IBB 2022

Additional Learning Ressource:

Neurology

Charles Watson, Friedrich Schwarz

April 2022
 Neurology
Neurology 1
Neurological problems can be caused by infections, neurodegenerative disorders, trauma, con-
genital defects, vascular problems, and tumors. This section is an introduction to neurological
Neurological Diagnosis 1 diagnosis and the main features of important neurological conditions.

Signs and symptoms of neurological conditions 1

Neurological Diagnosis
Motor Signs 2
Sensory loss 3 The first step in medical diagnosis is always a good history, looking at the patient's current prob-
lems, previous medical history, risk factors, family history, and use of medications. The medical
Cognitive and neuropsychological Symptoms 4 history is followed by a clinical examination to gather information on functions of the brain and
spinal cord, including the following:
Other neurological signs 5
- cranial nerve functions
Neurological Tests 7 - motor functions and reflexes
- skin sensation
Examining cerebrospinal fluid 8 - coordination
Imaging 9 - psychological states
Neurophysiological examination methods 10 Sometimes a diagnosis is already evident after these two examination steps. However, further
Biopsy 11 special tests are usually carried out to confirm the diagnosis or exclude similar diseases. These
tests may include imaging methods (CT and MRI), electroencephalography (EEG), elec-
tromyography (EMG), nerve conduction studies, lumbar puncture (spinal tap), blood tests, and
Neurological Disorders 11 biopsy. These tests will be described in a little more detail later.
Inflammatory processes in the central nervous system 11
Neurodegenerative Diseases 15
Stroke 19 Signs and symptoms of neurological conditions
Epilepsy 21 Our nervous system is at least partially involved in almost all regulatory processes of our body.
Trauma 22 Accordingly, functional deficits can also lead to a variety of symptoms. In the following, we
would like to present essential neurological symptoms, divided into four major areas: motor
Genetic Conditions 23 function, sensory function, cognition, and others.
Diseases of the peripheral nervous system 25 Unfortunately, a precise classification of the symptoms, and especially their causes, is not al-
ways possible. For example, stance or gait problems can have motor and/or sensory causes.
Non-genetic developmental disorders 26 More generally, identical symptoms can be triggered by various causes.
For example, damage to the speech center can be caused by a stroke or a nearby tumor. How-
Psychiatric disorders and disorders of behavior 28 ever, both cases result in a disturbance of speech. The physical examination cannot differentiate
between these two cases. Still, it provides crucial conclusions about the location of a problem
in the brain and enables specific further tests to be carried out in these areas.
On the other hand, identical causes can also lead to different symptoms. For example, a stroke
can trigger a wide variety of symptoms depending on the brain area in which it occurs.

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 In flaccid paralysis, tone and reflexes are either much diminished or lost. Peripheral paralysis is
Motor Signs also accompanied by muscle atrophy. If paralysis is caused by damage to a peripheral nerve, a
sensory loss is also present.
The most significant elements of the examination of motor functions are:
Incoordination
- detection of paresis or paralysis Inability to coordinate movements is a classic sign of cerebellar damage. When asked to touch
- changes in muscle tone and reflexes their nose with a finger, the patient's hand may move unaimed and randomly as it gets closer to
- abnormal spontaneous movements its target. More subtle forms of incoordination may be a sign of parietal lobe damage.

Paralysis Abnormal spontaneous movements

It is important to distinguish between central paralysis (impairment of the corticospinal tract Tremor
neurons) and peripheral paralysis (impairment of the motor neuron). Tremor is a rhythmic oscillation with the alternating activity of muscular agonists and antago-
Damage to the corticospinal tract neurons is usually associated with spastic paralysis, in which nists, resulting in shaking of the affected body part. A tremor in the hands is a well-known sign
loss of fine motor skills is associated with increased muscle tone (spastic tone) and exaggerated of Parkinsonism. However, it may also occur in multiple sclerosis, cerebellar damage, stroke,
reflexes. and traumatic brain injury. It can also occur in individuals with no underlying neurological dis-
When motor neurons are damaged, flaccid paralysis occurs. This type of paralysis is character- ease.
ized by loss or reduction in muscle strength, loss of muscle tone (flaccidity), loss of reflexes, The two most important forms of tremor are resting tremor and action tremor. In a resting
and loss of the paralyzed muscles' mass. tremor, the tremor disappears as soon as the corresponding muscles perform a voluntary move-
ment. Conversely, action tremor increases with the movement's strength and is not present at
rest.
Spastic paralysis
Spastic paralysis occurs after major central nervous system damage, such as after a stroke. In Tics
spastic paralysis, the main structures affected are the corticospinal tract and parts of the basal Tics are involuntary, rapid, repetitive muscle spasms that characteristically occur in Hunting-
ganglia – the corticospinal damage causes the paralysis, and the associated basal ganglia dam- ton's disease or Tourette's syndrome.
age causes increased tone and hyperreflexia. The most common site of damage in these cases
is the internal capsule (which contains the corticospinal tract) and the adjacent putamen, cau- Choreoathetoid movements
date, and globus pallidus. Choreoathetoid movements are slow writhing (twisting) movements of the limbs and trunk that
In spastic paralysis, the muscle tone is increased on the affected side, and reflexes (such as the are characteristically seen in severe cases of cerebral palsy or Chorea Huntington.
patellar reflex) are exaggerated. Often there is an abnormal reflex called the Babinski sign, in
which firm stroking of the sole of the foot causes the big to extend rather than flex.
Sensory loss
The diagnostic importance of the difference between spastic and flaccid paralysis led to
the use of an unfortunate nomenclature by neurologists in the twentieth century; spastic This section will focus on sensory loss associated with the skin, including loss of the senses of
paralysis was called 'upper motor neuron (UMN)' paralysis, and flaccid paralysis was touch, deep pressure, pain, and temperature. Sensory loss due to damage to individual cortical
called 'lower motor neuron (LMN)' paralysis. This nomenclature attempted to charac- sensory areas or the sensory cranial nerves supplying olfaction, vision, taste, hearing, and bal-
terize the corticospinal pathway as the upper motor neuron was a light-hearted way of ance will be dealt with separately.
saying that the pyramidal cells of the motor cortex were similar to the actual motor The most common cause of cutaneous sensory loss is peripheral neuritis – progressive damage
neurons in the brain stem spinal cord. This terminology is misleading and should be to peripheral nerves of the limbs that occurs in diseases such as diabetes. Damage to individual
avoided. spinal nerves or individual limb nerves (such as the radial or median nerves) is associated with
specific areas of sensory loss that can lead to a diagnosis. At this introductory level of study, it
will be sufficient to focus your attention on the following:
Flaccid paralysis
Damage to the motor neurons or their axons can occur in many different ways. In the cases of - damage to the C4, C6, T1, L4, and L5 spinal nerves
motor neuron disease and polio, the cell bodies of the motor neurons are directly affected. - damage to the axillary, radial, ulnar, median, and sciatic nerves
Nonetheless, the most common causes of flaccid paralysis are damage to the axons of motor
neurons, as occurs in the cranial and spinal nerves, the limb plexuses, and the individual nerves Damage to spinal nerves and limb nerves affects all types of cutaneous sensation. Nevertheless,
of the limbs. Cranial nerve motor neuron damage can affect the eye muscle nerves (oculomotor, central damage to sensory pathways in the spinal cord is restricted to certain sensations. Dam-
trochlear, abducens), trigeminal, facial, and hypoglossal nerves, and the nerves connected to the age to the dorsal column system affects touch and deep pressure sensations. In contrast, damage
ambiguous nucleus (glossopharyngeal, vagus, and cranial accessory). Paralysis caused by dam- to the spinothalamic tracts affects the sensations of pain and temperature (lateral spinothalamic
age to cranial nerves will be discussed in detail in another section. tract) or touch (anterior spinothalamic tract).

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 Cognitive and neuropsychological Symptoms Semantic and episodic memory
The ability of the human cortex to store thousands of memories allows us to make fine
Aphasia distinctions and accumulate detailed knowledge of the way the world works. This en-
Aphasias are acquired speech disorders. Damage to speech areas in the dominant cerebral hemi- ables us to make accurate and useful predictions about the results of planned behaviors.
sphere can result in a loss of ability to understand speech (receptive aphasia or sensory aphasia) The recollection of experience can be classified as either semantic or episodic. Semantic
or a loss of ability to communicate by speech (expressive aphasia or motor aphasia). The left memory relates to a generalized impression of several experiences, such as the move-
hemisphere is dominant in nearly every right-handed and in most left-handed people. Common ment of falling objects, the texture of water, and the meaning of a pattern of sounds.
causes of damage in the speech areas are arterial blockage, traumatic brain injury, or tumors. Semantic memory enables understanding rather than a recollection of specific experi-
ences.
The sensory speech area is located on the posterior third of the upper surface of the superior On the other hand, episodic memory is linked to specific experiences at a particular
temporal gyrus, posterior to the primary auditory cortex. The upper surface of the superior tem- time and place. The distinction between the two forms of memory is not always clear-
poral gyrus is called the planum temporale. In right-handed people, the surface area of the cut. For instance, we may know something to be true (semantic memory). Nevertheless,
planum temporale is much larger on the left side than on the right – consistent with the large we may recall a particular learning experience that taught us that fact (episodic mem-
area occupied by the sensory speech area. The sensory speech area is named after Carl Wer- ory). Many pieces of knowledge depend on many episodic experiences. However, the
nicke, a German neurologist of the late nineteenth century. It is defined as area 22 in the Brod- semantic memory can remain in the long term even when the individual episodes are
mann classification of cortical areas. forgotten.

The motor speech area is located in the inferior frontal gyrus of the dominant cerebral hemi- The case of Henry Molaison
sphere. Motor or expressive aphasia) is named after the French physician and anthropologist The hippocampus is primarily involved with the formation of memories, and it does not
Paul Broca, who lived in the middle of the nineteenth century. The inferior frontal gyrus com- appear to be directly involved in consciousness. However, without the hippocampus, an
prises three parts – opercular, triangular, and orbital (from posterior to anterior). The parts most individual may experience severe distortions of consciousness because, without access
closely associated with Broca's aphasia are the triangular part (Brodmann's area 45) and the to recent memories, they cannot create a context for their surroundings. This is sup-
opercular part (area 44). ported by studies of many patients with hippocampal damage, including the famous
case of Henry Molaison (HM), a patient of William Scoville whom Brenda Milner has
intensively studied. Henry Molaison underwent a bilateral removal of the medial com-
Apraxia ponents of the temporal lobes, including the hippocampus, in an attempt to treat non-
Apraxias are disorders of motor planning characterized by an inability to carry out skilled responsive, severe epilepsy. After the surgery, he reported that his conscious state was
movements and gestures on demand in the absence of sensory loss or paralysis. abnormal. He felt he was "constantly waking up from a dream" with "everything looking
Apraxia can be caused by trauma, stroke, or tumor. Apraxia is traditionally considered a sign of unfamiliar" and could not form new memories of his experiences after the surgery. He
parietal lobe damage, but it can also result from damage to the prefrontal cortex or the corpus was stunned and distressed by the aging of his face in the following decades, leading to
callosum. the removal of the mirrors from his accommodation.
It can present in several ways, the most common of which are orofacial apraxia and construc-
tional apraxia. Orofacial apraxia is the inability to carry out facial movements on demand, such
as licking one's lips, winking, or whistling, even though no paralysis is present. Constructional
apraxia is the inability to draw, construct, or copy simple patterns. These patients have difficulty Other neurological signs
copying a simple diagram or drawing basic shapes.
Epileptic attacks
Memory loss Epileptic attacks are caused by storms of electrical hyperactivity in the brain. The most striking
Short-term memory impairment refers to a reduced or suspended ability to remember informa- form of epilepsy is a generalized seizure: The person becomes unconscious and suffers violent
tion just received; long-term memory loss is an inability to recall learned information or expe- tonic-clonic muscle spasms. This type of seizure was traditionally called grand mal epilepsy.
riences from the past. In other forms of epilepsy, the episode appears as an 'absence,' a short period during which the
The brain area that initially registers episodic memories is called the hippocampus, a distinctive person appears to have lost touch with their surroundings and stares blankly ahead. These ab-
area of the three-layered cortex in the temporal lobe of the human brain. The hippocampus oc- sence seizures were formerly called petit mal seizures.
cupies more than 10% of the cerebral cortical volume in many small mammals. However, in Epileptic attacks can be triggered by various things besides the "classical disease epilepsy."
humans, the hippocampus's size appears small compared to the massive overgrowth of the Important triggers are drugs and medication, fever, tumors, electrolyte disorders, hypoglycemia
frontal and temporal lobes. The cortical folding in the mammalian hippocampal region is strik- (also due to insulin overdose), sleep deprivation, or extreme stress situations.
ing. It is easy to recognize the major subdivisions in histological sections: the dentate gyrus, the
CA regions, the subiculum, and the entorhinal cortex.
The hippocampus is crucial for memory formation, but it is believed that long-term memories Sleep disorders
are stored over a much wider area of the cortex. The ability of the cortex to remember underlies
our knowledge and understanding of the world, allowing patterns to be recognized and details Sleep is essential for all vertebrates. While we often think of sleep as a way to rebuild energy,
to be filled in when they are missing. In this way, most cortex connections are created based on the body, and the brain continue to use energy while we are asleep. Very deep sleep may be a
experience.

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 way to conserve resources when intelligent behavior is not required, such as hibernating over Neurological Tests
the winter of some animals.
In humans, sleep runs in 90-minute cycles. In each iteration, the proportion of slow-wave activ- Neurological tests are used to supplement information gathered from the history and physical
ity in the electroencephalograph gradually becomes greater, eventually reaching widespread examination.
slow-wave activity characteristic of deep sleep. The end of one cycle is followed by short peri- Each technique has its own advantages and disadvantages, so it is vital to use the proper method
ods in which brain activity resembles an awake state, called rapid eye movement (REM) sleep. for the suspected disease.
Subjects who were woken from various stages of sleep reported most often that dreams occur
during REM periods. On the other hand, the mental states of deep sleep are vague and not
dream-like. In addition to marked changes in the brain's electrical activity, the activity of vari- Liquor diagnostics (examining the cerebrospinal fluid) provides important information
ous neurotransmitter systems changes from deep sleep to REM sleep. REM sleep is character- about possible inflammatory processes in the central nervous system. It can also detect
ized by high levels of cortical acetylcholine (ACh), reflecting a high level of activity and some hemorrhages or tumors but is used less frequently.
arousal. During slow-wave sleep, ACh levels are much lower, and activation of the hippocam-
pal in this state is associated with the consolidation of experience into long-term memory. Neuroimaging can non-invasively image the structures of the skull and brain. Each
technique in this category is particularly good at imaging certain structures or pro-
Sleep regulation cesses. Magnetic resonance imaging (MRI) is best suited for imaging soft tissues, such
The regulation of sleep depends on the function of a small number of specific cell groups as the brain. Computer tomography (CT) is ideal for acutely examining the skull's bone
in the hindbrain, hypothalamus, and preoptic area. Certain areas in the brain stem and structure, such as a suspected skull fracture. For a quick and reliable diagnosis of
hypothalamus have widespread projections to the cerebral cortex responsible for keep- strokes, contrast media (substances that show up extremely well in imaging) can be ad-
ing us awake and alert. These 'awake' centers are the locus coeruleus, the serotonin ditionally administered.
raphe system, the dorsal tegmental nuclei, and the tuberomammillary nucleus of the
hypothalamus. An unusual feature of these nuclei is that each one relies on a specific While neuroimaging can visualize many anatomical structures, it is limited in its ability
transmitter substance not found in the other members of this group. In the case of the to visualize the activity or the function of neurons. This is an excellent strength of neu-
locus coeruleus, this is noradrenaline; in the raphe, it is serotonin; in the tegmental rophysiological examination methods. Electroencephalography (EEG) can show cere-
nuclei, it is acetylcholine; and in the tuberomammillary nucleus, it is histamine. Sleep bral dysfunctions and has a central role in epilepsy diagnostics. The measurement of
occurs when activity in these centers is shut down. nerve conduction velocity is essential for examining peripheral nerves, and electromyo-
In the 1990s, the Saper group at Harvard began an ambitious project to unravel the graphy (EMG) is used to differentiate between neuronal and muscular damage.
pathways that create sleep and awake states. By tracing the input connections of the
known awake centers, they discovered that a master sleep switch lies rostral to the hy- Biopsies, i.e., the explicit removal of tissue, are sometimes necessary to diagnose or
pothalamus in the preoptic area. The sleep switch is a small cell group called the ven- stage certain diseases precisely. They are mainly used to diagnose tumors or peripheral
trolateral preoptic nucleus (VLPO). The VLPO makes inhibitory connections with all nerve and muscle diseases.
the 'awake' centers (locus coeruleus, raphe nuclei, the cholinergic tegmental nuclei, and
the histamine nucleus of the hypothalamus). When the VLPO is activated, it switches off
the awake centers, and the cerebral cortex goes to sleep. Damage to the VLPO can pro-
duce pathological insomnia, a permanent inability to sleep. The activity of VLPO is
principally controlled by input from the visual pathway - fibers in the optic nerve con-
nect to the suprachiasmatic nucleus, which is the 24-hour clock in the brain. This nu-
cleus tells the VLPO when it is dark, and therefore a good time to go to sleep, and when
it is light and time to wake up.
A critical component of the sleep circuitry is the loop that stabilizes the system. If the
brain had only reciprocally interconnected centers for sleep and alertness, there might
be a tendency for behavior to flip unpredictably between sleeping and waking, as hap-
pens in narcolepsy. To prevent this, the dorsomedial nucleus of the hypothalamus has a
stabilizing role, continually monitoring activity and behavior and recognizing when
danger or other factors make sleep inappropriate, even when VLPO has calculated it is
time to sleep.

Sleep disorders are widespread and affect about 10% of the general population.
In most cases, these are due to external factors, poor sleep hygiene, physical or mental illnesses,
or medication use. Other causes are found in a smaller proportion and are often related to a
disruption of the regulatory networks mentioned above.

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 Examining cerebrospinal fluid Imaging
Cerebrospinal fluid (CSF) can be obtained by lumbar puncture (spinal tap). A long needle is Magnetic Resonance Imaging (MRI)
used to reach the CSF in the subarachnoid space in the vertebral canal between the fourth and MRI can produce detailed images of brain tissues without using harmful radiation. It can differ-
fifth lumbar vertebrae. Because the spinal cord extends no lower than the second lumbar verte- entiate major neuroanatomical structures (cortex, white matter, nuclei) and can reveal the pres-
bra, there is no risk of damage to the spinal cord in this procedure. Examination of CSF is es- ence of a variety of pathological processes, such as tumors, inflammation, ischemia, and degen-
sential in cases of suspected bacterial meningitis where pus can be found in the CSF or sub- eration with high sensitivity. MRI is widely used in hospitals and clinics for medical diagnosis,
arachnoid hemorrhage finding blood in the CSF. disease staging, and follow-up after treatment. Compared with CT scans, MRI scans typically
take longer, are noisy, and require the subject to lie in a narrow, confining tube.

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Different ways to perform a lumbar puncture.

[Link] staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Axial MRI of a human brain, with no pathology visible. Novaksean, CC BY-SA 4.0 via Wiki-
Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436., CC BY 3.0, via Wikimedia media Commons
Commons
CT scans
X-rays penetrate the head during a CT scan, and the absorption of radiation by different tissues
can be measured. Because different tissues have different densities, they absorb radiation in
different ways. In the CT scan, two radiation sources located at opposite sides of a circular x-ray
detector are rotated around the head of the patient. These data are then integrated to produce a
3D digital reconstruction of the skull and brain.
The CT scan was one of the first neuroimaging techniques to be used in patients and is still
widely used because it is cheap and fast. However, it has some significant disadvantages. X-
rays can be harmful. However, it is still commonly used because it is comparatively cheap and
fast. Furthermore, CT scans show the anatomy of the cranial bones in excellent detail, so CT is
often used in emergency room cases to check for fractures.

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 Neurophysiological examination methods Biopsy

Electroencephalography Biopsy involves the surgical removal of tissue for microscopic examination.
The electroencephalogram (EEG) records the electrical activity of the brain using surface A biopsy can provide information that could not be obtained through other methods. However,
electrodes placed on the scalp. The EEG is important in the diagnosis of epilepsy. The EEG a large brain biopsy will remove a functioning piece of the brain, which may have long term
can detect different electrical waveforms which reflect the state of alertness of the subject. consequences.
These include:

- alpha-waves indicate a relaxed state of awareness

- beta-waves appear during concentration and focused attention
- theta-waves indicate fatigue and the onset of sleep
- delta waves appear during deep sleep.

An EEG recording setup.

The EEG pattern does not mature until the teenage years, and the EEG in infants often shows
very slow and irregular waves.

Nerve conduction studies (NCS)

Nerve conduction studies are used to detect abnormalities in electrical conduction in peripheral
nerves. These studies are used to monitor the progress of demyelinating disorders of the periph-
eral nerves.

Electromyography
Electromyography measures muscle action potentials to assess whether the underlying problem
is related to nerve supply or intrinsic muscle disease. They can be used to assess the level of
muscle atrophy resulting from a peripheral nerve lesion. In this way, the impact of nerve injury
can be assessed over time.

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 Neurological Disorders tor neurons in the spinal cord below the mid-cervical region results in paralysis of one or more
limbs. The affection of motor neurons in the hindbrain and/or the upper cervical region lead to
Inflammatory processes in the central nervous system a paralysis of the swallowing and breathing muscles. This is fatal unless a mechanical respirator
is used to support the breathing.
Meningitis and encephalitis During the epidemics of the 1950s, hundreds of thousands of people worldwide were
Bacterial and viral infections can cause meningitis (if the meninges are affected) or encephalitis paralyzed by polio infections every year. Back then, the respirators were massive metal
(if the brain is directly infected). The two conditions can occur in combination, which is called containers called iron lungs.
meningoencephalitis.
The characteristic symptoms of meningitis are headache and neck stiffness in the presence of
fever. The most important diagnostic test is a lumbar puncture, which can reveal an elevated
white cell count and the presence of protein in the cerebrospinal fluid. Bacterial or viral infec-
tions usually trigger the diseases, less frequently by fungal, parasitic, or other infections. Bac-
terial meningitis can be effectively treated with antibiotics. Bacterial meningitis caused by
Haemophilus influenzae type B (HIB), Pneumococcus, and some forms of Meningococcus can
be prevented with childhood immunization.
Viral encephalitis can have serious long-term consequences such as deafness, epilepsy, hydro-
cephalus, and cognitive deficits.

Poliomyelitis
Poliomyelitis is a paralytic disease caused by the poliovirus. Since the introduction of vaccina-
tion programs, it has been eradicated nearly everywhere in the world. Nevertheless, the disease
illustrates some intriguing facts about neuroscience.

Hospital staff is examining a patient in a tank respirator, iron lung, during the Rhode Island
polio epidemic. The iron lung encased the thoracic cavity externally in an air-tight chamber.
The chamber was used to create negative pressure around the thoracic cavity, thereby caus-
ing air to rush into the lungs to equalize intrapulmonary pressure; This media comes from the
Centers for Disease Control and Prevention's Public Health Image Library (PHIL), id: 2624.

Prion Diseases

Creutzfeld-Jacob disease (CJD)

CJD is caused by so-called prions (for proteinaceous infectious agents) – the presence of an
abnormal variant of the normal prion protein. Prions are misfolded proteins with an increased
β-sheet structure. They can force healthy proteins into a conformational change. The normal
prion protein (PrPc) is physiologically a membrane-tethered protein, mainly expressed in lym-
World map representing the incidence of poliomyelitis (wild virus) according to the WHO
phocytes and neurons. The misfolded proteins (PrPsc) cannot be degraded by the body and ac-
2015, orange: 21 to 30 confirmed cases, yellow: 1 to 10 confirmed cases, grey: No wild virus;
cumulate into plaques. These aggregates disrupt the neuronal functions and cause rapidly pro-
Pazuzupa, CC BY-SA 3.0, via Wikimedia Commons.
gressive dementia, which leads to death usually within one year from the onset of the disease.
The prion CJD occurs spontaneously in one in every million people worldwide.
In most cases, the poliomyelitis infection occurs without any symptoms at all. Symptomatic
In addition to clinical symptoms, MRI images and cerebrospinal fluid diagnostics can provide
cases are most often accompanied by vomiting and diarrhea. Only about 1-2% of the cases in-
clues. A definitive diagnosis of CJD is only possible post-mortem by histopathological and im-
volve the central nervous system, which can lead to paralysis.
munohistochemical methods. There is currently no treatment available.
The poliovirus uses the neurotransmitter reuptake mechanism to enter the central nervous sys-
tem via the nerve-muscle synapse. The virus then travels retrogradely along the motor neuron
axons to reach the motor neuron cell bodies in the spinal cord or hindbrain. Once the poliovirus Variant Creutzfeld-Jacob disease (vCJD)
reaches the motor neuron cell body, it causes fatal damage, which results in paralysis. Unfortu- Variant CJD in humans was caused by the transfer of a prion disease from animals to humans
nately, the damage is permanent because the motor neurons cannot regenerate. Damage to mo- in the UK in the early 1980s. Scrapie is a prion disease in sheep which was transmitted to cattle.

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 It is most likely that scrapie was transmitted to cattle by adding sheep abattoir by-products to Multiple sclerosis (MS)
cattle stock feed supplements given to cows. The result was an epidemic of bovine spongiform
encephalopathy (BSE) in cattle in the UK. BSE is the bovine equivalent of scrapie and was Multiple sclerosis is a central nervous system disease with inflammatory (autoimmune) and
named mad cow disease. It was first thought that BSE could not be transmitted to humans eating neurodegenerative components. The disease causes focal central nervous system lesions char-
meat from afflicted cattle. However, this belief was tragically wrong, and many people were acterized by demyelination of nerve fibers and axonal damage. MS is a relatively common
infected in the UK. The human disease induced by the BSE prion is described as variant CJD cause of neurological disability, especially in young adults, affecting women up to three times
(vCJD). Beef products were withdrawn from sale in the UK, and thousands of infected animals more than men. The cause of the disease is currently unknown. However, recent studies provide
were slaughtered and burned. Despite eradicating the disease from farmed cattle, new human strong evidence that MS may be related to a previous infection with Epstein-Barr virus.
cases of vCJD continue to appear in the UK. This is because prion diseases can have very long
incubation periods, up to 30 years or more. MS is associated with dysregulation of the patient's immune. This leads to a mistaken
activation of T lymphocytes which then attack oligodendrocytes and the production of
Rabies antibodies against myelin by recruited B cells. Both mechanisms destroy the myelin
Rabies is caused by an eponymous virus present in the saliva of infected bats and dogs and can sheaths within the white matter (demyelination), ultimately causing neuronal cell
be transmitted by bites or scratches from these animals. The virus enters neuromuscular death.
synapses (like poliovirus) and then uses retrograde axonal transport to get to the motor neuron Since MS is a disease that usually progresses in relapses, the affected brain areas can
cell bodies in the spinal cord. The remarkable feature of the rabies virus is that it can cross partially regenerate and rebuild the myelin sheaths (remyelination) but not the neurons
synapses to reach all the neurons that connect with the infected neuron. In this way, the virus between two attacks. Insufficient regeneration leads to the formation of astrocyte scars
can slowly spread to virtually all the cells in the spinal cord and brain. Eventually, sometimes around the axons. These lesions are called plagues and are the characteristic signs of
years after the initial infection, the cells degenerate, and death inevitably follows. This terrible MS, eventually leading to the name of MS since the Greek word for "plaque" is skleros.
process can be interrupted if a particular vaccination is administered within a few days of trans-
mission from a bite or scratch from a rabid animal. The symptoms of multiple sclerosis characteristically follow a relapsing pattern, in which
In untreated cases, the first symptoms are usually headaches, depressive moods, fever, and ex- episodes of damage are separated by months without new symptoms. Over time the episodes of
haustion. Later, this escalates into confusion, hallucinations, aggressive behavior, and muscle damage become more frequent, and there is an overall gradual decline in the person's health.
spasms. The disease is almost always fatal within seven to ten days after the onset of neurolog- Symptoms vary from person to person, depending on the location of the lesions. However, a
ical symptoms. Diagnosis is made based on a history of an animal and, if necessary, neck skin common first episode involves damage to one optic nerve resulting in blurred vision or blind-
biopsy. ness. Later symptoms may include fatigue, muscle weakness, lack of coordination, sensory ab-
Neuroscience research uses the ability of the rabies virus to cross synapses for nerve tracing normalities, intention tremor, and paralysis.
techniques. Neural circuits can be retrogradely mapped using a pseudorabies virus, a non-dan-
gerous relative of the original rabies virus. When axons become demyelinated, saltatory conduction is no longer possible. Conse-
quently, action potentials must be generated more frequently, and excitations can
spread unspecifically in the tissue. The former results in a significantly increased energy
demand, explaining the general fatigue of many patients. The unspecific excitations
combined with the sheathed nerve cells' destruction can lead to general coordination
and perception disorders.

The diagnosis is made on the basis of clinical symptoms and the detection of plague lesions
with MRI. Antibodies against myelin, so-called oligoclonal bands, can be seen in CSF obtained
by lumbar puncture.
In recent years, effective symptomatic drug treatments for MS have been introduced.

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 Neurodegenerative Diseases

Dementia and Alzheimer's disease

Dementia is characterized by an acquired, progressive impairment of brain function. It is due
to progressive brain atrophy, disproportionately greater than age-related physiological cerebral
loss.
Individuals with dementia suffer progressive impairment in memory, thinking, and planning,
making it difficult to carry out everyday activities. There may also be emotional problems,
speech problems, and lack of motivation. The most common early symptom of dementia is
short-term memory loss, such as the inability to recall a particular word.
The most common cause of dementia is Alzheimer's disease, accounting for about 65% of
cases. The second most common cause is chronic vascular disease.

Alzheimer's disease (AD)

Alzheimer's disease is the most frequent cause of dementia worldwide. It is associated with a
progressive and relentless loss of nerve cells in the forebrain. While AD is much more common
in older individuals, dementia is not a normal aging process. The earliest symptoms may be
minor episodes of memory loss. However, as the disease advances, the cognitive decline be-
comes overwhelming, eventually making it impossible for the patients to take care of them-
selves.
The part of the brain first affected by Alzheimer's disease is the hippocampus, followed by tem-
poral and parietal lobe atrophy.
Histologically AD is characterized by the aggregation of specific proteins. Due to a defective
AP-protein (APP) degradation, amyloid-beta plaques accumulate extracellularly. Additionally, Amyloid-beta aggregations, Bielschowsky silver impregnation; Image courtesy of Prof. Chris-
hyperphosphorylated tau proteins accumulate intracellularly to form so-called neurofibrillary tine Stadelmann, University Medical Center Göttingen.
tangles.
Both of these protein deposits lead to a disturbance of normal cell functions, resulting in cell
death.
Patients commonly die of infections such as pneumonia within four years after AD diagnosis.

Schematic visualization of the main histopathological features of Alzheimer's Disease.

Hyperphosphorylated tau proteins accumulate intracellularly to form neurofibrillary tan-

gles, Bielschowsky silver impregnation; Image courtesy of Prof. Christine Stadelmann, Uni-
versity Medical Center Göttingen.

16 17
 Alzheimer's disease is usually diagnosed using neuropsychological tests like the mini-mental To counteract these effects, L-DOPA can be used in combination with inhibitors of dopamine-
state examination or other test batteries. A loss of cortical brain tissue can be observed in CT degrading enzymes and dopamine agonists.
and MRI images. Examination of CSF from lumbar puncture may reveal an increase in phos-
pho-tau (released by cell death) and a decrease in amyloid-beta (due to aggregation) content. In drug-resistant or younger patients, deep brain stimulation has been used to control
Despite intensive research on the underlying causation of AD, therapeutical options are mini- symptoms. In deep brain stimulation, electrodes are implanted to stimulate certain
mal. Acetylcholinesterase inhibitors are often prescribed to improve symptoms related to the brain areas continuously. Up until about 2005, the main target for electrode placement
degeneration of cholinergic neurons. This helps that even small amounts of neurotransmitters was the subthalamic nucleus which lies between the thalamus and hypothalamus, but
can still have an effect. more recently, the adjacent zona incerta has emerged as a much more suitable target.

Parkinsonism syndromes

Parkinsonism refers to a group of motor system diseases in which the cardinal symptoms are Amyotrophic lateral sclerosis (ALS)
tremor, rigor, akinesia, and postural instability due to a lack of dopamine.
Amyotrophic lateral sclerosis (ALS) is also called motor neuron disease. It is a rapidly progres-
sive neurodegenerative disease, first affecting mainly the motor neurons of the spinal cord and
brain stem but which may later affect the motor cortex and other cortical areas. Most patients
usually die within three years of diagnosis because of a paralysis of the respiratory and swal-
lowing muscles.
The disease commonly begins in middle age, and men are affected more often than women. The
underlying cause is unknown, but there is a genetic link in 5-10% of the cases.
There is no curative therapy, but numerous symptomatic treatment options can prolong survival
and improve quality of life.

Front and side views of a man portrayed to be suffering from Parkinson's disease; William
Richard Gowers (1886).

Parkinson's disease (PD)

Parkinson's disease (PD) is a motor system disease that mainly occurs in older adults, affecting
about 1% of individuals older than 60. Although the underlying cause of PD is unknown in the
majority of cases, the disease features a loss of the dopaminergic neurons in the substantia
nigra. The substantia nigra sends dopaminergic axons to the forebrain, mainly to the striatum
(caudate and putamen). In PD, most of the dopamine cells of the substantia nigra die, disrupting
its normal role in posture and movement. The main symptoms are tremor in the hands, a
shuffling walk, and muscular rigidity, making it difficult for the person to initiate a movement.
There is no paralysis, but the rigidity in many muscles makes it hard to carry out any voluntary
movement except very slowly. Because of this, the patient may appear to be emotionless and
apathetic.
Some cases of PD are accompanied by cortical degeneration, which may lead to dementia.
For many years, the main treatment of PD has been the administration of a dopamine precursor
to increase the production of dopamine in the remaining substantia nigra neurons. The chemical
precursor to dopamine is called L-dihydroxyphenylalanine (L-DOPA). This treatment can re-
duce the severity of symptoms in many cases, but it becomes less effective after some years
because too many neurons have died to make effective use of the L-DOPA.

18 19
 Stroke
A stroke is an acute disturbance of the brain's blood supply or parts of it. Due to this interrup-
tion, the neurons can no longer be supplied with oxygen and glucose and die as a result.

The term 'stroke' refers to an event in which a person is suddenly struck down by some-
thing that happens in their brain.

The occlusion of a blood vessel usually causes a stroke (ischemic stroke). Nevertheless, rupture
of blood vessels is also a possible cause (hemorrhage). The main risk factors for stroke are high
blood pressure, diabetes mellitus, heart conditions, smoking, and being male.
Depending on which artery (and therefore which brain region) is affected, a stroke might result
in paralysis, loss of touch sensation, loss of the ability to speak, or all of these. Characteristic is
the sudden onset of symptoms. Because each cerebral hemisphere controls muscles on and re-
ceives input from the opposite side of the body, the symptoms usually affect the opposite body
side as the stroke. The inability to speak (aphasia) is often seen when the speech-dominant
hemisphere (usually the left) is affected. In some cases of stroke, the damage may be very loc-
alized (such as paralysis of the leg muscles alone). In more severe cases, like massive arterial
bleeding, the damage may involve most of one cerebral hemisphere. In these critical cases, the
brain swelling may press the hindbrain respiratory centers against the skull, resulting in loss of
breathing and death.
One area of the cerebral hemisphere that is particularly sensitive to arterial damage is the inter-
nal capsule. The internal capsule is the great fiber sheet that connects the cerebral cortex with
the rest of the brain and spinal cord. Even relatively minor damage to this bundle can be cata-
strophic, in the same way as cutting a central telephone cable can affect a whole suburb.
The most important diagnostic step is to quickly distinguish between a stroke due to artery
blockage or bleeding. CT is usually used for this since it is fast. In the case of an ischaemic
stroke, reopening the blockage can be done by anticoagulants or mechanically.

To save as many neurons as possible, the reopening of the arteries must happen as
quickly as possible. This is why the following saying circulates among neurologists and
emergency physicians: "Time is brain!"

Anteroposterior (A and C) and lateral (B and C) images from a left internal carotid artery
angiogram obtained during the early (A and B) and delayed angiographic phases (C and D)
in a patient with acute ischemic stroke due to occlusion at the middle cerebral artery (arrow);
Gregory A. Christoforidis et al. AJNR Am J Neuroradiol [Link]-1797.

20 21
 Epilepsy Trauma
Epilepsy is a chronic brain disorder characterized by repeated epileptic seizures - convulsions Spinal cord damage
or fits. Physiologically, the cerebral cortex maintains a close balance between excitation and Spinal cord damage is most commonly caused by trauma (car accidents or falls). Nonetheless,
inhibition. When this balance fails, it can result in hyperexcitation, causing epilepsy. One over- it can also result from infections, insufficient blood flow, or tumors.
reactive region can stimulate others and cause storms of electrical activity to spread over the In the acute phase after severe injury, there may be a complete loss of all functions related to
whole cerebral cortex. Since the regulatory mechanisms for balancing excitation and inhibition the affected area. This is called spinal shock.
are complex, the causes of epilepsy are challenging to discern in many cases. In some cases, an Spinal cord injury in the neck region above C5 can cause respiratory paralysis and death. Spinal
evident focal cause, such as a tumor or injury, can be detected and treated with surgery. How- cord injury at lower cervical levels can result in tetraplegia (paralysis of all limbs). Lesions
ever, in most cases, people with epilepsy are treated with a combination of drugs that alter the below T1 can lead to paraplegia, affecting only the lower extremities. Spinal cord injuries com-
actions of excitatory or inhibitory neurotransmitters. monly result in paralysis of the same and loss of touch sensation and bowel and bladder control
Unfortunately, these medications affect the entire cortex, so side effects are very common and of the opposite body side. The vertebral damage can be assessed with an X-ray, CT scan, or
usually very frustrating. Often a long search has to be done to find a treatment balancing the MRI. For a comprehensive assessment of the spinal cord, MRI is usually used. An electromyo-
maximum benefits with minimal side effects. gram can be used to monitor muscle damage and eventually recovery.
The most important diagnostic tool for epilepsy is the EEG. The most striking form of epilepsy
is a generalized seizure. The person becomes unconscious and suffers violent tonic-clonic mus- Traumatic brain injury (TBI)
cle spasms. This type of seizure was traditionally called 'grand mal epilepsy. Traumatic brain injury is an injury to the skull with consecutive dysfunction and/or structural
damage to the brain. It can follow a blow or severe jolt to the head and can result in permanent
Temporal lobe epilepsy (TLE) is a particular form of epilepsy characterized by abnor- or temporary damage to the brain. Typical causes are falls, motor vehicle collisions, and vio-
mal behavior. TLE can be triggered by scarring from damage to the medial side of the lence. Brain trauma is one of the most common causes of death in patients under 40.
temporal lobe. These injuries can occur during a difficult birth when pressure on the During the impact, sudden acceleration and deceleration can smash the brain against the inside
cerebrum pushes the tip of the temporal lobe against a ridge of dura mater and causes of the skull, damaging the areas in contact. The movements can lead to local overstretching and
loss of blood supply and damage. Later in life, these areas of scar tissue may trigger tearing of nerve fibers. Additionally, blood vessels can disrupt, causing bleeding within the
electrical disturbances, which spread through the temporal lobe. Because aggressive brain.
behavior is sometimes a symptom of TLE attacks, many of the sufferers were sent to Immediately after trauma, the person may appear confused, may lose consciousness, or may
prison or psychiatric hospitals in the past. During the 1960s, it was recognized that this have blurred vision, leading to a diagnosis of concussion. In up to 90% of the cases, such post-
syndrome was simply a form of epilepsy, which can be successfully treated with anti- traumatic symptoms disappear within the next two weeks. Immobilization is normally not re-
epileptic drugs. TLE mainly affects structures on the medial side of the temporal lobe, quired, but in cases of concern, consciousness and the pupillary reflex should be checked during
including the hippocampus, uncus, and the amygdala. The study of patients with TLE the first 24 hours. If a headache occurs, it can be treated with pain killers.
may give us clues about the functions of these complex areas within the temporal lobe. In some cases, brain swelling after head injury leads to compression of brain areas that were not
For example, patients frequently experience abnormal smell sensations when having a damaged in the initial impact. This swelling can happen immediately or anytime up to 5 days
temporal lobe seizure, which we can reasonably attribute to the uncus. The uncus is the after the injury.
site of the primary olfactory cortex. Disturbances of memory function have been attrib- CT scans effectively diagnose skull fractures, and MRI can reveal details of cerebral contusion,
uted to abnormal function of the hippocampus, and aggressive symptoms have been at- hemorrhage, and hematoma.
tributed to alteration of function of the amygdala. During the first stage of a TLE
seizure, the person may experience an aura of olfactory hallucinations, feelings of déjà
vu or jamais vu, feelings of fear or terror, or feelings of depersonalization. As the seizure
spreads out to affect a wider temporal lobe area, the person may lose consciousness or
may continue to move in a dream-like state. They may perform abnormal repetitive
movements such as lip-smacking, chewing, tooth-grinding, or aggressive actions.

22 23
 Genetic Conditions Huntington's disease
Huntington's disease (also known as Huntington's chorea) is a rare autosomal dominant genetic
Down syndrome disease with the classic triad of symptoms: movement disorders, cognitive disorders, and psy-
Trisomy 21, also known as Down syndrome, is the most common chromosomal disorder in chiatric abnormalities.
newborns (about two-thirds of all cases) and the most common cause of mental retardation in The cause of the disease is a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene.
children. In this disorder, parts of or the entire chromosome 21 are present in a third copy. The mutated gene product has a toxic effect leading to brain atrophy, particularly affecting
The disease is associated with characteristic facial features, a delay in cognitive ability, and Gaba-ergic nerve cells in the basal ganglia; above all, medium-spiny neurons in the corpus
physical growth. As adults, subjects with trisomy 21 usually have the abilities of an 8-9 year striatum are damaged.
old child. Besides intellectual disabilities, Trisomie 21 carries an increased risk of other disor- Symptoms usually appear between the ages of 35 and 50, correlating inversely with the number
ders like a congenital heart defect or epilepsy. of repeats (the more CAG repeats, the earlier the onset). The earliest symptoms are subtle
Because it is almost always caused by mistake during meiosis, it is practically always not inher- changes in mood and mental abilities, followed by a lack of coordination and unsteady gait. As
ited. It is possible to identify the disorder prenatally (before birth). A definitive diagnosis fol- the disease progresses, choreatic movements like fast, involuntary spasms of the face and the
lows a chromosome analysis. distal parts of the extremities become more evident. Later symptoms include involuntary hyper-
There is no cure, but family support, education, and social integration can significantly improve kinesia, psychotic symptoms, and eventually dementia. Physical abilities gradually worsen un-
the life quality of those with Down syndrome. til the patient can no longer talk and walk. Once diagnosed, patients live ten to twenty more
years, on average. The definitive diagnosis is made after detecting the trinucleotide repeat ex-
pansion in the HTT gene, e.g., PCR.
Fragile X syndrome Currently, there is no causal therapy available. However, certain medications can reduce hyper-
Fragile X syndrome, sometimes called Martin-Bell syndrome, is the most common mono- kinesis, or antidepressants can alleviate the psychiatric symptoms.
genetic cause of intellectual disability and the second most common cause of congenital mental
retardation after trisomy 21. It is estimated to underlie at least 6% of all with intellectual dis-
abilities. Duchenne muscular dystrophy (DMD)
Duchenne type muscular dystrophy is the most common disease in the group of progressive
It is a genetic disorder typically due to a higher number of repetitions of a CGG-triplet muscular dystrophies, characterized by primary muscle fiber degeneration. Muscle cell death in
within the fragile X mental retardation 1 (FMR1) gene (trinucleotide repeat expansion). DMD is caused by a gene defect on the X chromosome in the dystrophin gene, making the
The insufficient production of the protein FMRP leads to an increased glutamate recep- muscles vulnerable to oxidative and mechanical stress. The degenerated muscle fibers are
tor 5 (mGluR5) synthesis, resulting in impaired synaptic plasticity. sometimes replaced by adipose or connective tissue so that swelling occurs, and the muscle
atrophy is not obvious. This process is called pseudohypertrophy.
Besides suffering from intellectual and memory disabilities, the affected children typically have The typical onset is between the first and the fifth year of life, leading to a rapid paresis and
an elongated face and protruding ears. Diagnosis follows the proof of a trinucleotide repeat muscle atrophy beginning from the pelvic girdle, progressing to the shoulders. Until the age of
expansion in the FMR1 gene by human genetic methods, like PCR. Currently, there are no 13, the patients are unable to walk alone, becoming paralyzed from the neck down. Due to car-
causal therapeutic options. diac or pulmonary insufficiencies, the patients usually die within 20 years.
DMD affects about one in 5000 males at birth. Women are usually the source of inheritance
because they have two X chromosomes. A muscle biopsy usually makes the diagnosis.
Rett syndrome No treatment exists yet for Duchenne muscular dystrophy. Nonetheless, medical and supportive
Rett syndrome is one of the most common genetic causes of mental retardation in girls. treatments can reduce morbidity, improve quality of life and prolong lifespan.
It is an X-chromosomal dominant disease that affects females almost exclusively. Males with
the condition either die before birth or do not live longer than two years.
Tourette's syndrome
The Rett syndrome is strongly associated with various mutations in the MECP2 gene Tourette's syndrome (originally called Gilles-de-la-Tourette syndrome) is a common neurolog-
found on the X chromosome. The physiological gene product binds to methylated DNA ical disorder with unknown etiology. As a higher familial incidence is observed, a genetic link
and is involved in regulating thousands of genes. The exact molecular effects depend on is presumed, but the involvement of a specific gene has not yet been proven.
the specific mutation but usually include changes in synaptic plasticity, neurotransmit- The syndrome is characterized by multiple motor and vocal tics, i.e., repetitive actions that can
ter imbalances, and cortical hyperexcitability. only be suppressed to a certain degree. They may affect the face, neck, and shoulder or may
cause vocal automatisms, including echolalia (obsessive repetition) or coprolalia (shouting ob-
The infant is commonly normal at birth but develops symptoms between 6 and 18 months of scene words). The severity of tics may wax and wane and usually persist for more than one year
age. Cognitive skills, especially speaking or walking, begin to stagnate or regress. Patients of- after the onset.
ten have small hands and feet, deceleration of the rate of head growth, and repetitive, stereo- Men are more commonly affected than women. The condition is normally diagnosed during
typed hand movements. Many patients have seizures, have no verbal skills, and cannot walk. early childhood, but patients experience peak tic severity before 18 years of age. The condition
Scoliosis and constipation are prevalent. Despite severe disabilities, affected women can live often improves after this time. The syndrome is often associated with an attention-deficit-hyper-
up to 40 years of age. activity-disorder (ADHD) or other psychiatric disorders, like obsessive-compulsive disorder.
The diagnosis is made after clinical presentation and detection of a genetic mutation. EEG and Treatment is based on medication, behavioral therapy, and social skills training.
motor abnormalities can be detected from symptom onset. Currently, there is no available treat- Diseases of the peripheral nervous system
ment.

24 25
 Myasthenia gravis Non-genetic developmental disorders
Myasthenia gravis is an autoimmune disease in which mistakenly produced antibodies block
and destroy postsynaptic acetylcholine receptors (nAChRs). This disrupts the neuromuscular Certain developmental insults can cause devastating damage to the developing brain and spinal
transmission at the motor endplate, resulting in exercise-dependent muscle weakness. The mus- cord. These include vitamin deficiency (neural tube defect), alcohol (fetal alcohol syndrome),
cle weakness worsens with activity and improves with rest. In most cases, myasthenia gravis is iodine deficiency, and infections (rubella). Each one of these can cause widespread damage to
associated with a pathological change in the thymus. The thymus is an organ of the immune the fetal brain. It is possible that viral infections may also cause cerebral palsy during preg-
system where T cells mature. The changes there probably lead to the development of T helper nancy.
cells against the nAChRs, which can initiate antibody production in B cells.
The eye, face, and swallowing apparatus muscles are most commonly affected. Double vision, Neural tube defect (NTD)
drooping eyelids, speech, and walking problems may occur. Neural tube defects are the most common malformations of the brain and spinal cord. Neural
EMG fatigue tests can be used to confirm the diagnosis. tube defect results from a disruption of the very early development of the neural tube, with
Treatment is based on the use of immunosuppressants and cholinesterase inhibitors, and incomplete closure at the rostral and caudal ends. The most common result of an incomplete
thymectomy (removal of the thymus) is sometimes effective. Spontaneous remissions some- closure is seen in the caudal part of the spinal cord, where it is called spina bifida. Depending
times occur. on how severe the closure defect is, one distinguishes between different forms (see figure).
Usually, the damage to the spinal cord results in paralysis of the lower limb and loss of control
of the bladder and bowel. Cases affecting the rostral neural tube can result in malformation of
Peripheral neuropathy the brain ventricles, resulting in hydrocephalus.
Peripheral neuropathy is a disease of the peripheral nervous system (PNS) with systemic causes
(e.g., toxic, infectious, or metabolic factors). Symptoms often include pain, sensory loss, pare- Some families have a genetic predisposition to NTD. However, the most critical factor has been
sis, and autonomic dysfunction, as motor, sensory and autonomic nerves can be affected. The shown to be a lack of vitamin folate. For this reason, all women who might possibly become
disease usually affects the longest nerves first, so the most common initial sign is numbness in pregnant should make sure that their folate intake is high – either by eating leafy vegetables and
the toes. other folate-rich foods or by taking folate vitamin tablets as a supplement. In many countries,
In Europe, diabetes mellitus (diabetic neuropathy) and alcohol dependence are the most com- bread flour and breakfast cereals are enriched with folate to ensure that the whole population
mon causes; in tropical and subtropical regions, it is malnutrition and leprosy. has adequate folate levels.
In addition to good medical history, EMG can be used for diagnostics. Therapeutically, the
causing disease must be treated.

Spina bifida aparta (Myelomeningocele): at the point where the spinal cord is not fused,
the spinal cord and the meninges protrude, forming a sac enclosing all spinal elements;
Spina bifida cystica (Meningocele): the meninges herniate between the vertebrae creating
a cyst;
Spina bifida occulta: the neural tube is closed correctly, but the vertebral arches are not
merged.

Congenital rubella
During the first three months of pregnancy, rubella infection (German measles) can cause sig-
nificant brain abnormalities, including deafness and blindness.

26 27
 Iodine deficiency Psychiatric disorders and disorders of behavior
Iodine deficiency during fetal development is probably the most important cause of mental re-
tardation worldwide. It affects millions of children in mountainous areas of Asia and South-East
Asia, where iodine has been leeched out of the soil. Iodine deficiency results in hypothyroidism Many neurological diseases are reasonably well understood in terms of the specific brain re-
that permanently damages the developing brain. The problem of iodine deficiency is easily gions that are affected. However, in the case of mental illness, the situation is much less clear.
remedied with the supply of iodine supplements in salt and oil, but this is not always easy to While the treatment of mental illness has improved a great deal in the past 50 years, there has
achieve because of logistic impediments. not been much progress in understanding the underlying pathological changes that cause these
conditions. Mental illness affects about one-third of all people at some point in their life.
Infantile cerebral palsy (CP)
Infantile cerebral palsy refers to a group of movement disorders in early childhood. The main
cause appears to be damage to the striatum and pallidum ('basal ganglia') in the last three Attention deficit hyperactivity disorder (ADHD)
months of pregnancy, possibly from an infectious agent. Because the cerebral cortex develops Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder character-
after birth, it usually escapes damage in cerebral palsy cases. ized by signs of inattention, hyperactivity, and impulsivity appearing outside our social norms.
Four subtypes of CP are distinguished: These symptoms must occur over at least six months and have to be observed in different envi-
ronments (typically school and home) for a diagnosis.
- spastic (most common, characterized by increased muscle tone); While the condition is usually diagnosed in children, it can persist into adult life. There are
- ataxic (lack of coordination of movement); considerably more boys than girls affected. The incidence of ADHD in children is estimated to
- athetoid (involuntary, slow movements of the extremities); be around 5% worldwide. For many years there has been controversy about the diagnosis and
- mixed. treatment of ADHD. However, there is now an international consensus that stimulant medica-
tion (methylphenidate) effectively reduces symptoms and makes it possible for the individual
There is no cure for cerebral palsy. The goal of treatment is to help the person be as independent to live a normal life.
as possible.

Autism spectrum disorder (ASD)

The term autism spectrum disorder refers to a range of developmental conditions, including
problems with social communication and unusual repetitive behavior. Although autism is one
of the best-known child psychiatric terms, the disorder is rare overall. Classical (early-child-
hood) Autism or Asperger syndrome are examples of this group of diseases. The symptoms
differ depending on which subtype the patient is affected by. As a rule, however, these are ac-
companied by disturbed social behavior and an inability to empathize. The classic variant is
usually accompanied by cognitive impairment, but Asperger's syndrome is not necessarily. In-
sular gifts, as seen in films, are extremely rare and a subtype of Asperger's syndrome. The cause
is still unknown. Several genes are associated with an increased risk of the disease.

A Lancet study from 1998 by Andrew Wakefield claimed to have shown that vaccination
against mumps, measles, and rubella was involved in the development of autism. Be-
cause Andrew Wakefield received dubious payments in the run-up to publication and
misrepresented results, the study was officially retracted by the Lancet in 2010. Andrew
Wakefield was banned from practicing in England, where he had previously been a doc-
tor. Although enormous resources were devoted to it, no subsequent study could repro-
duce his results.

28 29
 Affective disorders Schizophrenia
Schizophrenia is a psychotic illness characterized by abnormalities in the perception or expres-
Affective disorders are a group of psychological disorders, all featuring a clinically significant sion of reality. It is a severe and frequently chronic illness that often first appears in late adoles-
change in mood. They can be divided according to their so-called polarity and the time course. cence. Schizophrenia affects approximately 1% of the population and is the single largest cause
The polarity indicates the direction in which the mood change takes effect. Examples are de- of admissions to mental hospitals in western countries. It also accounts for the largest propor-
pression (pathological decline in the mood) or mania (pathological increase in the mood). If the tion of permanent residents in such institutions because it often results in severe levels of
change is only in one direction, it is called a unipolar disorder. If the mood is sometimes ele- impairment. Depending on which symptoms predominate, different subtypes can be classified.
vated and sometimes depressed, we speak of a bipolar disorder. The most common affective The most common is paranoid schizophrenia, mainly characterized by (auditory) hallucinations
disorder is unipolar depression, i.e., a disorder characterized by a depressed mood without and delusions. However, schizophrenia can also be accompanied by experiencing flattened af-
phases of euphoria or similar. fect (decreased emotional responsiveness), apathy, and withdrawal from society.
It is currently suspected that the disease is multifactorial, i.e., that it is caused by a combination
Unipolar depression of genetic and environmental factors, such as infections during pregnancy or high-dose
Depression is a state of low mood and lack of interest in everyday activity. Symptoms may cannabis consumption in childhood and adolescence.
include changes in appetite or sleep patterns, loss of energy, decreased libido, irritability, feel- There has been a great deal of research into the particular brain regions and neurotransmitters
ings of worthlessness, and thoughts of suicide. involved in the disease, but we still do not have a clear picture of the underlying pathology.
There is no single cause of depression, but it is associated with many factors, including family However, drug treatment is moderately effective in many cases. Some of these drugs work by
history, trauma, and stress. Neurotransmitter imbalance is thought to underly many cases of influencing the level of neurotransmitters such as serotonin and dopamine.
depression. Despite numerous studies, the exact neurotransmitters involved in depression are
still unknown. Current pharmacological treatment primarily aims to increase the activity of the
neurotransmitter serotonin in the brain. This is achieved either by decreasing uptake (selective Obsessive-compulsive disorder (OCD)
serotonin reuptake inhibitors – SSRIs) or increasing production. Several different drugs are cur- OCD is a neurotic disorder characterized by obsessions or compulsions, or both. Obsessions are
rently prescribed, with varying efficacies and side-effect profiles. The real value of pharmaco- recurring, intrusive thoughts that invade a person's consciousness and produce anxiety. Com-
logical treatment in cases of mild-to-moderate depression has been questioned, and there is a mon obsessions include worries about contamination from germs, thoughts about committing
great deal of current interest in the use of cognitive-behavioral therapy. violent acts, and constant doubt. Compulsions are repetitive behaviors or thoughts triggered by
Significant depression affects a third of the population at some point in their lifetime. The anxiety. Compulsions accompany obsessions in about 80% of cases and are usually simple acts
episodes generally begin in early adulthood. Women are recorded as being more commonly such as washing, checking, or counting. OCD affects between 2% and 3% of the general popu-
affected, but this may just represent a greater willingness of females to seek help. lation and occurs equally common in males and females. The precise areas of brain dysfunction
The diagnosis is mainly due to the clinical presentation. Sometimes a higher rate of REM sleep have not yet been found. Neurobiologically, it is assumed that there is a dysbalance in the reg-
can be observed. ulatory loop between the frontal brain, limbic system, and basal ganglia.
Selective serotonin reuptake inhibitors (which are used in the treatment of depression) have
Bipolar affective disorder been found to markedly reduce the symptoms of OCD in about 60% of patients. The success of
Bipolar affective disorder is defined by the presence of one or more major episodes of abnor- this drug has led to the suspicion that OCD could arise from the disruptions of neurotransmitter
mally elevated mood. These elevated states are clinically referred to as mania. It is common for systems.
individuals who experience manic episodes to experience depressive episodes as well, hence
the name 'manic depression. Because of these changes in both directions of mood distortions,
it is called a bipolar affective disorder. The cause is still unknown, but there is a tendency for
cases to cluster in families.
Some pharmacological and psychotherapeutic techniques have been applied to treat bipolar af-
fective disorders. However, the mainstays of treatment are mood stabilizers such as lithium
chloride (which affects intracellular calcium handling) or sodium valproate (which affects neu-
rotransmission).
It is crucial to distinguish between depression and bipolar disorder carefully. Medications for
(unipolar) depression can quickly move a misdiagnosed bipolar disorder from the depressive
phase to a very strong manic phase.

30 31
 Substance abuse
Substance abuse can be defined as the abnormal use of a substance that leads to impairment of
the physical, social, or occupational aspects of one's life. Substance abuse often leads to depen-
dence or tolerance. Dependence is the physical need to use a drug to maintain the effects pro-
voked by its intake. Dependent users experience withdrawal symptoms when they are unable
to maintain consumption of the drug. Addicted users crave the drug even if they know it dam-
ages their work, health, and family. Drugs at higher risk of dependence are cocaine, heroin, and
nicotine; drugs with lower risk are alcohol, cannabis, ecstasy, and amphetamine. During the
development of dependence, the body and brain slowly adapt to the repeated presence of the
drug, the lack of which then causes unpleasant feelings.
Tolerance to a drug is experienced when a specific dose, taken previously to generate a certain
physical state, is no longer effective, and higher doses are required. With regular use, tolerance
may develop. Higher doses or more frequent use are needed to produce the same level of plea-
sure and relief from withdrawal.
The main groups of substances of abuse are:

- stimulants: including caffeine, amphetamines, cocaine, and nicotine. The intake of stim-
ulants leads to heightened alertness, agitation, improved mood, increased heart rate, re-
duced appetite, and increased aggressive behaviors.
- sedatives: including alcohol, barbiturates, and benzodiazepine tranquilizers. They pro-
duce sedation, sleep, behavioral disinhibition, and a decrease in anxiety.
- opiates: including heroin, oxycodone, and morphine.
- hallucinogens: including LSD, phencyclidine, bromocriptine, and cannabinoids.

In most cases, addictive substances can generate feelings of pleasure by acting on the dopamine
reward pathway from the ventral tegmental area to the accumbens nucleus.
The primary goal of therapy is abstinence; if this is not possible, a reduction in consumption is
sought.

Wernicke-Korsakoff Syndrome (WKS)

Both Wernicke's encephalopathy and Korsakoff's syndrome are now considered as clinical vari- Surface rendered brains (top) and rendered ventricular system (bottom, green) of
ations of the same disorder. Wernicke's encephalopathy refers to the acute form, and Kor- a 59-year-old healthy man (A and C) and a 53-year-old man with WKS (B and D).
sakoff's syndrome is the chronic condition. The underlying cause is a lack of thiamine (Vitamin Note the shrinking of the cortical gyri and widening of the sulci (B) and expansion
B1), usually due to malnutrition as a consequence of alcohol abuse. Because of the high-calorie of the ventricles (D) of the WKS compared with the control (A and C).; Sullivan,
content of alcohol, severe alcoholics do not need much more food to reach their daily caloric Pfefferbaum, Neuroimaging of the Wernicke–Korsakoff Syndrome, Alcohol and
needs and thus fail to meet their vitamin needs. The absence of thiamine interrupts carbohydrate Alcoholism, 44;2-2009:155–165.
metabolism, leading to various neuronal and vascular damage, including demyelination, glial
and neuronal cell death, and small hemorrhages.
The most prominent symptom of WKS is the failure to form new memories. Patients may recall
events from the distant past but cannot recall what they had for breakfast. A characteristic fea-
ture of the memory loss is the invention of information to fill memory gaps – called confabula-
tion.
Laboratory diagnostics can detect a vitamin B1 deficiency. A corpora mammillaria's atrophy
can usually be diagnosed with MRI, explaining the inability to form new memories.
It can be treated by high-doses vitamin B1 supplementation. Patients with acute Wernicke-en-
cephalopathy usually continue to have a chronic Korsakoff-syndrome.
The prognosis is poor, and about 20% die some weeks after diagnosis.

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