EPILEPSY – INDIAN
PERSPECTIVE
Dr MADHUSUDHAN B.K.
MD(Int med),DM (Neurology)
Consultant Neurologist & Epileptologist
Fellowship in epileptology (university of Toronto- Canada)
Head Division of epilepsy
BGS GLEANEAGLES GLOBAL HOSPITAL,
BANGALORE
Definitions
• Seizure: the manifestation of an abnormal,
hypersynchronous discharge of a population of
cortical neurons
• Epilepsy: recurrent seizures (two or more)
which are not provoked by acute systemic or
neurologic insults
American Epilepsy
Society 2015 C-Slide 2
Epilepsy: Definition
New Definition as per
● Seizure:
ILAE
● Latin: Sacire “To take possession of”
● Greek: “To take hold of”
● Modern Terminology: Any sudden and severe event
● (Eg: He is having a heart seizure)
● Epileptic Seizure: An epileptic seizure is a
transient occurrence of signs and/or symptoms due
to abnormal excessive or synchronous neuronal
activity in the brain.
● Epilepsy: Epilepsy is a disorder of the brain
characterized by an enduring predisposition to
INTRODUCTIO
N
• Epilepsy is the second most common and frequently encountered neurological
condition that imposes heavy burden on individuals, families, and also on
healthcare systems.
• Recent study, 70 million people have epilepsy worldwide
• 90% -developing regions.
• developing countries median prevalence of 1.54% (0.48-4.96%) for rural
and 1.03% (0.28-3.8%) for
urban
• There are more than 12 million persons with epilepsy (PWE) in India, which
contributes to nearly one-sixth of the global burden.
Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: A meta-
analytic approach. Epilepsia 2010;51:883-90.
Epidemiology of
Seizures and Epilepsy
• Seizures
• Incidence: 80/100,000 per year
• Lifetime incidence: 9%
(1/3 febrile convulsions)
• Epilepsy
• Incidence: 45/100,000 per year
• Point prevalence: 0.5-1%
• Cumulative lifetime incidence: 3%
American Epilepsy
Society 2015
C-Slide 5
Epidemiology in India
• The overall prevalence of epilepsy in India is 3-11.9 per 1000.
• The incidence rate is 27.3/100,000 per year.
• Methodological differences in prevalence estimation include:
– variations in defining the epilepsy,
– failure to exclude pseudo-seizures, syncope, and other mimickers of
epilepsy, and
– missed cases because of concealment
They may influence the exact prevalence.
• The prevalence of epilepsy in males was reported to be significantly higher
than in females.
Ann Indian Acad Neurol. 2014 Mar; 17(Suppl 1): S3–S11
ILAE Classification of Seizures
Seizures
Partial Generalized
Simple Partial Absence
Complex Partial Myoclonic
Secondarily
Atonic
Generalized
Tonic
Tonic-Clonic
ILAE – International League Against
American Epilepsy
Society 2015
Epilepsy C-Slide 7
ILAE Classification of Seizures
Seizures
Partial Generalized
Simple Partial
Complex Partial
Secondarily Generalized
American Epilepsy C-Slide 8
Society 2015
ILAE Classification of Seizures
Seizures
Partial Generalized
Simple Partial
With somatosensory
or special sensory symptoms
With motor signs
With autonomic
symptoms or signs
With psychic or
experiential symptoms
American Epilepsy C-Slide 9
Society 2015
Complex Partial Seizures
Impaired consciousness Seizures
Clinical manifestations vary
with site of origin and degree
of spread
• Presence and nature of aura Partial Generalized
• Automatisms
• Other motor activity
Duration typically < 2 minutes
Complex
Partial
American Epilepsy C-Slide 10
Society 2015
Secondarily Generalized Seizures
Begins focally, with or Seizures
without focal neurological
symptoms
Variable symmetry, intensity,
and duration of tonic Partial Generalized
(stiffening) and clonic
(jerking) phases
Typical duration 1-3 minutes
Secondarily
Postictal confusion,
somnolence, with or without Generalized
transient focal deficit
American Epilepsy C-Slide 11
Society 2015
Epilepsy: Definition
New Definition as per
● Seizure:
ILAE
● Latin: Sacire “To take possession of”
● Greek: “To take hold of”
● Modern Terminology: Any sudden and severe event
● (Eg: He is having a heart seizure)
● Epileptic Seizure: An epileptic seizure is a
transient occurrence of signs and/or symptoms due
to abnormal excessive or synchronous neuronal
activity in the brain.
● Epilepsy: Epilepsy is a disorder of the brain
characterized by an enduring predisposition to
ILAE Classification of Seizures
ILAE – International League Against Epilepsy
EEG: Partial Seizure
Right Frontal
seizure
American Epilepsy C-Slide 18
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EEG: Partial Seizure
Continuation
of the same
seizure with
change in
amplitude and
frequency
American Epilepsy C-Slide 19
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EEG: Partial Seizure
Continuation of
the same seizure
with spread to the
other hemisphere
American Epilepsy C-Slide 20
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EEG: Partial Seizure
Continuation of the
same seizure with
spread to the other
hemisphere
American Epilepsy C-Slide 21
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ILAE Classification of Seizures
Seizures
Partial Generalized
Absence
Myoclonic
Atonic
Tonic
Tonic-Clonic
American Epilepsy C-Slide 22
Society 2015
Typical Absence Seizures
Brief staring spells (“petit mal”) with
impairment of awareness
Seizures
● 3-20 seconds
● Sudden onset and sudden resolution
● Often provoked by hyperventilation
● Onset typically between 4 and 14
years of age Partial Generalized
● Often resolve by 18 years of age
Normal development and intelligence
EEG: Generalized 3 Hz spike-wave
discharges
Absence
American Epilepsy C-Slide 23
Society 2015
EEG: Typical Absence Seizure
3Hz spike/slow
wave complexes
American Epilepsy C-Slide 24
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Atypical Absence Seizures
Brief staring spells with variably reduced responsiveness
● 5-30 seconds
● Gradual (seconds) onset and resolution
● Generally not provoked by hyperventilation
● Onset typically after 6 years of age
Often in children with global cognitive impairment
EEG: Generalized slow spike-wave complexes (<2.5 Hz)
Patients often also have Atonic and Tonic seizures
American Epilepsy C-Slide 25
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Atypical Absence Seizures
American Epilepsy C-Slide 26
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Myoclonic Seizures
Seizures
Epileptic Myoclonus
Brief, shock-like jerk of a muscle
or group of muscles
Differentiate from benign, Partial Generalized
nonepileptic myoclonus (e.g., while
falling asleep)
EEG: Generalized 4-6 Hz
polyspike-wave discharges Myoclonic
American Epilepsy C-Slide 27
Society 2015
Myoclonic Seizures
Generalized
polyspike-slow-wave
discharges
American Epilepsy C-Slide 28
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Tonic and Atonic Seizures
Tonic seizures
• Symmetric, tonic muscle contraction of extremities with tonic
flexion of waist and neck
• Duration - 2-20 seconds.
• EEG – Sudden attenuation with generalized, low-voltage fast
activity (most common) or generalized polyspike-wave. Seizures
Atonic seizures
• Sudden loss of postural tone Partial Generalized
• When severe often results in falls
• When milder produces head nods or jaw drops.
Tonic
• Consciousness usually impaired
• Duration - usually seconds, rarely more than 1 minute
Atonic
• EEG – sudden diffuse attenuation or generalized polyspike-
wave
American Epilepsy C-Slide 29
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Tonic and Atonic Seizures
American Epilepsy C-Slide 30
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Generalized Tonic-Clonic Seizures
● Associated with loss of consciousness
and post-ictal confusion/lethargy Seizures
● Duration 30-120 seconds
● Tonic phase
● Stiffening and fall
● Often associated with ictal cry Partial Generalized
● Clonic Phase
● Rhythmic extremity jerking
● EEG – generalized polyspikes
Tonic-
Clonic
American Epilepsy C-Slide 31
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Epilepsy Syndromes
Epilepsy Syndrome
Grouping of patients that share similar:
– Seizure type(s)
– Age of onset
– Natural history/Prognosis
– EEG patterns
– Genetics
– Response to treatment
American Epilepsy C-Slide 32
Society 2015
Epilepsy Syndromes
Epilepsy
Partial Generalized
Idiopathic Symptomatic Idiopathic Symptomatic
American Epilepsy C-Slide 33
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C-Slide 34
Etiology of Seizures and Epilepsy
Infancy and childhood
– Prenatal or birth injury
– Inborn error of metabolism
– Congenital malformation
Childhood and adolescence
– Idiopathic/genetic syndrome
– CNS infection
– Trauma
American Epilepsy C-Slide 35
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Etiology of Seizures and Epilepsy
Adolescence and young adult
– Head trauma
– Drug intoxication and withdrawal*
Older adult
– Stroke
– Brain tumor
– Acute metabolic disturbances*
– Neurodegenerative
*causes of acute symptomatic seizures, not epilepsy
American Epilepsy C-Slide 36
Society 2015
Questions Raised by a First Seizure
● Seizure or not?
● Provoked? (ie metabolic precipitant?)
● Seizure type? (focal vs. generalized)
● Evidence of interictal CNS dysfunction?
● Syndrome type?
● Which studies should be obtained?
● Should treatment be started?
American Epilepsy C-Slide 37
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● Which drug should be used?
Evaluation of a First Seizure
● History, physical
● Blood tests: CBC, electrolytes, glucose, calcium, magnesium,
phosphate, hepatic and renal function
● Lumbar puncture
(only if meningitis or encephalitis suspected and potential for brain herniation is excluded)
● Blood or urine screen for drugs
● Electroencephalogram (EEG)
● CT or MR brain scan
American Epilepsy C-Slide 38
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C-Slide 39
Seizure Precipitants
Metabolic and Electrolyte Imbalance
Stimulant/other proconvulsant
intoxication
Sedative or ethanol withdrawal
Sleep deprivation
Antiepileptic medication reduction or
inadequate
AED treatment
Hormonal variations
American Epilepsy
Stress
C-Slide 40
Society 2015
Fever or systemic infection
Seizure Precipitants (cont.)
Metabolic and Electrolyte Imbalance
● Low blood glucose
(or high glucose, esp. w/ hyperosmolar state)
● Low sodium
● Low calcium
● Low magnesium
American Epilepsy C-Slide 41
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Metabolic abnormalities and seizures
Type Comment
Osmotic shifts, disrupted ionic balance, in anoxia w/
Hyponatremia
shutdown of Na-K pump
Hypo- or Rare to cause seizure. Sometimes through
hyperkalemia hypomagnesemia
Hypo- or Usually other seizures first, such as tetany or
hypercalcemia altered consciousness
Hypoglycemia BS <50, disrupted Na/K pump
May exacerbate epilepsy but rarely is de novo
Hyperthyroidism
cause
BS = blood sugar.
American Epilepsy 42
Society 2015
Seizure Precipitants (cont.)
Stimulants/Other Pro-convulsant
Intoxication
IV drug use
Cocaine
Ephedrine
Other herbal remedies
Medication reduction
American Epilepsy C-Slide 43
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Seizure Precipitants (cont.)
Medications that can lower
seizure threshold
● Antidepressants
●Isoniazid
Bupropion
●Penicillins
Tricyclics
● Neuroleptics ●Cyclosporin
Phenothiazines ●Meperidine
Clozapine
● Theophylline
American Epilepsy
Society 2015 44
Differential Diagnosis of
Non-epileptic Events: Physiologic
● Syncope
● Cardiac (Arrhythmia)
● Non-Cardiac Syncope (Vasovagal, Dysautonomic)
● Metabolic (Hypoglycemia)
● Migraine
● Sleep Disorders (Narcolepsy)
● Movement Disorders (Paroxysmal Dyskinesia)
● Transient Ischemic Attacks
American Epilepsy C-Slide 45
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EEG Abnormalities
Background abnormalities: significant
asymmetries and/or degree of slowing
inappropriate for clinical state or age
Interictal abnormalities associated with
seizures and epilepsy
– Spikes
– Sharp waves
– Spike-wave complexes
May be focal, lateralized, generalized
American Epilepsy C-Slide 46
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EEG Abnormalities
Interictal
left
temporal
sharp
wave
consisten
t with a
diagnosis
of partial
epilepsy
of left
American Epilepsy temporalC-Slide 47
Society 2015
origin
EEG Abnormalities
Interictal
generalized
polyspike-
wave complex
consistent
with a
diaganosis of
idiopathic
generalized
epilepsy
American Epilepsy C-Slide 48
Society 2015
Medical Treatment of First Seizure
Whether to treat first seizure is
controversial
• 16-62% of unprovoked seizures will recur within 5 years
• Relapse rate may be reduced by antiepileptic drugs
• Relapse rate increased if:
● abnormal imaging
● abnormal neurological exam
● abnormal EEG
● family history
First Seizure Trial Group. Neurology. 1993;43:478–483. [PubMed]
Camfield et al. Epilepsia. 2002;43:662–663. [PubMed]
Quality of life issues are important (ie driving)
American Epilepsy C-Slide 49
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Antiepileptic Drug (AED)
Choice: Considerations
● Seizure type
● Epilepsy syndrome
● Efficacy
● Cost
● Pharmacokinetic profile
● Adverse effects
● Patient’s related medical conditions
(ie beneficial or deleterious effects on co-morbid conditions)
American Epilepsy C-Slide 50
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AED Choice: Attempt Monotherapy
Simplifies treatment
Reduces adverse effects
Conversion to monotherapy
– Eliminate sedative drugs first
– Withdraw antiepileptic drugs slowly over
several months
American Epilepsy C-Slide 51
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AED Choice: More Considerations
● Limited placebo-controlled trials available, particularly of newer
AEDs
● Several drugs are commonly used for indications other than those
for which they are officially approved/recommended
● Choice of AED for partial epilepsy:
– drug side-effect profile and patient’s preference/concerns
● Choice of AED for generalized epilepsy:
– predominant seizure type(s)
– drug side-effect profile and patient’s preference/concerns
See appendix for
ILAE Summary Guidelines and Summary of AAN evidence-based guidelines
American Epilepsy C-Slide 52
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AED Choice by Seizure Type
Broad-Spectrum Narrow-Spectrum
Agents Agents
Valproate Partial onset seizures
Felbamate Phenytoin
Lamotrigine Carbamazepine
Topiramate Oxcarbazepine
Zonisamide Gabapentin
Levetiracetam Pregabalin
Rufinamide* Tiagabine
Vigabatrin* Lacosamide*
Clobazam* Ezogabine*
Absence
Ethosuximide
* New AEDs (approved
Society 2015
since 2008)
American Epilepsy C-Slide 53
AED Choice: Focal Onset Seizures
Best evidence:
Carbamazepine**, phenytoin**, levetiracetam, zonisamide
Also shown to be effective, weaker evidence:
Valproate**, lamotrigine**, oxcarbazepine**, topiramate**,
phenobarbital**, gabapentin, vigabatrin
Limited or no data for monotherapy:
Pregabalin, lacosamide, rufinamide, ezogabine
** FDA approval for monotherapy
Glauser T, Ben-Menachem E, Bourgeois B et al. In Epilepsia, 54(3):551-
563, 2013.
American Epilepsy C-Slide 54
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C-Slide 55
AED Choice: Generalized-
Onset Tonic-Clonic Seizures
Best evidence and FDA Indication:
Valproate**, topiramate**
Also shown to be effective:
Zonisamide, levetiracetam, oxcarbazepine
Phenytoin**, carbamazepine** (may exacerbate absence and myoclonic sz )
Lamotrigine (may exacerbate myoclonic sz of symptomatic generalized epilepsies)
** FDA approved for monotherapy
American Epilepsy C-Slide 56
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AED Choice: Absence Seizures
Best evidence:
Ethosuximide (limited spectrum, absence only), valproate
Also shown to be effective:
Lamotrigine
May be considered as second-line:
Zonisamide, levetiracetam, topiramate, felbamate, clonazepam
May precipitate or aggravate absence seizures:
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, tiagabine, vigabatrin
American Epilepsy C-Slide 57
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AED Choice: Myoclonic Seizures
Best evidence:
Valproate
Levetiracetam (FDA indication as adjunctive tx)
Clonazepam (FDA indication)
Possibly effective:
Zonisamide, topiramate
May Precipitate or Aggravate:
Carbamazepine, gabapentin, oxcarbazepine, phenytoin, tiagabine,
vigabatrin, and possibly lamotrigine (in JME)
American Epilepsy C-Slide 58
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AED Choice:
Lennox-Gastaut Syndrome
Best evidence/FDA indication*:
Topiramate, felbamate, clonazepam, lamotrigine, rufinamide,
valproate, clobazam
* FDA approval is for adjunctive treatment for all except
clonazepam
Some evidence of efficacy:
Zonisamide, levetiracetam
American Epilepsy C-Slide 59
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AED Mechanisms of Action
Na+ Ca++ H-current Glutamate GABA Carbonic
AED Channel Channel enhance- Receptor Enhance- Anhydrase
Blockade Blockade ment Antagonism ment Inhibition
PHT X X (NMDA glycine)
CBZ, OXC X X (CBZ>OXC)
barb, benzo X (GABAA)
ESM X
VPA X X X
FBM X X X (NMDA) X
GBP X X X (NMDA glycine)
LTG X X X (kainate)
TPM X X X (AMPA,kainate) X X
TGB X (reuptake)
LEV X (kainate)
ZNS X X X
PGB X
LCM X (slow inact.)
Modified from White HS and Rho JM, Mechanisms of Action of AEDs, 2010.
RUF X
American Epilepsy P-Slide 60
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VGB2015 X (metab.)
Status Epilepticus
Definition
– More than 5 minutes of continuous
clinical or electrographic seizure activity
or
– Two or more sequential seizures without
full recovery between seizures
American Epilepsy C-Slide 61
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Status Epilepticus (SE)
A medical emergency
– Adverse consequences can include hypoxia,
hypotension, acidosis, hyperthermia,
rhabdomyolysis and neuronal injury
– Know the recommended sequential protocol for
treatment and distribute a written protocol to
emergency rooms, ICUs and housestaff.
– Goal: stop seizures as soon as possible
American Epilepsy C-Slide 62
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Mortality of SE by Age
Towne AR et al. Epilepsia. 1994;35:27-34.
American Epilepsy C-Slide 63
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Mortality of SE by duration
Towne AR et al. Epilepsia. 1994;35:27-34.
American Epilepsy C-Slide 64
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SE Treatment Algorithm
– Check emergency ABC’s
– Give O2
– Obtain IV access
– Begin EKG monitoring
– Check fingerstick glucose
– Draw blood for Chem-7, Magnesium,
Calcium, Phosphate, CBC, LFTs, AED
levels, ABG, troponin
– Toxicology screen (urine and blood).
– Thiamine [Link]
Arif H, Hirsch IV;Neurol.
Semin 50 ml of D50 IV
2008;28:342–354.
unless
American Epilepsy
adequate glucose known.
[PubMed]
C-Slide 65
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Status Epilepticus:
First-line Treatment Options
Class &
Maximum
Benzodiazepine Route Dosing Level of
Dose
Evidence
4mg @ 2mg/min
Class I
LORAZEPAM IV 0.1mg/kg May repeat x1
in 5-10 min
Level A
IM
Class I
MIDAZOLAM Nasal 0.2mg/kg 10mg
Level A
Buccal
Class IIa,
DIAZEPAM PR 0.2mg/kg 20mg
Level A
Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed]
American Epilepsy C-Slide 66
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Status Epilepticus: Second-line
Treatment Options
Maximum Class &
Rout Additional
AED Dosing Rate of Level of
e Dose
Infusion Evidence
5 PE/kg ,
150 Class IIa
Fosphenytoin IV 20 PE/kg 10 min after
PE/min Level B
loading dose
5-10mg/kg,
Class IIa
Phenytoin IV 20mg/kg 50mg/min 10 min after
Level B
loading dose
20mg/kg,
Valproate 20-40 3-6 Class IIa
IV 10 min after
Sodium mg/kg mg/kg/min Level A
loading dose
Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed]
American Epilepsy C-Slide 67
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Refractory Status Epilepticus:
Treatment Options
Class &
Continuous Adverse
Infusions Initial Dose Level of
Infusion Effects
Evidence
Respiratory
0.2mg/kg Class IIa
Midazolam 0.05-2mg/kg/hr depression
@ 2mg/min Level B Hypotension
Respiratory
1-2mg/kg Depression
30-200 Class IIb Hypotension*
Propofol @ Propofol infusion
mcg/kg/min Level B
20mcg/kg/min syndrome
Renal Failure
Respiratory
depression
Hypotension
Pentobarbita 5-15 mg/kg Class IIb
0.5-5mg/kg/hr Cardiac depression
l @ ≤ 50mg/min Level B Paralytic Ileus
Prolonged mental
status depression
American Epilepsy Brophy GM et al. Neurocrit. Care 2012; 17:3–23 [PubMed] C-Slide 68
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Epilepsy Surgery in India
• In India over 1 million people with medically
refractory epilepsies, of which nearly one half
are potential surgical candidates.
• The decision making for epilepsy surgery
needs a multidisciplinary approach.
• Knowing when not to operate, because of the
need for further investigations is as important
as selecting which patient may benefit from
Epilepsia. 2000; 41 Suppl 4:S31-4;
India. 2009 Jan-Feb; 57(1):4-6.
Neurol
surgery in a resource-limited setting.
Conclusions
• The burden of epilepsy could be reduced in
India by alleviating poverty and by reducing
the preventable causes, viz.
– perinatal insults,
– parasitic diseases, and
– head injuries.
• Empowering primary healthcare workers to
diagnose and start treatment might
significantly reduce the treatment gap and the
disparities between rural and urban areas.
In Nutshell
• The increasing burden of epilepsy in India in coming years due
to sociodemographic and epidemiological transition warrants
public health community to give priority for this eminently
preventable and manageable condition in healthcare delivery.
• A proper understanding of the epidemiology of epilepsy is
required to discern and delineate factors that are of relevance
(that can be modified) in prevention, management, and
rehabilitation.
