neurological

comorbidities that complicate "treatment as usual."

• E.g. A patient with chronic psychiatric illness who develops

migraines, epilepsy, or suffers a stroke

• Neuropsychiatry is a parallel but distinct discipline to Behavioral

Neurology, which generally focuses on diagnosis and treatment of
dementias

Clinical Neuropsychiatry
• Examples of neuropsychiatric disorders:

• Tourette's syndrome comprises tics, OCD, ADHD

• Traumatic brain injury often produces predominantly

neuropsychiatric symptoms: impulsivity, mood disorders, apathy,
cognitive impairment

• Functional Neurological Symptom Disorder (Conversion Disorder):

Patients who involuntarily exhibit neurological symptoms in the
absence of a detectable neurological disorder. E.g. Psychogenic
non-epileptic seizures, psychogenic tremor or gait disorders
functional weakness after injury

850
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Neuropsychiatry
• Neuropsychiatric evaluation

• Psychiatric mental status exam

• Neurologic exam

• Cognitive exam

• Consideration of further testing: MRI, EEG, LP,

neuropsychological testing

Clinical Neuropsychiatry
• Psychosis and mood disorders in epilepsy

• Experience of disability due to illness may precipitate depression

• Seizures themselves can affect mood, or produce anxiety or psychosis during the
seizures or in the inter-ictal period

• Anticonvulsant medications may have beneficial or harmful psychiatric side effects

• Levetiracetam: irritability and depression

• Zonisamide: depression

• Valproic acid: effective mood stabilizer

• Lamotrigine: mood-stabilizing antidepressant

851
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Neuropsychiatry
• Depression, dementia, and psychosis in Parkinson Disease

• Loss of dopamine-producing neurons affects movement, but also mood, attention, motivation

• Treatments for PD (which augment dopamine) can cause psychosis or impulsivity

• Medications used for psychosis or anxiety may worsen PD symptoms: all “typical” and most
“atypical” antipsychotics have dopamine-blocking effects

• Quetiapine and clozapine are antipsychotics that do not exacerbate PD. Clozapine is
more effective but used less due to need to monitor for agranulocytosis

• Pimavanserin is a new antipsychotic approved for psychosis in PD, which does not have
any dopamine-blocking activity

• Antidepressants (SSRIs, SNRIs) are effective for depression and anxiety in PD

• Cholinesterase inhibitor rivastigmine is approved for dementia in PD

Clinical Neuropsychiatry
• Traumatic Brain Injury

• Neuropsychiatric symptoms are common: impulsivity,

disinhibition, cognitive impairment, apathy

• Impulsivity and disinhibition can be treated with mood

stabilizers (e.g. divalproex) or centrally-active beta
blockers (e.g. propranolol)

• Apathy and cognitive slowing may benefit from

psychostimulants (e.g. methylphenidate, amphetamine)

• Memory and other cognitive difficulties may benefit from

cholinesterase inhibitors (e.g. donepezil)

852
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry vs.
Neuropsychology
• Neuropsychiatrists are physicians, trained in psychiatry
and Neuropsychiatry fellowship, or trained in both
neurology and psychiatry

• Neuropsychologists are generally PhD psychologists

who are trained in cognitive and psychological
assessment.

• "Neuropsych testing" generally refers to cognitive

assessment by a neuropsychologist, to assist in the
diagnosis of ADHD, dementia, learning disability, or
other cognitive disorders

Neuropsychiatry Case #1
• 46yo man, previously healthy,
presented to ED with subacute
bifrontal headache, found to
have multifocal
oligodendroglioma

• After resection of R frontal

mass, treated with
temozolomide

• Several weeks into treatment,

became manic, grandiose,
and delusional, and was
psychiatrically hospitalized
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry Case #1
• Symptoms were entirely consistent
with a primary manic episode

• Question: is this related to the tumor

or surgery, non-convulsive seizures,
or a medication reaction? Or has
the stress from his cancer
unmasked an underlying bipolar
disorder?

• Accurate diagnosis will affect

treatment, prognosis, and the
patient's and family's understanding
of these symptoms, as well as have
medico-legal consequences.

Neuropsychiatry Case #1
• Careful history with patient and family did not reveal
any history of past manic or depressed episodes

• While late-onset bipolar disorder does occur,

approximately 90% occurs before age 50

• No evidence of toxic/metabolic cause identified on

screening blood tests and urine toxicology

• Frontal lobe lesions are associated with personality

change, and right anterior frontal lesions are
associated with mania.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry Case #1
• Diagnosis: Mood disorder with psychotic
features, secondary to medical condition
(oligodendroglioma vs. resection)

• Treated with haloperidol and divalproex with

rapid resolution of symptoms

• After six months without psychiatric symptoms,

both medications were tapered and discontinued
successfully

Neuropsychiatry Case #2
• 65yo woman with history of depression, referred for
evaluation of cognitive impairment

• Over the previous 12 months, she has had a steady decline

in level of function, becoming withdrawn, easily confused,
and having tearful episodes, also with 40-lb weight loss

• Two months ago she had been psychiatrically hospitalized.

EEG showed diffuse but irregular slowing. Lumbar puncture
and serum testing for medical causes were unrevealing.

• Mood improved with antidepressant treatment, but cognitive

and functional impairments persisted

855
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry Case #2
• At the time of evaluation, mental status exam showed:

• Sparse verbal output, agrammatic speech

• Could follow 1-step commands but not more

• Could not demonstrate ability to read or write

• Neurological exam showed:

• Prominent breakdown of saccadic pursuit

• Increased tone in all limbs

• Prominent "frontal release signs" including grasp, glabellar, snout,

and suck reflexes

Neuropsychiatry Case #2
• Differential diagnosis included
catatonia of depression,
paraneoplastic or autoimmune
encephalitis, or rapidly
progressing dementia such as
Creutzfeld Jacob disease.

• Given the abnormal

neurological exam and the
report of 40-lb weight loss, we
admitted her to the Neurology
service for workup, favoring
diagnoses of paraneoplastic
syndrome or CJD.

856
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropsychiatry Case #2
• MRI showed T2 FLAIR and
DWI hyperintensity throughout
he cortex, as well as basal
ganglia and thalami.

• This finding is characteristic of

Creutzfeld-Jakob disease, a
spongiform encephalopathy.

• While there is no treatment,

accurate diagnosis allowed for
clearer prognosis, avoided
unnecessary and inappropriate
psychiatric hospitalization

Neuropsychiatry
• A medical subspecialty that treats patients whose illness
or symptoms "fall in between" neurology and psychiatry

• Expertise in diagnosis and treatment that draws from the

techniques, treatments, and knowledge of both fields

• For more information:

• American Neuropsychiatric Association

• Journal of Neuropsychiatry and Clinical

Neurosciences

857
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Neuroimaging

Joshua P. Klein, M.D., Ph.D.

Departments of Neurology and Radiology
Brigham and Women’s Hospital
Harvard Medical School

Disclosures
None
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Key point #1: A CT or MRI provides only a

MS is dynamic,
snapshot of a potentially dynamic process

Meier DS, et al. Am J Neuroradiol 2007;28(10):1956-63

Meier DS, Guttmann CR. NeuroImage 2006;32(2):531-7

Key point #2: Comparison to prior studies is key

Meier DS and Guttmann CR, Partners MS Center

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Approach to neuroimaging
Neuroimaging should be hypothesis-driven

Localize the problem from the history and

physical exam

Think about etiology of deficit

Contrast? If ddx includes demyelination,

tumor, or infection (incl. recent surgery)

CT: Hounsfield units

brain
Cerebrospinal fluid 15
White matter 20 to 30
Gray matter 35 to 45 bone
Acute hemorrhage/thrombus 60 to 100

860
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Brain window
24066409 Bone window

Contrast angiography (CT)

arteriogram venogram

Principles of Neurology, 10th Edition

861
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ischemia / Infarction

Contrast angiography (MRI)

arteriogram
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Contrast angiography (MRI)

venogram

MRI

T1: fat appears brighter than water, so WM is brighter

than GM, and edema and CSF are darker than
normal brain

T2: fat appears darker than water, so WM is darker

than GM, and edema and CSF are brighter than
normal brain

Radiographics 2006;26:513-37

863
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Contrast enhancement indicates blood-brain barrier

permeability and/or hypervascularity

T1 T1 with gadolinium

Klein JP, ACP Medicine, 2012

Fluid suppression (FLAIR sequence)

T2 T2-FLAIR
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diffusion weighted imaging (DWI)

Diffusion imaging measures the

restriction of free movement of
water molecules through tissue.

Water molecules normally

move isotropically (i.e. freely
in all directions).

The presence of “anisotropy”

(non-isotropic water diffusion
through tissue) produces DWI
signal change, and is in part the
basis for white matter tractography.

Diffusion weighted imaging (DWI)

Increased anisotropy (or reduced diffusivity, restricted
diffusion), can be seen along normal white matter tracts,
where free diffusion of water is preferentially “restricted”
along a particular vector, i.e., parallel to the axons.

corticospinal tract

corona radiata internal capsule cerebral peduncles

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diffusion weighted imaging (DWI)

Multiple pathophysiologic processes can further restrict the
free movement of water molecules

• cytotoxicity, reversible or irreversible (i.e. ischemia)

• pus (i.e. abscess)

• hypercellularity (i.e. dense masses and tumors)

• excitotoxicity, reversible or irreversible (i.e. seizures)

Figure 3

acute infarction, DWI

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cytotoxic injury = energy failure (Na+/K+ ATP-ase)

normal diffusivity reduced diffusivity

www.neurographics.org/2/2/1/13.shtml

(SI = signal intensity)

DWI hyperintensity can be driven by either

ADC hypointensity or T2 hyperintensity

Restricted diffusion Enhanced diffusion

(T2 shine-through)

867
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ischemia / Infarction

T2

reduced diffusivity “T2 shine-through”

AJNR 2001;22:637-44

infarctions, acute and chronic

DWI ADC

chronic chronic

acute acute

868
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

“T2 shine-through”

Refers to DWI hyperintensity that is not due to restricted

diffusion, but rather to high T2 signal.

True restricted diffusion shows a region of hyperintense DWI

signal with corresponding hypointense ADC signal.

In T2 shine-through, ADC signal is iso- or hyperintense.

We observe this phenomenon as ischemic strokes evolve

(i.e. as the T2 signal intensifies), as well as in chronic
microangiopathy / gliosis.

Ischemia / Infarction

bright DWI
bright DWI bright ADC
dark ADC bright T2
Extent
of
edema

www.neurographics.org/2/2/1/13.shtml
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cytotoxic injury = energy failure (Na+/K+ ATP-ase)

www.neurographics.org/2/2/1/13.shtml

Figure 3

abscess

T1-post DWI ADC

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Figure 3

B cell lymphoma
FLAIR T1-post

DWI ADC

Figure 3

hypoxic-ischemic injury
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Creutzfeldt-Jakob (prion) disease

Figure 3

focal status epilepticus

DWI ADC

872
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Figure 10

Stroke, arterial territories

Thromboembolic stroke

Anterior cerebral artery (ACA)

contralateral leg weakness

Posterior cerebral artery (PCA)

contralateral hemianopia
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thromboembolic stroke

Left middle cerebral artery (MCA)

contralateral (right) face/arm weakness
contralateral (right) face/arm numbness
aphasia

Right middle cerebral artery (MCA)

contralateral (left) weakness
contralateral (left) numbness
neglect

Figure 10

Arterial borderzones

874
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Neurology, 10th Edition

875
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Principles of Neurology, 10th Ed.

Principles of Neurology, 10th Ed.

876
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hemorrhage on MRI
A B
Hyperacute (a)
intracellular oxyhemoglobin

Acute (b)
intracellular deoxyhemoglobin
C D
Early sub-acute (c)
intracellular methemoglobin

Late sub-acute (d)

extracellular methemoglobin E F

Chronic (e, f)
hemosiderin

Statdx.com

Hemorrhage on MRI
A B
Hyperacute (a)
T1 isointense / T2 hyperintense

Acute (b)
T1 isointense / T2 hypointense
C D
Early sub-acute (c)
T1 hyperintense / T2 hypointense

Late sub-acute (d)

T1 hyperintense / T2 hyperintense E F

Chronic (e, f)
T1 hypointense / T2 hypointense

Statdx.com

877
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary

CT and MRI signal and interpretation

The use of contrast

Diffusion weighted imaging

Ischemic and hemorrhagic stroke

878
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuro-Rheumatology
Shamik Bhattacharyya, MD, MS
Brigham and Women’s Hospital
Harvard Medical School

Does this patient have neuropsychiatric lupus?

879
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Systemic Lupus Erythematosus

• Chronic, multi-systemic, inflammatory disorder
• Disproportionately affects women (80-90%)
during early adulthood
• More frequent in African-Americans, Hispanics,
and Asians
• Relatively common – 50/100,000 people in the
US

Diagnosing Lupus
Malar rash Erythema over malar regions of the face sparing the nasolabial
folds
Discoid rash Raised erythematous patches with keratotic scaling and follicular
plugging
Photosensitivity Skin reaction from sunlight (many types)
Oral ulcers Usually painless in oral cavity or nasopharynx
Arthritis Nonerosive with tenderness or swelling
Pleuritis or Either by history or evidence of pleural/pericardial effusion
pericarditis
Renal disorder Proteinuria of 0.5 grams daily or cellular casts
Neurologic disorder Seizures or psychosis without clear secondary provocative factor
Hematologic Hemolytic anemia or leukopenia or lymphopenia or
abnormality thrombocytopenia
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosing Lupus
Positive anti-nuclear Generally high-titer
antibody
Serology Positive anti-dsDNA (double strand DNA), anti-Sm (Sm nuclear
antigen), or positive antiphospholipid antibodies

Four out of eleven required for diagnosis.

Breadth of criteria reflect clinical heterogeneity of disease.

Systemic Lupus Erythematosus

• Unclear pathogenesis
– Genetic susceptibility
– Environmental factors (such as EBV exposure)
– Hormonal factors (women of childbearing age)
• Associated with autoantibodies against
intracellular antigens
– ANA: present in 95% but not specific
– Anti-dsDNA: can correlate with disease activity
– At least another >100 antibodies described

881
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurology in SLE
• In 1875, Hebra and Kaposi reported stupor
associated with clinical symptom of SLE
• Osler speculated on CNS vasospastic disease
similar to Raynaud’s
– “It seems not improbable that these transient
attacks were due to vascular changes in the brain,
the counterpart of those occurring in the skin.”
• Others proposed “lupus vasculitis” as cause of
symptoms continuing to this day

Osler W. Am J of the Med Sci (1904); 127: 629

Endocarditis

Libman E and Sacks B. Arch Intern Med (1924); 33:701

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pathology in NPSLE
• In 1968, Johnson and EP Richardson described 24
autopsy neuropathological studies from patients
with SLE:
– Most common finding in 80% was micoinfarcts with
microglial nodules
– No cases of generalized arteritis found
• Other autopsy series have also not shown
vasculitis as a frequent cause of neurological
symptoms

Pathophysiology in NPSLE
• H&E studies not sensitive to disorders affecting
neuronal function (such as by signaling changes)
• What about autoantibodies? Some
relevant/speculative ones for NPSLE
– Anti-phospholipid antibodies
– Anti-NMDAR NR2 subunit
– Anti-Ribosomal P
– Anti-Aquaporin 4
– Anti-MOG
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nomenclature
• Historically, many terms associated with SLE
affecting the nervous system
– Lupus cerebritis
– Neurolupus
– CNS lupus
– Lupoid sclerosis
• Current preferred term is: Neuropsychiatric
SLE (NPSLE)

Nomenclature

19 syndromes named to
provide standardized
nomenclature - does not
imply causation by SLE.
Other syndromes not
named but have been
observed like Posterior
Reversible Encephalopathy
Syndrome (PRES).

ACR. Arthritis & Rheumatism (1999); 42:599

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NPSLE
• Prevalence of NPSLE syndromes in SLE: 56%
(range from 12-95%)
– 28% have a neurological complaint at time of
diagnosis
• Prevalence of syndromes:
– Headache: 28-57%
– Mood disorder: 20-40%
– Cognitive disorder: 20-80%
– Cerebrovascular disease: 50-60%
– Seizure: 10%

Headache

Frequency of headache is similar to studies in general

population

Mitsikostas DD, Sfikakis PP, Goadsby PJ. Brain (2004); 127: 1200-1209

885
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Headache and SLE Activity

• Majority of studies do not find relation
between headache and SLE activity (out of 6
studies, 4 have been negative)
• No relation between serum anti-cardiolipin
Abs and headache

“Lupus headache” in isolation is likely not a marker of

disease activity. Treat headache in SLE symptomatically

Depression
• Prevalence of major depression in 20-47%
– Many methodological flaws (type of interviewing,
criteria used, etc.)
• Unclear whether increased prevalence related to
disease or chronic illness with disability
• Elevated disease activity increases the odds of
major depression modestly by 10%.

Possibly related to SLE but many confounders

Palagini L, Mosca M, Tani C, et al. Lupus (2013); 22:409

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Psychosis
• In a cohort of 537 patients, psychosis
prevalence: 17%
– Psychosis at disease onset: 21%
– Psychosis during course of SLE: 45%
– Corticosteroid psychosis: 31%
– Unrelated: 2%
• Psychosis correlates with elevated disease
activity

Appenzeller S, Cendes F, Costallat LTL. Rheumatol Int (2008); 28:237

Psychosis
• Often with prominent visual hallucinations. Auditory
hallucinations more common with steroids.
• CSF usually normal but can show elevated
protein/mild pleocytosis
• MRI often normal but can show non-specific lesions
• Antiphospholipid Abs risk factor for psychosis
• Anti-Ribosomal P Ab: Low sen, limited specificity
Often related to disease activity. First, check for steroid
psychosis. Otherwise, treat SLE including with steroids
and antipsychotics.

887
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stroke

• Stroke account for 10% of deaths in SLE

• Second leading individual cause of death after
bacterial sepsis
• Increased risk of stroke (eg. 21 fold increased
risk in 30-39 age group)

Cervera R, Khamashta MA, Font J, et al. Medicine (2003); 82:299

Mok CC, Ho LY, To CH. Scand J Rheumatol (2009); 38:362

Small Vessel Disease

• Reported early in neuropathological series

• Seen now as T2 hyperintense lesions on MRI
• Not explained by conventional risk factors like
hypertension or diabetes
• Correlates with cognitive dysfunction

888
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Small Vessel Disease

Small Vessel Disease

Sibbitt WL, Brooks WM, Kornfeld M, et al. Semin Arthritis Rheum (2010); 40:32

889
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hypercoagulability
• Independent of other variables, SLE itself is a
risk factor for thrombotic events
• Risk is higher for venous thromboembolic
disease
• Less robust epidemiologic data on arterial
thrombotic risk

Bazzan M, Vaccarino A, Marletto F. Thrombosis Journal (2015); 13:16

Embolic Infarcts
• From Libman-Sacks or infectious endocarditis
or paradoxical emboli or artery-to-artery
• Microembolic signals can be seen on TCD
– 9-15% of patients with SLE will have microembolic
signals when monitored for an hour over MCA
– Associated with ischemic infarcts
– Prevalence is not explained by presence of carotid
stenosis or entirely by antiphospholipid antibodies

890
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Anti-phospholipid Antibodies
• Anti-phospholipid antibodies are predictive of
ischemic stroke – present in majority of
patients with SLE and ischemic stroke.
• Can cause territorial strokes or small infarcts

Atherosclerosis
• Accelerated atherosclerosis in SLE
• Increased prevalence of conventional risk
factors such as hypertension, diabetes,
dyslipidemia
• These factors do not entirely explain the
elevated risk of atherosclerosis in SLE such as
carotid stenosis

891
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Vasculitis
• Does it exist?
• yes but very rare
• Individual cases exist in the literature

Goel D, Reddy SR, Sundaram C, et al. Neuropathology (2007); 27: 561-565

Stroke
- Check for anti-phospholipid Abs (lupus anticoagulant,
anti-cardiolipin IgG/IgM isotype, anti-β2-glycoprotein I
IgG/IgM)
- Screen for infective/Libman-Sacks endocarditis (if
imaging and syndrome suggestive, proceed to TEE; TTE
sensitivity about 11% for LS)
- SLE NOT a contraindication for IV tPA for acute stroke
- Control of modifiable risk factors
- Secondary prevention with anti-platelets or
anticoagulation if anti-phospholipid syndrome

892
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nausea/Vomiting
• 14 year old girl with diagnosis of SLE
– Arthralgias, pleuritis, ANA 1:10240, serology
positive for anti-dsDNA, anti-Ro, anti-cardiolipin
IgG
– Controlled with Plaquenil and methotrexate
• Presented with intractable nausea/vomiting
– No identifiable source found
– In pediatric ICU for weeks

Area postrema (circled) lesion that is enhancing

893
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Area Postrema Lesion

• Intractable nausea/vomiting or hiccupping
with area postrema lesion is a core clinical
syndrome of neuromyelitis optica
• Tested for NMO-IgG against Aquaporin-4 and
found to be positive

Longitudinal enhancing spinal cord lesions

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SLE Myelitis

NMO negative paraplegia with SLE

SLE - PRES

28 year old woman with SLE with new onset headache and seizures
Jonsson AH and Bhattacharyya S. Rheumatologist (2015); March
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SLE - Hypophysitis

34 year old woman with SLE and unexplained hyponatremia

Yang N, Bhattacharyya S, Weinblatt M. J of Rheumatology (2017); epub

Is this antiphospholipid syndrome?

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Antiphospholipid Syndrome
• Prothrombotic state associated with
autoantibodies
• For diagnosis of syndrome, currently require a
clinical event and laboratory criteria
• Can occur in the context of other autoimmune
diseases such as SLE or be primary

Laboratory Criteria
• Lupus anticoagulant positivity
• Anti-cardiolipin IgG or IgM present in high
titres (>40 GPL/MPL or >99th percentile)
• Anti-β2-glycoprotein I IgG or IgM present in
greater than 99th percentile titer

Measurements need to be repeated at least 12 weeks apart to be

considered definite. Transient positive results are not specific.

897
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Criteria
• Arterial or venous thrombotic event in any
tissue or organ
• Pregnancy complication:
– One or more unexplained death of a healthy fetus
beyond 10th week of gestation
– One or more premature birth of normal fetus
before 34th week from eclampsia or severe pre-
eclampsia
– Three or more consecutive unexplained
spontaneous abortions before 10th week

Two Hit Hypothesis

Ruiz-Irastorza G, Crowther M, Branch W, et al. Lancet (2010); 376: 1498-1509

898
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurological Complication
• Arterial ischemic stroke
– Associated with thrombosis affecting large or
small caliber arteries
– Cardioembolism from Libman-Sacks endocarditis
– Paradoxical embolism from deep venous
thrombosis
• Cerebral venous sinus thrombosis

Rare Associations
• Epilepsy
• Headache
• Chorea
• Cognitive Dysfunction
• Psychiatric disorders
Unclear whether causative from autoantibodies or from vascular
injury or associated with comorbid autoimmune diseases

899
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Catastrophic APS

• Subset of APS with widespread thrombosis

– Presence of antiphospholipid antibodies
• Three or more thrombotic events in a week
• Biopsy confirmation of microthrombotic event

Anticoagulation

No overall benefit or
harm with higher INR
goal (difference not
significant) in patients
with mostly venous
disease

Crowther MA, Ginsberg JS, Julian J, et al. NEJM (2003); 349:1133-1138

900
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Management

Asymptomatic carrier Unclear, no therapy or aspirin

APS and venous event Anticoagulation with INR 2-3

Area of controversy; INR 2-3 with aspirin versus

APS with arterial event
higher INR target (such as 2.5-3.5)
Arterial event with low-titre
Usual treatment
antiphospholipid antibodies

• Insufficient data on newer direct antithrombotic agents

• Limited data on immunomodulatory therapy
• Steroids and plasma exchange/IVIg used for catastrophic
APS

Does this patient have neurological complications of

Sjögren syndrome?

901
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sjögren Syndrome

• Sicca syndrome: Dry mouth and dry eyes

• Focal lymphocytic infiltration of exocrine
glands particularly salivary and lacrimal glands
• 20 fold predominance of women
• Average age of diagnosis is 55 years
• Affects 2-4 million people in US

Symptoms and Signs

Dry ocular symptoms for at least three months

Dry oral symptoms for at least three months

Ocular exocrine dysfunction sign – Positive Schirmer Test or

Rose Bengal stain
Salivary gland dysfunction sign – Decreased salivary flow or
abnormal parotid sialography or abnormal salivary
scintigraphy
Histopathology of salivary gland showing lymphocytic foci

Positive serology for anti-Ro/SSA or anti-La/SSB

Either histopathology or positive serology required for diagnosis

In primary SS, sensitivity for anti-Ro and/or anti-La about 60-80%
Often occurs in context of other autoimmune diseases such as RA and SLE

902
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sjögren Syndrome
• Traditional classification criteria focus
primarily on dry eyes and mouth
• Extra-glandular signs are common and
disabling in SS
– Thyroid dysfunction, 45% of patients
– Diffuse arthralgias
– Dry skin, dry respiratory system (chronic cough)
– Tubulointerstitial renal dysfunction
– Increased risk of lymphoma

Neurology in SS
• Wide spectrum of involvement. Prevalence
depends on definition
• Most common: Extreme debilitating fatigue
– Occurs in 50%
– Cause is usually undetermined
– Major contributor to decreased functional status
– Often diagnosed initially as fibromyalgia or chronic
fatigue
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurology in SS
• Common complaints of attention and memory
difficulty
– Neuropsychology testing often shows frontal
executive and verbal memory dysfunction
• Unclear whether from SS, psychological
reaction to it, or effect of treatment
• MRI often shows increased burden of white
matter T2 hyperintensities

SS Myelitis
• Often presents as longitudinally extensive lesion
• ~90% are seropositive for AQP4 antibody
• At present, should be treated like neuromyelitis
optica

904
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SS Encephalitis – Not all NMO

• Recurrent aseptic meningoencephalitis
• Syndrome complex:
– Fever
– Myalgia, headache
– Meningismus
– Confusion
• Significant pleocytosis in CSF
• Imaging can be normal or leptomeningeal
enhancement or focal lesions
• Can spontaneously remit or responds to steroids

SS Limbic Encephalitis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Peripheral Neuropathy
• Many patterns of neuropathy in SS
– Pure sensory
• Non-length dependent ganglionopathy (best known)
• Painful distal neuropathy
– Symmetric sensorimotor axonal neuropathy
– Others:
• Demyelinating neuropathy
• Cranial neuropathy (such as trigeminal neuropathy)

Testing
• Sensitivity for serology is poor:
– Anti-Ro: 40-50%
– Anti-La: 10-20%
• Schirmer test may be positive in majority
• Lip biopsy for salivary gland pathology is also
positive in majority

906
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Management
• Generally hard to treat
• Symptomatically treated with neuropathic
agents
• Unclear which immunomodulatory regimen to
use:
– Corticosteroids: 30-40% response rate
– IVIg: 30-40% response
– Rituximab
– Infliximab

Conclusions
• Majority of the rheumatological diseases can
cause neurological symptoms via a variety of
mechanisms
• Treatment needs to be tailored to the
mechanism (ie. no generic treatment for lupus
cerebritis)
• We are still learning about how many of the
systemic autoimmune diseases cause
neurological symptoms
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, Chairman
Miriam Sydney Joseph Professor of Neurology
Harvard Medical School

Miriam Sydney
Joseph Samuels

Disclosures
• None

908
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Neurology of, Electrolyte and

Acid Base Disorders
Problem Based Learning of
Common Problems in Metabolic
Neuromedicine

Concepts to Understand Metabolic Encephalopathy

• A-a gradient
• Osmolality and tonicity
• Volume status by physical exam (JVP, BP, HR)
• Calcium status
• Uric acid status
• Azotemia (renal vs pre-renal)
• Anion gap
• Respiratory acidosis and alkalosis (acute vs
chronic)
• Metabolic acidosis and alkalosis

909
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Alveolar Arterial Gradient

The alveolar arterial (A-a) gradient reflects

the barrier to oxygen diffusion from the
alveolus to the arterial blood

Calculating the A-a gradient

• A-a = (760 torr-47 torr)(FiO2)-paCO2/.8-paO2

760 = atmospheric pressure
FiO2= fraction of O2 in inspired air (.21 in room
air)
paCO2 = measured arterial partial pressure of
CO2
0.8 = diffusion coefficient for CO2 (constant)
PaO2 = measured arterial partial pressure of O2

910
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

A-a Gradient in Room Air

A-a = (150 – PaC02/0.8) – PaO2

Normal A-a = age/4 + 4

At age 40 = 40/4 + 4 = 14
At age 100 = 100/4 = 4 = 29

Thus, normal = 0-30 rising with age

Causes of Increased A-a

Gradient
• Lung that is perfused but not ventilated
– Alveolar pulmonary edema
– Pneumonia

• Lung that is ventilated but not perfused

– Pulmonary embolism

911
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman

A 43 year old woman with a right frontal

grade 3 astrocytoma, previously treated
with temozolimide and radiation
therapy, develops lethargy and a low
grade fever. Her medications are:
dexamethasone 1 mg q.d., famotidine
20 mg b.i.d., and nifedipine 60 mg. q.d.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman Exam

BP = 96/70; HR = 112; JVP = 3 cm.

Lungs clear
Cardiac exam normal
Abdomen shows striae
Neurological exam: drowsy; no
papilledema No focal signs

Relevant Laboratory Studies

• Na = 157 • pH = 7.44
• K = 3.1 • pCO2 = 36
• Cl = 116 • pO2 = 119
• BUN = 131 • Urine Na = 34
• Creatinine = 1.9 • Urine K = 32
• Calcium = 11.2 • Urine Creatinine = 45
• Glucose = 314 • LFTs = normal

913
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Which Of The Following Would You

Recommend?
• Mannitol and hyperventilation
• CT, LP, MRI and EEG
• Emergency Hemodialysis
• Acetazolamide and 50% dextrose
• .45% saline at 150 cc/hr
• Stop dexamethasone
• Sodium bicarbonate 44 meq IV

Osmolality and Tonicity

• Normal is 275-295
• May be directly measured by freezing point
depression or calculated
• Effective osmolality is called tonicity, indicating
the effect that osmolality has in moving water in
and out of cells
• Increasing BUN will increase osmolality but not
tonicity because urea passes into cells freely,
whereas hypernatremia and hyperglycemia will
increase osmolality and tonicity, because
sodium and glucose do not cross readily into
cells

914
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Calculate the Serum Osmolality

2Na + Glucose/18 + BUN/2.8

2(157) + 314/18 + 131/2.8 = 378

43 Year Old Woman

Acid-Base Status
pH above 7.42

PCO2 below 40

Therefore: Respiratory Alkalosis

915
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman

BUN:Creatinine ratio normal 20:1

131:l9 = 60:1

Therefore: pre-renal azotemia due to

catabolic steroids

916
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman

Urine sodium = 34

Urine is inappropriately dilute

Therefore: Osmotic diuresis or diabetes

insipidis

43 Year Old Woman

Volume Status
Jugular venous pressure = 3 cm.

BP = 96/70

HR = 112

Therefore: Hypovolemia

917
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman

Glucose Status
Glucose = 314

Therefore: Hyperglycemia probably

secondary to steroids

43 Year Old Woman

Calcium Status
Calcium = 11.2

Therefore: Hypercalcemia, probably

secondary to the calcium channel blocker
(nifedipine); hypercalcemia also promotes
a dilute diuresis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

43 Year Old Woman

Pathogenesis
Volume depletion due to:

Dexamethasone
Diabetes insipidus ( due to brain tumor)
Hypercalcemia ( due to calcium
blocker)

Which Of The Following Would You

Recommend?
• Mannitol and Hyperventilation
• CT, LP, MRI and EEG
• Emergency Hemodialysis
• Acetazolamine and 50% dextrose
• .45% Saline at 150 cc/hr
• Stop the dexamethasone
• Sodium bicarbonate 44 meq IV

919
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hyperosmolar States
General Principles

• Frequently seen in critically ill patient

• Typically associated with volume depletion
• Possible causes include:
– Central diabetes insipidus
– Nephrogenic diabetes insipidus
– Osmotic diuresis: glucose, mannitol, urea
nitrogen
– Impaired thirst mechanisms
– Fever causing increased insensible losses

Hyperosmolar States
Management Principles

• Address Primary metabolic abnormality

• Medications and nutrition are potential
culprits
• Determine volume needs by physical exam
• Determine free water needs separately:
– Calculate the free water deficit
– Calculate ongoing free water losses
– Calculate insensible (evaporative) water losses
(500-1000 ml/day) increasing by 125ml/day for
each degree of body temperature of 37°

920
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Calculation of the Free Water

Deficit
• Calculate the normal total body water
(NTBW)
– NTBW = Body weight (kg) x 0.6
• Estimate the total body solute (TBS)
– TBS = NTBW x 140meq/L
• Calculate the patient’s body water (PBW)
– PBW = TBS/patient’s serum Na

• Calculate the patient’s water deficit (PWD)

– PWD = NTBW - PBW
• Add more for large ongoing losses in the
urine (osmotic diuresis, diabetes insipidus) or
sweat (fever)

43 Year Old Woman

Treatment

Volume for hypovolemia (dilute saline)

Small dose of insulin for hyperglycemia

Discontinue nifedipine

Potassium supplementation

Work around the dexamthasone

921
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

72 Year Old Man

A 72 year old man with a left middle
cerebral artery stem embolism, who has
a history of NIDDM, hypertension, PAF,
and interior MI with residual left
ventricular dysfunction is on the
following medications: aspirin 325 mg
q.d.; glyburide 10 mg. q.d.; and
propranolol 80 mg. b.i.d.

72 Year Old Man

Examination
BP = 118/80; HR = 62/min; JVP = 5 cm.
Lungs clear
Heart normal
Abdomen: midsystolic abdominal bruit and
right femoral bruit
Distal pulses: diminished
Neurological exam: right hemiplegia and
aphasia

922
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

72 Year Old Man

Initial Clinical Course

ECG: unchanged from prior study

CXR: normal
U/A: 10-15 WBCs/hpf with some bacteria
Rx: IV heparin and oral trimethoprim-
sulfamethoxazole plus his usual
medications
TTE: hypokinesis of the inferior and high
lateral walls without evident thrombus
Telemetry: periods of atrial fibrillation

72 Year Old Man

Relevant Laboratory Studies
• Na = 134 • LDH = 208
• K = 6.8 • Alkaline phos = 113
• BUN = 43 • Urine Na = 7
• Creatinine = 1.5 • Urine K = 35
• Calcium = 10.4 • Urine creatinine = 64
• Uric acid = 8.4 • pH = 7.35
• Cholesterol = 282 • pCO2 = 34
• Glucose = 294 • pO2 = 93
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

72 Year Old Man

Hyperkalemia

Propranolol inhibits K intake into cells

Heparin inhibits aldosterone

Trimethoprin blocks renal secretion of K

72 Year Old Man

Acid Base Status
Pure Metabolic Acidosis
Gap = 134- (109 + 17) + 9 (normal)

Therefore: Non-gap metabolic acidosis

Diagnosis: Renal tubular acidosis type 4

(the diabetic renal syndrome)

924
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Renal Tubular Acidoses

Type 1 RTA Type 2 RTA Type 4 RTA

Reduced proximal
Impaired distal Decreased aldosterone
Primary defect bicarbonate
acidification secretion or effect
reabsorption

Plasma Variable, may be below

Usually 12 to 20 meq/L Greater than 17 meq/L
bicarbonate 10 meq/L

Variable, greater than 5.3

Urine pH Greater than 5.3 if above bicarbonate Usually less than 5.3
reabsorptive threshold

Usually reduced but

Reduced, made worse by
hyperkalemic forms
Plasma bicarbonaturia
exist; hypokalemia Increased
potassium induced by alkali
largely corrects with
therapy
alkali therapy

925
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

72 Year Old Man

Osmolality
2(Na) + Glucose/18 + BUN/2.8

2(134) + 294/18 + 43/2.8 = 298

Therefore: Hyperosmolality is present

72 Year Old Man

Volume Status
• JVP = 5 cm
• BP = 118 systolic
• HR = 62 beats/minute on a beta blocker

• Therefore: slight hypovolemia is present

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

72 Year Old Man

Pathogenesis
Renal tubular acidosis type 4

Hyperglycemia

Hyperkalemia

Mild volume depletion

72 Year Old Man

Treatment
Volume as sodium bicarbonate for acidemia
Small dose of insulin for hyperglycemia
Stop trimethoprin
Stop propranolol
Replace heparin with warfarin
Calcium for cardiac protection
Continuous monitor of ECG
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

A 94 year old woman is seen because

the medical service noted an “altered
mental status.” She has a past medical
history of tuberculosis in the distant
past, breast cancer and hypertension.
She reports taking no medication.

94 Year Old Woman

Examination and Initial Evaluation
BP = 132/85; HR = 96; JVP = 5cm
Lungs are clear; scar over the posterior
throrax
Heart: atrial gallop
Abdomen: normal
Skin: wrinkled and tented
Neurological exam: confusional (inattentive
state)
CXR: prior surgery and apical scarring
ECG: left ventricular hypertrophy, PVC’s, long
corrected QT interval
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

Relevant Laboratory Values
• Na = 118 • Alkaline phos = 87
• K = 3.1 • Cholesterol = 212
• Cl = 79 • ALT = 8
• HCO3 = 36 • AST = 11
• BUN = 32 • Urine Na = 37
• Creatinine = 1.3 • Urine K = 34
• Calcium = 8.3 • Urine Cl = 86
• Uric acid = 9.4 • pH = 7.53
• Mg = 1.3 • PCO2 = 43
• Glucose = 92 • pO2 = 88

Which of the Following Would You

Recommend?
• Salt poor albumin & loop diuretic
• Geriatrics consult
• Free water restriction
• Urine drug screen
• 0.45% saline at 150 cc/hr
• Dolbutamine holiday
• Transfer to another hospital
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

Long QT Interval Means Hypo…
• Hyponatremia

• Hypokalemia

• Hypomagnesemia

• Hypocalcemia

94 Year Old Woman

Volume Status
• Euvolemia

• Skin tenting, wrinkling are normal at age 94

• Volume assessment is done using neck veins,

cardiac exam and orthostatic signs

• Reduced skin turgor is the least reliable sign

930
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

Hyponatremia

• Many causes are possible including:

– Salt wasting
– SIADH related to breast cancer or TB
– Resetting of the osmostat

94 Year Old Woman

Acid Base Status

• pH = 7.53 (alkalosis)

• HCO3 = 36 (chronic metabolic)

• Therefore: pure metabolic alkalosis

931
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Brain MRI showed a T2 hyperintense lesion

in the central pons.
plaue

932
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Brain MRI showed T2/FLAIR hyperintense

lesions in the bilateral thalami and basal ganglia.

The central pontine lesion was quite

striking on T1 sequences as well.

933
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CT scan one week prior to the MRI (these images were all obtained 2 months
into the course) were striking for hypointensity in bilateral thalami and pons.

Both on T2 MRI (left) and CT scan (right) abnormal signal could be seen in the
high frontal cortex (arrows) suggestive of cortical laminar necrosis.

934
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

Hypothesis

• Suspicion of thiazide use because:

– High urine chloride
– Metabolic alkalosis (loss of HCl)
– Hyperuricemia

N.B. Many people are taking thiazides;

people with an altered mental status may
not know

94 Year Old Woman

Proposed Pathogenesis
• Thiazides caused:
– Urinary loss of NaCl (salt wasting) leading to
hyponatremia and hypochloremia
– Urinary loss of KCl caused hypokalemia
– Urinary loss of HCl caused metabolic
alkalosis
– Hypo, hypo, hypo caused long QT interval
– Hyponatremia caused confusional state

935
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hyponatremia
All hypotonicity is associated with hyponatremia,
but not all hyponatremia is hypotonic

• Isotonic: pseudo-hyponatremia (eg lipid;

protein)
• Hypertonic: external osmoles (eg mannitol)
• Hypotonic
– Hypervolemic: edematous (eg liver, renal, heart failure)
– Hypovolemic: diuretics; blood loss; Salt wasting nephropathy
including cerebral form; Addison disease
– Isovolemic: osmotic (eg hyperglycemia; reset osmostat;
spinal cord injury; hypothyroidism; massive polydipsia;
SIADH (lung, CNS, or inflammatory disease, such as
Guillain-Barre syndrome

Management of Hyponatremia
• Isotonic: no treatment
• Hypertonic: remove external osmoles, if
possible
• Hypotonic
– Hypervolemic: sodium restriction and Rx of disease
– Hypovolemic: volume (including Na) administration
– Euvolemic
• Acute (less than 48 hours): hypertonic (3%) saline
• Chronic (longer than 48 hours): water restriction; loop diuretics;
demeclocycline or lithium; argeninine vasopressin (ADH)
antagonist, conivaptan (Vaprisol)

936
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rate of Correction of
Hyponatremia Depends on Rate
of Its Development
• In acutely developing (less than 48 hours)
hyponatremia, the brain cells will swell,
causing increased intracranial pressure that
can be life threatening.
• In chronically developing hyponatremia, the
brain is the only organ that compensates by
extruding osmoles. If, upon this
compensated substrate, a hyperosmolar fluid
is administered (even normal saline), then the
brain cells will rapidly shrink, causing osmotic
demyelination (formally known as central
pontine myelinolysis.

Which of the Following Would You

Recommend?
• Salt poor albumin & loop diuretic
• Geriatrics consult
• Free water restriction
• Urine drug screen
• 0.45% saline at 150 cc/hr
• Dolbutamine holiday
• Transfer to the Beth Israel Deaconess

937
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

94 Year Old Woman

Treatment

• Free water restriction

• Intravenous Mg for cardiac protection

during the correction process

• Discontinue the thiazide diuretic

Acute vs Chronic Hyponatremia

Acute Chronic
• Day, weeks or
• A few hours months

• No time for • Solute extruded

compensation
• Rapid correction
• Brain edema is problem causes brain
shrinkage
• Hypertonic saline • Hypertonic saline is
required contraindicated

938
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 Year Old Man

64 year old man with coronary artery
disease, diabetes mellitus, emphysema
is found confused and complaining of
dyspnea. His medications are: aspirin
325 mg q.d.; chlorpropamide 250 mg.
q.d.; verapamil 80 mg. t.i.d.; He was
noted to have a generalized seizure in
the emergency department so
neurology was called.

64 Year Old Man

Initial Evaluation
BP = 110/84; HR = 82 (irregular); JVP = 14 cm
Lungs: diffuse rales are heard
Heart: summation gallop is appreciated
Extremities: peripheral edema and cyanosis
noted
Neurological exam: confused with evidence for a
primarily sensory symmetrical length dependent
peripheral neuropathy
ECG: poor R waver progression, ventricular
hypertropy, multifocal atrial tachycardia
CT brain without contrast: atrophy; no acute
lesions
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Relevant Laboratory Studies

• Na = 123 • ALT = 283
• K = 4.7 • AST = 204
• Cl = 91 • LDH = 466
• HCO3 = 19 • Alkaline phosphatase =
• BUN = 37 139
• Creatinine = 1.8 • Urine Na = 7
• Calcium = 8.7 • Urine K = 23
• Uric acid = 12.4 • pH = 7.29
• Glucose = 42 • PCO2 = 40
• PO2 = 52

64 Year Old Man

Acid Base Status

pH = 7.29 (acidosis); HCO3 = 19(metaboic)

Is there any respiratory compensation? To find
out, apply Winter’s formula:
1.5 (HCO3) + 8 = predicted pCO2
1.5 (19) = 30 + 8 = 38
Measured pCO2 is 40.
Therefore: Pure metabolic acidosis

940
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 Year Old Man

Calculation of the Anion Gap
Na – (Cl + HCO3) = the anion gap (n<12)

123 – (91 + 19) = 123-110 = 13

ΔGap=Gap-12=13-12=1
Corrected HCO3=measured HCO3-ΔGap=19+1=20

Therefore, this is a gap metabolic acidosis secondary

to lactic acid generated by the seizure
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 Year Old Man

Calculation of the A-a
Gradient
• A-a = (150-pCO2/0.8) – pO2
• A-a – (150-40/0.8) – 52 = 100 – 52 = 48
• Normal A-a for 64 year old is 64/4 + 4 =
20
• Therefore: there is an increased A-a
gradient probably because of lung that
is perfused but poorly ventilated
because of congestive heart failure
(pulmonary edema)

64 Year Old Man

Abnormal Liver Function

• High hepatic transaminases with

relatively more normal alkaline
phosphatase and bilirubin suggests the
abnormal LFT’s are due to passive
congestion of the liver because of heart
failure.

942
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 Year Old Man

Hyponatremia

The hyponatremia is the hyotonic,

hypervolemic type, caused by the
edematous state of congestive heart
failure.

64 Year of Man
Hyperuricemia

The hyperuricemia is due to the lactic

acidosos

943
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 Year Old Man

Pathogenesis

CHF causes hypotonic, hypervolemic

hyponatremia

Hyponatremia causes seizure

Seizure causes lactic acidosis

Lactic acidosis causes hyperuricemia

64 Year Old Man

Treatment

• Treat CHF with after load reduction with

captopril

• Supplemental Oxygen

• 50% dextrose in water for hypoglycemia

• Free water restriction

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

17 Year Old Woman

A 17 year old woman with a long-

standing severe seizure disorder is
admitted to the Neuro-ICU in status
epilepticus. In the past she took
phenytoin and phenobarbital. Two
weeks earlier, carbamazepine was
added.

17 Year Old Woman

Initial Evaluation
BP = 160/100; JVP not determined
Chest: clear; Cardiac exam: normal
Abdomen: normal
Extremities: no cyanosis or edema
Neurological examination: no papilledema;
constant generalized seizures noted
Propofol infusion results in temporary
improvement of the seizures, but they recur.

945
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

17 Year Old Woman

Relevant Laboratory Studies
• Na = 109 • ALT = 23
• K = 4.7 • AST = 155
• Cl = 78 • LDH = 402
• HCO3 = 10 • Cholesterol = 157
• BUN = 9 • Alkaline phosphatase =
• Creatinine = 0.7 87
• Calcium = 8.5 • Urine Na = 56
• PO4 = 3.6 • Urine K = 61
• Uric acid = 2.9 • Urine creatinine = 30
• Mg = 2l2 • pH = 7.07
• Glucose = 188 • pCO2 = 46
• pO2 = 109

17 Year Old Woman

Acid Base Status

• pH = 7.07 (acidosis); HCO3 = 10 (acidosis)

• Thus a metabolic acidosis is definitely present.
• Anion gap = 109 – (78 + 10) = 21; It’s a gap
acidosis.
• Is there a respiratory component as well? To find
out, apply Winter’s formula:
• Calculated pCO2 = 1.5 (10) + 8 = 23
• Measure pCO2 = 46
• Therefore, there is also a respiratory acidosis

946
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

17 Year Old Woman

Hyponatremia

• Hypotonic, isovolemic hyponatremia

• SIADH, probably caused by
carbamazepine
• Low serum uric acid (2.9) is typical of
SIADH
• Low hepatic transaminases is also
suggestive of SIADH

947
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

17 Year Old Woman

Pathophysiology – a mad cycle

• Carbamazepine causes SIADH

• SIADH causes hyponatremia
• Hyponatremia causes aggravation of seizures
• Seizures cause lactic acidosis & aggravate
SIADH
• Phenobarbital causes depressed level of
consciousness which causes respiratory
acidosis
• Mixed acidosis further aggravates seizures

17 Year Old Woman

Treatment

• Hypertonic (3%) saline, 400 cc bolus

• Free water restriction
• Fluid replacement as sodium
bicarbonate
• Discontinue the carbamazepine and
phenobarbital

948
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

27 Year Old Man

A 27 year old man, who was involved in
a major motor vehicle accident, came to
the ED in shock and was resuscitated
with IV crystalloid, packed red cells and
dopamine. Laparotomy revealed a
ruptured spleen and hepatic contusions.
He has multiple fractures. CT head
shows a large subdural hematoma with
shift. The SDH was evacuated and a
compartment syndrome of the right leg
was treated surgically.

27 Year Old Man

Post-Operative Evaluation

• BP = 116/55; JVP = 6 cm
• Lungs: clear
• Heart: S3 gallop and a systolic flow
murmur
• There was no urine output
• Neurological exam: Deeply comatose;
no eye movements to passive head
turning; pupils 3 mm are barely reactive;
no reflexes; toes mute

949
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

27 Year Old Man

Relevant Laboratory Studies
• Na = 120 • ALT = 134
• K = 5.3 • AST = 576
• Cl = 86 • LDH = 2721
• HCO3 = 11 • Alkaline phosphatase =
• BUN = 31 132
• Creatinine = 2.0 • Hct = 28
• Calcium = 8.2 • Prothrombin time = 16.3
• PO4 = 7.2 • CK = 21,300
• Uric acid = 9.9
• pH = 7.25
• Mg = 2.2
• Glucose = 102 • pCO2 = 40
• pO2 = 83

27 Year Old Man

Acid Base Status

• pH = 7.25 (acidosis)
• HCO3 = 11 (metabolic acidosis)
• Anion gap = 120 – 97 = 23
• Therefore, this is a gap acidosis
probably due to lactic acid from tissue
injury

950
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

27 Year Old Man

Calculation of the A-a Gradient
A-a = (150-pCO2/0.8) – pO2

A-a = (150 – 40/0.8) – 83 = 100 – 17 = 17

Normal A-a for a 27 year old is 27/4 + 4 =

11

Therefore, there is an increased A-a

gradient

951
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

27 Year Old Man

Pathogenesis

• Trauma causes rhabdomyolysis

• Rhabdomylyisis causes renal failure
(ATN)
• Renal failure causes metabolic acidosis,
hyperkalemia and elevated enzymes
• Therefore, the main metabolic problem
is acute renal failure

27 Year Old Man

Treatment

• Acute hemodialysis

• Hyperventilation
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

21 Year Old Engineering

Student
A 21 year old engineering student is
brought to the emergency department by
his friends because of staggering gait,
lethargy, weakness and slurred speech.
The people who brought him to the ED
disappeared before any questions could
be asked and no past medical history is
obtainable.

21 Year Old Engineering Student

Initial Evaluation
BP = 88/50; HR = 132 (regular)
Heart: a midsystolic click is heard
Lungs: diffuse wheezing
Abdomen: diffusely tender without rebound
Skin: a facial vescicular rash was noted
Neurological exam: awake but confused; could
not test memory; no aphasia. He was dysarthric
and ataxia of all four limbs prevented him from
being able to stand or walk. Reflexes were
average in amplitude and equal bilaterally; toes
were both flexor.

953
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

21Year Old Engineering Student

Relevant Laboratory Studies
• Na = 127 • ALT = 65
• K = 2.0 • AST = 32
• Cl = 113 • LDH = 201
• HCO3 = 4 • Alkaline phosphatase = 78
• BUN = 53 • Urine Na = 25
• Creatinine = 1.7 • Urine K = 10
• Calcium = 10.7 • Urine creatinine = 185
• PO4 = 1.4 • pH = 6.97
• Uric acid = 2.3 • pCO2 = 43
• Mg = 1.8 • pO2 = 54
• Glucose = 98

Which of the Following Would Your

Recommend?
• 0.9% saline
• 0.45% saline with 66 meq/L NaHCO3
• Albuterol
• CT, LP, EEG and MRI
• Plasma hippurate level
• Ethanol infusion and acute hemodialysis
• Skin biopsy with Tzanck preparation

954
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

21 Year Old Engineering Student

Acid Base Status

• pH = 6.97 (severe acidosis)

• HCO3 = 4 (metabolic acidosis)
• Anion gap = Na – (Cl + HCO3) = 127 – 117 –
10
• Therefore, this is a severe hyperchloremic
non-anion gap metabolic acidosis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

21 Year Old Engineering Student

Calculating the A-a Gradient

• A-a = (150-pCO2/0.8) – pCO2

• A-a = (150 – 43/0.8) – 54 = 96 – 54 =
42
• Normal for a 21 year old = 21/4 + 4 = 9
• Therefore, there is a huge A-a gradient
probably reflecting lung that is perfused
but not well ventilated (diffuse
wheezing)

21 Year Old Engineering Student

Pathogenesis

• Toluene inhalation causes a metabolic

acidosis which causes an encephalopathy
• Toluene inhalation causes bronchospasm
which leads to hypoxemia with a large A-a
gradient, which aggravates the
encephalopathy
• Hyponatremia and hyokalemia are due to
excretion of sodium and potassium
hippurate

956
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

21 Year Old Engineering Student

Toluene Poisoning

• Non-anion gap metabolic acidosis with

hyponatremia and hypokalemia
• May be due to direct toxicity-induced distal
renal tubular acidosis
• An alternative explanation is overproduction
of hippurate, a major toluene metabolite,
which drags Na and K into the urine when
excreted
• Toluene is inhaled, often producing a
vescicular rash around the nostrils

21 Year Old Engineering Student

Pathogenesis

• Toluene inhalation causes a metabolic

acidosis which causes an encephalopathy
• Toluene inhalation causes bronchospasm
which leads to hypoxemia with a large A-a
gradient, which aggravates the
encephalopathy
• Hyponatremia and hyokalemia are due to
excretion of sodium and potassium
hippurate
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Which of the Following Would Your

Recommend?
• 0.9% saline
• 0.45% saline with 66 meq/L NaHCO3
• Albuterol
• CT, LP, EEG and MRI
• Plasma hippurate level
• Ethanol infusion and acute hemodialysis
• Skin biopsy with Tzanck preparation

21 Year Old Engineering Student

Management
• Urine hippurate level to document the
cause

• Sodium bicarbonate for acidosis

• Respiratory support as necessary

958
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, Chairman
Miriam Sydney Joseph Professor of Neurology
Harvard Medical School

Miriam Sydney
Joseph Samuels

959
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurocardiology

Disclosures
• None
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Borderlands of Neurology and

The Rest of Medicine
Martin A. Samuels, MD, DSc (hon), MACP, FAAN
Chairman, Department of Neurology
Brigham and Women’s Hospital
Professor of Neurology
Harvard Medical School

The Borderlands
• Neurocardiology
• Neuropulmonology
• Neurohematology
• Hypercoagulable States
• Inflammation and Neurologic Disease
• Neurohepatology
• Acid-Base and Electrolyte Neurology
• Neurologic Aspects of Organ Transplantation
• Neurologic Aspects of Rheumatic Disorders

961
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

From Cannon to
Voodoo to
Takotsubo
A Prototype for the Influence of the Nervous System on the Visceral Organs

Prologue
Ideas are constantly changing memes that bubble
up from an evolutionary cauldron. Like genes,
those that reproduce themselves survive, by
infecting other brains. Research is therefore the
process whereby a mind (brain) hosts some
memes for a brief time as they pass from the
brains before us to those that will follow. To
imagine that one actually “discovers” anything is
the height of hubris. The story that follows traces
one such process over about a hundred years,
including my own involvement over the last 40.

962
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

My (virtual) Lab
• Ivan Pavlov • Stephen Oppenheimer
• Hans Selye • William Talman
• Walter Cannon • Claude Bernard
• Curt Richter • Vladimir Hachinski
• John Romano • David Cechetto
• George Engel • Felix Meerson
• Harold Levine • Ilan Wittstein
• George Burch • James Skinner
• Bernard Lown • Matthew Levy

Acts
Chapter 5
Verses 1-10
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Opening of the Peter Bent Brigham Hospital 1913

Edsall Osler Councilman

Cannon Minot Cushing Christian
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ivan Pavlov with Walter Cannon in Boston in 1929

H. Houston Merritt
Q. How do you keep up
on the literature?

A. I skip the articles on

treatment
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

966
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Eng and Chang, “The Siamese Twins” in an Early Woodcut

Eng and Chang at Their Wedding

967
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Plaster Cast of Eng and Chang, “The Siamese Twins”

Made at the Autopsy Done at the College of Physicians, Philadelphia

968
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

970
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

971
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Karoshi

Death
By
Overwork
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

973
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Fan Has Heart Attack as Bettis Fumbles

Terry O'Neill, 50, of Pittsburgh, was watching the game at a barand had a heart attack seconds after Jerome Bettis fumbled trying to score from
the 2-yard line late in the fourth quarter. Quarterback Ben Roethlisbergerprevented the Colts' Nick Harperfrom returning the recovered ball for a
touchdown and the Steelers hung on for a 21-18 win.
O'Neill said Bettis is his hero.
"I wasn't upset that the Steelers might lose," he said. "I was upset because I didn't want to see him end his career like that. A guy like that deserves
better. I guess it was a little too much for me to handle."
O'Neill, who was recovering at a hospital, credits two firefighters with saving him.
"The Steelers won the game and I'm still alive, so I guess I'm doing pretty good," he said.
He will have a pacemaker implanted to control an irregular heartbeat and he was prescribed medication to deal with the hypertension.
And while he would like to go to the bar to thank the guys who saved him, O'Neill said, "but for the most part I guess I should probably take it
easy and watch the game at home."
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sudden Death During Excitement

During Sporting Events
• World cup games (2006) in which the
German team was involved were compared
to other games
• A statistically significant increase in cardiac
events (2.66 X controls), including sudden
death, occurred in Germany during on days
when the German team was playing
Wilbert-Lampen U, et al. Cardiovascular events during
World Cup Soccer 2008; NEJM 358: 475-483

975
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

976
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

977
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

978
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Bowler collapses and dies after rolling 300 game

RAVENNA, Mich. (WZZM) - Teammates in his bowling league think

after rolling a perfect 300 game Don Doane's heart just gave out.

"You get nervous shooting a 300," says teammate Todd Place. "The
pressure keeps building," says bowling alley owner Jim Nutt.
Minutes after achieving the life long goal of a perfect game the 62 year
old bowler collapsed and died at Ravenna Bowl in Ravenna. "Don just
collapsed," says alley owner Nutt. " At first we thought he just fainted."
"Then when I rolled him over I realized it wasn't good," says teammate
The teammates say he was giving a high-five minutes before. They tried
to revive him but Doane never spoke

979
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Slobodan Milošević

Dies of “heart attack” in his cell, March 11, 2006

980
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Kenneth Lay
Enron Founder Dies Before
Sentencing
July 5, 2006

Bernard Madoff

? ?

981
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuro-Cardio-Neurology

75 year old woman, passed out on news of

her son’s death (case courtesy of Joel
Morgenlander, M.D., Neurology, Duke
University
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Two Sisters

A woman in her 70’s collapses and is

brought to the emergency department by her
sister, who is told the the problem is a lethal
intracerebral hemorrhage. Upon hearing the
news the second sister also collapses.

Sister 1

Sister 2

983
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Life Setting in Which Sudden Death

Occurs (George Engel, 1971)
• Collapse or death of a close person
• During acute grief
• Threat of loss of a close person
• During mourning or on an anniversary
• On loss of status or self-esteem
• Personal danger or threat of injury
• After danger is over
• Reunion, triumph, or happy ending

26 Year Old Man with Subarachnoid Hemorrhage

984
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Circulation 1954
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Major Types of
Electrocardiographic Changes in
Patients with Neurologic Disease

Repolarization Changes
Arrhythmias
“Ischemic” changes

50 Year Old Woman’s Routine Admission ECG

986
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

50 year old woman immediately after left middle cerebral embolism

64 year old man admitted for blood in stool, routine ECG

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

64 year old man, repeat ECG with no clinical changes noted

64 year old man, brain dead after status epilepticus

988
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

38 year old women after subarachnoid hemorrhage

32 year old man with a subarachnoid hemorrhage

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Top of Basilar Aneurysm Repair, Under Anesthesia

Top of Basilar Aneurysm Repair; Traction on Neck of Aneurysm

990
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Top of Basilar Aneurysm Repair; Release Traction on Aneurysm Neck

Top of Basilar Aneurysm Repair; Aneurysm Clip is Now in Place

991
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Top of Basilar Aneurysm Repair, Surgery Over

50 Year Old Woman with Abdominal Pain in the Emergency Department

992
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

50 Year Old Woman With Abdominal Pain and Drowsiness

50 Year Old Woman With Abdominal Pain, Now in Coma

993
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

50 Year Old Woman With Abdominal Pain, Now Brain Dead

50 Year Old Woman with Abdominal Pain; in Coma

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

50 Year Old Woman with Abdominal Pain; Gross Autopsy

46 Year Old Man with Absence Spells and Dizziness

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

46 Year Old Man with Absence Spells and Dizziness

46 Year Old Man with Absence Spells and Dizziness

996
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

46 Year Old Man with Absence Spells and Dizziness

46 Year Old Man with Absence Spells and Dizziness

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

46 Year Old Man with Absence Spells and Dizziness

The Policeman
• 40 year old policeman was abruptly told that a
complaint had been lodged against him
• He was unaware of any such complaint and the
details of the accusation were not provided
• He was discharged from his job and forced to turn in
his badge on the spot
• On his way home, he began to experience episodes of
palpitations, often culminating in syncope during
which his eyes were noted to be “rolled up”

998
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Policeman
• He was admitted after one such spell and the
baseline ECG was normal
• Cardiac MRI, ETT and EP study were all
normal
• As he related the details of the experience of
being suspended to his psychiatrist and
cardiologist, he developed palpitations and lost
consciousness
• The following ECG was recorded during the
spell

40 year old man with normal heart and intense

emotional distress, during recollection of events.

999
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Policeman
• He was treated with cognitive behavioral
therapy
• The episodes of palpitations and syncope
stopped and he was discharged on no
medications
• He was ultimately exonerated of all charges
• No further episodes have occurred

30 Year Old Man

• 30 Year old man was admitted for a medical
indication but had severe depression
• He made his way to the roof of a 16 story
hospital and threatened to jump
• After a 20 minute unsuccessful negotiation,
he leapt to his death

1000
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

30 Year Old Man who Jumped to His Death after 20 Minutes on Roof

Man Jumps
from Eiffel
Tower
After 20
Minute
Negotiation
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cardiac Contraction Band Necrosis

1002
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Mineralization of Cardiac Contraction Band Necrosis

Spectrum of Electrocardiographic
Changes in CNS Disease
P Wave - Tall and peaked
PR Interval - Prolonged or shortened
Q Wave - Pathological
S in V1 + - Exceeding 35mm (“LVH”)
R in V5
ST Segment - Elevated or depressed
T Wave - Peaked, flattened or inverted
QTc Interval - Prolonged or shortened
U Wave - Tall (exceeding 1mm) or inverted

1003
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Characteristics of
Contraction Band Necrosis
• Recognizable early
• Cells die in contracted state
• Cells may calcify early
• Mononuclear cell response
• Multifocal distribution
• Subendocardial predisposition
• Left ventricular apex maximum
• May be hemorrhagic

Contrasts Between Coagulation Necrosis

and Contraction Band Necrosis
Coagulation Necrosis Contraction Band Necrosis
Takes hours to recognize Recognizable rapidly

Cells die in relaxed state Cells die contracted

Early calcification rare Early calcification the rule

Polymorphonuclear response Mono & RBC response

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Synonyms for Contraction Band Necrosis

(Caulfield, 1959)
• Myofibrillar degeneration
• Coagulative myocytolysis (Baroldi)
• Acute focal myocarditis (Stoffan, 1888)
• Acute interstitial myocarditis (Fiedler, 1899)
• Digitalis induced myocardial necrosis (Lewitzky, 1904)
• Adrenalin induced cardiac necrosis (Erb, Fischer, Ziegler ‘05)
• Ergosterol induced cardiac necrosis (Selye, 1929)
• Exercise induced cardiac necrosis (Buchner & Lucadoo ‘34)
• Potassium deficiency induced cardiac necrosis (Schrader ‘37)
• Electrolyte-steroid-cardiopathy with necrosis (Selve, 1957)
• Artifact ( physiologic change) in endocardial biopsy material

Models for the Production of

Neurogenic Cardiac Lesions

• Catecholamine effect
• Stress ± steroid
• Nervous system stimulation
• Reperfusion

1005
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Production of Neurogenic Cardiac

Lesions by Catecholamines

• Josue’s adrenalin infusions (1907)

• Cardiac pathology and EKG changes (Chapel, ‘57)
• Catecholamine cardiomyopathy (Reichenbach, ’70)
• Excitatory neurotransmitter toxicity

Production of Cardiac Lesions by Stress

• The Pavlovian School
• Hans Selye’s Stress Concept (1936)
• The Chemical Prevention of Cardiac Necroses, Electrolyte-
Steroid-Cardiopathy with Necroses (ESCN) - Selye, 1957
• ESCN Blocked by Antiadrenergic Agents (Rabb, 1961)
• Sudden Death During Psychological Stress (Engel, 1971)
• Human Stress Cardiomyopathy (Cebelin & Hirsh, 1980)
• Psychological Factors in Sudden Death (Lown & DeSilva, 1980)
• Earthquake (Trichopoulas, 1981)
• Stress Damage to Nonischemic Parts of the Heart After
Myocardial Infarction (Meerson, 1983)
• Panic Attacks (Coryell, 1986)
• Sudden Unexpected Nocturnal Death Syndrome (Parrish, 1987)
• Catastrophe induced sudden deaths (September 11, 2001)
• Neurohumoral effects of myocardial stunning (Wittstein, 2005)
• Takotsubo (octopus pot)-like cardiomyopathy-apical balooning
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hans Selye
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Patient Case History

(courtesy of Leonard Lilly, M.D.)
• 62 year old woman, previously healthy,
presented to hospital with chest
discomfort
• Symptoms began 6 hours earlier,
described as a diffuse anterior heaviness
with shortness of breath; started minutes
after being told that her son was
seriously injured in an automobile
accident

1008
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Laboratory Studies

Creatine Kinase:
Total: 204 (Normal < 218 U/L)
MB: 7.6 (Normal < 5.0 ng/mL)

Cardiac troponin I:
1.07 (Normal < 0.04 mcg/L)

Echocardiogram

1009
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LAD Coronary Angiogram

Right Coronary Angiogram

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Left Ventriculogram

1011
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Course
• Remained clinically stable: chest
discomfort resolved; no heart failure or
arrhythmias
• Maintained on aspirin, beta-blocker,
ACE inhibitor; No diuretic requirement
• Discharged on hospital day 3
• Returned for repeat echocardiogram

Repeat Echocardiogram
Two weeks later

1012
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cardiac Biomarker Elevation

In Takotsubo-like Cardiomyopathy
(Gianni M et al. European Heart Journal 2006;27:1523.)

Troponin 86.2 %
CK - MB 73.9 %

Usually mild elevations, despite

marked ECG and wall motion
abnormalities

Regional variation in beta-adrenergic receptor density in cats

1013
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Myocardial Damage and EKG Changes

Reflect the Distribution of Catecholamines

1014
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Production of Cardiac Lesions by

Nervous System Stimulation
• Karplus’ stimulation of the Hypothalamus (1908)
• Heart and GI Lesions Produced by Hypothalamic Stimulation (Watts
and Fulton, 1935)
• Production of ECG Changes and Cardiac Necrosis by Lateral
Hypothalamic Stimulation; Prevention of this phenomenon by Lesions
in the Sympathetic Outflow (Melville, 1963)
• Adrenalectomy Does not Prevent These Changes From Occurring
(Hawkins & Cloner, 1971)
• Sudden Death in Epilepsy (Jay & Leestma, 1981)
• Reversible Prevention of Cardiac Lesions by Cooling Limbic
Connection to Hypothalamus (Skinner, 1981)
• Insular Cortex Stimulation Produced Arrhythmias and Caridac Lesion
(Oppenheimer, 1991)
• Myocardial Stunning After ECT (Zhu, 1992)
• Myocardial Dysfunction and NPE Caused by SAH (Fink, 1993)

Hypothalamic Stimulation in an Animal Model

ST segment
Normal elevation

Q waves
ST segment
depression

1015
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Bilateral Hypothalamic Stimulation for 20 Minutes

Before After

Cardiac Electron Micrograph after 20 Min. of Hypothalamic Stimulation

1016
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Production of Cardiac Lesions by

Reperfusion
• Cardiac Surgery (Cooley’s “Stone Heart” - 1972)
• Regions Around Myocardial Infarction
• After Angioplasty or Fibrinolytic Therapy
• Vasospasm followed by vasodilation
• Reperfusion - A Double Edged Sword
(Braunwald & Kloner, 1985)
– Mechanisms
• The calcium paradox (Zimmerman)
• The oxygen paradox (Hearst)

• Possible explanation for some of the takotsubo

phenomenon

Models for the Production of

Neurogenic Cardiac Lesions

• Catecholamine exposure
• Stress ± Steroid
• Nervous System Stimulation
• Reperfusion of the heart
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Schematic Diagram of the Innervation of the Heart

(after Truax)

Sympathetic and Parasympathetic Innervation of the Heart

1018
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Schematic Representation of the Major Cardiac Reflexes

Gross Wiring Diagram for the Major Cardiac Reflexes

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Detailed Central Nervous System Connections of the Cardiac Reflexes

Cartoon of the Receptor Operated Cardiac Calcium Channel

1020
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

From Lyon, et al. Nature Clinical Practice, 2008

Cardiac Regional Differences in

Response to Catecholamines
• Apex
– Epinephrine is dominant catecholamine
– Reaches heart via circulation from adrenal
– β2-adrenergic receptors are most dense
– β2-adrenoreptors are negatively inotropic
• Base
– Norepinephrine is the dominant catecholamine
– Reaches heart via sympathetic nerves
– β1-adrenergic receptors are more dense
– β1-adrenoreceptors are positively inotropic

From: Lyon, et al. Nature Clinical Practice, 2008

1021
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Structure and Metabolism of Adrenochrome, One of the Free Radical

Generating, Toxic Products of Catecholamines

Felix Z. Meerson
and
a fan

1022
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cartoon of Mechanism of Cardiac Damage by Free Radicals

(after Meerson)

Neurocardiac Damage Cascade

1023
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Medical Disorders Related to Neurocardiac

Phenomena
• Sudden death in middle aged men
• Sudden infant death syndrome (SIDS)
• Sudden death during asthma attacks
• Sudden unexplained nocturnal death syndrome (SUNDS)
• Sudden death during epileptic convulsions
• Sudden death during and after natural and manmade catastrophe
• Voodoo death
• Sudden death during excitement (e.g. sporting events)
• Sudden death related to cocaine use
• Sudden death during delirium
• Sudden death from threat of suicide
• Cardiac arrhythmias related to epilepsy
• Cardiac failure & enzyme release in neurologic catastrophes
• Takotsubo-like cardiomyopthy (myocardial stunning)

Treatment Strategy for Neurocardiac Damage

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurocardiology Baseball Quiz

Who is this?

Pete’s Revenge

1025
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Kenesaw Mountain
Landis

Shoeless Joe
Jackson
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Revenge
of Shoeless Joe

Summation
Death from fright is not a disease. Rather, in the
ancient world it was the small downside risk of
having the enormous benefit of an autonomic
nervous system, whose evolutionary advantage
may be summarized in one word – anticipation.
For this enormous advantage we pay the price of
being able to worry about a lion around the corner,
whether it is indeed present or not. In the modern
world, we are confronted by risks that are not
manageable with an autonomic storm. Indeed,
“staying cool” under stress has become a
characteristic for which the current forces of
evolution may be presently selecting.

1027
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

1028
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

Disclosures
• None

1029
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROHEMATOLOGY
The vital link between the blood and
the brain
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Insomnia
57 y/o man complains of insomnia; can’t
sleep because of a “crawling sensation” in
the legs. Polycyclic and SSRI anti-
depressants did not help. A neurologist
prescribed clonazapam which worked for
three months; then Sinemet which worked
less well for about a month. A diagnostic
test was performed.

1031
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurological Effects of Iron Deficiency

• Increased viscosity of rigid red blood cells
• Obsessive-compulsive-like disorders
– Restless legs
– Pica behaviors
• Starch (amylophagia)
• Ice (pagophagia)
• Earth (geophagia)
• Ekbom syndrome: OCD behaviors in iron deficiency
• May explain the unusual eating habits in pregnancy
• Appears to be a dopamine deficiency syndrome
• Treatment: dopamine agonists and benzodiazepines
• Mechanism is not fully elucidated, but could be:
– Fe is a co-enzyme for tyrosine hydroxylase
– Fe deficiency may change iron content of basal ganglia

Patient Follow Up

• Six months later he developed hematochezia

• Endoscopy revealed a cecal carcinoma

• Surgery was performed but there were hepatic

metastases from which he died

1032
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Nobel Prizes Related to

Cobalamin

• 1934: Whipple, Minot, Murphy – liver cure

• 1964: Hodgkin – x-ray crystalography
• 1965: Woodward – organosynthesis
• 1981: Fukui, Hoffman – quantum
mechanics

Anesthesiologist conclusions

• Pernicious anemia (auto-immune

gastritis)

• Superimposed nitrous oxide toxicity

• Anesthesia paresthetica
– Kinsella LJ, Green R. “Anesthesia paresthetica”: nitrous
oxide-induced cobalamin deficiency. Neurology 1995; 45:
1608-10.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dementia and Gait Disorder

42 y/o African American teacher
became rapidly demented and unable
to walk over a two month period. She
had a remote history of thyroiditis. A
brain biopsy had been suggested by a
neurologist. Exam showed severe
abulia and inability to walk because of
spasticity and proprioceptive problems.
Vision was untestable, but discs were
pale. She had vitiligo and a horizontal
scar on the neck.

Lab Studies in the Teacher

• Hct = 20
• MCV = 115
• Cobalamin = 0 (repeat = 0)
• Folate = 20
• Methylmalonic acid = 4.0
• Homocysteine = 68
• Anti-intrinsic factor antibodies 1:128
• Anti-parietal cell antibodies 1:64
• EMG/NCV: no significant neuropathy

1034
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis in The Teacher

• Pernicious anemia (auto-immune

gastritis)
• Associated other auto-immune
conditions
– Vitiligo
– Thyroiditis

Treatment and Follow-up on The

Teacher
• Treated with parenteral cobalamin for two
weeks followed by oral therapy

• Back to work in three months“better than

ever”

1035
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Epidemic
• In the 1990’s an epidemic occurred in the
western hemisphere
• Over five years 20,000 people were
affected by an illness characterized by
– Progressive blindness
– Progressive spastic ataxia
– Progressive deafness

Cuba

1036
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cause of The Epidemic

The Strachan Syndrome

• Impoverished diet, poor in B vitamins

• Cyanide toxicity from cigar smoke and
cassava
• Alcohol use
• The alcohol-tobacco amblyopia
• Strachan syndrome (William Henry Williams
Strachan (1874-1921) describe in WWI
starving prisoners of war
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Follow up on The Epidemic

A widespread public health program was

initiated consisting of oral administration of
oral B vitamins (folate, cobalamin,
thiamine and pyridoxine). Within six
months the epidemic ended and no new
cases occurred.

74 Year Old Man

•74 year-old man with a history of partial
gastrectomy (1973) due to gastric bleeding
developed 9 months of progressive LE numbness
and weakness. He has faithfully taken vitamin
supplements since the gastrectomy.

•Motor: bilateral quadriceps atrophy, 4/5 hip flex,

4/5 knee ext/flexion, 4/5 dorsi/plantar flexion.

•Sensation: No sensory level, dense loss in all

modalities from waist down.

•Reflex: 2/4 arms, 2/4 patellar, 1/4 ankles,

+Babinski bilaterally.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

74 Year Old Man

•Macrocytic anemia (Hct 31, MCV 105, retic
0.3%)
•Normal iron, folate, B12 (519),
homocysteine (9.2), MMA 0.39, SPEP, TSH,
HgA1C, vitamin A, B6, anti-Ro/La, HBV/HCV,
HIV, anti-MAG, anti-sulfatide, anti-GM1, anti-
Hu, anti-Yo, RPR, urine metal screen.
•EMG: a generalized, symmetric, length-
dependent, predominantly axonal,
sensorimotor polyneuropathy.

A Diagnostic Test Was Obtained?

1039
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

74 Year Old Man

Serum copper = 11 (normal = 70-155)

Diagnosis: Copper deficiency secondary to zinc,

which was part of his vitamin supplementation
regimen

Copper was repleted and the entire syndrome

remitted.

Young Woman with ICH’s

A 25y/o African American woman had

had at least three episodes of
intracerebral hemorrhage: right frontal
pole, left temporal tip and the latest was
a primary intraventricular hemorrhage.
A diagnostic test was performed.

1040
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1041
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1042
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Young Woman with

Movement Disorder
19 year old woman is seen because of a
progressively worsening movement disorder,
manifested by oral, buccal and lingual tics and
involuntary stiffening of the limbs. She is
adopted and knows nothing about her genetic
background. She has also been doing worse
in school, but cannot be certain whether this is
due to the movement disorder,failing cognitive
function or anxiety and depression

Young Woman with Movement

Disorder Exam
• Attention and episodic memory are judged
abnormal, but language is intact
• There is chorea, mainly seen around the mouth
and there is evidence for chronic tongue biting
• The limbs occasionally extend involunarily, but
between episodes there is no spasticity
• There is no muscle wasting
• There are no sensory abnormalities
• There is no ataxia
• Reflexes are brisk, but there are no Babinski
signs
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Young Woman with Movement

Disorder: Laboratory Studies
• Routine labs: all normal
• Copper and ceruloplasmin: normal
• Slit lamp examination: normal
• Huntington disease gene test negative
• MRI: slightly increased iron deposition
in the basal ganglia
• CSF: normal
• EEG: normal
• Routine CBC and blood smear: normal
• A diagnostic test is obtained
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis of Acanthocytosis

• Genetic tests are available for only a minority

of the disorders associated with
acanthocytosis
• Standard hematological tests (e.g. dry
smears of EDTA blood samples) show low
sensitivity
• A technique using isotonically diluted blood of
unfixed wet preparations allows for
quantitative measurement of acanthocytosis
(normal <6%)

Clinical Features of Neuro-

acanthocytosis
• Strikingly similar to Huntington disease
• Progressive cognitive decline
– Memory disburbances
– Frontal lobe syndromes are common
• Psychiatric symptoms
– Depression
– Anxiety
– Mania
• Movement disorder
– Akinetic-rigid syndrome
– Chorea/ballism
– Dystonia/athetosis
– Tics
– Extensor posturing
– Tongue biting
• Myopathy with elevated CK
• Axonal neuropathy in about half the cases

1045
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuro-Acanthocytosis
• Bassen-Kornzweig (abetalipoproteinemia, fat malabsorption, ataxia
and retinitis pigmentosa)
• Levine syndrome (1952): Boston VA case of hereditary neurological
disorder with acanthocytosis and normal lipoproteins
• Critchley syndrome (1967): Kentucky case of probable Levine
syndrome
• Amyotrophic chorea with acanthocytosis (1980): Japanese cases of
probable Levine-Critchley syndrome
• McLeod syndrome with a variant in the Kell blood group system due
to a mutation in the XK gene (x-linked; deletions in the CHAC gene
coding for the protein chorein)
• Walker syndrome (1997): autosomal dominant neuroacanthocytosis
due to a triplet repeat with intranuclear inclusions, due to a mutation
in the JPH3 gene
• Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa,
pallidal degeneration (HARP syndrome): an allelic form of
panthothenate kinase associated neuroegeneration (PANK 2
mutation)

Israeli Man

A 40 y/o Israeli man complained of

double vision. A neurologist found a left
abducens paresis. Work-up was
negative for diabetes, systemic
vasculitis and leptomeningeal
metastases. The weakness of the left
lateral rectus did not improve and was
joined by right lateral rectus weakness.
An image had prompted referral to a
neurosurgeon.

1046
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1047
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Israeli Man continued

Because of the appearance of the lesion

on the clivus and the patient’s ethnicity, a
diagnostic test was obtained.

1048
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Israeli Man Treatment and Follow Up

• The diagnosis of thalassemia with
extramedullary hematopoiesis was made

• He was treated with low dose radiation

and the lesion melted away with complete
resolution of the bilateral abducens palsies

Greek Man with Subdurals

A 64 year old man of Greek ancestry

had bilateral subdural hematomas
discovered on a CT scan that was done
for evaluation of brief dizzy spells. A
neurosurgeon recommended an
operation, but while waiting for a bed to
open in the hospital he suddenly
collapsed, was taken to an ED where he
was found in ventricular fibrillation.
Resuscitation failed.

1049
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1050
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1051
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Paget and Paraparesis

A 68 y/o man with Paget disease of
bone presents with a subacutely
progressing painless spastic
paraparesis. Ten years earlier he was
operated for the removal of a pelvic
mass which proved to be a
myelolipoma. Review of the CXR done
at the time of the surgery shows some
widening of the mediastinum, which
was not appreciated at the time

1052
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1053
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Extramedullary Hematopoiesis
• Part of a myeloproliferative disorder
– Agnogenic myelofibrosis with myeloid metaplasia
– Polycythemia rubra vera
– Myelogenous leukemia
– Essential thrombocytosis
• Compensation for bone marrow failure
– Myelophthisis: tumor, tuberculosis
– Thalassemia
– Spherocytosis
– Pernicious anemia
– Bone marrow toxicity: chemotherapy, benzene
• Incompetence of bony cortex
– Paget disease of bone
– fractures

Hemophiliac Becomes
Comatose

31 y/o man with factor VIII hemophilia

and AIDS from earlier blood
transfusions, stops receiving any factor
therapy at his own request. He
suddenly collapses into a deep coma.

1054
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

APML with Seizure

28 y/o man with acute promyelocytic
leukemia is observed to have a focal
motor seizure involving the left arm and
face, followed in minutes by drowsiness
and a left hemiplegia which does not
resolve when the seizure activity stops.
His platelet count is 27,000.

1056
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1057
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Numb Chin
A 70 y/o man notices while shaving that he
has no pain sensation over his left jaw in
the distribution of the inferior alveolar
nerve. He has no past medical history and
no other abnormalities are found on the
examination. A diagnostic test is
performed.

1058
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1059
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Subacute Weakness, Ataxia and

Altered Mental Status
68 year old man; July began making
financial mistakes; August became
unsteady on his feet; September
developed intermittent giving out of the
legs and paresthesias in the calves;
generally fatigued and admitted in early
October. Angioplasty 5 years ago; 2 ppd
smoker; screening colonoscopy in June
negative. He was from Brazil and was
there in the past year but was not ill as far
as he knew.

68 year old man continued

Neuro exam: confused (inattentive); no
cranial nerve abnormalities; slightly weak
distally; no sensory loss identified; equally
unsteady with eyes open or closed; gait
very abnormal requiring full assistance;
reflexes brisk except absent AJs; bilateral
Babinski signs.

1060
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Relevant Laboratory Studies

• Hct = 39.8 • Β-2-microglobulin = 4391

• C-reactive protein = 8.1 • Cryoglobulin = absent
• ESR = 63 • CH50 < 10
• Blood viscosity = normal • Anti-Hu = negative
• Cobalamin = 841 • Anti-MAG = negative
• Folate = 14 • CSF protein = 67
• ANA = 1:640 • CSF cells = 13 rbcs; 2
(homogeneous) lymphs
• SPEP = M component • CSF cytology = negative
• CXR = normal • CSF oligoclonal bands =
• SIEP = IgM lambda 958 absent
• MRI/A = non-specific white
matter disease

68 year old man continued

Over the next two weeks, he became
rapidly weaker and more encephalopathic.
EMG/NCV suggested axonal neuropathy;
Bone marrow biopsy: average cellularity
with scattered abnormal appearing plasma
cells averaging 10-15% of the nucleated
cells; sequential MRIs showed rapid
accumulation of ischemic lesions in the end
arterial territories bilaterally; TEE negative;
blood cultures negative; Hct fell to 23.7;
ANA rose to 1:1280; LDH rose to 531; Anti-
MAG=2635; viscosity=1.1 (normal)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ten Days Later

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
1064
Types of Plasma Cell Disorders
• Myeloma
– Multiple
– Osteosclerotic (plasmacytoma)
• Plasma cell leukemia
• Waldenstrom macroglobuliemia
• Immunoglobulin-related amyloidosis
• Monoclonal gammopathy of unknown
sugnificance (MGUS)
 Waldenstrom
Macroglobulinemia
• Described by Jan Waldenstom described in 1944

• Rare illness (about 10% as common as myeloma)

• Lymphoplasmacytoid lymphoma/immunocytoma

• Monoclonal IgM (kappa or lambda)

Intravascular Lymphoma
of the Brain

1066
 Abulic Doctor
A 60 year old doctor is noted to have a
change in his personality, in that he has
become unusually laconic and slow over the
past two months. He is not paralyzed but is
slow in thinking and responding to any
stimulus. No other abnormality of the
neurological examination is found. He had
generalized lymphadenopathy and a palpable
spleen. His blood counts and smear showed
a mild lymphocytosis. A diagnostic test is
performed.

1067
The Brigham Department of Neurology
Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

1068
 Insomnia

Milena Pavlova, M.D.

Department of Neurology, Brigham and Women’s Hospital
Assistant Professor, Harvard Medical School
Medical Director, Faulkner Sleep Testing Center

Disclosures – has
received research grants
from Biomobie, and
Lundbeck, inc.

1069
Diagnosing insomnia

Is there enough Is there a sleep Does it cause a

sleep Does it recur
fragmenting factor problem
•>3/week
opportunity •Medications •> 3 months
• Impaired function
•Environmental •Sleepiness
• >7 hours •Malaise/fatigue
•Primary sleep disorder – OSA,
• Adequate, RLS, Circadian rhythm
consistent timing disorder

Insomnia –criteria for diagnosis –

ICSD3
A. The patient reports, or the patient's parent or
caregiver observes, one or more of the following
1. Difficulty initiating sleep.
2. Difficulty maintaining sleep.
3. Waking up earlier than desired.
4. Resistance to going to bed on appropriate schedule.
5. Difficulty sleeping without parent or caregiver
intervention.

1070
B. The patient reports, or the patient's parent or
caregiver observes, one or more of the following
related to the nighttime sleep difficulty:
1. Fatigue/malaise.
2. Attention, concentration, or memory impairment.
3. Impaired social, family, occupational, or academic
performance.
4. Mood disturbance/irritability.
5. Daytime sleepiness.
6. Behavioral problems (e.g., hyperactivity, impulsivity,
aggression).
7. Reduced motivation/energy/initiative.
8. Proneness for errors/accidents.
9. Concerns about or dissatisfaction with sleep.

C. The reported sleep/wake complaints cannot be

explained purely by inadequate opportunity (i.e.,
enough time is allotted for sleep) or inadequate
circumstances (i.e., the environment is safe, dark,
quiet, and comfortable) for sleep.
D. The sleep disturbance and associated daytime
symptoms occur at least three times per week.
E. The sleep disturbance and associated daytime
symptoms have been present for at least three months
F. The sleep/wake difficulty is not better explained by
another sleep disorder.

1071
Insomnia subtypes
Idiopathic insomnia - a longstanding complaint mostly since
infancy or early childhood
without discernible cause and to persist over time without sustained
periods of remission
thought to arise from either genetically determined or congenital
aberrations in the sleep-inducing or arousal systems in the brain
No consistent genetic markers
Psychophysiological insomnia - heightened arousal and learned
sleep-preventing associations
difficulty sleeping in their usual sleep setting at home but in a novel sleep
setting
excessive focus on and worry about sleep and suffer from elevated levels
of cognitive and somatic arousal, particularly at bedtime.
Paradoxical insomnia, - previously called sleep state
misperception - complaint of severe sleep disturbance without
corroborative objective evidence of the degree of sleep disturbance
claimed.
a marked propensity to underestimate the amount of sleep
normative amounts of sleep on PSG, complaint of sleep loss

Insomnia subtypes
Inadequate sleep hygiene - sustained by daily
living activities that are inconsistent with the
maintenance of good-quality sleep and normal
daytime alertness.
daytime napping,
maintaining a highly variable sleep/wake schedule,
routinely using sleep-disruptive products (caffeine,
tobacco, alcohol) too close to bedtime,
engaging in mentally or physically activating or
emotionally upsetting activities too close to bedtime,
routinely using the bed and bedroom for activities
other than sleep, or
failing to maintain a comfortable environment for
sleep.
 Predisposing Precipitating Perpetuating

Major stress Maladaptive behaviors,

Inherited such as:
Illness
Other • Rumination
physiologic • Anxiety about not
change being able to fall
asleep
• Substance use –
caffeine to counteract
the resulting fatigue,
alcohol at bedtime

Insomnia prevalence – general

population

Full clinical syndrome of chronic insomnia disorder -

10% of the population
Transient insomnia - 30% to 35% of the population

1073
Comorbid disorders to consider
Sleep apnea
Movement disorders
RLS/PLMD anemia
parasomnias
Circadian rhythm disorders
Endocrine thyroid
Pain/neuropathy
Bipolar disease/anxiety
Medication effect

Restless Legs Syndrome and Periodic

Limb Movements of Sleep
RLS: indescribable uncomfortable sensations
that make the patient move limbs
PLMD – PLMS seen on PSG + symptoms
(fragmented sleep, daytime sleepiness, etc.)
Diagnosis: by history; PSG can give
confirmation of PLMS
Evaluation: other medical problems, sleep
disorders, ferritin level

1074
RLS/PLMD treatment
Dopamine-agonists (usually Pramipexole starting
at 0.125-0.25 - or Ropinirole 0.25-0.5 mg)
The dose of dopamine agonists should be kept low
to avoid augmentation
Gabapentin/gabapentin enacarbil
Fe supplementation if indicated (Ferritin<50),
to be continued until >100
Opiates – late in the disease for more severe
situations
Benzodiazepines – sometimes helpful with caution
 Homeostatic and circadian effects on
wakefulness

Homeostatic drive Sleep

Circadian drive Melatonin secretion

Circadian rhythm disorders

Delayed sleep wake 6 pm noon
phase disorder Typical

Advanced sleep wake Delayed -DSWPD

phase disorder Advanced ASWPD
Irregular sleep wake
phase disorder
Non-24 hour
Non-24 hour Non-24 hour
Non-24 hour
Non-24 hour
Treatment of circadian rhythm
disorders
Bright/blue light –
signals day
Melatonin – signals
night
Chronotherapy
Stress importance of
consistency

Treatment of insomnia
Counseling:
Sleep hygiene
Cognitive behavioral therapy
Relaxation techniques
Medications:
Benzodiazepines
Other hypnotics
Melatonin agonist
Antidepressants
Others

1077
CBT vs Medications – 5 studies
Consistently:
equal or better effects for CBT-I at post-treatment
significantly greater effects for CBT-I at long-term follow-up
Study: CBT vs N, mean age Follow-
up
McClusky et al. Am J Psychiatry 1991 TZ 30, 32 9 weeks
Morin et al. JAMA 1999 TM vs 78, 65 2 years
PL
Jacobs et al. Arch Intern Med 2004 ZP vs PL 63, 47 1 year
Sivertsen et al. JAMA 2006 ZP vs PL 46, 62 6 months
Wu et al. Psychother Psychosom. TM vs 71, 38 8 months
2006 PL

TZ = triazolam
ZP= zoplicone
PL = placebo

Good Sleep Rules

Determine time in bed – most need 7-9 hrs of sleep, do
not stay in bed longer
Use bed for sleep/intimacy only
Turn clock, so it is not visible from the bed
Naps, if taken at all, should be early afternoon at latest
Schedule regular wake times
Allow ample amount of light during the day
Allow dimmer light in the evening
Moderate or limit caffeine - last intake at noon
Moderate alcohol – best not close to bedtime

1078
Medications for insomnia
Benzodiazepines
Lorazepam, temazepam, oxazemapam
Other hypnotics
Zolpidem, zaleplon, eszopiclone
Melatonin agonists
Ramelteon, Tasimelteon
Orexin antagonist
Suvorexant
Antidepressants
Mirtazapine, trazodone, amitriptilyne, etc.
Others

Benzodiazepines
Advantages:
Cheap and ubiquitous
Problems:
Excessive sedation
High frequency of falls, esp. in elderly – due to
nonselective GABA effects
Hypotension
Tend to lose efficacy after longer use
Muscle relaxant effect
Significant cognitive effects
Long term cognitive effects.
Other hypnotics
Zolpidem, Zolpidem XR, Intermezzo (zolpidem
ultrashort acting, 3mg)
Zaleplon
Eszopiclone
Advantages
some are very short acting (Intermezzo, Zaleplon)
Some are FDA approved for chronic insomnia treatment
(eszopiclone, zolpidem CR).
Problems
Common side effects – parasomnia, over-sedation, etc.
Some also have a potential to lose efficacy

Antidepressants
Trazodone, Mirtazapine, Amitriptyline, low dose
doxepine
Advantages
More suitable for long-term use
May have advantages when combining treatment of
insomnia and pain (e.g. amitriptyline)
Problems
Anticholinergic side effects – dry mouth constipation,
etc.
Orthostatic hypotension

1080
Others
Antihistamines
Melatonin
Melatonin agonist
Orexin antagonist
Other substances

A 37-year-old woman with epilepsy, presents with

severe insomnia
Onset – briefly during first pregnancy
Sleep fragmentation with her first pregnancy
No childhood history of insomnia
No prior complaints of disturbed sleep
During the second pregnancy, she again experienced
similar difficulties, but they continued after the second
delivery
Typical bedtime - 11 p.m., difficulties with
sleepinitiation
No difficulties with sleep maintenance
Typical wake-time - 7 in the morning

1081
 PMH – epilepsy - 2 unprovoked generalized convulsions, both
of which occurred at around 6 in the morning; aura of
indescribable fear
lorazepam taken at times of aura to prevent generalized
convulsions
The patient was very concerned with the continuous and
slowly increasing dose needed to achieve sustained sleep
A dose of 0.5 mg of lorazepam was initially sufficient to let
her fall asleep, but was less effective after 4-5 months
the dose was increased to 1 mg and subsequent to that, she
was told to take 2 mg if need be

Follow-up
Over the next 24 months the patient
Improved her sleep hygiene
Became intermittently anxious that she will lose
sleep, the sleep loss will provoke a seizure and that
the convulsion may threaten her child
We discussed repeatedly the pro-s and con’s of
benzodiazepine use for insomnia in the setting of
epilepsy
She met with a psychologist to discuss anxiety
We discussed strategies to optimize exercise – she
did daily and intense exercise prior to the
pregnancy

1082
 With resuming exercise, insomnia
gradually improved, the patient slowly
tapered lorazepam
24 months after the initial visit she did not
need lorazepam for sleep initiation

Summary
Assess for sleep disruptors
Assess for comorbid conditions and primary sleep
disorders
Evaluate course and chronicity
Educate the patient
Medications should be used juditiously
1084
 Excessive Sleepiness

Milena Pavlova, M.D.

Department of Neurology, Brigham and Women’s Hospital
Assistant Professor, Harvard Medical School
Medical Director, Faulkner Sleep Testing Center

Disclosures – has received

research grants from Biomobie,
and Lundbeck, inc.

1085
Diagnosing hypersomnia

Is there Is there a sleep

enough sleep Does it recur
fragmenting factor
opportunity •>3/week
•Medications •> 3 months
• >7 hours •Environmental •Despite >7 hrs per night
•Primary sleep disorder – opportunity
• Adequate, OSA, RLS, Circadian
consistent rhythm disorder
timing

Optimal sleep need

In adults – 7-9 hrs
More in children
Consequences of insufficient sleep:
Worsening of other disease
Mood disorder
Cognitive
Impaired immune function (influenza vaccination)
Endocrine
abnormal leptin regulation
decreased glucose tolerance
disturbances of thyroid axis
abnormalities in stress hormone regulation
failure to suppress cortisol levels at night
acute release of cortisol after morning awakening

1086
 Consequences of Sleep
Restriction - Attention

1 7 14 1 7 14
Day in study Day in study

Van Dongen et al, SLEEP, Vol. 26, No.

2, 2003

Obstructive Sleep Apnea

Common cause of sleepiness

May also present with insomnia, esp. in
women
Snoring/apneas/gasping upon awakening
Aggravated by alcohol, sedatives, supine
sleep position, weight gain
Age increases risk, esp in women after
menopause
OSA -Nonspecific symptoms

Morning headache,
Attention deficits,
Mood disturbance
Aggravation of other disease (for example in a
patient with epilepsy who had well controlled
seizures for many years, and has breakthrough
seiures without other explanation)
Hypertension
Others – nocturia, night sweats, etc.

OSA - pathology

Individual events: partial or complete

cessation of breathing with preserved
respiratory effort (obstructive hypopnea or
apnea)
Results in desaturation and/or an arousal
Manifests as crescendo snoring, diminished
or absent airflow, and/or paradoxical chest
wall movements
Abnormal rate – currently >5 events per
hour;

1088
 Ways to evaluate OSA
PSG – overnight test in laboratory
Informative, but expense has lead to insurance denials
Allows evaluation for other sleep disorders (PLMS, RBD etc.), allows evaluation of sleep
structure and how OSA depends on sleep stage and body position
HST – 3 channels only (nasal airflow, oxymetry, respiratory effort)
Cheaper and easier
Gives no information about sleep or movement disorders
Screening for OSA (STOP BANG)
Snoring ?
Do you Snore Loudly (loud enough to be heard through closed doors or your bed-partner elbows you for snoring at
night)?

Tired ?
Do you often feel Tired, Fatigued, or Sleepy during the daytime (such as falling asleep during driving or talking to
someone)?

Observed ?
Has anyone Observed you Stop Breathing or Choking/Gasping during your sleep ?

Pressure ?
Do you have or are being treated for High Blood Pressure ?

Body Mass Index more than 35 kg/m2?

Age older than 50 ?
Neck size large ? (Measured around Adams apple)
For male, is your shirt collar 17 inches / 43cm or larger?
For female, is your shirt collar 16 inches / 41cm or larger?

Gender = Male ?

STOP BANG Scoring

• For general population

OSA - Low Risk : Yes to 0 - 2 questions
OSA - Intermediate Risk : Yes to 3 - 4
questions
OSA - High Risk : Yes to 5 - 8 questions
or Yes to 2 or more of 4 STOP questions +
male gender
or Yes to 2 or more of 4 STOP questions +
BMI > 35kg/m2
or Yes to 2 or more of 4 STOP questions +
neck circumference 17 inches / 43cm in
male or 16 inches / 41cm in female

1090
PAP treatment
Pressure can be determined via PSG titration
Auto-titrating devices are now most commonly used as first line
Standard follow-up measures:
Hours of use
Residual AHI
Other measures
Peak average pressure

Example of PAP compliance report -

brief
Individual nights

Typical visit structure

Identify disturbance (PMD or sleep specialist)
Diagnostic study (HST or PSG)
If negative HST followup PSG to confirm
If OSA – treatment, most commonly PAP, but always
discussed all options
Reevaluation at ~2 months – review compliance
If adherent and satisfied, can followup in a year or 6 months
If not – examine reasons:
Mask
Humidification
Pressure
Idiosyncratic problems
Comorbidities: insomnia for other reason, parasomnia/RBD, PLMS,
claustrophobia….
Reevaluation – if still problems, discuss other options again

1092
 Dental devices – for mild-moderate OSA, some severe
OSA
60-80% effective

Provent therapy
OSA – Other Treatment Options

Surgery – for select cases

Hypoglossal nerve stimulator
Conservative measures – to use with another
treatment or for few symptoms and mild OSA
Sleep position
Weight loss
Avoidance of ‘relaxants’ close to bedtime

OSA and incident of stroke –

Sleep Heart Health Study
SHHS: 5422 subjects without stroke – longitudinal cohort study
from 1995 and 1998
Exposure: OAHI
Outcome: incident of stroke
PSG at home
Follow-up – median of 8.5 years
Results: 193 ischemic strokes
Men
highest OAHI quartile (>19) adjusted hazard ratio 2.86, (95%
CI:1.1,7.4)
Mild to moderate range (OAHI 5-25) – with each unit of OAHI risk of
stroke rose by 6% (95% CI:2-10%)
Women
Increased risk for OAHI>25
Redline et al, 2010

1094
Patients were recruited at 89 clinical centers in 7 countries
Minimum level of adherence 3 hours
Run- in period (1 week)
Randomized either CPAP therapy plus usual care (CPAP group) or usual
care alone (usual-care group).
All – healthy sleep advice
 Results

CPAP group - mean adherence 3.3 hrs/night

Mean residual AHI, from 29.0/hr to 3.7/hr
Mean follow-up of 3.7 years, No significant effect on any
individual or other composite cardiovascular end point was
observed.
CPAP significantly reduced snoring and daytime sleepiness and
improved health-related quality of life and mood
Propensity score–matched analyses: CPAP adherent patients
had a lower risk of stroke than those in the usual-care group
(hazard ratio, 0.56; 95% CI, 0.32 to 1.00; P = 0.05)
And also a lower risk of the nonprespecified composite end
point of cerebral events (hazard ratio, 0.52; 95% CI, 0.30 to
0.90; P = 0.02)

CPAP group significantly improved in:

Epworth Sleepiness Scale score (adjusted difference

in change -2.5 [−2.8 to −2.2]) p<0.001
Hospital Anxiety and Depression Scale
Anxiety score -0.4 (−0.6 to −0.2) p=0.002
Depression score -0.8 (−1.0 to −0.5) p<0.001

SF-36 Physical-component summary score 0.9 (0.3 to

1.4) p=0.002
Mental-component summary score 1.2 (0.6 to 1.8)
p<0.001
EQ-5D utility score (European quality of life)
Consumer discussion

Most US insurances would refuse PAP coverage if adherence is <4

hrs/night
Duration of follow up may need to be longer to observe effect?

1097
Central hypersomnia

Narcolepsy type 1 (with cataplexy)

Narcolepsy type 2 (no cataplexy)
Idiopathic hypersomnia
With long sleep time
Without long sleep time
Recurrent hypersomnia

Narcolepsy – disorder of REM regulation

Classic symptoms
Sleepiness
Sleep paralysis
Hypnagogic hallucinations
Cataplexy in narcolepsy type 1 –
loss of muscle tone typically with positive emotions
(laughing/telling a joke, surprise, can be anger)
Can be mild or unilateral
Can be more severe
Naps are short and refreshing
HLA associations - DQB1*0602
Orexin – low in CSF type 1

1098
Diagnosis

Clinically
Objective documentation - MSLT
on the day after a PSG
5 nap opportunities x 20 min
short sleep latency (<8 min.)
‘SOREM’: >2 naps containing REM or
REM in one nap and a REM latency
on the preceding PSG <15 min.
HLA typing
CSF measurement of hypocretin –
not commercially available in US

Treatment:
Sleepiness:
Modafinil
Armodafinil
Stimulants
Cataplexy:
Antidepressants
Sodium oxybate
Cautions:
Side effects from long term treatment
RBD, present in as much as 10% of narcolepsy
patients may be worsened by SSRI
Other causes of hypersomnia

Secondary to medical, neurological, psychiatric disorder

or medications
Recurrent (Kleine-Levin syndrome, menstruation-
related hypersomnia)
Posttraumatic
Post-viral
Idiopathic

Idiopathic Hypersomnia

Presentation: long, non-refreshing naps

With long sleep time
Without long sleep time
MSLT criteria: sleep latency <8 minutes, no SOREM
Treatment often challenging
Modafinil or Armodifinil at higher doses
Other stimulants
Summary – evaluation of
hypersomnia
Sufficient sleep opportunity
Sleep disruptors
Primary sleep disorders (OSA, Circadian rhythm disorders,
other sleep disorders)
Medications
Central hypersomnia
Narcolepsy
Idiopathic hypersomnia
 Sleep Problems in
Neurological
Diseases
Milena Pavlova, M.D.
Department of Neurology Brigham and Women’s Hospital
Assistant professor of Neurology, Harvard Medical School
Medical Director, BWFH Sleep Testing Center

Disclosures
Research Grants: Lundbeck
pharmaceuticals
 Agenda
• Poor sleep and cognitive function
• Poor sleep and stroke
• Restless legs syndrome and
neurological conditions
• Sleep and epilepsy
Poor sleep and control of seizures
NREM parasomnia – differentiation from
seizures
• REM behavior disorder and neurological
conditions

Why Do We Sleep At All?

Adaptive theory
Instinctive theory
Energy conservation
Thermoregulation
Memory reinforcement
Synaptic and neuronal network integrity

1103
Consequences of Loss of Sleep
Worsening of other disease
Mood disorder
Cognitive
Impaired immune function (influenza vaccination)
Endocrine
abnormal leptin regulation
decreased glucose tolerance
disturbances of thyroid axis
abnormalities in stress hormone regulation
failure to suppress cortisol levels at night
acute release of cortisol after morning awakening

Spiegel et al Lancet 1999. Spiegel et al JAMA 2001. Spiegel et al JCEM 2004

Consequences of Sleep
Restriction - Attention

1 7 14 1 7 14
Day in study Day in study

Van Dongen et al, SLEEP, Vol. 26, No. 2, 2003

Poor sleep and stroke –
a modifiable risk factor

1105
 OSA and Incidence of Stroke –
Sleep Heart Health Study

SHHS: A longitudinal cohort study

Inclusion 1995 - 1998
Included 5422 subjects without stroke
Exposure: OAHI (obstructive apnea-hypopnea
index per hour of sleep)
Outcome: incident of stroke
PSG performed at home
Follow-up – median of 8.5 years

Redline et al, 2010

SHHI - stroke - results

Results: 193 ischemic strokes

Men
The highest OAHI quartile (>19) adjusted hazard ratio 2.86,
(95% CI:1.1,7.4)
Mild to moderate range (OAHI 5-25) – with each unit of
OAHI risk of stroke rose by 6% (95% CI:2-10%)
Women
Increased risk for OAHI>25

1106
 OSA and Stroke -
Treatment
Martínez-García et al 2009 Continuous positive
airway pressure treatment reduces mortality in
patients with ischemic stroke and obstructive sleep
apnea: a 5-year follow-up study
166 patients with PSG
96 had an AHI of 20 or greater (moderate or severe OSA)
If no CPAP (n = 68) increase adjusted risk of mortality
(hazards ratio [HR], 2.69; 95% confidence interval [CI], 1.32-
5.61) compared with patients with an AHI of less than 20 (n
= 70)
and an increased adjusted risk of mortality (HR, 1.58; 95%
CI, 1.01-2.49; P = 0.04) compared with patients with
moderate to severe OSA who tolerated CPAP

CPAP effect on risk of stroke or

cardiovascular outcomes – from
meta-analysis

Kim et al, PLOS online, January5,2016

1107
 Sleep and Epilepsy

Effects of Seizures on
Sleep
Sleep fragmentation (Tachibana et al
1996)
Decreased amount of REM sleep in
epilepsy patients (Besset 1982, Baldy-
Moulinier 1982)
Anticonvulsants may also affect sleep
(Bazil et al 2000)
 Effect of Seizures on
Sleep

Tachibana et al 1996

Effect of Sleep Deprivation

on Seizures
Sleep loss is frequently reported as a factor
that provokes seizures in epilepsy patients
EEG can become abnormal after sleep
deprivation
Sleep deprivation is often used in LTM units
to facilitate recording of seizures
Sleep fragmenting disorders may worsen
seizure control
Anecdotal reports suggests that treatment of
even mild OSA may improve seizure control

1109
 Patient AA
35 year old RH professor of economics
First seizure occurred in the setting of overseas travel.
After a second seizure treatment started (PHT)
Due to excessive cognitive side effects changes to VPA;
he stopped it as well
Seizures continued every 6 months – always from sleep
Depression started
A psychologist ordered a sleep study
Mild OSA noted PAP started
He had no further seizures for 3 years – refused AED

OSA and Epilepsy

Malow et al, (2000, Neurology) 1/3 of 39 patients
with medically refractory epilepsy had RDI>5
Chihorek et al (2007) older adults with new or
poorly controlled seizures have more frequent
OSA
Malow et al - pilot trial of PAP to help seizure
control: 35 of 45 epilepsy patients with PSG had
OSA, of them the 32% treated with therapeutic
CPAP had a 50% or greater reduction in
seizures than those receiving sham CPAP
(15%).
Restless Legs Syndrome
and Neurological
Conditions

Restless Legs Syndrome

RLS: indescribable uncomfortable sensations that make the
patient move limbs
Common - prevalence of 5% to 10%
Sensation is present at rest, worse in the evening
Criteria for diagnosis:
An urge to move the legs, usually accompanied or caused by uncomfortable
and unpleasant sensations in the legs
The urge to move or unpleasant sensations begin or worsen during periods
of rest or inactivity, such as lying or sitting
The urge to move or unpleasant sensations are partially or totally relieved
by movement, such as walking or stretching, at least as long as the activity
continues
The urge to move or unpleasant sensations are worse in the evening or
night than during the day, or only occur in the evening or night

1111
 RLS/PLMS and
Neurological Conditions
Deriu et al, 2009 – 45% patients with
MS reported RLS symptoms
Silvestri et al, 2007 – 26 % of children
with ADHD had RLS symptoms
Malow et al., 1997 – RLS may worsen
sleepiness in patients with epilepsy as
well as controls

1112
 RLS/PLMD treatment
Dopamine-agonists or Levodopa
Pramipexole
Ropinirole
Gabapentin
Fe supplementation if indicated
Start if ferritin<50,
Continue until it reaches >100
Opiates and benzodiazepines have
more limited role

RLS in Pregnancy

Common, probably associated with iron

distribution
Parity increases risk of RLS later in life
Naturally improves or resolves after
delivery

1113
 RLS in Pregnancy
Treatments starts with non-
pharmacologic methods
Massaging or hot bath in the evening
Applying a hot or cold compress to leg muscles
Relaxation exercises such as yoga or tai chi
Walking and stretching

Iron supplementation if appropriate

continue until ferritin level reaches >150

Differential Diagnosis of
Nocturnal Events

1114
 NREM Parasomnias
A large variety of behaviors – hallucinations, eating,
locomotion, aggression, sex, terrors, paralysis
Precipitating factors – sleep deprivation, stress, fever,
medications/substances
Frequent amnesia for the event
Behaviors may be from the same group (usually eating or
usually talking), but variable in presentation (saying
different phrases
Several different behaviors can co-occur, e.g. sleepwalking
and s as a child + sleep eating as an adult;
Distinction from seizures/postictal confusion is crucial

Sleepwalking
Complex, directed, non-stereotypic
behaviors
Patient may leave the bed, room, or even
building
Examples of hazardous behaviors:
Agitation and violence
Driving
Eating and cooking
Common in children, do not commonly start
in adulthood
Family history of sleepwalking is common
 Derry et al, Arch Neurol.
2006;63:705-709

NI2801137

Derry et al, SLEEP

2009;32(12):1637-1644
 Patient BB
21 year old woman with history of anxiety, depression,
recent stress
Reported unusual behaviors from sleep. This was
attributed to dream enactment – in the setting of SSRI
treatment
Reported many sleep problems in part related to anxiety
and stress. She had very fragmented sleep, resistant to
treatment with trazodone and other antidepressants;
clonazepam lead to intolerable sedation.
Reported events of staring/ loss of contact with a more
recent onset – within several months of evaluation

1117
 Patient BB – further
evaluations

EEG – abnormal with left temporal

slowing, rare left mid-temporal sharp
waves
MRI – polymycrogyria
Treatment with antiepileptic medications
controlled the events

REM behavior Disorder

(RBD) and Parkinsonian
Syndromes
 Normal REM Sleep
Physiology

EEG Brain activity - comparable to

wakefulness
Oxygen consumption, cerebral blood flow,
and glucose utilization – all increased
Sensory input is blocked
Motor output is blocked through active
hyperpolarization of alpha motor neurons
(REM atonia)

Medullary hyperpolarization Alpha

Pons inhibitory motor
region neurons

1119
REM Behavior Disorder
Essential features:
Abnormal behaviors, emerging from REM
sleep
Occur in the later parts of the night
Typical behaviors: talking, screaming,
punching, kicking
Associated with a vivid dream recall

Diagnostic Criteria
Polysomnographic
Excessive EMG tone during REM
OR
Excessive limb EMG
Absence of epileptiform activity
Behavioral
History of problematic sleep related behaviors
OR
Documented REM sleep behaviors during PSG
(without epileptiform EEG changes)

1120
Of 703 patients with sleep disorders,
34 patients with RBD (27 men; 7
women)*
• RBD - idiopathic in 11 patients
• Symptomatic in 23 patients
• parkinsonian syndromes -(n=11),
• use of antidepressants (n=7),
• narcolepsy with cataplexy (n=4),
• pontine infarction (n=1).

* Frauscher B et al, Sleep Med. 2010 Feb;11(2):167-71.

Summary
Insufficient sleep directly affects attention
Major sleep disorders may lead to worsening
of neurologial disorders
Sleep apnea is a risk factor for stroke
Sleep fragmentation can result from common
sleep disorders: OSA, RLS/PLMS, parasomnias
Sleep fragmentation may lead to poor seizure
control
REM behavior disorder has a direct
association with neurological disorders,
especially parkinsonian syndromes

1121
 Good Sleep Rules
Determine time in bed – most need 7-9 hrs of sleep,
do not stay in bed longer
Use bed for sleep/intimacy only
Turn clock, so it is not visible from the bed
Naps, if taken at all, should be early afternoon at
latest
Schedule regular wake times
Allow ample amount of light during the day
Allow dimmer light in the evening
Moderate or limit caffeine - last intake at noon
Moderate alcohol – best not too close to bedtime

1122
 Head Trauma

William J. Mullally M.D.

Associate Chief of Clinical Neurology
Brigham and Women’s Faulkner Hospital
Director of Sports Neurology
Department of Neurology
Brigham and Women’s Hospital

Disclosures
• None

1123
 HISTORY

• First descriptions of concussion over 2400 years ago by

Hippocrates
• “falls down immediately, loses speech, cannot see or
hear.”
• Constellation of symptoms a mystery
• Derived from the latin “concussus” meaning “to shake
violently” ?

HISTORY

• 14th Century- Lanfrancus - “Commotio Cerebri” Transient paralysis of cerebral function

as opposed to “Contusio Cerebri”

• 1928- Martland “ Punch Drunk” syndrome then modified in 1937 to Dementia

Pugilistica by Millspaugh

• 1960s- Chronic Traumatic Encephalopathy

• 2002- Omalu described the 1st football case of CTE with extensive tau deposition

• 2009- McKee et al- 68 of 85 brains with a history of repetitive mild TBI revealed
evidence of CTE

4
 INCIDENCE
• 1.7 million ER visits / yr for TBI- over $60 billion!
• Estimates of sports-related mild traumatic brain injury
(mTBI) range from 1.6–3.8 million affected individuals
annually in the United States, many of whom do not obtain
immediate medical attention.
• More than 90% of head injuries do not result in a loss of
consciousness.
• Estimated 250,000 to 2.25 million more cases unidentified
each year.

INJURY RATE PER 1000 ATHLETES

EXPOSED
• Football (2.34)
• Men’s Ice Hockey (1.47)
• Women’s Soccer (1.42)
• Wrestling (1.27)
• Men’s Soccer (1.08)
• Women’s Lacrosse (0.70)
• Field Hockey (0.57)
• Women’s Basketball (0.50)
• Men’s Basketball (0.32)
• Softball (0.25)
• Baseball (0.19)
• Volleyball (0.15)

The vast majority of head injuries do not result in loss of

consciousness
 SPORTS CONCUSSION
• Due to more males studied, total number of concussions is
greater for males than females for all sports combined.
• Concussion risk is greater for female athletes participating
in soccer or basketball.
• Greater concussion risk with American football and
Australian rugby
• History of concussion, poorer outcomes

Giza CC., et al. Summary of evidence-based guideline update: Evaluation and management of concussion in sports. Report of the Guideline
Development Subcommittee of the American Academy of Neurology. Neurology June 11, 2013 vol. 80 no. 24 2250-2257

FOOTBALL/RUGBY
• Risk is probably greater among
linebackers, offensive linemen,
and defensive backs than
receivers
• Body mass index greater than 27
kg/m2 and training time less than
3 hours weekly likely increase
the risk of concussion
• Playing on artificial turf is
possibly a risk factor for more
severe concussions
CONCUSSION CONUNDRUM

• What is a concussion?

• What is traumatic brain injury?

• Does every blow to the head

that results in symptoms constitute
a concussion?

AMERICAN ACADEMY OF NEUROLOGY

2013

Concussion is defined as a clinical syndrome of

biomechanically induced alteration of brain function
typically affecting memory and orientation, which
may involve loss of consciousness.
ZURICH INTERNATIONAL SYMPOSIUM
ON CONCUSSION IN SPORTS - 2012

The definition from the Zurich International

Symposium placed emphasis on functional
changes following a head injury rather than loss of
consciousness or posttraumatic amnesia.

AMERICAN ACADEMY OF NEUROLOGY

1997
• Concussion was defined as a trauma induced alteration in
mental status that may or may not result in loss of
consciousness.
• From a clinical standpoint the most useful definition

1128
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CASE 1- SOCCER

• 21 year old male who while playing soccer was tripped

while going for the ball and scraped the right side of his
head against the ground. The patient did not lose
consciousness or experience a change in mental status.
There was swelling of the area with an abrasion and
discomfort at the site. No other symptoms and neurologic
exam was normal.

CASE 2- SOCCER

• 16 year old female who while attempting to head the ball after a corner
kick bumped her head against the head of another player. She did not
lose consciousness or experience a change in mental status. There
was no period of confusion or amnesia but following the trauma she
experienced a global headache with slight nausea and photophobia.
Neurologic exam was normal including cognitive function. The pain
gradually lessened after several days then resolved.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CASE 3 - FOOTBALL

• 26 year old male who while playing football was struck on the left
side of his head by the helmet of another player. He immediately
“saw stars” and felt dazed. He did not lose consciousness or
experience anterograde amnesia. Following he had a global
headache with nausea and photophobia. He felt as if he was in a
“fog”. Neurologic exam was normal.

CASE 4- RECREATION

• 45 year old male who fell from his bicycle. He sustained trauma to
the right side of his head and his helmet was cracked. According to
his companion he was unconsciousness for 5 minutes then slightly
confused for 20 to 30 minutes. He was taken to a hospital
emergency room where he complained of a headache but
neurologic exam was normal with the exception of slight
unsteadiness of gait. A CT scan was performed.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

SUBDURAL HEMATOMA

Case 5 - MVA

33 yo male who was the restrained passenger in a car that was struck
from behind by another vehicle traveling at 30 mph. The patient’s head
was thrown backward then forward but there was no direct head
trauma or loss of consciousness.
Scenario 1- there is a sudden but brief change in mental status with
slight confusion and disorientation.
Scenario 2- there is no change in mental status.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CASE 6

• 21 year old female with the gradual onset of a global throbbing

headache accompanied by nausea, photophobia and dizziness. In
association with the pain the patient complained of mental
fogginess. She has a history of similar headaches in the past often
occurring in association with menses. Neurologic exam was normal.
The symptoms gradually resolved over 3 days and following she felt
“hungover” for 1 day.

Rather than dwell on the term, concussion, our

main focus should be to identify as quickly as
possible when a traumatic brain injury/TBI has
occurred and then managing the patient/athlete
accordingly

1132
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

INVESTIGATIONS
• Emergent neuroimaging to exclude severe brain injury
– Usually contributes little to the mild head injury
evaluation
– Use when suspicion of structural lesion exists:
• focal neurologic deficit
• worsening symptoms
• Prolonged disturbance of consciousness

TRAUMATIC BRAIN INJURY

• Trauma from skull impact and/or penetrating injury to brain

– Includes blast injuries

– Flexion and extension of the cervical spine

1133
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PATHOPHYSIOLOGY OF
PUNCH CAUSING ROTATIONAL
CONCUSSION BRAIN INJURY

Mechanical shearing of endothetial cells in Mechanical stretching and disruption of

small cells axonal plasma membranes

Impaired regulation Deregulated ion flux

Release of Calpain activation Mechanical
of blood-brain with efflux of
excitatory amino by increased breakage of
barrier and cerebral potassium and
acids intracellular calcium microtubules
blood flow. influx of calcium

Increased Proteolytic
Binding of
membrane pump breakdown of Microtubule
glutamate to NMDA
activity to restore neurofilament disassembly
receptors
ionic balance. proteins

Neuronal Glucose
depolarization Consumption
Focal ischemia and
Axonal transport
blood-brain barrier
defect
damage
Acute widespread
Energy crisis in
suppresion of
damaged neurons
neurons

Acute failure in neuronal function

CONCUSSION/KNOCKOUT

SIGNS AND SYMPTOMS

• Cognitive impairment (e.g. feeling like “in a fog”, memory
and concentration impaired, slow reaction time)
• Headache, confusion, orthostatic lightheadedness,
dizziness/vertigo, vision blurring/fatigue eyes, tinnitus, bad
taste in the mouth, fatigue/lethargy
• Neck pain
• Depression, anxiety, personality changes, mood lability,
irritability, aggression, acting out, and social
inappropriateness
• Sleep disturbance (e.g. drowsiness, insomnia)

1134
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POST TRAUMATIC HEADACHE

Source: Vic Muniz

• Mild head injury, as a result of direct head trauma or forcible flexion

extension of the cervical spine, may also stimulate the trigeminal
sensory afferents resulting in sequential activation of second and
third order neurons in the pain pathways in the brainstem,
hypothalamus and thalamus causing a headache often with
migrainous features and accompanying symptoms.
• This does not necessarily denote a TBI.

• PTH can occur after mild, moderate or severe TBI but more
common after a mild injury.

1135
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Headache attributed to head

and/or neck trauma

Acute headache attributed to traumatic injury to the

head or whiplash

Persistent headache attributed to traumatic injury to

the head or whiplash

Headaches begin within 7 days of the traumatic

insult

TYPES OF POST TRAUMATIC

HEADACHE
• Tension type headache
• Migraine headache
• Occipital neuralgia
• Cervicogenic headache
• Cluster headache
• Supraorbital and infraorbital neuralgia
• Low pressure headache due to CSF leak
• Structural lesions
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

INCIDENCE OF POST TRAUMATIC

HEADACHE
• 25- 90% of patients who have suffered head trauma
• 15 – 78% continue for more than 2-3 months
• 4% of all symptomatic headaches
• Estimates of relative causes in industrialized countries-
MVA- 45%, occupational accidents- 10%, falls- 30%,
recreational accidents- 10%, assaults- 5%
• 25% will develop persistent headaches

SAME DAY RETURN TO PLAY?

•NO!
• Unanimously agreed that no RTP should occur on the
day of a suspected traumatic brain injury

1137
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

TRADITIONAL MANAGEMENT

• Initial period of physical rest

No training, playing, exercise, weights
Beware of exertion with activities of daily living?
Cognitive Rest
Avoid television, extensive reading, video games,
telephone, texting
Caution re: daytime sleep

Rest is for wimps…

Is it 5th down yet?

• Is there data to support complete

cognitive and physical rest?

• Can cognitive or physical activities

delay recovery or potentially do
harm?

1138
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PHYSICAL REST
• 88 patients ages 11-22 within 24 hours of concussion were
randomized to strict rest for 5 days (45) vs 1-2 days of rest
followed by stepwise return to activity (43).
• There was no clinically significant difference in
neurocognitive or balance outcomes.
• Strict rest resulted in more daily postconcussive symptoms
and slower symptoms resolution.

• Pediatrics February 2015 Thomas et al

33

COGNITIVE REST
• 335 patients ages 8-23 (mean age 15, 62% male; 19%
suffered LOC and 39% with a prior concussion) after
suffering a concussion were placed in one of 4 groups:
cognitive rest with minimal activity; moderate cognitive
activity; significant cognitive activity; full Cognitive activity.
• The highest quartile took approximately 100 days to recover
• The lower 3 quartiles took approximately 20 - 50 days and
patients in those quartiles had similar duration of symptoms.
• Pediatrics February 2014- Brown et al

34

1139
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• The emerging concept of cognitive and physical

deconditioning as a cause of persistent symptoms

• Are ongoing headaches a contraindication to resuming

unrestricted vigorous physical exercise?

MANAGEMENT

• Expect gradual resolution within 7-10 days

• Gradual return to school and social activities that does not
result in significant exacerbation of symptoms
• When symptoms resolve or return to pre-injury baseline
proceed through step-wise return to sport / play (RTP)
protocol after receiving medical clearance
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CONCUSSION TREATMENT -
MULTIDISCIPLANARY
• Physical therapy, occupational therapy, speech/language
therapy, vestibular therapy, psychology/psychiatry, and
social support.
• Pharmacotherapy
Prolonged symptoms (headache, vertigo, orthostatic
dizziness, sleep disturbance, anxiety, cognitive difficulty)

RECOVERY
•May take longer in children and adolescents
•Pre-existing medical problems such as migraine, ADD,
mood disorders, learning disability may delay recovery
•History of prior traumatic brain injury
•Females may recover at a slower rate
•Higher post concussion symptom score

1141
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

RECOVERED?

• History
• Neurologic exam- May include BESS (Balance Error
Scoring System) balance assessment.
• Neurocognitive testing – (ImPACT – Immediate Post
Concussion Assessment and Cognitive Testing
computerized test that is only helpful when it can be
compared to a pre-injury baseline test).

SECOND IMPACT SYNDROME

Fact or Fiction

1142
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PREPARTICIPATION EVALUATION

• History:
– Type of sport?
– Previous symptoms of head injury?/length of
recovery (recall unreliable from teammates,
coaches)
– Prior head, maxillofacial, spine injuries?
– Non-sporting head injuries?
– Type of player (“physical”?)
– Ability to “take a hit”
– Protective equipment (helmet, age)
• Opportunity to Educate!

PERSISTENT POST
TRAUMATIC HEADACHE
• 25 % at 4 years
• History of headaches specifically migraine
• History of prior TBI
• Rebound from abortive medication
• Comorbid psychiatric disorders
• Effect of litigation

42

1143
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MEDICATION- ABORTIVE
• Simple analgesics
• NSAIDS
• Triptans
• Muscle relaxants
• Midrin
• Avoid narcotics

MEDICATION- PREVENTATIVE
• Antidepressant medication
• Beta blockers
• Antiepileptic drugs

1144
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ALTERNATIVE TREATMENT
• Occipital nerve blocks
• Trigger point injections
• Botulinum toxin injections
• Physical therapy
• Relaxation therapy and biofeedback
• TENS
• Cognitive and behavioral therapy

PREVENTION
• Protective equipment
• Mouthguards have benefit in prevention oral injury, but
no evidence of TBI reduction
• Head gear and helmets show reduction in biomechanical
forces, but have not translated to a reduction in TBI
incidence
• Helmets reduce head and facial injury in skiing and
snowboarding and are recommended for alpine sports
• Helmets reduce other forms of head injury (e.g. fracture)
in cycling, equestrian, motor sports

1145
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE)

• Acknowledge potential for long-term problems in all athletes

• CTE- unknown incidence in athletic populations; cause/effect
not yet proven between CTE and mild TBI or exposure to
contact sports
• How many injuries is too many?

1146
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

Disclosures
• None
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Metabolic Encephalopathy

Metabolic Encephalopathy
A brain disorder caused by a failure of the
metabolic systems that allow for the
normal function of the neurons and their
supporting cells and structures.

It may be inherited or acquired. In adult

medicine most metabolic
encephalopathies are acquired and
potentially reversible

1148
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Syndrome of Metabolic

Encephalopathy
• Disorders of consciousness
– Confusion
– Delirium
– Drowsiness
– Stupor Coma
• Movement disorders
– Myoclonus and asterixis
– Tremor

Important Principles of Metabolic

Encephalopathy
• Usually symmetrical
• Usually reversible, at least for a while
• Level of consciousness is usually affected
• Central nervous system is more
susceptible than the peripheral nervous
system
• As people age, they become more
susceptible to a given metabolic insult

1149
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Most Important Causes of

Metabolic Encephalopathy
• Hypoxemia/ischemia • Toxins
• Hypercapnia • Alcohols
• Hypgoycemia • Carbon monoxide
• Azotemia • Prescribed drugs
• Portosystemic • OTC drugs
(hepatic) • Recreational drugs
encephalopathy • Thyroid disorders
• Infection (e.g. UTI)

Important Disorders that May Mimic

Metabolic Encephalopathy
• CNS infections (e.g. encephalitis)
• Vascular disease (e.g. multiple strokes)
• Immune mediated diseases (e.g. paraneoplastic
disorders)
• Tumors (e.g. glioblastoma)
• Hydrocephalus
• Traumatic Brain Injury
• Seizures (particularly non-convulsive seizures)
• Degenerative brain diseases (e.g. Alzheimer
disease)
• Psychiatric disorders

1150
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tests That May be Useful in

Metabolic Encephalopathy
• Electroencephalogram
• Lumbar puncture
• Acid base status
• Toxic screen (may have to be individualized)
• Body temperature
• CBC, ESR and CRP
• Thyroid function tests
• Renal, hepatic, pulmonary, rheumatic blood
tests

Treatment of Metabolic
Encephalopathy
• Time is of the essence (what might be
reversible now can become irreversible)

• Focus therapy on the cause

• Allow time to recover before giving up on a

therapeutic approach

1151
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachusetts

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Brigham Department of Neurology

Martin A. Samuels, M.D., Chairman

Brigham & Women’s Hospital, Boston, Massachussetts

Disclosures
• None

1153
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Consciousness
and
The Lack Thereof

CONSCIOUSNESS DEFINED
“Consciousness is a being such that in its being its
being is constantly in question insofar as this
being is a being other than itself“

1154
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CONSCIOUSNESS DEFINED
“Consciousness is a being such that in its being its
being is constantly in question insofar as this
being is a being other than itself“

Jean Paul Sartre

Being and Nothingness
1956

1155
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

PATHOPHYSIOLOGY OF
COMA

• Bilateral diffuse hemisphere disease

• Brainstem reticular formation disease
• Thalamic relay nuclei disease

1156
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

CLINICAL STATES OF
REDUCED RESPONSIVENESS
• Appears awake (eyes open) - akinetic mute
1. Abulia (bilateral prefrontal disease)
2. Psychogenic (catatonia; dissociation)
3. Locked-in (pontine stroke)
4. Non-convulsive seizures

• Appears asleep (eyes closed)

1. Drowsiness, stupor, minimally conscious state,
vegetative state (awake unawareness), coma
2. Pseudocoma (psychogenic)

1157
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

ESSENTIALS OF HISTORY
• Pace (i.e. rate of onset)
• Toxins and drugs (alcohol, meds, CO)
• Trauma
• Fever
• Headache
• Similar episodes in the past

1158
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROLOGICAL EXAM
OBSERVATION
• Posture - comfortable or unnatural
• Respiratory pattern
1. Normal
2. Periodic (Cheyne-Stroke or other)
3. Hyperventilation (compensatory vs. primary)
4. Apneustic (pontine)
5. Ataxic (medullary)
6. Apnea
• Automatisms
• 1. Good - yawn; sneeze
• 2. Bad - cough; swallow; hiccough

NEUROLICAL EXAM
MENTAL STATUS
• Responds to voice - drowsy
• Responds to pain - struporous
• No useful response - comatose

1159
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NERUOLOGICAL EXAM
CRANIAL NERVES
• I- not testable; smelling salts tests pain (V)
• II - visual threat for fields & acuity; fundi
• III, IV, VI, VIII
1. Pupils - size; reaction (No PERRLA)
2. Eye movements - no head turning allowed
A. spontaneous
B. ice water calorics
• V, VII - corneal reflex
• IX, X - gag reflex and swallowing
• XI, XII - not tested acutely

1160
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROLOGICAL EXAM
MOTOR SYSTEM
• Spontaneous movement - compare sides
• Induced movement (noxious stimuli)
1. Paralysis - does not localize
2. Triple flexion - spinal segment
3. Antigravity postures
A. Decerebration - above medulla
B. Decortication - above midbrain
4. High level - abduction; seizure

NEUROLOGICAL EXAM
SENSORY SYSTEM

• Hemisensory deficit

• Level on the trunk - myelopathy

1161
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROLOGICAL EXAM
REFLEXES
• Proprioceptive (tendon jerks)
• Nocioceptive (plantar; corneal)
• Antigravity (decerebration; decortication)
• Release (suck; grasp)

GLASGOW COMA SCALE

Eyes open Spontaneously 4
Verbal command 3
Pain 2
Eyes do not open 1
Best motor response Obeys commands 6
with pain Localizes 5
Flexes withdraws 4
Decorticates 3
Decerebrates 2
No response 1
Best verbal response Oriented 5
Disoriented 4
Confused 3
Sounds only 2
No response 1
Total 3 - 15
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

LABORATORY STUDIES
• Spinal fluid examination - indications
• Imaging studies
• Toxic screen
• Complete blood count
• Routine chemistries
• Arterial blood gases
• Electroencephalography indications

1163
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1165
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1167
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Neurology of Alcohol

Michael E. Charness, M.D.
Chief of Staff, VA Boston Healthcare System
Brigham and Women’s Hospital
Professor of Neurology and Faculty Associate Dean, Harvard Medical School
Professor of Neurology and Associate Dean, Boston University School of
Medicine

Disclosures
• None

1168
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DSM-5 Alcohol Use Disorder

At least two from the list below:
1. Had times when you ended up drinking 8. More than once gotten into situations while
more, or longer, than you intended? or after drinking that increased your chances
2. More than once wanted to cut down or of getting hurt (such as driving, swimming,
stop drinking, or tried to, but you couldn’t using machinery, walking in a dangerous
Craving, Inability to Control Drinking
3. Spent a lot of time drinking? Or being Medical
area, or Consequences
having unsafe sex)? of Drinking
sick or getting over other aftereffects? 9. Continued to drink even though it was
4. Wanted a drink so badly you couldn’t making you feel depressed or anxious or
think of anything else? (new in DSM-5) adding to another health problem? Or after
5. Found that drinking—or being sick from having had a memory blackout?
drinking—often interfered with taking 10. Had to drink much more than you once did
care of your home or family? Or caused to get the effect you want? Or found that
job troubles? Or school problems? your usual number of drinks had much less
6. Social
Continued to drink even though
Consequences it was
of Drinking effect than before?
causing trouble with your family or 11. Found that when the effects of alcohol were
friends?
Tolerance and Physical Dependence
wearing off, you had withdrawal symptoms,
7. Given up or cut back on activities that such as trouble sleeping, shakiness,
were important or interesting to you, or restlessness, nausea, sweating, a racing
gave you pleasure, in order to drink? heart, or a seizure? Or sensed things that
were not there?

Mild: 2-3; Moderate: 4-5; Severe: 6-11 items from the list

Epidemiology of DSM-4 Alcohol Use

Disorder: NESARC
Prior to NIAAA’s large (40,000+) general population
epidemiologic studies (NLAES and NESARC), alcohol
dependence was thought to be a chronic disease affecting
primarily the middle-aged

Earlier studies captured only clinical populations

NESARC revealed the highest prevalence of alcohol dependence

among Young Adults (18-30 yrs)

72% of individuals who develop an AUD have only one episode –

often recover without clinical intervention

28% relapse - average of 5 relapse episodes

1169
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Epidemiology of DSM-5 Alcohol Use

Disorder: NESARC 2015
Cohort of 36,000 non-clinical subjects

Lifetime prevalence of 29.1%: 36.0% men; 22.7% women

68.5 million Americans

Past 12-mo prevalence of 13.9%: 17.6% men; 10.4% women.

32.6 million Americans

Significant Association with lifetime and 12-mo AUD: other

substance use disorders; major depression; bipolar disorder I;
specific phobias; and antisocial and borderline personality
disorders.
Grant JAMA Psychiatry 2015

Pharmacology of Alcohol

Intoxication

Tolerance

The alcohol withdrawal syndrome

1170
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Passed-out Rats and

an Alcohol Antagonist

Ethanol Enhances
GABA Activation of
the GABAA Receptor

GABA is the principal

inhibitory neurotransmitter
in the brain.

Alcohol enhancement of
GABA release and
receptor activation
contribute to alcohol-
induced sedation and
ataxia.

1171
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ethanol Selectively Inhibits NMDA

Receptor-Gated Ion Currents
Control 50 mM Washout
Glutamate is the principal
excitatory neurotransmitter

NMDA
in the brain and acts in part
through NMDA receptors.

Kaintate
AMPA

Lovinger, D.M. et al. Science 243, 1721-4 (1989)

Alcoholic Blackouts
Selective amnesia for events occurring while
intoxicated
Occurs after heavy drinking, both in alcoholics
and non-alcoholics
Glutamate activation of NMDA receptors is
necessary for learning
Alcohol might cause blackouts by blocking
glutamate activation of NMDA receptors

1172
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Dopamine Reward System

All drugs of abuse (nicotine,
cocaine, amphetamine,
heroin, alcohol) increase DA
release in the nucleus
accumbens (NAc).

ethanol

serotonin, endorphins
naltrexone

NOVEL REWARD SIGNAL dopamine release

Naltrexone for Alcohol Dependence:

Cochrane Database Systematic Review
Rosner et al. 2010

50 randomized control trials in 7793 patients

Reduces rates of heavy drinking by 17%

Decreased drinking days by 4%

More effective OPRM1 A118G mutation

Effective and safe strategy in alcoholism treatment (FDA

1994)

Side effects: GI intolerance, sedation

Naltrexone depot (2006); acamprosate (2004); disulfiram

1173
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Medical management plus naltrexone is equivalent to

medical management and combined behavioral
intervention in reducing days with heavy drinking.

Medical management: initial assessment and eight 20-minute

sessions delivered by a nurse or physician over 16 weeks.

Anton et al. JAMA 2006: 295,2003-2017

Relation between Drinking and

Blood Alcohol Concentration

1174
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Threshold Levels of Safe

Drinkinghttp://rethinkingdrinking.niaaa.nih.gov/
Males: Not more than 14 drinks per week
and 4 drinks on any one day
Females: Not more than 7 drinks per
week and 3 drinks on any one day
Pregnant females: No alcohol

One drink = 0.6 oz (14 gm) of pure alcohol

12 fluid oz beer (5% alcohol)
5 fluid oz wine (12% alcohol)
1.5 fluid oz 80-proof distilled spirits (40% alcohol)

Risk of Fatal Single-Vehicle Crashes

Zador, J Stud Alcohol, 52: 302, 1991

Number of drinks in one hour on an

empty stomach to attain 80 mg/dl:

170 lb Male: 4
137 lb Female: 3

1175
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Clinical Pharmacology of Ethanol

Molar Weight/Vol
mM mg/dl

Incoordination 8 35
Intoxication 17.6 80
Death 100 461
Record survival 327 1510

Acute Tolerance in a Non-drinker

Mirsky, I.R. et al. Quart J Stud Alc 2, 35-45 (1941)

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Brain Adaptation Underlies

Alcohol Withdrawal Syndrome

Down-regulation and
uncoupling of selective
GABAA receptor
subunits.
Changes in GABAA
receptor subunit
composition
Up-regulation of NMDA
receptors
Finn D, Crabbe JC. Alcohol Health Research World
21:149,1997

The Alcohol Withdrawal Syndrome

Victor, M. & Adams, R.D. Res Publ Assn Nerv Ment Dis 32, 526-573 (1953).

1177
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment of Alcohol Withdrawal

SEDATION – symptom-triggered
Benzodiazepines: lorazepam, diazepam
Clonidine
Propranolol

HYDRATION

NUTRITION
Intravenous or intramuscular thiamine
Replace magnesium 2 mEq/kg

52 Year Old Man

10 AM: Checks into detox center

10 PM: Generalized tonic clonic seizure
11 PM: Second seizure in ER
12 MN: Sleepy
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alcohol Withdrawal Seizures

Typically occur after years of drinking and
multiple episodes of withdrawal.
Onset 12-48 after last drink
Generalized tonic-clonic
Multiple, within 6 hours
Post-ictal drowsiness < 1 hour
Victor and Brausch; Epilepsia 1967; 1-20

Encephalopathy in Alcoholics

Acute Trauma
Subdural hematoma
Subarachnoid hemorrhage
Intracerebral hemorrhage
Contusion, frontal and
temporal tips

1179
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Encephalopathy in Alcoholics
Metabolic Encephalopathy
Wernicke's encephalopathy
Hepatic encephalopathy
Alcohol intoxication
Hypoglycemia
Hyponatremia
Drug, toxin ingestion
Alcohol or drug withdrawal
Post-ictal state
Sepsis, meningitis

Brain Lesions in Alcoholics

Wernicke’s encephalopathy
Hepatocerebral degeneration
Trauma
Central Pontine Myelinolysis
Marchiafava-Bignami Syndrome
Fetal Alcohol Syndrome
Pellagra
Alcohol Neurotoxicity

1180
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Wernicke’s Encephalopathy
Encephalopathy
• Withdrawn, apathetic state

Oculomotor dysfunction
• Lateral rectus palsy
• Conjugate gaze palsy
• Nystagmus

Ataxia
• Selective ataxia of gait and station

Wernicke’s Encephalopathy:
Response to Thiamine
Onset of Complete
improvement recovery
(median) (%)
Ocular palsies 1-24 hours 100
Global confusion 2-7 days 100
Nystagmus 2-7 days 40
Ataxia 2-7 days 38
Memory loss 1 month 21

1181
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Wernicke’s Encephalopathy:
Epidemiology

Autopsy incidence: 0.8-2.8%

Clinical diagnosis: 0.04-0.05%

Is the classic clinical triad diagnostically

insensitive?

Acute Wernicke’s Encephalopathy:

Clinical-Pathological Correlation

22 acute cases diagnosed at autopsy.

All patients died within 3 weeks of autopsy on
medical and surgical services of teaching
hospitals in Oslo.
Drowsiness and coma only in 18/22 (82%)
Correct clinical diagnosis in 1/22 (4.5%)

Torvik A et al. J Neurol Sci 1982; 56:233-248.

1182
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Wernicke’s Encephalopathy:
Diagnosis in Alcoholics
Caine Criteria - Two of the following:

1. Dietary deficiency
2. Oculomotor abnormalities
3. Cerebellar dysfunction
4. Altered mental status or mild memory
impairment
Caine D. et al., J Neurol Neurosurg Psychiat 1997; 62: 51-60

Wernicke’s
Encephalopathy:
Symmetrical abnormalities,
diencephalon
Endothelial hyperplasia.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Wernicke’s Encephalopathy:
Periaqueductal Grey

MRI reveals mammillary

body shrinkage in
chronic Wernicke’s
Encephalopathy

Charness, M.E. & DeLaPaz, R.L. Ann. Neurol. 22, 595-600 (1987)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Treatment of Acute Wernicke’s

Encephalopathy: Parenteral Thiamine
Thiamine is safe, inexpensive, and effective
Oral thiamine is not reliably absorbed in alcoholics and
malnourished patients
Wernicke’s encephalopathy is difficult to diagnose;
therefore treat all probable cases presumptively with high-
dose parenteral thiamine
Thiamine 500 mg three times daily for two days, followed
by:
Thiamine 500 mg once daily for three days

Alcoholic Cerebellar Degeneration

Toxic and nutritional etiology
Cerebellar pathology similar to that of Wernicke’s
encephalopathy.
Midline ataxia affecting gait and stance more than limb
coordination.

1185
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alcoholic Cerebellar
Degeneration

Marchiafava-Bignami Disease

First described in Italian red wine drinkers

Recognized world-wide in consumers of all alcoholic beverages
Most cases diagnosed post-mortem prior to MRI era
Dementia, impaired inter-hemispheric transfer

1186
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Central Pontine
Myelinolysis

Cerebral Atrophy in Alcoholism

Control Alcoholic

Courtesy of Dr. Adolf Pfefferbaum

1187
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Control Dendritic
Morphology
Alcoholic patients have
smaller, less elaborately
branched dendrites than
non-drinkers.

Is this a toxic effect of

alcohol or a result of
malnutrition?

Alcoholic

Ethanol Decreases Dendritic

Complexity in Well-Nourished Rats
Control Ethanol
McMullen, P.A., Saint-Cyr, J.A. &
Carlen, P.L. J Comp Neurol 225,
111-118 (1984).

1188
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Brain Recovery following Abstinence

Bartsch, Brain 07

Dendritic
simplification
occurs with aging
and is accelerated
in aging alcoholics.
Alcohol inhibits the
release and
function of
neurotrophic
factors.
Could alcoholic
neurotoxicity result
from a loss of
neurotrophic
support?

1189
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Alcoholic Peripheral Neuropathy

Mellion et al. Muscle Nerve 2011

Alcohol toxicity, sometimes complicated by

nutritional deficiency
Primarily sensory, distal symmetric, length-
dependent neuropathy affecting feet, legs, and
hands
Small fiber axonal loss with some demyelination
Burning pain is often prominent
Autonomic neuropathy may be present

Alcoholic Myopathy
Urbano-Marquez et al. Muscle Nerve 2004

Occurs in up to 40-60% of alcoholics

Toxic myopathy affecting skeletal and cardiac
muscle. Elevated creatine kinase
Pelvic and shoulder girdle weakness develop
over weeks to months. May be asymptomatic
Occasional acute cases with rhabdomyolysis
Cardiomyopathy with arrhythmias and ventricular
dysfunction
Improvement with abstinence
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Fetal Alcohol Syndrome (FAS)

Hoyme et al;, Pediatrics 2016, in press

With or without confirmed maternal

ethanol exposure
Specific pattern of minor facial anomalies
Pre- and/or postnatal growth deficiency:
height or weight <10%
Evidence of central nervous system
dysfunction: structural brain
abnormalities or head circumference
<10% or recurrent non-febrile seizures
Neurobehavioral Impairment:
Neurocognitive or Neurobehavioral
Photo courtesy of Teresa
impairment or Developmental Delay (for Kellerman
children <3)

Prevalence of FAS and FASD in US

May et al. Pediatrics 2014

FAS: 6-9 per 1000 live births

FASD: 2.4-4.8% of first graders
Prevalence similar to or greater than
autism spectrum disorders
Children with FASD grow up to
become adults with FASD
Adults with FASD have increased
prevalence of alcohol use disorder
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROTOXICOLOGY –
CNS Toxins
Michael Ganetsky, MD
Assistant Professor of Emergency Medicine, Harvard Medical School
Core Medical Toxicology Faculty, Harvard Medical Toxicology
Fellowship, MA/RI Poison Control Center
Director, Medical Toxicology Consult Service
Department of Emergency Medicine
Beth Israel Deaconess Medical Center

Disclosures

None

1192
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Objectives

Overview of neurotoxicology
– Study of drugs, chemicals, or other toxins
which have an effect on the nervous
system
– Somewhat contrived
Discuss historical toxins, events and
syndromes to provide examples of
injury/effect at various sites

Overview

CNS Toxins
– Direct injury
– Neurotransmitter modulation
PNS toxins
– Neuropathies
– Sodium channel toxins
Acetylcholine/NMJ toxins

1193
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Mechanisms

Direct Neuronal Injury

– Enzyme inhibition
Interference with ATP production
Inhibition of protein synthesis
Inhibition of neuronal transport
– DNA injury
– Free radical production
Nerve Conduction
– Directly open or close ion channels

Mechanisms

Neurotransmitter modulation
– Receptor agonism
Enhanced NT release
Decreased NT uptake in synapse
Direct receptor stimulation by toxin
– Receptor antagonism
Prevention of NT release
Post-synaptic competitive or non-competitive receptor
antagonism
Decreased NT synthesis
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuroanatomy

Central Nervous System

– Brain anatomy of toxicologic importance
Basal Ganglia
Cerebellum
Cortex
– Spinal Cord
Dorsal and Ventral Nerve Roots
– Neurotransmitters
DA, 5-HT, ACh, GABA, Glycine, NE, E, Glutamate

Direct Neuronal Injury

Illicit Drugs
– MDMA, MPTP, Hydrocarbon huffing,
“chasing the dragon”
Metals
– Methylmercury, Mn, Triethyltin, Lead
Cellular asphyxiants
– CO, CN
Chlordecone

1195
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MDMA – “Ecstasy”
Increases release of serotonin at nerve
terminals
– Lesser amphetamine-like effects (NE,E)
Acute effects
– Euphoria, confusion, poor concentration
– Depression, “Tuesday crash”
Chronic effects
– Depression from permanently damaged
serotonergic neurons
– Animal models suggest free radical
mechanism

MPTP

San Jose, CA 1982: Clandestine

synthesis of meperidine analog MPPP
(1-methyl-4-phenyl-4-propionoxy-
piperidine)
Contaminated with MPTP (1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine)
MPTP metabolized via Monoamine
Oxidase to MPP+

1196
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

MPTP

MPP+ selectively enters substantia nigra

cells via dopamine transporter
– Inhibits mitochondrial electron transport
chain
– Reactive oxygen radicals and degeneration
of dopaminergic neurons
Severe irreversible Parkinson's
Distinguished from non-toxic etiology
by the absence of resting tremor

Inhalant Abuse

Variety of household products used for

“huffing,” “bagging,” and “sniffing”
Aliphatic hydrocarbons
– Lighter fluid, spray paint
Aromatic hydrocarbons
– Brake fluid, various solvents, glue

1197
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Inhalant Abuse

Acute toxicity
– Ataxia, slurred speech, hallucinations
common to both aliphatic and aromatic
Chronic toxicity
– Aliphatic
Irritability, poor attention span, poor
work/school performance, weakness and
numbness in extremities
Loss of grey-white interface on CT scan

Inhalant Abuse

Chronic toxicity
– Aromatic
Cerebellar findings – ataxia
Cerebellar atrophy on CT scan

1198
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

“Chasing the Dragon”

Netherlands, 1980’s
– 47 heroin users
developed mutism and
spastic quadriparesis
– All were inhaling vapors
from powdered heroin
heated on aluminum foil
– Spongiform
leukoencephalopathy
– Mechanism unknown

Minamata Bay

Chisso Corporation was a chemical plant

manufacturing vinyl chloride and
acetaldehyde (1932-1968)
Kumamoto – fishing town on the bay
Fish was staple diet of locals
1950’s – noticed strange disease, 4000
people affected linked to fish diet
CNS effects, birth defects, “cat dancing”

1199
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Methylmercury

Dumped Hg into the bay

– Fish had high levels of methylmercury
General severe cognitive impairment,
tunnel vision, deafness, numbness of
extremities (centrally mediated)
Birth defects (MR, CP, di/paraplegic,
microcephaly)

Minamata Bay
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Methylmercury

Iraq, 1971 – Grain intended for planting was

treated with methylmercury as fungicide
Inadvertently sold as food resulting in over
400 deaths
MRI revealed atrophy of cerebellar
hemispheres, post-central gyri, and
calcarine area
– Ataxia, sensory neuropathy, visual field
constriction respectively

Manganese
Manganese commonly used in metals,
alloys, catalysis
MnCl2 can vaporize and be absorbed via
pulmonary beds
Initial manifestations are alterations in
mood and abnormal behavior (“locura
magnanis”)
Continuing exposure produces injury to
dopaminergic neurons
– Parkinson’s-like illness (without resting tremor)

1201
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Triethyltin

France, 1954 – “Stalinon affair”

Stalinon – oral medication for skin infection,
osteomyelitis, anthrax
– Contaminated with triethyltin
Potent metabolic inhibitor (mitochondrial
injury, disruption of ATP synthesis)
217 of 1000 patients symptomatic
– Headache, seizures, cerebral edema
– 102 died

Lead

Severe: encephalopathy, failure of blood-

brain barrier from lead accumulation in
microvasculature
More subtle, chronic
– Glial cell differentiation, calcium channel
disruption, stimulates CNS protein kinases,
impairs most neurotransmitter systems
– Disorganized synaptic pruning
– Developmental delays, hyperactivity, hearing
deficits, neurocognitive (5-point lower IQ)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cellular Asphyxiants

Carbon monoxide, cyanide

Interfere with cellular ability to utilize
oxygen and form ATP
Basal ganglia particularly vulnerable to
injury

Carbon Monoxide

CO – byproduct of incomplete combustion

– Cars, heaters, zambonie, forklift
– Also from hepatic metabolism of methylene
chloride (paint stripper)
Acute exposure: headache, dizziness, chest
pain, dysrhythmia, seizures
CT scan findings appear within days of
severe exposures (decreased density of
central white matter and globus pallidus)

1203
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Carbon Monoxide

Delayed effects after acute exposure

– Manifest days to weeks later
– Include headaches, memory deficits,
dementia, psychosis, chorea
No clear evidence to show long term
sequellae following chronic low level
exposure
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Chlordecone

James River, Virginia 1975

Chemical factor producing Chlordecone
(Kepone), an organochlorine insecticide
High incidence of neurologic abnormalities
among workers
– Tremor (Kepone shakes), weakness, fatigue,
ataxia, chaotic eye movements, neurocognitive
impairment, slurred speech

Chlordecone

Chronic toxicity may be more

prevalent than with other
organochlorine pesticides due to lipid
accumulation and slow metabolism
Mechanism unclear
– Inhibition of ion pumps (Na-K-ATPase,
Ca-ATPase)?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurotransmitter Toxins

Glutamate
– Domoic acid, PCP, ketamine
GABA
– INH, Gyromitra spp., water hemlock,
tetramine
Glycine
– Strychnine, tetanus
Acetylcholine
– Numerous, both CNS and PNS toxin

Glutamate

Major CNS excitatory neurotransmitter

Receptors
– Ionotropic (Ca2+, Na+ influx): NMDA, AMPA,
kainate receptors
– Metabotropic (G-protein): mGluRs
“Excitotoxicity”- neural injury due to excess
glutamate, intracellular Ca2+
Glutamate antagonists decrease drug cravings
in ethanol, benzo and opiate addiction

1206
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Amnestic Shellfish Poisoning

Caused by domoic acid

– Glutamate structural analog
– Produced by diatom Nitzschia pungens, taken up
by shellfish (crab, clams, muscles, scallops)
– Kainate >> NMDA receptor activation
Outbreaks in Canada, Washington State,
Oregon
Vomiting, diarrhea, abdominal pain
Confusion, agitation, anterograde memory
deficits, seizures, coma, death (2%)

Gamma-aminobutyric
Acid (GABA)
One of two primary inhibitory
neurotransmitters in CNS
GABA agonists used as
anticonvulsants, sedatives, anesthetics
GABA antagonists cause CNS
excitation and seizures
GABA synthesis requires pyridoxine
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Isoniazid

Inhibits pyridoxine phosphokinase

preventing formation of active form
(pyridoxal-5-phosphate)
Reacts with pyridoxal-5-phosphate forming
hydrazone complex
Functional pyridoxine deficiency leads to
decreased GABA synthesis
Triad of refractory seizures, coma, acidosis

Gyromitra esculenta
More common poisoning in Europe
Mistaken for morel mushroom (Morchella
esculenta)
Contains gyromitrin (N-methyl-N-formyl
hydrazone)
Converted to monomethylhydrazine
– Rocket fuel
MMH interferes with pyridoxine in similar
manner to INH producing GABA deficiency
Seizures, coma, acidosis

1208
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Water Hemlock (Cicuta

maculata)
Mistaken for parsnip, turnip, or parsley
Contains cicutoxin
– Found in all parts of plant (highest in tuber)
– 2cm of root is lethal
– GABA receptor antagonism
Abdominal pain, mydriasis, seizures,
opisthotonus, hemiballismus, coma

1209
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Glycine

Postsynaptic inhibitory
neurotransmitter
Brainstem and spinal cord
Binding of glycine to its receptor opens
Cl- channels
– Membrane hyperpolarization
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Strychnine

From seeds of Strychnos nux-vomica

Historically used as rodenticide and in
Cambodian herbal remedies
Post-synaptic antagonism at glycine
receptors in spinal cord
Extensor spasm, opisthotonus, “risus
sardonicus,” mental status intact
– Spinal seizures

1211
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tetanus
Infection from Clostridium tetani leads to
the production of tetanospasmin
Inhibits release of glycine from presynaptic
nerve terminals in brain stem and spinal
cord
Clinical picture is similar to that of
strychnine poisoning
Trismus, muscle spasms, laryngospasm,
respiratory paralysis, death

1212
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Summary

CNS Neurotoxicology
– Lots of unfortunate events
– Direct neuronal injury
– Neurotransmitter modulation
PNS Neurotoxicology next

1213
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEUROTOXICOLOGY –
PNS Toxins
Michael Ganetsky, MD
Assistant Professor of Emergency Medicine, Harvard Medical School
Core Medical Toxicology Faculty, Harvard Medical Toxicology
Fellowship, MA/RI Poison Control Center
Director, Medical Toxicology Consult Service
Department of Emergency Medicine
Beth Israel Deaconess Medical Center

Disclosures

None

1214
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Objectives

Discuss historical toxins, events and

syndromes to provide examples of
injury/effect at various sites

Overview

CNS Toxins
– Direct injury
– Neurotransmitter modulation
PNS toxins
– Neuropathies
– Sodium channel toxins
Acetylcholine/NMJ toxins
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuroanatomy

Peripheral Nervous System

– Somatic
Sensory neurons of dorsal root ganglia and
cranial nerve ganglia
Axons of motor fibers from ventral root
– Autonomic
Sympathetic
Parasympathetic

Mechanisms
Neuropathies
– Axon
TOCP, Tl, As, INH, pyridoxine, n-hexane
– Nerve body
Pyridoxine
– Myelin
Diphtheria, TCE, Lead
Na+ channel effects
– Marine toxins: saxitoxin, tetrodotoxin, ciguatoxin

1216
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neuropathies

Divided into 3 broad groups

– Distal axonopathy with “dying back” axon
degeneration
– Myelinopathy with primary segmental
demyelination
– Neuronopathy affecting cell body
(especially in dorsal root ganglion)

Axonopathy

Most common toxin-induced

neuropathy
Symmetric, diffuse, stocking-glove
sensory and motor loss
“Coasting” effect after drug withdrawn
Regeneration at 2mm/day
– Prolonged recovery, denervation atrophy

1217
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Triorthocresyl phosphate
Jamaican ginger paralysis -
U.S. 1930-1931
“The Jake” sold as medicinal
supplement bypassing
prohibition
In additional to ethanol,
usually mixed with castor oil
Rising cost of castor oil lead
to substitution with TOCP

TOCP

50,000 people developed symptoms of

upper and lower extremity weakness or
paralysis and gait instability
– “Ginger Jake paralysis” or “Jake leg”
TOCP is an organophosphate with minimal
cholinergic effects
Inactivates neurotarget esterase (NTE) in
peripheral nerves leading to axonal
degeneration

1218
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

TOCP
Jake Bottle Blues Alcohol and Jake Blues
Lemuel Turner, 1928 Tommy Johnson, 1930

Jake Walk Blues Jake Liquor Blues

Allen Brothers, 1930 Ishman Bracey, 1930

Jake Leg Wobble Jake Leg Blues

Ray Brothers, 1930 Mississippi Sheiks, 1930

Jake Leg Blues Jake Leg Blues

Byrd Moore, 1930 Daddy Stovepipe and Mississippi Sarah, 1930

Got The Jake Leg Too Jake Walk Papa

Ray Brothers, 1930 Asa Martin, 1933

Jake Leg Rag Jake Leg Blues

Narmour and Smith, 1930 Willie Lofton, 1934

TOCP

1959 Morocco
10,000 cases of weakness and
paralysis resulting from cooking oil
contaminated with turbojet lubricant
Outbreaks from cooking oil and
mineral oil in Sri Lanka and Vietnam
also linked to TOCP

1219
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Thallium

Early 1900s – treatment of syphilis,

gonorrhea, TB, tinea capitis
Several deaths from depilatory use
– Alopecia, specifically lateral portions of
eyebrows
Effective rodenticide – banned from
U.S. in 1975
Used as homicidal agent

Thallium

Chemically behaves like potassium

Inhibits K+-dependent enzymes, particularly
in nerve tissue
Interferes with disulfide bonds and protein
synthesis
Leads to dying back axonopathy of
peripheral nerves
– Sensory nerves more affected than motor
– Painful ascending peripheral neuropathy

1220
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Arsenic

Historical use for treatment of syphilis

Still used for trypanosomiasis and
promyelocytic leukemia
Present in some herbicides
Many cases of intentional poisonings
Ground water contaminant (Bangladesh)

Arsenic

Multiple mechanisms of injury

– Inhibition of pyruvate dehydrogenase
Interferes with citric acid cycle
Decreased ATP
– Uncouples oxidative phosphorylation
– Direct DNA damage
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Arsenic

Acute effects include severe

gastrointestinal distress and
cardiovascular collapse
Subacute – 1 to 3 weeks after large
exposure
– Sensory loss first, followed by ascending
motor weakness
– Severe pain to light touch can occur as
with Thallium

Isoniazid

Produces pyridoxine deficiency which

appears to be mechanism of neural injury
Primarily a sensory neuropathy in stocking-
glove distribution, but may involve
weakness
Optic neuritis may also occur
B6 (pyridoxine) supplementation prevents
neuropathy

1222
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pyridoxine (chronic)

Chronic high dose therapy

Progressive sensory ataxia, profound
loss of position, vibration sense
Widespread sensory nerve axonal
degeneration
Improvement over time with drug
abstinence

n-hexane, methyl n-butyl

ketone
Common solvents in lacquers and glues
Occupational and recreational
– Hyperhidrosis in glue-sniffers
Both metabolized to 2,5-hexanedione
Interferes with phosphorylation
reactions in nerve cells
Axonal degeneration with chronic
exposure

1223
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Myelinopathy
Generalized weakness
– Large motor fibers dependent on myelin
Impaired proprioception, vibration, and
touch
– Mediated by large myelinated sensory fibers
Mild impairment to pain, temperature, and
autonomic senses
– Small, generally unmyelinated, fibers
Re-myelination generally rapid once toxin
withdrawn

Trichloroethylene

TCE used in rubber manufacturing, dry

cleaning, metal degreasing agent
Mechanism of toxicity unclear
Classically affects trigeminal nerve
– Facial numbness
– Difficulty chewing

1224
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lead

Schwann cell destruction,

demyelination, axonal degeneration
Motor neuropathy
Wrist and foot drop

Polychlorinated Biphenyls

Plasticizers and electrical insulation

PCBs pollutants of waterways and marine life
Cooking oil contamination in Japan (1968)
and Taiwan (1978)
– Mild self-limited sensory neuropathy
– Acne, brown-pigmented nails, meibomian gland
discharge
Unknown pathogensis of PCB neuropathy
Alleged, unproven neurodevelopmental toxin

1225
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diphtheria

Corynebacterium diptheriae
Toxin inhibits myelin production in Schwann
cells
Pharyngitis
– Acute effects: palatal weakness, blurred vision
– Late effects (1 to 3 months): Proximal motor
weakness, spreads distally
Recovery is complete

Neuronopathy

Least common of toxic neuropathies

Predilection for dorsal root ganglia
– Sensory symptoms most common
– Generally dermatomal distribution
Can have anterior horn cell
involvement (motor) or involvement of
autonomic system
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pyridoxine (acute)

Acute massive overdose

Widespread sensory loss, sensory
ataxia, autonomic instability
Motor function preserved
Poor prognosis

Sodium Channel Toxins

Red Tide
– Saxitoxin
Puffer Fish (Fugu)
– Tetrodotoxin
Ciguatera
– Ciguatoxin

1227
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Red Tide

Harmful Algal Bloom

Various dinoflagellate species produce

red tide when “blooming”
– Alexandrium tamarense
Saxitoxin is one byproduct causing
human illness via ingestion of
contaminated shellfish
– Paralytic Shellfish Poisoning (PSP)
Block Na+ channels, prevents
conduction
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Paralytic Shellfish Poisoning

Facial/oral paresthesia, weakness,

ataxia, paralysis, respiratory failure
Victims conscious
Resolves in 2 to 3 days with
supportive care

Fugu Sashi

Tetrodotoxin concentrated
in liver and ovaries
Small amount produces
mouth and tongue
paresthesia
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Tetrodotoxin

Found in certain variety of puffer fish,

horseshoe crab eggs, newts, and blue
ringed octopus
Blocks Na+ channels
Clinically similar to PSP
Perioral numbness, muscle weakness,
paralysis, respiratory failure
Treatment is supportive

Ciguatera Poisoning

Dinoflagellates make ciguatoxin

Little fish eat dinoflagellates
Big fish eat little fish
– Sea bass, snapper, grouper, etc.
People eat big fish

1230
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Ciguatera

Ciguatoxin binds Na+ channels,

increases permeability
GI distress, sensation of dental pain
and instability, perioral parasthesias,
cold allodynia, extremity parasthesias
GI symptoms resolve in 1-2 days
Neurologic symptoms may persists for
days to weeks

Acetylcholine
Major neurotransmitter in CNS and PNS
Binds muscarinic and nicotinic ACh receptors
CNS – muscarinic diffusely located in brain,
nicotinic in spinal cord
PNS
– Autonomic
Nicotinic at autonomic ganglia
Muscarinic at parasympathetic target organs
– Somatic
Nicotinic at neuromuscular junction (NMJ)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acetylcholine
Variety of clinical scenarios depending on
specificity of agent
Receptor antagonism
– CNS = central anticholinergic syndrome
Hallucinations, agitation, mumbling speech,
myoclonus, tremor
– PNS (autonomic) = peripheral anticholinergic
syndrome
Muscarinic = Mydriasis, anhidrosis, urinary retention,
ileus
Nicotinic = paralysis (e.g. nondepolarizing NMB)

Acetylcholine

Receptor agonism
– CNS = rigidity, coma, seizures
– PNS
Autonomic
– Muscarinic = bradycardia, miosis, salivation,
lacrimation, vomiting, diarrhea, bronchospasm,
bronchorrhea, micturation
– Nicotinic = mydriasis, hypertension, tachycardia
Somatic = initially fasciculations, followed by
paralysis

1232
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acetylcholine

Cholinomimetics Cholinolytics
ACh release Direct nicotinic
– Black widow antagonist
Anticholinesterase – Nondepolarizing NMB,
succinylcholine
– Organophosphates,
“nerve agents” Direct muscarinic
Direct nicotinic antagonist
– Nicotine, coniine, – Atropine, scopolamine
succinylcholine Inhibit ACh release
Direct muscarinic – Botulinum toxin
– Bethanachol

Black Widow
(Latrodectus mactans)
Alpha-latrotoxin binds at presynaptic nerve
terminals causing release of ACh (also NE)
Primary effect is peripheral – severe muscle
spasms, particularly chest, abdomen, face
(“facies latrodectismica”)
Hypertension, diaphoresis, salivation,
vomiting, and seizures may occur
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Acetylcholinesterase
Inhibitors
ACh hydrolyzed to acetic acid and choline in
synaptic cleft by acetylcholinesterase
Enzyme inactivated by organophosphates
– Pesticides: parathion, malathion, chlorpyriphos,
dichlorvos
– “Nerve agents”: Tabun (GA), Sarin (GB), Soman
(GD), VX
Results in increased ACh concentration in
synaptic cleft

Sarin

Matsumoto, Japan – June 27, 1994

– Aum Shinrikyo cult
– Converted refrigerator truck parked in
residential neighborhood
– Computer controlled release of sarin
cloud
– 7 dead, 500 taken to hospital

1234
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Sarin

Tokyo, Japan – March 20, 1995

– Aum Shinrikyo cult
– Plastic bags wrapped in newspaper place
on 5 separate subway cars
– Punctured with umbrella tip
– 12 dead, 3,800 taken to hospital

Sarin

Ocular complaints most common in

the attacks – miosis, eye pain, dim
vision
Cough, nausea, headache, dizziness
Severely affected - rapid onset of
coma, seizures, fasciculations,
paralysis, apnea

1235
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Poison Hemlock

Conium maculatum
Likely responsible for the death of Socrates
Very similar in appearance to water hemlock
Coniine, alkaloid structurally related to nicotine
– Initial symptoms include vomiting, salivation,
mydriasis, tachycardia
– Stimulates autonomic ganglia (mixed sympathetic
and parasympathetic picture)
– Ascending paralysis due to stimulation at NMJ
– Death from respiratory failure

Poison Hemlock

1236
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Scopolamine

Direct acting antimuscarinic agent

325 cases of anticholinergic poisoning
among heroin users (scopolamine
adulterant) - US east coast 1995-6
CNS – hallucinations, agitation
PNS – anhidrosis, tachycardia, ileus,
urinary retention

Botulism
Clostridium botulinum - botulinum toxin
Binds presynaptic nerve terminals at NMJ
preventing ACh release
If foodborne, mild GI distress may precede
neurologic symptoms
Constipation, dry mouth, blurred vision,
dysarthria, diplopia, descending symmetric
paralysis
Sensation and mental status intact
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Botulism

Foodborne
– Most common in infants
– 1 to 3 months old, constipation, “floppy
baby”
Wound botulism
– Trauma victims and heroin users
Vanity botulism

Summary

PNS Neurotoxicology
– Still lots of unfortunate events
– Neuropathies
Axonopathy
Myelinopathy
Neuronopathy
– Sodium channel toxins
– Acetylcholine toxins (combination of CNS
and PNS effects)

1238
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurorehabilitation

Sabrina Paganoni, MD, PhD

Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital (MGH)
Boston, MA

Disclosures
I have no disclosures relevant to this talk

I have received research funding from NIH, Target ALS,

MGH ALS Therapy Fund, the Salah Foundation, the Spastic Paraplegia
Foundation.

1239
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurorehabilitation

An oxymoron?

What is it exactly?

Options for your patients

3

Rehabilitation is the process of assisting a person

to maximize function and quality of life

Therefore rehabilitation matters

to patients with neurologic diseases because
it helps them reach their fullest potential
despite the presence of a disability
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The ICF model. Source: “Towards a Common Language for Functioning,

Disability and Health”, World Health Organization, Geneva, 2002 5

Disease-centered
Mobility
“There is nothing we can do”
Community ADLs

Commu-
Caregiver Patient nication

Symptom
Nutrition
Management

Patient-centered Breathing

“There is always something we can do”

6

1241
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Stroke
Rehabilitation
Traumatic Brain Injury

Spinal Cord Injury

Multiple Sclerosis
?
Neuromuscular Disease

Where does Rehabilitation take place?

HOME
SNF
-Rehab 1-3x/wk (Skilled Nursing Facility)
-MD appt <1x/wk
-Rehab 0-2 hrs/day
-MD/NP visits 1-5 times/wk
Home Care -Nursing
Outpatient
-RN,SW Rehab
-Rehab

IRF LTAC
(Inpatient Rehab Facility) (Long Term Acute Care)

•Rehab needs paramount -Medical needs paramount

•Rehab 3+ hrs/day -Rehab 0-2 hrs/day
•MD visits 5-7 days/wk -MD visits 5-7 days/wk
•Nursing -Nursing

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

1242
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Challenges: transitions/coordination of care

ACUTE
CARE
HOSPITAL

IRF
(Inpatient Rehab Facility)
LTAC
(Long Term Acute Care)

SNF
(Skilled Nursing Facility)

HOME
Home Care Outpatient Rehab

Basic tenets
1.Rehabilitation is a team effort
- physicians, nurses
- physical therapists (PTs)
- occupational therapists (OTs)
- orthotists (braces)
- speech and language pathologists (SLPs)
- assistive technology experts (e.g., AAC)
- social workers, community program representatives
- respiratory therapists

2. It starts at the first patient encounter and is a

dynamic process

3. Compensation, adaptation, restoration of function

10

1243
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Compensation and adaptation

11

Adaptive equipment
for ADLs

12

1244
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Meal preparation and self-feeding

A: scoop plate (yellow), rocker knife, fork with soft foam handle,
plate guard (white), long straw.

B-D: universal cuff. Provides people with little to no finger control

the ability to hold objects. In C, the cuff has been modified to
support a weak wrist.
13

Dressing and bathing

A: reacher, dressing stick, long-handled shoe horn, sock aid.

B: Patient using a sock aid.
C: Patient using a reacher.
D: Button hook.
E: Long-handled sponge. 14

1245
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Bracing

15

Ankle-foot-orthoses
(AFOs)

16

1246
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Not all AFOs are created equal

17

“I am not going to wear a brace”

18

1247
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Knee-ankle-foot orthoses
(KAFOs)

19

Night-time AFO

20

1248
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Hand splints

Used for people with intrinsic hand weakness.

A: resting hand splint to maintain muscle length in people at risk
of finger flexion contractures.

B: opponens splint for people with prehension difficulties due to

thumb weakness (keeps thumb in abducted and opposed
position).
C: cock-up splint to support wrist in 20-30° of extension for
people whose wrist extension weakness prevents them from
grasping. 21

Neuromuscular Electrical Stimulation

(NMES)

Used for people with weakness due to central lesions

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

1249
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Upper extremity NMES

Benefits
• Improve passive ROM
• Prevent contracture
• Inhibit antagonist muscle spasticity
• Maintenance of muscle bulk
• Muscle strengthening?

Lower extremity NEMS

Used for foot drop

Assist with gait
1

1250
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Battery powered
exoskeletons
-Motorized quasi-robotic suit
-User initiates movement
-Sensors in crutches
-Requires full upper body strength
-Paraplegics, hemiplegics

Restoration of function?

26

1251
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Gait training

27

Traditional rehab gait training-

Overground

• Parallel bars
• Hemiwalker
• Quad cane
• Straight cane

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

1252
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Partial Body Weight Support

• Early gait training

• 2 therapists

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

Original Article
Body-Weight–Supported Treadmill Rehabilitation
after Stroke
Pamela W. Duncan, P.T., Ph.D., Katherine J. Sullivan, P.T., Ph.D., Andrea L.
Behrman, P.T., Ph.D., Stanley P. Azen, Ph.D., Samuel S. Wu, Ph.D., Stephen E.
Nadeau, M.D., Bruce H. Dobkin, M.D., Dorian K. Rose, P.T., Ph.D., Julie K.
Tilson, D.P.T., Steven Cen, Ph.D., Sarah K. Hayden, B.S., for the LEAPS Investigative
Team

N Engl J Med
Volume 364(21):2026-2036
May 26, 2011

1253
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The LEAPS trial

• 408 patients, 2 months after stroke

• Randomized to either PT or body weight
supported treadmill training
• At 1 year, 52% of all participants had
increased functional walking capacity

• Body-weight support in stepping on a treadmill

was not shown to be superior to progressive
exercise at home managed by a physical
therapist

Cochrane Review, 2014

Treadmill training and body weight support
for walking after stroke

• 44 trials with 2658 participants

• Overall, people after stroke who receive treadmill
training are not more likely to improve their ability
to walk independently compared with people after
stroke not receiving treadmill training
• BUT walking speed and walking endurance may
improve
• Specifically, stroke patients who are able to walk
(but not people who are not able to walk) appear
to benefit most from this type of intervention

1254
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Robotic Gait Training

(courtesy of Dr Paolo Bonato, Spaulding Rehabilitation Hospital) 33

Robotic gait trainers

(courtesy of Dr Paolo Bonato, Spaulding Rehabilitation Hospital)

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Virtual Reality Exercise systems

• Patients stand in front of a

"green screen" that is
digitally removed, leaving
only the patients actual body
images placed within the
video environment.
• No headgear or wires, only a
lightweight glove on one
hand and no system
calibration is required.

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

(courtesy of Dr Black-Schaffer, Spaulding Rehabilitation Hospital)

1256
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

VR exercise benefits
• Virtual environments motivate participation

• Allow measurement of changes in

performance

• Enable high number of repetitions of

specific exercises in short period of time

• Increase patients’ independence in

exercise programs – reduce therapist time

Task oriented training for

upper extremities

38

1257
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Task Oriented Training

• Repetitive functional tasks

• Challenging enough to engage patient in new

learning

• Appropriate for patient’s skill level and

progressive

• Interesting enough to invoke active

participation

Constraint Induced Movement Therapy

for stroke

• Constraint of good
extremity
• Massed practice of tasks
with affected extremity
• Shaping of tasks

Wolf SL et al. The EXCITE Randomized

Clinical Trial. JAMA, 2006; 296: 2095.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The EXCITE trial

• 222 patients, at least 1 year post stroke

• Randomized to either usual care or CIMT

• Treatment lasted 2 weeks

• CIMT produced statistically significant and clinically

relevant improvements in arm motor function

Task Oriented Training

• Continued practice will
lead to ongoing
improvement

• Neuroplasticity?

• Optimal timing/dosing
unclear

1259
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rehabilitation Robotics
Over the past two decades we have
witnessed the development of a
number of robotic systems for
rehabilitation.

(courtesy of Paolo Bonato, Spaulding Rehabilitation Hospital) 43

Virtual Reality (VR) based Exercise Systems

-Arm weight support

- grasp and release
- pro- / supination
- wrist flexion / extension
- reach and retrieval
-Measurement software

http://pmr.medicine.pitt.edu/content/RehabProgress_summer_2010.pdf

1260
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Three-dimensional, task-specific robot therapy

of the arm after stroke: a multicentre, parallel-
group randomised trial

Klamroth et al., Lancet Neurology, 2014

-77 stroke patients with moderate-to-severe arm

paresis, at least 6 months post-stroke

-Randomized to either robotic therapy or usual care

-task-oriented training with an exoskeleton robot

enhanced improvement of motor function more
effectively than conventional therapy

Rehabilitation
matters…

maximize function
and
quality of life

through
compensation, adaptation,
? restoration of function
46

1261
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Adaptive sports

47

Picture Credits: www.networkofcaring.org; www.mda.org;

Spaulding Rehabilitation Hospital; AccessSportAmerica

Picture Credit: Spaulding Rehabilitation Hospital 48

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Rehabilitation research
urgently needed!

49

Acknowledgments
Spaulding Rehabilitation Hospital
Ross Zafonte, DO
Randie Black-Schaffer, MD
Joe Giacino, PhD
Leslie Morse, DO
Paolo Bonato, PhD

University of Washington
Jared Olsen, MD

50
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Questions?

Sabrina Paganoni
[email protected]

51

1264
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Autonomic Disorders
Peter Novak, MD, PhD
Brigham and Women’s Faulkner
Hospital
Harvard Medical School

Disclosure: Reports no commercial interest

off label use of medication will be discussed

Autonomic Disorders
Plan of talk:
• Autonomic nervous system
• Autonomic symptoms
Review of common autonomic disorders:
• Diabetic Autonomic Neuropathy
• Postural Tachycardia Syndrome (POTS)
• Orthostatic Hypotension
• Syncope
• Small fiber neuropathy
• Inflammatory and other autonomic neuropathy

1265
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Autonomic Nervous System

Small fibers – innervate all organs:
Autonomic “proper” (efferent or motor) small fibers
Sensory (afferent) small fibers

Autonomic system:
Sympathetic –”fight or flight”
Parasympathetic-”rest and digest”

Autonomic fibers
Motor, therefore we cannot feel them
Dysfunction is causing “dysautonomia”
Autonomic dysfunctions manifests
as end organ dysfunction
– For example the enteric autonomic
neuropathy may cause constipation

Dysfunction of sensory (afferent) fibers

-painful small fiber neuropathy

Vinik A, Erbas T, Casellini C. (2013). Diabetic cardiac autonomic neuropathy,

inflammation and cardiovascular disease. Journal of Diabetes Investigation. 4
(1), 4-18; Novak et al, (2001). Autonomic impairment in painful neuropathy,
Neurology, 56:861-868, Novak et al. (2009) J Cutan Pathol 36:296-301
3

Autonomic Symptoms
• Orthostatic (characteristic for dysautonomia):
– Lightheadedness or dizziness
– Palpitations
– Sense of weakness
– Tremulousness
– Shortness of breath
– Chest pain
– Exacerbation by heat, exercise, meals, menses
– Hyper-, hypo-hydrosis
• Nonorthostatic:
– Nausea, vomiting
– Bloating
– Diarrhea, constipation
– Abdominal pain
– Bladder symptoms
– Pupillary symptoms
• Diffuse:
– Fatigue
– Sleep disturbances
– Exacerbation of migraine
– Myofascial pain
– Neuropathic pain

Thieben at al. (2007). Postural Tachycadia syndrome: The Mayo Clinic experience. Mayo Clinic Proc. Proceedeings 82, 308-313, Vinik
A, Erbas T, Casellini C. (2013). Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. Journal of
Diabetes Investigation. 4 (1), 4-18; Novak et al, (2001). Autonomic impairment in painful neuropathy, Neurology, 56:861-868, Novak 4
et al. (2009) J Cutan Pathol 36:296-301

1266
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Quantitative Autonomic Testing

• Parasympathetic: deep breathing

• Sympathetic and parasympathetic:
– Valsalva maneuver, Tilt test
• Sympathetic cholinergic: sudomotor testing
• Small fibers: skin biopsies
• Catecholamines supine and standing (for example in the hyperadrenegic form
of POTS where norepinephrine is elevated)
• Ganglionic acetylcholine receptor antibody for suspected autoimmune
mechanisms

• Open access video article shows details of testing, J Vis Exp. 2011 Jul 19;(53).
• http://www.jove.com/video/2502/quantitative-autonomic-testing

Indication for Autonomic Testing

Autonomic failure:
Orthostatic dizziness/lightheadedness
Falls
Syncope, LOC
Suspected autonomic failure in neurodegenerative disorders (MSA, PAF)
SOB
Postprandial symptoms
Chest pain
Heat intolerance, Hyper-, hypo-hydrosis

Small fiber neuropathy (+skin biopsy):

Diabetic neuropathy complicated by autonomic failure (very common, > 1 million in US)
Painful small fiber neuropathy (common, 1% of US population)
Sjogren syndrome and other inflammatory connective tissue disorders
Amyloid neuropathy
Idiopathic neuropathy with normal EMG
Complex regional pain syndrome
Idiopathic hyperhydrosis (very common, up 10% of people in US)

6
American Autonomic Society guidelines, 2015
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Autonomic Disorders
Secondary
• Diabetes
• HTN
• Multiple sclerosis
• Parkinson disease
• CHF
• Pulmonary disorders - COPD

Primary
Prominent orthostatic symptoms=Orthostatic Intolerance:
• Postural tachycardia syndromes (POTS)
• Orthostatic hypotension (OH)
• Neurally mediated syncope
Nonorthostatic: (orthostatic symptoms are usually not main feature)
• Small fiber neuropathy

Diabetic Autonomic Neuropathy

• Prevalence, incidence, pathophysiology of diabetic autonomic neuropathy
• Clinical significance-outcomes
• Classification
• Testing- HUT
• Characteristics patterns
• Treatment

1268
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diabetic Autonomic Neuropathy (DAN)

• DAN is among the least recognized and understood complication of
diabetes

• Affects 20 % of diabetic patients (depending on the type of test 5-90%)

• Major source of increased cost in caring

• Diabetes diffuse and widespread damage of autonomic nerves and

small vessels

Vinik A, Erbas T, Casellini C. (2013). Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular
disease. Journal of Diabetes Investigation. 4 (1), 4-18. 9

Diabetic Autonomic Neuropathy

Duration of
diabetes

Extent of
impairment

Nerve
Degree of
funtion
glycemic
decline with
control
age

Prevention: Mantainance of near-normal blood glucose

Vinik A, Erbas T, Casellini C. (2013). Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular
disease. Journal of Diabetes Investigation. 4 (1), 4-18. 10

1269
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diabetic Autonomic Neuropathy

Symptoms - eyes:

• Iris
• Early parasympathetic autonomic dysfunction.
• Impaired iris constriction measured by pupilometry.
• Inability to see in dark places, difficulty driving at night.

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
nervous system. Oxford: Elsevier. p477-481 11

Diabetic Autonomic Neuropathy

Symptoms – GI system:
• Esophagus
• Dysphagia
• Esophageal and pharyngeal motility dysfunction
• Stomach
• Gastric emptying abnormalities - gastroparesis
• Gallbladder
– Diarrhea, gallstones
• Colon
– Constipation
– Diarrhea

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
nervous system. Oxford: Elsevier. p477-481 12
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diabetic Autonomic Neuropathy

• Urinary and sexual
– Inability to feel the need to void
– Atonic bladder, incontinence
– Erectile dysfunction
• Sudomotor
– Abnormal sweating

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
nervous system. Oxford: Elsevier. p477-481 13

Diabetic Autonomic Neuropathy

Symptoms – Cardiovascular = poor prognosis
• Exercise intolerance
• Painless myocardial ischemia
• Attenuation of nocturnal blood pressure fall
• Orthostatic hypotension
• Supine hypertension

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
nervous system. Oxford: Elsevier. p477-481 14

1271
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diabetic Autonomic Neuropathy

• Diagnosis
Clinical grounds
Consider autonomic testing if:
- severe orthostatic symptoms, dizziness or falls
- severe constipation
- severe incontinence
- unexplained pain

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
15
nervous system. Oxford: Elsevier. p477-481

Diabetic Autonomic Neuropathy

• Management
Optimal glycemic control
Weight control
Exercise, diet
Antioxidants and aldose reductase inhibitors can reduce symptoms

Therapy of autonomic symptoms will be discussed with management

of orthostatic hypotension and dysautonomia
Orthostatic hypotension - midodrin,florinef, pyridostigmine,
droxydopa) + diet + life style changes
Constipation – pyridostigmine (if stool softeners fail)
Hyperhydrosis - anticholinergics, botulinum toxin
Urinary problems - anticholinergic, botulinum toxin,
depends on type of urinary dysfunction

Peltier A, Davis S. (2011). Diabetic Autonomic Dysfunction. In: Robertson D, Biaggioni, I. Primer on the autonomic
16
nervous system. Oxford: Elsevier. p477-481

1272
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Postural tachycardia syndrome (POTS)

• Prevalence, incidence, pathophysiology of postural tachycardia syndrome

• Clinical significance-outcomes
• Classification
• Testing
• Characteristics patterns
• Treatment

17

POTS - Incidence & prevalence

• Prevalence 1,000,000 – 3,000,000 in the US

• Women to men ratio 5:1
• Ages from adolescent (>15) –adults (usually < 50 yrs old)

Freeman et al: Consensus statement: Autonomic Neuroscience 2011:161; 46-48 18

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Postural tachycardia syndrome (POTS)

Definition:
• 1. Symptoms of orthostatic intolerance (> 6 months)
+
• 2. Sustained and exaggerated heart rate increment > 30 beats per minute
during the 10 min of head up tilt test or active standing in the absence of
orthostatic hypotension

• Standing heart rate >120/bpm

• ECG sinus rhythm

Low PA, Schondorf R, Novak V, Sandroni P, Opfer-Gehrking TL, Novak P. Postural tachycardia syndrome. In: Low PA, ed.
Clinical Autonomic Disorders: Evaluation and Management. 2nd ed. Philadelphia, Pa: Lippincott- Raven; 1997:681– 697.
Low PA,Novak V, Spies JM, Novak P, Petty GW. Cerebrovascular regulation in the postural tachycardia syndrome (POTS)
Am.J. Med. Scie. 317 (2) 124-33;1999. 19

POTS - Symptoms
• Postural lightheadednes, dizziness, shortness of breath, tiredness
(48%), palpitations, leg weakness, tremulousness, blurred vision,
flushing, cold hands and feet, diaphoresis, chest pain, nausea, exercise
intolerance, and–relieved by return to supine position
• Occasionally loss of consciousness – syncope (25%)
• Exacerbation of symptoms: eating, showering, low intensity exercise-
high degree functional disability
• Mental clouding “brain fog”, anxiety
• Over representation of migraine and sleep disorders (32%)

20
Grubb BP et al: The postural orthostatic tachycardia syndrome: Current concepts in pathophysiology and diagnosis. J. Interv.cardiol Electrophysiol
2001; 5:9-16

1274
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS - Pathophysiology
• Heterogenous condition
• Main forms:
– Neuropathic –form of small fiber neuropathy
– Hyperadrenergic- associated with elevated norepinephrine
– Hypovolemic- due to volume depletion

• Immune mediated autonomic neuropathy-a variant of idiopathic

pandysautonomia
• Increased venous pooling to legs and splanchnic area
• Deconditioning

21

POTS – Association with underlying diseases

-Amyloidosis;
-Autoimmune Diseases such as Autoimmune Autonomic Ganglionopathy,
-Sjogren's Syndrome, Lupus, Sarcoidosis, Antiphospholipid Syndrome;
-Chiari Malformation
-Diabetes and pre-diabetes
-Ehlers Danlos Syndrome – and other collagenoses
-Genetic Disorders/Abnormalities;
-Infections such as Mononucleosis, Epstein Barr Virus, Lyme Disease, extra-
pulmonary Mycoplasma pneumonia and Hepatitis C;
-Multiple Sclerosis;
-Mitochondrial Diseases;
-Mast Cell Activation Disorders;
-Paraneoplastic Syndrome - rare small tumors of the lung, ovary, breast and
pancreas
-Toxicity from alcoholism, chemotherapy and heavy metal poisoning.
-Traumas, pregnancy or surgery;
-Vaccinations;
-Vitamin Deficiencies/Anemia;
22

1275
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS – Cerebral Hypoperfusion

• Upright posture –> hyperventilation- CO2 decline
• Hyperventilation -> cerebral vasoconstriction, increased cerebrovascular
resistance, and peripheral vasodilatation, decreased peripheral vascular
resistance, leading to increased venous pooling and symptomatic cerebral
hypoperfusion
• Hypocapnia is reversible with CO2 rebreathing
• EEG- greater modulation at slower frequencies

Novak V et al: Stroke 29:1876-1881, 1998

23

Control POTS
HR [BPM]

HR [BPM]
BP [mmHg]

BP [mmHg]
CBFv [cm/sec]

CBFv [cm/sec]

Modified from Novak: Cerebral blood flow, heart rate and blood pressure patterns during the tilt test in common orthostatic syndromes,24
Neuroscience Journal, in revision 2016

1276
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Cerebral Hypoperfusion in POTS

POTS CONTROLS

HR=heart rate, CVR=cerebrovascular resistance, MBP=mean blood pressure, BFV-brain

blood flow velocity, pulse pressure, pulse flow, CO2-end tidal,TPR-total peripheral
resistance Novak V et al: Stroke 29:1876-1881, 1998
25

Cerebral Hypoperfusion in POTS

150

120

90
Tachycardia

50
140

120

100

70

40
45 Hypocapnia
35
30
25

15 Mean CBFv uncorrected

110 Mean CBFv corrected for ET-CO2

Low Flow
80

50

Supine Tilt Sup.

15
25.7 30.1 34.5 38.8 43.2 26
G:\BWHF\Hardman Time [min]
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS: Case Report

• A 22 yr old woman, symptoms for 2 yrs
• PMH: migraines since age 6
• Flu like illness for 2 weeks: fever, diarrhea

• Several weeks later symptoms:

tachycardia
shortness of breath
tremulousness,
anxiety during standing and stress
frequent headaches,
chest pain,
nausea,
hold hands and feet

Tilt test: excessive heart rate increment with heart rate > 150 bpm

Novak V, Mendell JRM: Evaluation of the peripheral neuropathy patient using autonomic reflex tests. In: Mendell JRM, Kissel JT, Cornblath
DR, editors. Diagnosis and management of peripheral nerve disorders. Contemporary Neurology Series 59. Oxford: University Press; 2001, 27
p.43-65.

POTS - Therapy
Combination of:
• Diet
• Life style
• Medication

28

1278
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS - Diet
• Effective hydration , > 1.5 - 2 liter of fluid daily
• High salt diet, > 8 gram of sodium daily ( if no hypertension)

• Avoid large meals, take small meals

• Avoid alcohol and food high in carbohydrates
• Avoid excessive caffeine

29

POTS - Physical therapy and reconditioning

• Most effective in combination with initial pharmacotherapy and volume
loading
• Reconditioning- lower extremities strength training
• Counter maneuvers to relief orthostatic stress -leg crossing, squatting
• Weight training
• Cardiac training- cycling
• Yoga – to relieve anxiety
• Aquatic training
• Start in supine or semi-recumbent position to avoid orthostatic symptoms

30
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS – Medical Treatment

• Reconditioning Aerobic exercise 20 min 3 times/wk - too vigorous, may worsen symptoms –(PD,H)
• Hydration 2 L qd PD - Edema (PD)
• Salt > 6 g/d PD - Edema (PD)
• Bupropion (Wellbutrin XL) 150–300 mg qd - Tremor, agitation, insomnia- PD,H
• Clonidine HCI (Catapres) 0.1–0.3 mg bid; 0.1–0.3 mg patch/wk - Dry mouth, blurred vision (H)
• Desmopressin acetate (DDAVP) 0.1–0.2 mg qhs - Hyponatremia, headache (PD)
• Duloxetine HCI (Cymbalta) 20–30 mg qd PD, - Nausea, sleep disturbance (PD,H)
• Erythropoietin (Epogen, Procrit) 10 000–20 000 U SC/wk - Pain at injection site, expensive (PD)
• Escitalopram oxalate (Lexapro) 10 mg qd - Tremor, agitation, sexual problems (PD,H)
• Fludrocortisone acetate 0.1–0.2 mg qd - Hypokalemia, hypomagnesemia, edema (PD)
• Labetalol HCI (Trandate, Normodyne) 100–200 md bid - Fatigue (H)
• Propranolol 10 mg daily fatigue (H)
• Methylphenidate (Ritalin) 5–10 mg tid - Anorexia, insomnia, dependency (PD)
• Midodrine (ProAmatine) 5–10 mg tid - Nausea, itching scalp, supine hypertension (PD)
• Octreotide acetate (Sandostatin) 50–200 g SC tid - Nausea, diarrhea, gallstones (PD)
• Pyridostigmine bromide (Mestinon) 30–60 mg qd - Nausea, diarrhea (PD)
• Venlafaxine HCI 75 mg qd or bid PD - Nausea, anorexia, tremor (PD,H)
• Note: The Food and Drug Administration has not approved any drug for treating POTS.

• H indicates hyperadrenergic; PD- partial dysautonomia SC, subcutaneous.

31
Grubb BP: Postural tachycardia Syndrome ; Circulation 2008:117:2814-2817, Low P. POTS, J cardiovasc Electrophysiol, 2009, 20, 352-358

POTS – Medical Treatment

Simplified recommendations:

• POTS with elevated blood pressure (hyperadrenergic form)

beta blockers, ca blockers

• POTS with normal or low blood pressure or hypovolemic

- mestinon, florinef or midodrin

• Many patient require combination medication

32
Grubb BP: Postural tachycardia Syndrome ; Circulation 2008:117:2814-2817
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

POTS - Prognosis
• Majority of patients recover
• > 50% of pts with postviral onset recover over 2-5 years
– Will have relative absence of orthostatic symptoms and minimal impairment of daily
living activities
• Few get worse
• > 90% respond to combination of physical therapy and medications

33
Grubb BP: Postural tachycardia Syndrome ; Circulation 2008:117:2814-2817

Orthostatic Hypotension
= Marker of sympathetic autonomic failure

• Prevalence, incidence, pathophysiology

• Clinical significance-outcomes
• Classification
• Testing- HUT, sudomotor, other –hormonal tests
• Characteristics patterns
• Treatment

34

1281
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Definition of Orthostatic Hypotension (OH)

• Definition:
– Systolic BP drop ≥20 mmHg or diastolic BP drop ≥10 mmHg at the 3th minute of standing
or head up tilt
• Autonomic adrenergic failure most common cause
• OH with autonomic failure about 30% of patients with diabetic autonomic
neuropathy or 40% of patients with Parkinson disease
• OH is also common in pt with uncontrolled HTN

35
Ooi,WL. Am J Med. 2000 Feb;108(2):106-11.

Control OH
HR [BPM]

HR [BPM]
BP [mmHg]

BP [mmHg]
CBFv [cm/sec]

CBFv [cm/sec]

Modified from Novak: Cerebral blood flow, heart rate and blood pressure patterns during the tilt test in common orthostatic syndromes,36
Neuroscience Journal, in revision 2016

1282
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

OH asymptomatic OH symptomatic
stable cerebral blood flow reduced cerebral blood flow
120 150

100

60
40 50

210 180

115 100

20 20
45 45

33 33
30 30

20 20
65 65

stable flow reduced flow

48 48

Supine Tilt Sup. Supine Tilt Sup.

30 30
7 11.1 15.2 19.2 23.3 12.5 16.2 19.8 23.5 27.1
Time [min] GeherTILT.mat Time [min]
CurtainTilt.mat
37

Orthostatic Hypotension - Mild

Transient Delayed

Novak P: Cerebral blood flow, heart rate and blood pressure during the tilt test in common orthostatic syndromes. Neurosci J. 2016 38

1283
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Example of Severe Orthostatic Hypotension

Novak P: Cerebral blood flow, heart rate and blood pressure during the tilt test in common orthostatic syndromes. Neurosci J. 2016 39

OH - Causes
• Iatrogenic-multiple medications, particularly in elderly (mainly diuretics and
nitrates)
• Diabetes
• Uncontrolled hypertension
• Generalized autonomic Failure
• Adrenergic sympathetic failure
• Parkinson’s disease, multiple system atrophy (MSA), pure autonomic failure
(PAF)
• Lewy’s body disease
• Amyloidosis
• Peripheral neuropathies
• Dysautonomia of old age- hypovolemia, dehydration
• Tumors

40

1284
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

OH - Mortality
• Honolulu Heart Study (Masaki et al, 1998)

• OH was associated with an increased rate (adjusted RR = 1.6) of all-cause, four-

year mortality in an elderly cohort (ages 71 to 93) of Japanese American men

• OH – common among those who scored higher on several measures of physical

frailty

41

OH - Cognitive Decline

42
Novak V, Nature Review 2010

1285
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

OH - Falls
• Number one cause of morbidity and mortality in the elderly
• Health care cost-fall related injuries (fractures), burden of patients, family
and health care
• Orthostatic hypotension (BP drop after 1 min of standing) in 50% of elderly
• Fallers: a history of previous falls in the past 6 months) those with OH had
an increased risk of recurrent falls [adjusted relative risk (RR) = 2.1; 95%
confidence interval (CI), 1.4 to 3.1 ] (N=844)
.
• The risk of subsequent falls was greatest in previous fallers who had
orthostatic hypotension at two or more measurements (RR = 2.6; 95% CI, 1.7
to 4.6)

Ooi,WL. Am J Med. 2000 Feb;108(2):106-11. 43

OH and Risk for Falls

Controlled HTN no risk for falls

Uncontrolled HTN (BP> 140/90) - increased
p=0.43
risk for falls rate >2 p<0.001
722 participants, >70 yrs old, The Maintenance of Balance, Independent Living, Intelect and
44
Zest (MOBILIZE Boston) cohort Ganagvati A: JAGS 59 : 3: 2011

1286
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Normal BP and BFV

Normal
autoregulation
No BP/BFV
correlations

OH with normal autoregulation

Expanded
autoregulation
Flat slope of
correlation

OH with autoregulation failure

Autoregulation
failure
Steep slope

45
Novak V et al: Stroke 1998; 29:104-111

OH – Management
• Autonomic function assessment
(head- up tilt, with TCD monitoring, 24 hour ambulatory BP
monitoring), tilt vs. sit-standing test
• Patient education
• Adjustment of the diet
• Physical maneuvers
• Pharmacologic treatment

46

1287
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

OH – Patient Education
• The single most important factor
• Explain mechanisms of maintenance of the blood pressure
• Use automatic blood pressure cuff for regular BP monitoring at
home
• Patients should be able to recognize symptoms of orthostatic
intolerance and to react properly
• Avoid exposure to hot weather, straining and vigorous exercise
• Exercise in supine or semi recumbent position

47

OH –Diet

• Adequate hydration – MINERAL WATER ! a minimum of 2-2.5 L per day,

400 mL with meals and 200 mL between the meals
• Acute ingestion of 450 mL water will increase the systolic BP by 40 mm
Hg
• Increase salt intake 150-250 mEq, 10-20 g of salt per day
• Small, frequent meals with reduced carbohydrate content
• Caffeine (blocks adenosine-mediated postprandial splanchnic
• vasodilatation) – 2 cups of coffee (200-250 mg of caffeine) a.m.
• Avoid alcohol (precipitates splanchnic vasodilatation), low dose of
alcohol before sleep reduces supine hypertension

48
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

OH - Physical Maneuvers
• Physical maneuvers increase postural tolerance:
Leg crossing and squatting
- elevates BP by 10-15 mm Hg
- increase peripheral resistance
- effective in prevention of loss of consciousness

• Leg press exercises in supine position

• Avoid lying flat, elevate head during the sleep
– reduce supine hypertension
• Compression stockings – prevent venous pooling
– Can be prescribed, the most effective are pantyhose size,
– hose pressure 20-30 mmHg or more if tolerates
• Corset (elastic abdominal binder) -prevents splanchnic pooling

49

OH – Medical Management
Commonly used:

Pyridostigmine sympathetic ganglia stimulant mild OH diarrhea, muscle twitching

Florinef Mineralocorticoid moderate OH CHF, end organ damage
Midodrine α1-adrenergic agonist severe OH CHF, end organ damage
Droxydopa catecholamine precursor symptomatic OH HTN

Erythyropoetin increases red cell mass severe OH + anemia

Indomethacin prostaglandin inhibitor postprandial OH
Ibuprofen prostaglandin inhibitor postprandial OH

Rarely used:
Ephedrine sympathomimetic, indirect moderate OH
Phenylpropanolamine sympathomimetic, direct severe OH
Ergotamine α-adrenergic agonist adjuvant
Dihydroergotamine (DHE) adjuvant
Yohimbine α2-adrenergic antagonist partial adrenergic failure
Pindolol β-blocker hyperbradykininism
Clonidine α1-adrenergic agonist OH+postgangl.lesion
Octreotide somatostatin analog postprandial OH multiple side effects
Desmopressin V2 vasopressin agonist nocturnal polyuria

50

1289
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pyridostigmine (Mestinon)
Acetylcholine esterase inhibitor
Enhances sympathetic ganglionic transmission
Suggested for tx. of SH + OH

Single dose of 60 mg Improves orthostatic hypotension without aggravating

supine hypertension (Singer et al., J Neurol Neurosurg Psych, 74, 2003)

Dosing: 30-60 mg bid-tid,

Side effects: diarrhea, bradycardia

Can cause severe cardiac rhythm problems in pt’s with preexisting disease
of conduction system (bradycardia + hypotension, tachycardia, syncope
(Arsura et al., Am J Med. Sci., 293, 1987)

51

Fludrocortisone (Florinef)
Synthetic mineralocorticoid (125 x more potent in Na retention than
cortisol)

At small doses sensitizes vessels to norepinephrine

At larger doses retains sodium and expands volume

Full pressor effect after 1-2 weeks

Dosing: start 0.1 mg QD or BID, titrate in 0.1 mg increments at 1- 2 weeks

typically to 0.4 mg/day, max. 1mg/day

Fluid retention -> expected weight gain 2-5 pounds, may develop benign
pedal edema

Side effect: supine hypertension, CHF, hypokalemia (50%-within 2 weeks),

hypomagnesemia (50%) headache in young subjects
52
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Midodrine (ProAmatine)
α1-adrenergic agonist, peripheral
It is a pro-drug, requires liver metabolism for active compound
(desglymidodrin)

Potent peripheral vasoconstrictor, no central effect, FDA approved 1996

Reliable absorption (93%), predictable half-life (prodrug 1 hour,
desglymidodrin 3 hours)
Dosing: start a trial dose 2.5 mg , check the blood pressure supine/standing
in 1 hour, the dose is titrated up according the response
initial dose 2.5 mg a.m. and noon, increase until satisfactory response,
max 30-40 mg/day, last dose at 6 p.m. may be given more often – q4 or
q2
Side effect: piloerecton, paresthesia in the scalp, pruritus (11.5%),
supine hypertension (17.5%) = patients should avoid spending time in
supine position,
- Can induce CHF and renal failure

53

Northera (Droxydopa)
-L-threo-dihydroxyphenylserine
-synthetic precursor of norepinephrine
-cross the blood-brain barrier

Potent centrally and peripherally acting vasoconstrictor

FDA approved in 2014 for treatment of neurogenic orthostatic hypotension

Dosing: start 100 mg tid po, last dose 3 hours before bedtime,
check the symptoms and blood pressure supine/standing in 1 hour, the dose
is titrated up according the response
maximal dose 600 mg tid po

Side effect: supine hypertension, headache, dizziness, nausea, fatigue

54
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Erythropoetin (Epogen)
Second line in treatment of OH in autonomic failure, effective in patients with
anemia
Recombinant erythropoetin,
Increase of hematocrit in 2-6 weeks
Increases standing blood pressure 10-15 mmHg

Dosing: 25-75 U/kg (~4000U) 2-3 times per week SQ, the goal is to
normalized the hematocrit, than continue with maintenance 25 U/kg 3
times per week

Side effect/disadvantage: exacerbation of supine hypertension, expensive,

requires SQ, = usually reserved for inpatients with severe autonomic
failure complicated by anemia

55

Syncope

• Prevalence, incidence
• Clinical significance-outcomes
• Classification
• Testing
• Characteristics patterns
• Treatment

56
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Syncope-definition
• Syncope “ a pause in music”, “black out”, ”collapse”, a transient loss of
consciousness
• Very common, in any age
• Caused by a sudden (temporary) interruption of blood flow to the brain
= global cerebral hypoperfusion
• Occurs at any age
• Multifactorial: cardiovascular, neurally mediated, epilepsy, unknown,
psychogenic

57

Syncope Incidence and Prognosis

• 7814 participants of Framingham Heart Study, followed for 17 yrs
• Incidence of 1st syncope: 822 (=10.5%) 6.2/1000
• Causes : vasovagal 21.2%, cardiac 9.5%, orthostatic 9.4% , unknown 36.6%
• Multivariate adjusted hazard ratio for those with any syncope and compared to non-syncope:
-death from any cause 1.31(95% confidence interval 1.14-1.51)
-myocardial infarction or cardiac death 1.27 (0.99-1.41)
-stroke fatal and non-fatal 1.06 ( 0.77-1.45)
• Multivariate adjusted hazard ratio for those with syncope due to cardiac causes:
-death from any cause 2.1 (95% confidence interval 1.48-2.73)
-myocardial infarction or cardiac death 2.66 (1.69-4.19)
-stroke fatal and non-fatal 2.01 (1.06-3.80)
• Multivariate adjusted hazard ratio for those with neurological syncope of unknown causes:
-death from any cause 1.32 (95% confidence interval 1.09-1.60)
-death from any cause 1.54 (1.12-2.12)
• Vasovagal- no increased risk of death

58
Soteriades ES, NEJM 237: 878-885 2002

1293
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Syncope, vasodepressor Syncope, mixed with asystole

HR [BPM]

HR [BPM]
Asystole

Syncope
BP [mmHg]

BP [mmHg]
CBFv [cm/sec]

CBFv [cm/sec]

Modified from Novak: Cerebral blood flow, heart rate and blood pressure patterns during the tilt test in common orthostatic syndromes,59
Neuroscience Journal, in revision 2016

Syncope Incidence per Decade

60

1294
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Syncope Survival Rate

Cardiac syncope: increased risk of death from any cause and cardiovascular
Syncope of “unknown cause” : increased risk of death of any cause
Vasovagal syncope seems to have a benign prognosis.
61

Flow chart for the diagnostic approach to the patient with syncope

Strickberger, S. A. et al. J Am Coll Cardiol 2006;47:473-484 62

Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

1295
 Neurally Mediated Syncope
• Cardio-inhibitory
-BP decline triggers bradycardia, even cardiac asystole
• Vasodepressor
-sympathetic withdrawal leads to decrease of peripheral
resistance, compensatory tachycardia
• Mixed
- combination of both patterns

Dg: tilt test, positive in 37%, 6% in normals

(=specificity 94%)

Diff. Dg: cardiac cause arrhythmic/non-arrhythmic, seizures, hypoglycemia,

TIA, psychogenic

The mechanisms leading to neurally mediated syncope are not known !

63

Tilt test patterns

64
Novak P: Cerebral blood flow, heart rate and blood pressure during the tilt test in common orthostatic syndromes. Neurosci J. 2016

1296
 Triggers of neurally mediated syncope
• Prolonged standing
• Increased venous pooling
• Straining (Valsalva maneuver)
• Weightlifting
• Micturition
• Cough Reduced venous return
• Hyperventilation
• Carotid sinus compression Reduced cerebral
perfusion
(neck tie syndrome)
• Meal (with OH)
Baroreflex
• Emotions
• Sympathetic withdrawal tachycardia x
• Palpitations bradycardia

65

Symptoms of Orthostatic Intolerance and Impeding Syncope

• Dizziness
• Lightheadedness
• Blurred, tunel vision
• Nausea
• Fatigue
• Weakness Syncope
• Headache
• Neck ache Falls
• Shortness of Breath
Seizures
• Sweating
• Palpitations
• Pale appearance

66

1297
Neurogenic Syncope -Treatment
• Single episode-reassurance
• Education of patients:
– avoid trigger events,
– recognize the symptoms,
– perform manoeuvres to abort episode (leg crossing, squatting, lying down, etc.)
• Modification of hypotensive drug treatment for concomitant conditions
– Diuretics, nitrates, alpha blockers, consider switch to ACE’s if patients need medication for
HTN
• Volume expansion through increased salt and high fluid intake
• Exercise training
• SSRI’s ?
• Florinef
• Midodrin
• Mestinone,
• Permanent pacing (severe cardioinhibitory syncope or asystole)

67

Idiopathic Small Fiber Neuropathy

Small fiber neuropathy common, affects millions of people worldwide
Dysfunction of small nerves
sensory -> pain, burning sensation
autonomic->dysautonomia
Most common small fiber neuropathy is mixed
1. Secondary: 50% secondary, the cause is:
impaired glucose tolerance, metabolic syndrome, thyroid dysfunction, B12 deficiency, HIV,
autoimmune syndromes, neurotoxic medication, paraneoplastic syndromes, alcohol abuse,
paraproteinemias, connective tissue disorders
2. Primary: 50%, cause unclear “idiopathic small fiber neuropathy”:
Diagnosis: Combination of:
1) Clinical signs (Hyperalgesia+Allodynia, burning sensation at feet is typical)
2) Abnormal skin biopsy
= diagnostic accuracy > 80%
Treatment: pain control, except of autoimmune small fiber neuropathies

Heijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies—advances in diagnosis, pathophysiology and
management. Nature Reviews Neurology 2012;8, 369-379. 68
 Autoimmune Autonomic Neuropathies
= Sudden onset of severe dysautonomia (OH, anhidrosis, constipation, urinary
incontinence and/or pain)
• Primary autoimmune neuropathy (ganglionopathy)
• Acute panautonomia
• Guillain-Barre syndrome
• Acute cholinergic neuropathy
• Pseudoobstruction
• Some forms of postural tachycardia syndrome (POTS)
• Acute paraneoplastic neuropathy
• Probably autouimmune and associated with neuronal antibodies
– Antibodies against ganglionic acetylcholine receptor

• Should be treated aggressively (steroids, IVIG, chemotherapy)

• If suspect these conditions, refer to neurology !

69

Treatable Hereditary Autonomic Neuropathies

• Fabry disease
– mutations of α-galactosidase A, X-linked
– Therapy: agalsidase alpha (0.2 mg/kg every second week intravenously) or beta (1.0 mg/kg every
second week intravenously)

• Transthyretin-related familial amylodosis

– a point mutation within the TTR gene, autosomal dominant
– Therapy: liver transplantation and the TTR kinetic stabilizer tafamidis (20 mg/d)

• Pompe disease
– glycogen storage disease type 2, lysosomal storage disorder
– acid alpha-1,4-glucosidase mutation , autosomal recessive
– Therapy: alglucosidase-alpha (20 mg/kg every second week intravenously).

• All may manifest as small fiber neuropathy (burning pain and dysautonomia)

70

1299
 Women’s Neurology

Mary Angela O’Neal, M.D.

Assistant Professor, Department of Neurology, Harvard Medical School
Director of the Women’s Neurology Program
Director of the Neurosciences clinic

Disclosures

I have no disclosures

1300
 Objectives

Use Cases to:

• Discuss gender specific neurological concerns

• Review the pathophysiology of the neurologic

disorder as it relates to gender
• Describe treatment specific concerns for
women with neurologic disease
MS, Migraine, Stroke in pregnancy, Eclampsia &
Stroke Risk Factors in Women

Women’s Life Cycle

Menarche Pregnancy Menopause

Multiple Sclerosis

Migraine

Alzheimer's
Dementia

Stroke
 Women’s Life Cycle

Menarche Pregnancy Menopause

Eclampsia

Stroke

Issues to discuss when caring for Women in their

Reproductive years

Family planning

Discussion of medication risks in pregnancy

Effects of pregnancy on the underlying

disease

Effects of the underlying disease on

pregnancy

1302
 FDA Pharmaceutical Pregnancy Categories

A Adequate and well controlled human studies have failed to demonstrate a risk to the
fetus in the first trimester of pregnancy ( and there is no risk in later trimesters).
B Animal reproduction studies have failed to demonstrate a risk to the fetus and there
are no adequate and well controlled studies in pregnant women OR Animal studies have
shown an adverse effect, but adequate and well-controlled studies in pregnant women
have failed to demonstrate a risk to the fetus in any trimester.
C Animal reproduction studies have shown an adverse effect on the fetus and there
are no adequate and well-controlled studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite potential risks.
D There is positive evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks
X Studies in animals or humans have demonstrated fetal abnormalities and/or there
is positive evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience, and the risks involved in use of the drug in
pregnant women clearly outweigh potential benefits

Reproductive Health and Pregnancy Concerns

• Multiple Sclerosis

• Migraine

1303
 Case 1

A 28 year old women with

relapsing remitting MS
who has stable disease.
She is on interferon beta-
1b and an oral
contraceptive.

She wants to get pregnant.

Questions

• What should I do about my medication?

• How will pregnancy effect my MS?

• What if I have a relapse?

• Is it safe for me to breast feed?

1304
 Immuno- FDA Drug Half Fetal and maternal risks Secretion in breast milk
modulating Class Life
agents
C 10 hours
Interferon β-1-b Spontaneous abortions in animals. not seen in
Minimal
and β-1-a humans
B 7 hours
Glatiramer acetate None reported Minimal
C 25 - 32
Intravenous
days Probably safe in pregnancy Unknown
immunoglobulin
Fingolimod C 6-9 days Teratogenicity seen in animals and humans. No Avoid in lactation
specific pattern observed.

Dimethyl Fumarate C 1 hour increased spontaneous abortion in animals. Not Avoid in lactation
reported in humans
Teriflunomide X 18-19 days Teratogenicity seen in animals; precursor leflunomide Avoid in lactation
is a known human teratogen. No malformations in
humans observed thus far.

Daclizumab C 20 days Embryofetal deaths observed in animals with early Avoid in lactation
exposure. No fetal malformations in humans observed
thus far.

Natalizumab C 7-15 days Yes (at supratherapeutic doses in primates). Transient Avoid in lactation
hematologic abnormalities in late pregnancy exposure
in humans.

Alemtuzumab C 12 days Animals. No human malformations seen, but thyroid Avoid in lactation
monitoring necessary for mother throughout
pregnancy. No evidence for spontaneous abortion or
birth defects.

Rituximab/ C 22 days/26 Animals. No human malformations seen; transient B- Avoid in lactation

days cell depletion in human neonates following pregnancy
Ocrelizumab
exposure

Immune System and Pregnancy

Low Estrogen
MS
Th1 IL-2
IFN
LT
Th

Th2 IL-4
High Estrogen
IL-5
IL-6
IL-10

1305
 Multiple Sclerosis Relapse Rate
Annual RR P value
Year before pregnancy 0.7 --

First trimester 0.5 0.03

Second trimester 0.6 0.17

Third trimester 0.2 <0.001

1-3 months postpartum 1.2 <0.001

4-6 months postpartum 0.9 0.17

7-9 months postpartum 0.9 0.15

10-12 months postpartum 0.6 0.59

Breastfeeding

Who’s at risk?

Effects of breast feeding

Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis.
Arch Neurol 2009 Aug;66(8):958-63.
Exclusive Breast feeding and the Effect on Postpartum Multiple Sclerosis Relapse. JAMA Neurol 2015 OCT:1132-1138

1306
 Reproductive Health and Pregnancy Concerns

MS

Migraine

Case 2

A 23 year old women with migraine without aura

is now 8 weeks pregnant. Her migraines had been
well controlled with sumatriptan.

She’s now having her usual headaches with nausea

and vomiting 2-3 times a week.

1307
 Migraine during Pregnancy

60-70 % migraines undergo remission

Small percent of new onset migraine during

pregnancy

Increased risk of preeclampsia/ eclampsia

1308
 Migraine Treatment in Pregnancy

Planning

Symptomatic therapy

Other

Symptomatic Therapies
Generic Name Level of Risk in Breastfeeding- Hale
Pregnancy Lactation Rating

Acetaminophen B L1

B (D in 3rd trimester) L1-L2

NSAIDS

Metoclopramide B L2

Prochlorperazine C L3

Dihydroergotamine X L4

Magnesium A (D) L1

Triptans C L3

1309
 Preventative Medications
Drug Class Generic Name Level of Risk in Breastfeeding
Pregnancy

Beta- blockers Atenolol D Caution

Propranolol C (D at term) Compatible

Gabapentin C Compatible
Antiepileptics Topiramate D Caution
Valproate X Caution

C Compatible
Tricyclics Amitriptyline

Triptans and Pregnancy

Data from the Sumatriptan/Naratriptan Pregnancy

Registry

Data from Norwegian Mother and Child Cohort

 Migraine and Lactation

Triptans considered safe

Several Preventative drugs also

safe

LactMed

Pregnancy Related Disorders

Ischemic Stroke

Eclampsia

1311
 Case 3

A 28-year-old woman G2P1 at 30 weeks gestation

was last seen well at 10 am. She was found on the
ground not speaking or moving her right side at
10:50 am.
On initial exam at noon, she was mute with left
gaze deviation and dense right hemiplegia.

NIHSS* was 15.

How should you treat this lady?

What imaging is most appropriate?

A. Head CT/ CTA Neck and Brain

B. Brain MRI, Vessel Imaging

 How should you treat this lady?

What imaging is most appropriate?

A. Head CT/ CTA Neck and Brain

B. Brain MRI, Vessel Imaging

Radiation Exposure

DETERMINISTIC EFFECTS

1313
 Radiation Exposure

STOCHASIC EFFECTS

Imaging

Neuroimaging can be performed safely

MRI versus CT

Gadolinium is avoided

1314
1315
 Use of IV t-PA in Pregnancy

Use of IA t-PA in Pregnancy

 Causes of Ischemic Stroke in Pregnancy

Cardiac emboli
Dissection
Pre-eclampsia/ Eclampsia
Coagulopathy
Cerebral Venous Thrombosis
Reversible Cerebral Vasoconstriction Syndrome
Other

Pregnancy Related Disorders

Ischemic Stroke

Eclampsia

1317
 Case 4

A 35 year old woman G1 P0 at 31 and 5/7 weeks of

gestation was woke with a severe headache. She
began seeing visual spots, and a half hour later she
completely lost her vision.

Shortly thereafter, she developed the worst

headache of her life and blacked out. At the
outside hospital her blood pressure was 170/120.
She was transferred to our hospital.

Red Flags

• Change in headache character or pattern

• Headaches with characteristics of elevated ICP

• New headaches

• Associated with elevated BP

• Unusually severe headache

• Abnormal neurologic exam

• Headaches associated with systemic disorders

 Frequency and Headache Type by Trimester

Migraines

Idiopathic Intracranial Hypertension

Preeclampsia/Eclampsia

Post Dural Puncture Headache

Cerebral Venous Thrombosis

First Trimester Second Trimester Third Trimester Postpartum

Pre-eclampsia/Eclampsia Definition

Diagnosed when a pregnant woman develops

High blood pressure (two separate readings taken
at least six hours apart of 140 or more in systolic
blood pressure and/or 90 or more in diastolic
blood pressure)
300 mg of protein in a 24-hour urine sample
(proteinuria
Onset of seizures and change in mental status
defines eclampsia

1319
 Pathogenesis of Eclampsia

Pre-eclampsia/ Eclampsia

PEE is associated with both significant maternal

and fetal morbidity and mortality
Maternal complications include abruption
placentae, disseminated coagulopathy, acute renal
failure, stroke, hemorrhage, death and long term
cardiovascular morbidity
Fetal complications include premature delivery,
low birth weight, hypoxic neurologic injury, and
death.
Maladaptation to placental
implantation

Axial Flair MRI

1321
 Treatment of Eclampsia

• Blood Pressure control

– Labetalol

• Magnesium Sulfate
– Prevention of progression from preeclampsia to
eclampsia and eclamptic seizures

Lucas et al. A comparison of magnesium sulfate and phenytoin for the prevention of eclampsia.
N Engl J Med 1995;333:201–5.

Postmenopausal Health

Stroke

1322
 Case 5

A 76 year old woman with a PMH of DM has new

onset atrial fibrillation. She does not smoke and
drinks 1-2 alcoholic beverages a week. She has never
had a TIA or stroke. She is normotensive and not
overweight.

What gender specific questions should be asked?

What is her stroke risk?

Stroke in Women

Third leading cause

of death

Incidence

1323
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Pregnancy complications and long term

stroke risk

Gestational diabetes

Preeclampsia/Eclampsia

Pregnancy induced hypertension

Preeclampsia and stroke risk in later life

Study date Total no. of Design OR - 95% CI
subjects

Lykke-2009 782,287 Retrospective cohort 1.36-1.66 (1.29-2.14)

Funai- 2005 37,061 Retrospective cohort 3.07 (2.18-4.33)

Kestenbaum- 2003 124,141 Case control study 2.53 (1.70-3.77)

Irgens- 2001 626,272 Retrospective cohort Preterm PE 5.0

(2.09-12.35)

1324
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Atrial Fibrillation

Female sex is an independent predictor of stroke in

patients with AF

Higher risk in older women than men

1325
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Women’s Issues in Neurology- expected take home points

Reproductive Health & Pregnancy MS, Migraine

Concerns

Pregnancy Ischemic Stroke, Eclampsia

Postmenopausal Stroke
Health

1326
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Palliative Neurology
Kate Brizzi, MD
Assistant in Neurology
Assistant in Palliative Care
Massachusetts General Hospital

Disclosures
I have no conflicts of interest to disclose
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Outline
1) Define palliative care
2) Review the unique palliative care needs of neurology patients
3) Explore communication strategies that can be utilized when
discussing serious illness
4) Discuss symptom management of neurologic, non-neurologic, and
psychosocial issues of neurology patients with life-limiting illness

What is Palliative Care?

• Center to Advance Palliative Care (CAPC) Definition:
“Palliative care is specialized medical care for people living with serious
illness. It focuses on providing relief from the symptoms and stress of a
serious illness. The goal is to improve quality of life for both the patient
and the family.”

• Focus is on living well with a serious illness

1328
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

What distinguishes palliative care?

• Can be used alone or alongside curative therapies and research
therapies
• Focuses on both the patient and the family
• Goal is to alleviate suffering
• Is appropriate at any stage of an illness
• Emphasizes a team approach

Palliative care spans the duration of a serious

illness and beyond

Eric D. Adler et al. Circulation. 2009;120:2597-2606

Copyright © American Heart Association, Inc. All rights reserved.

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

What kind of neurology patients could benefit

from palliative care?
• Motor Neuron Disease
• Parkinson’s Disease
• Dementia
• Huntington’s Disease
• Muscular Dystrophy
• Multiple Sclerosis
• Autoimmune Diseases
• Brain tumors

The spectrum of neurologic diseases with

palliative needs also includes patients with non-
degenerative conditions
Function

Function

Time Time
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

We can all provide basic palliative care to our

patients

Tertiary
Palliative Care

Secondary Palliative Care

Consultative Palliative Care Specialists

Primary Palliative Care

Palliative care delivery by the patient’s primary provider

The neurological patient presents unique

challenges for palliative care providers
• Neurological Symptom Assessment
• Prognostic Uncertainty
• Communication challenges
• Increased need for surrogate decision makers

1331
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The neurological patient has unique palliative

care needs
• Neurological Symptom Assessment
• Prognostic Uncertainty
• Communication challenges
• Increased need for surrogate decision makers

Neurological Symptom Assessment

• Changes in speech
• Cognitive decline
• Behavioral changes
• Seizures
• Motor impairment

1332
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The neurological patient has unique palliative

care needs
• Neurological Symptom Assessment
• Prognostic Uncertainty
• Communication challenges
• Increased need for surrogate decision makers

Prognostication in neurology is a complex task

• High degree of uncertainty and
variability
• Prognostication tools often have
limitations
• Recovery process can be prolonged
• Patient’s views of acceptable
quality of life may change over
time
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The neurological patient has unique palliative

care needs
• Neurological Symptom Assessment
• Prognostic Uncertainty
• Communication challenges
• Increased need for surrogate decision makers

Communication challenges can occur early

and often
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Many types of communication challenges can

occur in patients with neurological disorders
• Impaired motor (speech) function
• Aphasic speech
• Cognitive impairment
• Reliance on family members for interpretation

The neurological patient has unique palliative

care needs
• Neurological Symptom Assessment
• Prognostic Uncertainty
• Communication challenges
• Increased need for surrogate decision makers
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Skill areas needed for the primary palliative

care provider
• Communication Skills
• Symptom management
• Advance Care Planning
• Caregiver Needs Assessment
• Ability to recognize need for referral

Boersma I et al. Neurology. 2014 Aug 5;83(6):561-7

Communication strengths can be developed

• Key palliative care intervention
• Can be learned and practiced!

• Physicians skilled at communication

demonstrate:
• Empathy
• Good listening
• Non-abandonment
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Key information to elicit in an interview

Illness Hopes and

Understanding Fears

Information
Sharing
Preferences

Conversation Guides can help structure

difficult conversations
Serious Illness Conversation Guide
-What is your understanding of where you are with your illness?
-How much information about what is likely to be ahead with
your illness would you like from me?
-What are your biggest fears and worries about the future?

-If your health situation worsens, what are your most important
goals?
-How much would you be willing to go through for the possibility of
more time?

1337
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

https://www.ariadnelabs.org

There is a natural oscillation in hopefulness

during the course of illness

Hopes less likely to Hopes more likely

be realized to be realized

Adapted from Jacobsen J et al. J Palliat Med. 2014 Apr; 17(4):463-8.

 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Communication Pit-falls

Blocking Lecturing

Premature
Collusion
reassurance

Back AL et al. CA Cancer J Clin. 2005 May-Jun;55(3):164-77

Responding to Patient Emotion

• NURSE mnemonic:
N = Naming
U = Understanding
R = Respecting
S = Supporting
E = Exploring

Back AL et al. CA Cancer J Clin. 2005 May-Jun;55(3):164-77

1339
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Breaking bad news

• SPIKES mnemonic:
S = Setup
P = Perception
I = Invitation
K = Knowledge
E = Empathize
S = Summarize and strategize

Back AL et al. CA Cancer J Clin. 2005 May-Jun;55(3):164-77

Sharing prognostic information with patients

• Two types of prognostic information:

How Long? vs How Well?

• Prognostication tends to be less accurate the closer the patient-

physician relationship
• Some data suggests that in stroke neurology, physicians are overly
pessimistic in patients with do-not-resuscitate orders

Holloway RG et al. Neurology. 2013 Feb 19;80(8):764-72

Hemphill JC 3rdet al. Stroke. 2004 May;35(5):1130-4.

1340
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Assessing palliative care symptom needs in

neurology patients
Neurologic Symptoms Non-neurologic Emotional/Spiritual
symptoms symptoms
Delirium Pain Grief
Hallucinations Dry mouth Depression
Cognitive Decline Constipation Anxiety
Speech impairment Loss of Appetite Demoralization
Movement impairment Fatigue Loss of dignity
Difficulty swallowing Insomnia Spiritual suffering
Seizures Weakness

Spiritual and psychosocial needs

• Feelings of Grief/Loss
• Anxiety/Depression
• Loss of sense of self
• Changes in relationships
• Worries about family
• Worries about financial stressors
• Spiritual concerns

Block S. Journal of Palliative Medicine. 2006;9(6):1414-1434.

1341
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Caregiver burden for neurologic patients is high

• Depression and suicidal
ideation are not
uncommon among
caregivers
• Aggressive care at end-of-
life is associated with
worse bereavement
• Cardiovascular disease and
mortality are higher in
caregivers than controls
Wright A et al. JAMA. 2008;300(14):1665-1673.
O’Dwyer ST et al. Aging Ment Health. 2016;20(2):222-30.
Miyashita M et al. J Neurol Sci. 2009 Jan 15;276(1-2):148-52
Boersma I et al. Neurology. 2014 Aug 5;83(6):561-7.

When should targeted palliative care

approaches be utilized?
• Starting at the time of diagnosis?
• After a set interval of time?
• Symptom based triggers?
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Routine discussions and Event-driven milestones

have been suggested as triggers for serious illness
conversation in Parkinson’s Disease
Routine Periodic with scheduled visits

Event-driven milestones Presence of dementia

Sleep disturbances
Hospitalization
Considerable caregiver strain
Increased symptom burden
Decreased nutritional intake
Decreased functional capacity
Other important co-morbidity

Creutzfeldt d et al. Neurology: Clinical Practice. 2016; 6(1):40-48

When to refer to a specialist

• Significant symptom burden or refractory symptoms
• Caregiver distress
• Complicated family/psychosocial dynamics
• Spiritual concerns
• Assistance with advance care planning

1343
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Take-away points
• Patients with neurological disorders have unique palliative care needs
• Communication skills are important when discussing serious illness
• Palliative care assessment should include assessment of neurologic,
non-neurologic, and emotional/spiritual symptoms

References
1. Adler ED, Goldfinger JZ, Kalman J, et al. Palliative care in the treatment of advanced heart failure. Circulation.
2009;120:2597-2606.
2. Boersma I, Miyaskai J, Kutner J, Kluger B. Palliative care and neurology: time for a paradigm shift. Neurology.
2014 Aug 5;83(6):561-7.
3. Jacobsen J, Kyale E, Rabow M, et al. Helping patients with serious illness live well through the promotion of
adaptive coping. J Palliat Med. 2014 Apr; 17(4):463-8.
4. Back AL, Arnold RM, Baile WF, et al. Approaching difficult communication tasks in oncology. CA Cancer J Clin.
2005 May-Jun;55(3):164-77.
5. Holloway RG, Gramling R, Kelly AG. Estimating and communicating prognosis in advanced neurologic disease.
Neurology. 2013 Feb 19;80(8):764-72.
6. Hemphill JC 3rd, Newman J, Zhao S, Johnston SC. Hospital usage of early do-not-resuscitate orders and outcome
after intracerebral hemorrhage. Stroke. 2004 May;35(5):1130-4.
7. Wright AA, Zhang B, Ray A et al. Associations between end-of-life discussions, patient mental health, medical care near
death, and caregiver bereavement adjustment. JAMA. 2008;300(14):1665-1673.
8. O’Dwyer ST, Moyle W, Zimmer-Gembeck M et al. Suicidal ideation in family carers of people with dementia. Aging Ment
Health. 2016;20(2):222-30.
9. Miyashita M, narita Y, Sakamoto A et al. Care burden and depression in caregivers caring for patients with intractable
neurological diseases at home in Japan. J Neurol Sci. 2009 Jan 15;276(1-2):148-52.

1344
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

10. Block SD. Psychological issues in end-of-life care. J Palliat Med. 2006;9(6):1414-1434
11. Krishnan S, York MK, Backus D, Heyn PC. Coping with Caregiver Burnout When Caring for a Person with
Neurodegenerative Disease. Arch Phys Med Rehabil. 2017 Apr; 98(4):805-807.
12. Creutzfeldt CJ, Robinson MT, Holloway RG. Neurologists as primary palliative care providers. Neurology: Clinical Practice.
2016; 6(1):40-48

1345
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Neurology in Global Context

Aaron Berkowitz, M.D., Ph.D.
Director, Global Neurology Program
Associate Neurologist, Division of General Neurology
Brigham and Women’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Health and Policy Advisor in Neurology, Partners In Health

No relevant disclosures

Royalties from:
McGraw-Hill (Clinical Neurology and
Neuroanatomy: A Localization-Based Approach)

MedMaster (Clinical Pathophysiology Made

Ridiculously Simple)

Oxford University Press (The Improvising Mind)

1346
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The World by Land Mass

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

Distribution of Population

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

1347
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Distribution of Wealth

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

Distribution of Poverty
(People Living on ≤ $1/day)

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

1348
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Distribution of Public Spending on Health

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

Distribution of Physicians

© Copyright Sasi Group (University of Sheffield) and Mark Newman (University of Michigan).

1349
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Distribution of Neurologists

WHO Atlas: Country resource for neurological disorders, 2004

Worldwide Distribution of Neurologists

• High-income countries: 3 per 100,000 population

• Low-income countries: 3 per 10,000,000 population

WHO Atlas: Country resource for neurological disorders, 2004

1350
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Worldwide Distribution of Neurologists

• High-income countries: 4.75 per 100,000 population

• Low-income countries: 3 per 10,000,000 population

The Global Burden of Neurologic Disease

1351
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

DALYs= Years of life lost + Years of life lived with disability

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Mortality (2015)

• ~ 56 million deaths
Injuries
9%

Global Burden of Mortality (2015)

Injuries

9% Communicable
Neonatal
20% Maternal
Nutritional

1353
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Mortality (2015)

Injuries

9%
Communicable
Neonatal
20% Maternal
Nutritional
71%

Noncommunicable

Global Burden of Neurologic Mortality (2015)

• 4% global deaths due
to ‘neurological
disorders’
• 3.4%: dementia
• 0.2%: epilepsy
• 0.2%: Parkinson’s
• 0.06% motor neuron disease
• 0.03% multiple sclerosis
• 0.1%: “other neurologic
diseases”
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Neurologic Mortality (2015)

• 4% global deaths due
to ‘neurological
disorders’

• 11.3%: stroke

Global Burden of Neurologic Mortality (2015)

• 4% global deaths due
to ‘neurological
disorders’
• 11.3%: stroke
• 1%: meningitis/
encephalitis
• 0.4%: nervous system
cancers
• 0.2%: tetanus,
cysticercosis, dengue,
rabies

1355
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Neurologic Mortality (2015)

• 16.8% global deaths
due to neurological
disorders

• Not including:
– HIV/AIDS deaths due
to CNS opportunistic
infections
– Tuberculosis deaths
due to TB meningitis
– Injury-related deaths
due to head trauma
– Malaria deaths due to
cerebral malaria
– Cancer-related deaths
due to CNS metastases
– Etc…

Global Burden of Mortality (2015)

16.8%

1356
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Disability (2015)

10.2%

Global Burden of Neurologic Disorders (2015)

DALYs MORTALITY

1357
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Neurologic Disorders (2015)

Global Burden of Neurologic Disorders (2015)

(SDI based on average income

per person, educational
attainment, and total fertility
rate)

1358
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Global Burden of Stroke

Lower national income was associated with higher

relative mortality (P<0.001) and DALYs (P<0.001)
from stroke as compared to ischemic heart disease.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• 16,894,536 strokes in 2010

– 5,304,242 (31.4%) in high-income countries
– 11,590,294 (68.6%) in low/middle-income countries
• 5,874,182 deaths due to stroke in 2010
– 1,709,888 (29.9%) in HIC
– 4,164,293 (70.1%) in LMIC
• 102,232,304 DALYs lost due to stroke in 2010
– 22,820,996 (22.3% ) in HIC
– 79,411,312 (77.7%) in LMIC

• Incidence rate (per 100,000 person-years)

– 217 in HIC vs. 281 in LMIC

• Rate of DALYs lost (per 100,000 person-years)

– 982.11 in HIC vs. 1821.14 in LMIC

• Mortality rate
– 60.54 in HIC vs. 104.98 LMIC
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

HIC LMIC
1970-79

1980-89

1990-99

2000-08
42% 100%
Decrease Increase

What is driving the increased (and

increasing) burden of stroke in
LMIC?

1362
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Global Burden of Stroke Risk Factors

Global Burden of Stroke Risk Factors

1363
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1364
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

If it is not risk factors…?

• The strongest predictor of stroke mortality
and DALY loss rates (even after adjustment for
cardiovascular risk factors) is national per
capita income

• Lower per capita GDP (adjusted for purchasing

power parity) is associated with:
– Higher incident risk of stroke
– Higher case-fatality from stroke
– Greater proportion of hemorrhagic strokes
– Lower age at stroke onset
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The World by Proportion of Public

Spending on Health

Greater stroke incidence, disability,

and mortality in LMIC

Where is the lesion?

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Greater stroke incidence, disability, and

mortality in LMIC- where is the lesion?
• Primary prevention
• Acute treatment
• Secondary prevention
• Rehabilitation

Acute Stroke Care Worldwide

1367
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• High income countries: 50% (35/70)

• Upper-middle income countries: 33% (18/54)
• Lower-middle income countries 19% (10/54)
• Low income countries: 3% (1/36)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Secondary Stroke Prevention Worldwide

1370
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Global Burden of Epilepsy

The Global Burden of Epilepsy

• Estimated 70 million cases of epilepsy
worldwide
– 6.8 million in HIC (9.8%)
– 63 million in LMIC (90.2%)

• Incidence of epilepsy:
– 45.0/100,000/year (IQR 30.3–66.7) for HIC
– 81.7/100,000/year (IQR 28.0–239.5) for LMIC

1371
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Why is epilepsy incidence/prevalence

higher in LMIC?

• Less access to prenatal/perinatal care

• More head trauma
• More CNS infections
– Neurocysticercosis may be the cause of up to 7.6
million epilepsy cases worldwide (Coyle et al., PLOS NTD 2010;6(5):e1500)
– Neurocysticercosis may cause up to 30% of cases of
epilepsy in endemic regions (Ndimubanzi et al., PLOS NTD 2010;4(11):e870.)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

• Residing in rural locations had significantly higher

risk of untreated epilepsy (RR 1.63; 95% CI 1.26–
2.11).
• Significantly lower risks of untreated epilepsy
were observed for:
– Higher physician density (RR 0.65, 95% CI 0.55–0.78),
– Presence of a lay (RR 0.74, 95% CI 0.60–0.91) or
professional association for epilepsy (RR 0.73, 95% CI
0.59–0.91)
– Presence of a postgraduate neurology training
program (RR 0.67, 95% CI 0.55–0.82).

1373
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The epilepsy treatment gap

Where is the lesion?

The epilepsy treatment gap- where is

the lesion?
• Access to care
• Access to specialized training
• Epilepsy as a preventable disease
– Pre/peri-natal care
– Vaccination against meningitis pathogens
– Improved sanitation/animal husbandry
– Improved road safety, motorcycle helmets,
seatbelts

1374
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Worldwide Distribution of Neurologists

WHO Atlas: Country resource for neurological disorders, 2004

1375
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

How Neurologists Think

What My Mistakes Taught Me
Martin A. Samuels, M.D.
Chair
Department of Neurology
Brigham & Women’s Hospital
Miriam Sydney Joseph
Professor of Neurology
Harvard Medical School
Boston, Massachusetts

No relevant disclosures.

1376
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

The Error Hysteria

• IOM 1999 report: To Err is Human, alleged that:
– 98,000 Americans die annually from inpatient errors
– More than MVA’s, breast cancer & AIDS, combined
• The Error Prevention Movement
– Institute for Healthcare Improvement
– The Leapfrog Group
– Consumer’s Checkbook, etc., etc., etc.
• Memes (Susan Blackmore & Richard Dawkins)
– The cultural analogues of genes
– A error-free culture is stagnant

1377
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Shortcuts or “Heuristics”* in
Diagnostic Reasoning
• Such shortcuts are common and are
quite useful to clinicians, because they
often lead to ‘correct’ diagnosis with
efficiency, given complexity of clinical
diagnosis
• Goal is not their elimination, but to be
aware of their pitfalls and have a menu
of corrective strategies for minimizing
errors that may arise from their use
*Greek: discovery

Case 1*
Framed in Mexico

A 49 year old woman developed

rapidly progressive weakness while
vacationing in Mexico.

Initial thoughts?

*Thanks to my friends at UCSF for providing the opportunity for me to make this error

1378
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1: History
• Patient traveled to Mexico for vacation
• Mild muscle pain in thighs which partially resolved with
massage ~1.5 weeks PTA
• Pain returned 1 week PTA and gradually worsened over
several days
• Two evenings PTA she noted mild leg weakness:
tripped on step going in to restaurant for dinner. After
dinner was unable to stand up. With assistance and a
wheelchair, she returned to hotel.
• Awoke next day with upper extremity weakness; within
two hours she noticed weakness in trunk and neck.
• On admission to hospital in Mexico, she could not move
arms or legs but respiratory status was stable.

Case 1
History Continued
• PMH: TTP eight years earlier, treated with
splenectomy
• ROS: long-standing facial paresthesias
and dry mouth. No dysphagia, diplopia,
dysarthria. No fevers, night sweats, recent
URI or diarrheal illness.
• Otherwise healthy, taking OCPs, working
in computer industry, no bad habits.

1379
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1
Examination in Mexico
• Vital Signs: normal
• General exam: Dry mucous membranes, otherwise
unremarkable. No respiratory distress.
• MS: normal
• CN: mild weakness trapezius and SCM; no bifacial
weakness, ptosis, or ophthalmoparesis; normal
swallowing and speech; complained of facial
paresthesias but no objective sensory loss
• Motor: decreased tone, normal bulk, no fasciculations.
Bilateral severe proximal > distal weakness; direct
muscle excitability absent.
• Sensory exam: normal
• Coordination: no cerebellar ataxia
• Reflexes: normal; no Babinski signs

Case 1

49 Year Old Woman Who

Developed Weakness in Mexico

What is your diagnosis?

1380
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1
Diagnosis
Guillain-Barré Syndrome was diagnosed,
and patient was transferred from Mexico to
UCSF, where other possibilities were
entertained

Is a myelopathy possible?
Is Psychogenic muscle weakness possible
given the sparing of respiratory muscles,
speech and swallowing, normal muscle
stretch reflexes and absent Babinski sign?

What do you think?

1381
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1: Dr. Samuels’s Thoughts

• I excluded GBS on the premise that a
peripheral neuropathy this severe should
have obliterated the muscle stretch reflexes
• I excluded the possibility of psychogenic
weakness because of absence of direct
muscle excitability
• I asserted that a myelopathy was very
unlikely because of the absence of sensory
findings and Babinski signs
• I decided it was an acute painful myopathy

What do you think?

Diagnosis?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1: Martin A. Samuels’s

Diagnosis and Rationale
I confidently diagnosed acute trichinosis,
acquired in Mexico: muscle pain followed by
severe weakness due to inflammatory
myopathy, sparing respiratory muscles and face
myopathy because of the pure motor, proximal
greater than distal syndrome, with preservation of
muscle stretch reflexes and absence of direct muscle
excitability
Trichinosis because….there must be a tie to Mexico

Is there any disagreement?

Case 1: Labs

• Na=137; K=1.6; Cl=116; HCO₃=13 (anion

gap<12=normal)
• BUN=15; Cr=1.4
• Liver panel: AST 29, ALT 19, APhos 67, TBili: 0.7
• Coagulation studies: normal
• ESR: 68 mm/hr
• Urine electrolytes: Cl=33; K=9.8; Na=33 (anion gap=9.8)
• Urine pH=7.0
• PFT’s normal
• EKG: QT prolonged at 686; U waves in V4-V6

1383
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

A Nephrologist is Called

Case 1: Labs

• Na=137; K=1.6; Cl=116; HCO=13 (anion gap<12=normal)

• BUN=15; Cr=1.4
• Liver panel: AST 29, ALT 19, APhos 67, TBili: 0.7
• Coagulation studies: normal
• ESR: 68 mm/hr
• Urine electrolytes: Cl=33; K=9.8; Na=33 (anion gap=9.8)
• Urine pH=7.0
• PFT’s normal
• EKG: QT prolonged at 686; U waves in V4-V6

1384
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non-Gap Metabolic Acidosis

• Non-gap acidosis: renal (RTA) vs. extrarenal (diarrhea)
• Urine Anion Gap: Na + K – Cl
– In diarrhea, one loses HCO3- in the stool; the kidney excretes NH4+ to
compensate.
– To maintain electric balance, Cl- is excreted in the urine and the urine
anion gap is <0.
– If there is a defect in NH4+ excretion, Cl- excretion does not go up and
the urine anion gap is >0.
• Urine lytes: Cl 33, K 9.8, Na 33
– 33 + 9.8 – 33 = 9.8
• RTAs:
– Type I (distal): Inability to secrete H+ in distal tubule.
– Type II (proximal): Inability to reabsorb HCO3 leads to loss of HCO3 in
the urine.
– Type IV (distal): Inability to produce and secrete NH3 in distal tubule.

The Nephrologist Considers the

Case From Diagnostic Alternatives
Not Related to Mexico, and
Suggests More Labs
• SPEP/UPEP negative
• TSH 3.68, free T4 12
• Vitamin D normal
• Cryoglobulins absent
• dsDNA, C3, C4 normal
But…
• ANA >640, RF 134, SSA >5.0, SSB 1.5

1385
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 1
Penultimate Diagnosis

Rapidly progressive weakness due to

hypokalemia from renal tubular acidosis
caused by Sjögren Syndrome, either
primary or secondary to lupus

Buy Why Did the Weakness

Persist Long After the Potassium
Was Corrected, and even after
direct muscle excitability
returned?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Psychogenic Weakness

A Psychiatrist was Consulted Who

Gave the Patient A Strong Suggestion
That The Weakness Would Improve,
Which It Promptly Did

Case 1
Final Diagnosis

Rapidly progressive weakness due to

hypokalemia from renal tubular acidosis
caused by Sjögren Syndrome, either
primary or secondary to lupus, probably
the latter with superimposed
psychogenic weakness

1387
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Lessons
• Pay more attention to the history
– History of TTP
– Dry mouth
– Facial paresthesias
• Not everyone who was in Mexico has a
regional disease
• Know some internal medicine

16 residents in OB asked whether

would intervene in labor for each of
3 cases (48 pairs of responses)

Given one of 2 different formats for

each case (steep vs shallow – same
data) initially, and the other format 2
months later

Order randomized; study

hypotheses not revealed

RESULTS:
18 instances – same management
30 instances – different management
recommendation across the two
formats: 21/30 in direction of more
likely to intervene when presented
data in steeper format (p<0.05)
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEJM, 1982306:1259-62

Hypothesis:
Variation in how information on outcomes is framed to
influences people’s choice of radiation or surgery for lung
cancer.

Lung cancer chosen because involves tradeoff in

preference for risk of perioperative (immediate) death vs.
better 5-year survival for surgery relative to radiation.

Samples:
119 veterans with different chronic diseases interviewed,
presented descriptions of alternative treatments, then
cumulative probability data in text and table form

NEJM, 1982306:1259-62
Half of sample randomized to receive:

Half of sample randomized to receive:

1389
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

NEJM, 1982306:1259-62

Choose
radiation over
surgery
Survival frame 22% Differs at
P<0.0001
Mortality frame 40%

Preferences also elicited from:

167 radiologists: 16% vs. 50%
297 graduate students at a business school: 17% vs. 43%
Same findings for these two “sophisticated” groups

Case 2
Anchored in Morning Report
• 46 year old man complains of gradually
worsening generalized, non-descript
headache, worse on standing and
improved by lying down.
• He was in the military and had several
head and neck injuries, but never lost
consciousness
• Diagnosis?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2

My Diagnosis

Intracranial Hypotension
Advice to Residents:
“Don’t Order an MRI as We Know It Will
Show Pachymeningeal Enhancement”

The Residents Ignored Me

1391
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2
Dr. Martin A. Samuels’s Diagnosis

I confidently diagnosed low pressure

headache and warned against any further
lumbar punctures which could worsen the
problem

Case 2
• The residents ignored me and performed a
lumbar puncture, which showed an
opening pressure of 160 mm of water
• Protein = 90
• 37 cells (15 neutrophils, 15 lymphocytes, 7
monocytes; no atypicals)
• Cytospin negative
• A diagnostic test was obtained
• What could it be?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

But…..
• The attending was not comfortable with
the degree of pachymeningeal
enhancement
• A Dural biopsy was performed

46 Year Old Man

1393
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Non-Caseating Granumoma
Confirmatory tests were obtained…

Revised Diagnosis ?
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

An Evaluation for Sarcoidosis

• Chest CT Scan normal
• PET scan showed only dural enhancement
• Serum ACE normal
• CSF ACE normal
• HIV negative
• Neuroophthalmological exam: no iritis
• Careful skin exam normal

And Then:
• An old pathologist sees the slides

• And additional studies obtained

1395
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2
Syphilis serology: strongly positive in
blood and spinal fluid

• In retrospect, while in the Army he had

venereal disease

• Can’t remember how or whether he was

treated.

Heuristic That Can Lead to Diagnosis Errors

Case 2 Example: Anchoring
Anchoring: Initial probability of a diagnosis (anchor)
is made, then adjusted based on new clinical data
(more history, referral opinion, test result, etc.)

This heuristic’s potential pitfall is that such

adjustments yield biased estimates because of:
• Tendency to place anchors at extremes (0% or 100%)
• Failure to adjust the probability estimates properly based
on new clinical information

1396
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Illustration of Anchoring
Subjects were asked to estimate the
percentage of various items, i.e., % of
countries in Africa that are in the UN
For each item, a # from 0 to 100 was
generated by spin of a wheel (the anchor)
with subject present
Subjects were asked to estimate the value of
the item by adjusting up or down from the
spun anchor #
Subjects were grouped by anchor value, and
median final estimated percentages for each
item were calculated for each group
Tversky and Kahneman, 1974

Example of Anchoring (cont’d)

If starting point (‘anchor’ drawn at
random out of 0-100) = 10:
Median final estimate of % of
countries in Africa that are in UN
= 25%

If starting point (‘anchor’ drawn at

random out of 0-100) = 65:
Median final estimate of % of
countries in Africa that are in UN
= 45% Tversky and Kahneman, 1974

1397
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3A
A Correct Diagnosis?
42 y/o African American teacher became
rapidly demented and unable to walk
over a 2-month period.
A brain biopsy was recommended by a
neurologist in North Carolina, but the
patient’s brother was a cardiologist at the
Brigham who asked me for a Pike
(curbside) consultation.
I said the brain biopsy was a crazy idea
and to have the patient come to Boston
to see me.

1398
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3A
Examination
General:
• Horizontal scar on her anterior neck
• Widespread vitiligo

Neurological:
• Severe abulia
• Pale discs
• Spastic ataxia
• Reflexes were all present
• Bilateral Babinski signs were present

• Diagnosis?

Case 3A
MRI of the Spine

1399
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

What is the diagnosis?

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3A
Labs
• Hct = 20
• MCV = 115
• Cobalamin = 0 (repeat = 0)
• Folate = 20
• Methylmalonic acid = 4.0
• Homocysteine = 68
• Anti-intrinsic factor antibodies 1:128
• Anti-parietal cell antibodies 1:64
• EMG/NCV: no significant neuropathy

Case 3A
I Make a (Correct) Diagnosis

• Pernicious anemia (auto-immune gastritis)

• Associated other auto-immune conditions
– Vitiligo
– Thyroiditis

Patient was treated with parenteral cobalamin

for 2 weeks followed by oral therapy
Back to work in 3 months “better than ever”!
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3B: A Readily Available Diagnosis

Within a month, I see a 74 year old man

who had a partial gastrectomy 20 years
earlier for gastric bleeding. He swears that
he has been taking vitamin
supplementation faithfully since then.
Over the past 9 months, he developed a
gait disturbance characterized by
incoordination, particularly when in the dark
or the shower. There is no pain but the
legs feel “numb.”

Case 3B: Exam

• Mental Status and Cranial Nerves: Normal
• Sensation: No sensory level on the trunk; profound loss
of vibration sense from groins down; Romberg floridly
positive.
• Motor: bilateral quadriceps atrophy, but no fasciculations
are noted, 4/5 hip flex, 4/5 knee ext/flexion, 4/5
dorsi/plantar flexion.
• Reflexes: 2/4 arms, 1/4 patellar, 0/4 ankles, +Babinski
bilaterally.
• Gait: very poor because of a combination of spasticity
and proprioceptive loss
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.
 Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3B: Dr. Martin A. Samuels’s

Diagnosis

• Neurological picture of subacute combined

degeneration
• Macrocytic, megaloblastic anemia
• Second case of cobalamin deficiency seen in
a month
• Cobalamin deficiency related to gastric
surgery
Comments about my thinking?

Case 3B
I Obtain Confirmatory Labs, but…
•Hct 31, MCV 105, retic 0.3%
•WBC = 5K; 40% neutrophils

•B12=519, homocysteine=9.2, MMA=0.39 (all normal);

folate and iron also normal
And…
•EMG: a generalized, symmetric, length-dependent,
predominantly axonal, sensorimotor polyneuropathy

Given this, did neuropathy work-up, and….

1404
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Your Thoughts?

Google Exercise:
Myeloneuropathy
Diagnosis?

Case 3B
Serum copper = 0.11 (normal = 0.70-1.55 µg/ml)
Serum zinc = 1.38 (normal = 0.66-1.10 µg/ml)
Zinc induces metallothionein in mucosal cells, for
which copper has high affinity
Diagnosis: Copper deficiency due to zinc, which
was part of his vitamin supplementation regimen;
added in the past year on his own initiative
Copper was repleted (2mg/d), zinc was
discontinued, and the entire syndrome remitted.
In retrospect, the absolutely normal mental status
and severity of peripheral neuropathy did not fit
cobalamin deficiency

1405
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 3B
Shortcut Leading to Diagnostic
Error: Availability Heuristic
• Likelihood of a diagnosis is influenced by the
ease of recall of similar examples
• More efficient than looking up probabilities of
each feature in a case from prognostic,
population-based studies; needed probability
data may not be available from the literature in
some circumstances
• But it is well-documented that there are biases
due to ease of ‘retrievability’ of prior instances:
recent case (Example 3b), impact of case…

Example: Transfusion Decisions

and Availability Heuristic
• Survey of 122 surgeons and anesthesiologists
• Assessed their knowledge about transfusion
risks
• Analyzed association of prior adverse
experience from withholding transfusion and
estimates of actual risk
• Median risk estimates differed (p=0.03):
– 10% among physicians who had personally treated a
patient who suffered an adverse outcome that might
have been avoided by a transfusion
– 5% among physicians without such a prior experience
(Risk range per expert panel = 1 to 5%; mean =4%)
Salem-Schatz et al, JAMA 1990

1406
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 4
Blind Obedience
• 50 year old left-handed woman complained of
headache, neck stiffness and nausea for 2-3
days
• Morning of admission, found speaking “jibberish”
• In community hospital ED, several generalized
seizures were observed
• Lorazepam, diazepam and phenytoin all failed
• Transferred to the Brigham where propofol was
started

Case 4
• Temperature:
101.8
• CSF:
pressure 32;
100 WBC’s
(80%
neutrophils);
protein 400;
glucose 100
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis?

Case 4
• Acyclovir, ampicillin, cefriaxone and
vancomycin started
• Antibiotics narrowed to acyclovir when all
cultures were negative
• HSV PCR negative

Comments on diagnosis?

1408
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 4
Course:
• Failed propofol
• Pentobarbital coma controlled the seizures
• Pentobarbital weaned to levetiracetam
• Very poor memory

Decided to order more labs:

• Paraneoplastic panel sent
• Voltage gated potassium antibody sent
• HHV 6 PCR sent
• CSF exam repeated: Pressure 22; WBC 5 (90%
lymphocytes); protein 80; cultures & cytology neg

Revised Diagnosis?

1409
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 4
• Paraneoplastic panel returned negative

• Voltage gated potassium channel antibody

returned negative

• But this time…HSV PCR +

Course:
Patient improved considerably but was left with an
AED requirement and a significant memory
disturbance

Diagnostic Error: Blind Obedience

due to Overreliance on Test Result
• Overly discouraged by the negative laboratory
test (i.e. CSF HSV PCR)
• Over-reliance on the imaging appearance
• Failed to remember that diagnostic tests are
virtually never ‘perfect’ in detecting or ruling out
disease; this may have contributed to not
noticing or inquiring further on certain aspects of
history
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

‘Blind Obedience’ due to

Overreliance on Test Result
CSF samples tested for < 2 days 3-7 days
HSV by PCR, in since since
confirmed cases of HSV symptom symptom
encephalitis onset onset
PCR positive 7 14
PCR negative 1 1

Overall, sensitivity is 21/23 = 91%

Fomsgaard 1997

Test Performance and Prevalence of Disease

Woolf and Kamerow, 1990

1411
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 5
A Systematic Disease
A 61 year old man complains of headaches in the
past, but over the past three months he
developed a new type of right sided pain. He
had had a right sided vestibular Schwannoma
successfully resected five years previously
leaving him with some facial weakness.
The neurosurgeon who removed the Schwannoma
brought him to my office, bearing a recently
done CT scan.

1412
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 5: History
• Head pains occur in distinct attacks,
lasting ~20 minutes each
• Always centered around the right eye; not
associated with ptosis, pupillary
abnormalities, change in conjunctival or
scleral color, or nasal stuffiness.
• OTC NSAIDs and several triptans already
tried when referred for second opinion

Diagnosis?

1413
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 5
Dr. Martin A. Samuels’s Diagnosis

• I diagnosed chronic paroxysmal

hemicrania

• I prescribed an indomethacin test dose of

50mg IM

Case 5
Response to Therapy
Oral indomethacin was started with remarkable
success (he and the neurosurgeon practically
kissed my feet), but a month later he called to
say that the head pain had recurred, but this
time with a “black eye.”
He came to the emergency department where
he was found to have a prominent peri-orbital
ecchymosis not associated with any
abnormality of eye movements or pupils.
There was no proptosis.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Diagnosis?

1415
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Periorbital Ecchymosis in Migraine

Brasch M, Levinsohn G. Ein Fall von Migraene mit Blutungen in die
Augenhohle waehrend des Anfall. Berl Klin Wschr 1898; 35: 1146-50.

Case 5
Dr. Martin A. Samuels’s Reaffirmed
Diagnosis
• Chronic Paroxysmal Hemicrania with
periorbital ecchymosis diagnosed with
confidence and a flourish
• Indomethacin IM given with good
response; oral indomethacin continued
and patient sent home
• Everyone (even the emergency
physicians) kissed my feet

1416
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 5
And then:

An Inspector Calls

Believe it or not, about a month after the CT was

obtained, a neuroradiologist reviews it and calls
the patient directly and tells him that he has a
nasopharyngeal cancer that was missed on the
prior scan. (The initial scan had been read by a
general radiologist, neurosurgeon and
neurologist).
Comments about what happened?

Case 2 CT scan

Fossa of
Rosenmüller

1417
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 5
The patient was sent for an urgent consultation
with an otorhinolaryngologist, who agreed there
was a mass that he felt was almost certainly a
cancer of the nasopharynx.

I felt terrible

Lessons?
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case Closed?

Case 5

The biopsy showed necrotizing

granulomatous vasculitis with aseptic
necrosis

A chest CT scan was recommended

1419
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2 CT Chest

Case 5

• C-ANCA was found to be positive

• The patient was referred to a
rheumatologist, who immediately
diagnosed Wegener’s granulomatosis
and initiated treatment with
methotrexate, cyclophosphamide and
dexamethasone
• The patient rapidly responded with
disappearance of the headache and
repeat CT showed resolution
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 2 after treatment

Case 5: What is the Cause of this Error?

• I believe the major error in this case was hubris
– Chronic paroxysmal hemicrania may be a secondary
headache
– Failure to look at the skull base and nasopharynx on
images
• But from a ‘systems’ perspective, this was not
hubris but a failure of communication: although
redundancy was appropriately built into the
system for interpreting imaging, there was:
– A considerable lag (one month) in timing of review by
neuroradiologist
– A broken procedure for communication between
neuroradiologist and the patient’s main clinician (MS)
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

FUTURE: Systems Solutions*

Clinical Typical Problem Low High
Scenario Technology Technology
Solution Solution
Visual diagnosis Failed visual Independent and Computer-assisted
(e.g., pathology, pattern recognition timely second feature matching
radiology) reads
Complex Information Structured Data visualization
hospitalized overload amid diagnostic tools
patient (e.g., multiple protocols/
critical illness, physiologic algorithms
major trauma) derangements
Routine Complacency “Don’t-miss- Symptom-oriented
ambulatory patient regarding diagnosis” diagnostic
(e.g., headache, uncommon checklists at sick decision support
fatigue) dangerous causes visits
Patient with rare Lack of specialized Streamline triage Using internet
symptoms or knowledge of rare to diagnostic search engines for
unusual symptoms/diseases experts information on
constellations of possible
symptoms diagnoses
*Table from Newman-Toker, JAMA 2009

Case 6: Israeli Man

An Expert Call

A 40 y/o Israeli man complained of

double vision. A neurologist found a left
abducens paresis. Work-up was
negative for diabetes, systemic
vasculitis and leptomeningeal
metastases. The weakness of the left
lateral rectus did not improve and was
joined by right lateral rectus weakness.
An image had prompted referral to a
neurosurgeon.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1423
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 6: Israeli Man continued

Because of the appearance of the bone,

only noticed by the neuroradiologist, and
the patient’s ethnicity, a diagnostic test
was obtained.

1424
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 6
Israeli Man: Treatment & Follow Up
• The diagnosis of thalassemia with
extramedullary hematopoiesis was made

• He was treated with low dose radiation

and the lesion melted away with complete
resolution of the bilateral abducens palsies

Lessons from the Israeli Man

• Expert opinion is valuable
• Not all errors are due to heuristic misuse
• Framing might have helped here
• Know some internal medicine
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 7
80 Year Old Man
An 80 year old man, previously healthy
except for a CABG eight years earlier, got
lost twice while driving. He had the
presence of mind to use his GPS to find
his way home from ordinarily familiar
locations. His family thought there was a
subtle loss of memory that had become
evident over the past month.

Case 7
80 Year Old Man
His neurological examination showed only
very mild memory impairment. The
geographical disorientation, noted by
history, was not demonstrable by exam.
There was no aphasia, agnosia or apraxia
and his cranial nerve, motor, sensory,
coordination and reflex exam were all
normal. His general physical exam
revealed a 6 cm non-tender mass in the
right buttock. He believed it had been
there for some time.
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 7
80 Year Old Man

Case 7
80 Year Old Man

Chest CT scan revealed a mass in the left

pectoralis major muscle that neither the
patient nor the examiners (even after the
image was seen) could appreciate.

A diagnostic test was obtained.

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 7
80 Year Old Man
Biopsy of the gluteal mass revealed a B
cell lymphoma

The hematologists stated that the

lymphoma was of sufficiently low grade
that they would ordinarily not treat it were
it not for the brain lesion, but they would
bow to the neurologist’s opinion regarding
the need to treat the brain disease

Case 7
80 Year Old Man

Another diagnostic test was obtained

Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 7
80 Year Old Man

Biopsy of the right temporal lesion

revealed a glioblastoma multiforme

Case 7
Lessons from the 80 Year Old man
• The parsimony of nature only goes so far

• The appearance of the brain lesion by MRI

and the neurological history are so
characteristic of GBM that the low grade
systemic lymphoma should have been
considered a separate problem

1429
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 8
83 Year Old Woman
Complains of progessive gait disorder,
which she described as a “balance”
problem. She had episodes of “pins and
needles” in the right leg, that radiated to
the great toe, and was unstable on her
feet, particularly in the dark. Her hands
were unaffected and there was no bladder
or bowel dysfunction. She had no
cognitive complaints.

Case 8
83 Year Old Woman
Mental status: normal
Cranial nerves: normal
Motor: spastic paraparesis L>R
Sensory: moderate loss of position sense and vibration
sense in both legs; Romberg positive. Noxious stimuli
were normally perceived and there was no level on the
trunk
Coordination: No cerebellar ataxia; gait practically
impossible because of spastic ataxia
Reflexes: Increased in both arms and legs, slightly less
so at the ankles bilaterally. Bilateral Babinski signs were
present.

Diagnosis?

1430
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 8
83 Year Old Woman

B12 = 395; folate=8.0; electrolytes, LFT’s,

RFT’s, Blood sugar, rheumatologic
battery: all negative; CBC normal

Diagnosis?

Case 8
83 Year Old Woman
I diagnosed an extramedullary cervical spinal
cord lesion (probably a meningioma) and
essentially ignored the radicular symptoms in
the leg; rationalizing them as being an
independent complaint or a trivial radiculopathy
that was exacerbated by the myelopathy. I
explained away the upper extremity hyper-
reflexia as being probably due to mundane
cervical spondylosis. When asked by a innocent
medical student why I thought the symptoms
had progressed so rapidly, I said “we see this”
and referred to the “falling off the table
syndrome of pseudoacuteness”
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 8
83 Year Old Woman

Microcatheter tip in segmental artery

Fistulous point
where neural
sleeve branch
of R segmental
artery T10 enters
dura and drains
into perimedullary
veins
aorta
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

Case 8
83 Year Old Woman
• The major error was ignoring the parsimony of
nature
• Foix-Alajouanine disease is due to spinal-dural
fistula
• The major pathology is venous hypertension,
which accounted for the distant signs (increased
upper extremity reflexes and left leg radicular
symptoms)
• Venous occlusive disease (e.g.
hypercoagulability) may be the cause or effect

SUMMARY THOUGHTS
Physicians use heuristics to help them sort through complex clinical information
and formulate diagnoses and treatment strategies.

There are some pitfalls to the use of heuristics that appear to be general
phenomena. It may be possible to improve decision-making through techniques
to raise awareness and put in place behavioral strategies to minimize bias, but
few have been tested.

Much of the focus on errors in healthcare currently is on systems. To redress

systems errors, there is a need to design ‘smart’ interventions to change the
way care is organized and information communicated, and test them in an
experimental fashion.

Not all errors are due to misuse of heuristics or system problems

As in genetics, without errors (mutations) there is no chance for improvement

1433
Copyright © Oakstone Publishing, LLC, 2018. All Rights Reserved.

1434