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Box
12.6
While there are many effective anti-bacterial agents that
target specific bacterial processes, it is much more challenging to develop drugs that will inhibit viruses without
harming the host, because viruses survive by utilizing many
of the normal metabolic processes of the host eukaryotic
cell. Acyclovir exploits the need of the virus to produce
new viral DNA, which it does using a viral DNA polymerase
that is different from the mammalian enzyme. Acyclovir is
a guanine derivative that is converted to the monophosphate by thymidine kinase. This occurs most rapidly in the
virus- infected cells, as the viral kinase is much more effective than the host enzyme. The host cell kinases then convert the monophosphate to acyclovir triphosphate. This
compound inhibits the DNA polymerases, thus blocking
DNA synthesis. The drug has a poor availability after oral
administration, and intravenous administration is required
in order to reach high concentrations in target tissues.
Acyclovir is effective in encephalitis caused by the herpes
simplex virus, herpes zoster virus and the varicella zoster
virus. It has no activity against enteroviruses.
cine, and Gertrude Elion, the pharmacologist involved in
its discovery, was awarded the Nobel Prize. The drug was
approved in 1981, and its importance is reflected in its
inclusion in the World Health Organization List of Essential
Medicines, which contains the safest and most effective
medicines needed in health systems.
Acyclovir and anti-viral therapy
Acyclovir is one of the major discoveries in modern medi-
As mentioned previously, infection with the SARSCoV- 2 virus, which has caused the COVID- 19 pandemic,
has shown that this corona virus can trigger long- term
neurological consequences: more than 50% of patients
can still have neurological symptoms at 3 months after
disease onset. The neurological manifestations of the
disease are either a consequence of the virus itself or the
immune response to the virus. The initial presentation of
the infection includes as cardinal symptoms: fever, headaches, loss of smell and taste, and myalgia. Subsequent
systemic complications, such as coagulopathy, the
intense proinflammatory cytokine storm and multiple
organ dysfunction, also contribute to neuronal damage. Finally, the long stay in intensive care of severely ill
patients, under invasive ventilation, leads to the usual
complications seen in critical care units, such as confusion and weakness. There is prolonged cognitive impairment and also a significant level of persistent anxiety and
depression.
Cerebral abscesses
Brain abscesses may be a consequence of trauma or surgical interventions, or can develop after spread of an
infection in adjacent structures such as the middle ear
12
INFECTION IN THE CENTRAL NERVOUS SYSTEM
Fig. 12.11 Enhanced axial computed tomography scan showing a
right frontal abscess. (From Forbes CD, Jackson WF. (2002) Colour
atlas and text of clinical medicine, third ed. Mosby International Ltd.)
or certain paranasal sinuses, or systemic infection. A
range of bacteria, fungi and protozoa (e.g. Streptococcus,
Staphylococcus, Bacteroides and Proteus) can cause focal
areas of infection, leading to abscesses in the brain and
spinal cord. As the infection could reach the brain from
infectious sites elsewhere in the body (e.g. endocarditis
or pulmonary infections), or from a contiguous location
(dental, sinus or ear infections), identification and treatment of the primary source of the infection should form
part of the overall treatment.
The majority of cases occur between the third and
fifth decade of life. The patient usually has a combination of progressive headache, focal neurological signs,
altered mental status, seizures and fever. The investigation of choice is a CT or magnetic resonance imaging
scan. Lumbar puncture should not be performed because
of the risk of herniation, but could be considered when
there is evidence of a limited mass effect. CSF analysis
may reveal pleocytosis (high number of lymphocytes),
high levels of protein and decreased glucose. A few
weeks after infection, an abscess becomes encapsulated
and can be clearly seen (Fig. 12.11). The central area of
the abscess will have a low- density appearance, there
will be prominent ring enhancement of the lesion, which
appears bright, and there will be an oedematous surrounding area of low density. Because of the mass effect
of the abscess, there may also be a shift in the midline
and compression of the ventricles. Aerobic organisms
269THE NERVOUS SYSTEM
12
Viral maturation
(e.g. streptococci), more so than anaerobic organisms, are
involved in abscesses.
Treatment in most cases involves surgical intervention. This involves excision or CT- guided aspiration. The
latter is also preferred when there are multiple abscesses
requiring drainage. Abscess recurrence after aspiration
is not uncommon. Antibiotics are required (e.g. cephalosporins with added metronidazole) and also treatment
for cerebral oedema (e.g. mannitol or hypertonic saline)
if there is a risk of herniation.
Brain infections in the immunocompromised patient
An increasing number of patients have compromised
immune systems. This may result from treatment with
cytotoxic drugs or immunosuppressant steroids, or longterm severe general illness. In these patients, there is an
increased risk of infection with bacteria and fungi. One
of the largest groups of immunocompromised patients
INFECTION IN THE CENTRAL NERVOUS SYSTEM
are those with immune deficiency due to infection with
the human immunodeficiency virus (HIV).
Infection with HIV can cause neurological disease at
any stage, but most problems occur when patients have
progressed to acquired immune deficiency syndrome
(AIDS), with significant impairment of their immune
systems. A few weeks or months after HIV infection,
a patient can develop meningoencephalitis, when the
infection involves both the meninges and the brain
parenchyma. Like other immunocompromised patients,
HIV patients are prone to a wide range of infections,
both with organisms that are normally pathogenic but
cause more severe infections in these patients, and with
organisms that are not normally pathogenic (i.e. opportunistic infections). HIV infection and AIDS remain leading causes of years of life lost to disability.
HIV can infect and replicate in the microglial cells of
the brain, which can act as a reservoir of infection. The
active replication of HIV in the brain leads to increased
permeability of the BBB, allowing easier access to infecting organisms and, as a consequence, 80% of HIV- positive
patients develop neurological disease. Any treatment aiming to eradicate HIV must also be able to eradicate the
virus present in the brain, because the movement of macrophages across the BBB could result in re- infection.
The neurological condition specific to HIV infection is HIV- associated dementia. This slowly developing dementia is thought to be due to a direct effect of
HIV infection of the brain (see Chapter 14 for more
details). Anti-retroviral therapy has evolved significantly in recent decades and suppresses viral replication,
decreases viral load, reconstructs the immune system,
reduces the risk of transmission, improves the quality of
life and prolongs life expectancy. Therapy consists of various classes of drugs: (1) nucleoside reverse transcriptase
inhibitors (NRTI), (2) non-nucleoside reverse transcriptase inhibitors (NNRTI), (3) fusion inhibitors, (4) protease inhibitors, (5) integrase strand transfer inhibitors and
(6) C- C chemokine receptor type 5 (CCR5) inhibitors. The
Docking
Fusion/entry
inhibitors
RTI
NRTI
NNRTI
Double-stranded
DNA
Fig. 12.12 The life cycle of HIV and therapeutic targets. The diagram illustrates the mode of action of major anti-viral strategies. The numbers
indicate the targets and mechanisms. NNRTI, Non-nucleoside reverse transcription inhibitors; NRTI, nucleoside reverse transcription inhibitors; RT,
reverse transcription; RTI, reverse transcription inhibitors. (From Atta M.G. et al, (2019). Clinical Pharmacology in HIV Therapy. Clinical Journal of
the American Society of Nephrology. 14:435-44.
2
RT
+nucleosides
Transcription with
reverse transcriptase
Integrase
inhibitors
1
Single-stranded
RNA
Integration into
host DNA
Integrase
3
4
HIV
Protease
inhibitors
6
Protease
Transcription of
5
mRNA encoding
viral proteins
Mature virus
7
and budding
270 SYSTEMS OF THE BODY
12
first five classes target various steps in the viral life cycle
(shown in Fig. 12.12), whereas the CCR5 inhibitors—
more recently developed drugs—have as a rationale the
role of the CCR5 receptor in the process by which HIV
enters cells and then spreads. Hence, antagonists of this
receptor are entry inhibitors. Drugs can be used as monotherapy or in combination, and evidence suggests that
combinatorial treatments are more effective. Present recommendations favour the use of triple combination therapy as first- line treatment, for example, two NRTIs plus
one NNRTI, protease inhibitor, fusion inhibitor or integrase strand transfer inhibitor. Pharmaco- enhancers (e.g.
cobicistat, which inhibits liver microsomal enzymes and
thus enhances the effect of anti-retroviral drugs), can also
be added. Finally, preventive treatment with neutralising
HIV antibodies is also a growing area of interest.
Self- assessment case study
A young woman aged 24 years is admitted to hospital
complaining of severe headache, neck stiffness, fever and
photophobia. On examination, she has no signs of papilloedema, and a lumbar puncture is performed. This
shows clear cerebrospinal fluid (CSF) with an increased
number of lymphocytes, a slightly raised protein level
and a normal CSF glucose level. The woman is admitted
and given acyclovir. However, subsequent analysis of the
CSF shows no evidence of herpes simplex virus infec-
tion. After 4 days, the patient is sent home and, although
she continues to have headaches for a couple of weeks,
she has no other sequelae.
After studying this chapter you should be able to
answer the following questions:
1. What do the presenting symptoms suggest about her
condition?
The presenting symptoms suggest that she is suffering from meningitis. This may be due to many possible
causes but it is very likely that this patient has a viral
meningitis.
2. What is the clinical significance of the lack of
papilloedema?
This suggests that there is a lack of raised intracranial
pressure, therefore carrying out a lumbar puncture was
safe.
3. What do the CSF results indicate?
The CSF results confirm the possibility that this
patient suffers from viral, not bacterial, meningitis.
4. Why was she given acyclovir?
Acyclovir is an efficacious anti-viral drug, which prevents the replication of the virus by blocking DNA synthesis. It was given as a precautionary measure, while
waiting for the results of the exploration of the CSF and
the identification of the virus type.
INFECTION IN THE CENTRAL NERVOUS SYSTEM
271THE NERVOUS SYSTEM
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EPILEPSY
Chapter summary
1. Epilepsy is a generic term for a type of brain disorder characterized
by recurrent unprovoked seizures, which result from abnormalities
in the electrical activity of the brain. Focal seizures generally
involve limited brain areas, and sometimes spread to affect larger
areas. Generalized seizures start in both brain hemispheres and are
associated with a loss of awareness. Status epilepticus is a specific
type of epilepsy characterized by prolonged seizures and is a lifethreatening medical emergency. Epilepsy can be associated with
many co- morbidities and it increases the risk of premature death.
2. The aetiology of epilepsy is diverse: structural, genetic, immune,
infectious or metabolic. In some cases the cause is unknown. Analysis
of the electrical activity of the brain (electroencephalogram) and
structural imaging can help diagnose the epilepsy type and identify
brain areas likely to be the cause of epilepsy.
3. The abnormal activity of the brain leading to emergence of seizures
can involve changes in glutamatergic or GABAergic transmission,
thereby changing the balance excitation/inhibition in the brain,
or can also be a consequence of alterations in ion channels, which
change intrinsically neuronal excitability. Many types of juvenileonset epilepsies are channelopathies, as they are underlied by
specific mutations in ion channels such as the sodium channel.
Mutations in pathways involved in cell growth and development are
also associated with epilepsy.
13
4. The pharmacological treatment of epilepsy is based on the use of
a variety of anticonvulsant drugs. First generation drugs include
phenytoin, carbamazepine, sodium valproate and ethosuximide,
while more recent drugs include lamotrigine, topiramate, tiagabine,
levetiracetam, stiripentol and perampanel. These drugs act through
13
EPILEPSY
Introduction
In adults, once the brain has reached maturation, control
over sensorimotor and autonomic functions is expected,
as well as complete awareness of one’s behaviour and
reactions under various social circumstances. One of
the commonest neurological diseases, epilepsy, often
deprives an individual of this control and can lead to a
dramatic loss of contact with reality, through loss of consciousness. This is illustrated in the case history in Box
13.1. As will be discussed, epilepsy is a major medical
problem that poses a therapeutic challenge, can significantly disrupt the course of normal life and its quality
and may bring social stigma to the sufferer.
General description of epilepsy
Epilepsy is the name given to a heterogeneous group of
conditions characterized by the occurrence of spontaneous, unprovoked seizures. A seizure is a sudden, abnormal, paroxysmal change in the electrical activity of the
brain; it reflects large- scale synchronous discharges of
groups of neurons and can cause changes in behaviour,
movement, mood, sensation and levels of consciousness.
Epilepsy exists in all mammals. It is an ancient disorder
that can be traced back to the first medical records in the
history of humanity. In ancient times, it was considered
a condition due to the control exerted on individuals by
‘evil spirits’. This was associated with significant stigma,
which could culminate in the individual being sacrificed
for the perceived benefit of the community. In the 5th
century BCE Hippocrates clearly stated his belief that
‘the brain is the seat of this disease’. Significant progress
has been made in the neurobiology of epilepsy and its
clinical management, in recent decades, but the stigma
associated with this condition, at least in some societies,
is still significant.
a variety of mechanisms: voltage- dependent ion channel blockers,
ligand- gated ion channel antagonists or allosteric modulators,
or inhibitors of neurotransmitter uptake or neurotransmittermetabolizing enzymes. Approximately one-third of epileptic patients
are treatment- resistant.
5. Non-pharmacological approaches to the management of epilepsy, to
address the issue of treatment- resistance, include surgery (to remove
an identified epileptogenic focus), corpus callosotomy (to abolish the
spread of seizures) and vagus nerve stimulation. A ketogenic dietary
approach based on a high fat/protein to carbohydrate ratio is very
effective in some forms of epilepsy in children.
For a diagnosis of epilepsy there must be evidence that
there have been at least two seizures on separate occasions. The types of seizure that occur in epilepsy are very
varied. They range from generalized seizures, with loss
of consciousness and body muscle spasms (commonly
known as ‘grand mal’), to the much less overwhelming
absence seizure (also known as ‘petit mal’), the only sign
of which is that the person stops what they are doing and
appears to be staring into the distance. Seizures are generally self- limiting phenomena. However, in some cases,
generalized seizures are not self- limiting, and the patient
may have recurrent seizures for 10–20 min, without
regaining consciousness. This is status epilepticus and is a
serious, life- threatening medical emergency.
There are three levels of diagnosis in epilepsy: seizure
type, epilepsy type and epilepsy syndrome. From the
perspective of onset of a seizure, there are focal seizures
(the term used previously was ‘partial seizures’), which
begin focally, in a limited brain area and sometimes
may spread to both hemispheres; generalized seizures,
which involve both hemispheres of the brain from the
onset; and seizures of unknown onset. This leads to several epilepsy categories: focal, focal/generalized, generalized and unknown. Finally, epilepsy syndrome refers
to a cluster of specific seizure features, brain electrical
activity profile and brain imaging changes. An epilepsy
syndrome could include associated psychiatric and cognitive abnormalities, sometimes mental retardation, and
the definition of a syndrome has significant prognosis
and management implications.
Overall, there are still ambiguities even using this system based on several diagnostic levels, and the clinical
presentation is often very complex. This complexity is
reflected in the extended classification, which is regularly reviewed and updated, to incorporate new knowledge and insights. This detailed classification system was
devised by the International League Against Epilepsy
(ILAE). The latest ILAE classification is shown in Fig. 13.1.
274
SYSTEMS OF THE BODY
13
Box
13.1
Gaby is a 22- year- old student who is studying to become a
teacher. She has no previous serious medical history. One
day, as she relaxes with her fellow students after an examination, she feels strange, with butterflies in her stomach
and a sensation of fear and anxiety. She then collapses rigidly onto the floor. She has strong convulsions for about
2 min, during which she knocks against a chair. Her body
then relaxes and, for the next 3 min, she is unarousable.
When she wakes up she is confused and tired, and also
bruised from hitting the chair. She is taken to hospital by
her colleagues, where the doctor tells her she has had a seizure. There is no family history of seizures. She undergoes
a series of tests, including an electroencephalogram (EEG)
and a brain scan. A few weeks later, she has a second seizure at home. Following a consultation with the hospital
specialist, she starts taking sodium valproate. Gaby is also
advised to change her type of contraceptive pill. She is very
concerned about the implications of having this disease for
her career choice as a teacher.
1. What is epilepsy?
2. What does an EEG measure and how is it used in the
3. What are the mechanisms of excitation and inhibition
4. What types of epilepsy are there?
5. How is epilepsy treated?
6. What restrictions are there for patients with epilepsy?
Case history
This case gives rise to the following questions:
diagnosis of epilepsy?
in the brain and how are seizures produced?
The different types of seizure associated with various types of epilepsy are associated with different patterns of muscular activity. Myoclonic seizures involve
either localized or widespread, rapid, irregular jerking
of muscles, while in tonic seizures there is a sudden
rigidity of muscles, either extended or flexed. Clonic
seizures involve the rhythmic jerking of many muscles,
and in tonic–clonic seizures, there is clonic jerking after
initial tonic rigidity. Atonic seizures involve sudden
generalized muscle relaxation.
A presentation of seizures is not uncommon in emergency medicine. Patients presenting with seizures may
have a history of a seizure disorder. If possible, obtaining a history will establish if there is any alcohol or substance abuse or recent traumatic injuries. The individual
may carry a card identifying them as an epilepsy patient.
The first steps in emergency management are: protect the
person against injury by cushioning their head, remove
glasses, keep them comfortable and do not restrain them,
and make sure there are no harmful objects nearby; when
the seizure stops, place the individual in the recovery
position until they recover consciousness, and request
hospital admission.
Epidemiology and causes of epilepsy
Epilepsy is a common neurological disorder. The prevalence of the various types is 0.5%–1% worldwide and
the lifetime incidence is 1%–3%. Epilepsy is the third
biggest contributor to the global burden of neurological
disease. A majority of epileptic patients live in resourcelimited, developing countries, which has implications for
EPILEPSY
Focal onset
Aware
Impaired awareness
Motor onset
Automatisms
Atonic
Clonic
Epileptic spasms
Hyperkinetic
Myoclonic
Tonic
Non-motor (Absence)
Autonomic
Behavior arrest
Cognitive
Emotional
Sensory
Focal to bilateral tonic-clonic
Fig. 13.1 Classification of seizure types by the ILAE (2017 version).
Generalized onset Unknown onset
Motor
Tonic-clonic
Clonic
Tonic
Myoclonic
Myoclonic-tonic-clonic
Myoclonic-atonic
Atonic
Epileptic spasms
Non-motor (Absence)
Typical
Atypical
Myoclonic
Eyelid Myoclonia
Motor
Tonic-clonic
Epileptic spasms
Non-motor
Behavioral arrest
Unclassified
THE NERVOUS SYSTEM
275
13
EPILEPSY
the correct diagnosis and management of the condition.
The World Health Organization estimates that up to 70%
of people living with epilepsy could live seizure- free, if
they were properly diagnosed and treated. In poor countries, epilepsy is often associated with infectious diseases
such as malaria and neurocysticercosis.
Epileptic seizures generally have three phases: a prodromal phase where the person is aware that a seizure is coming
and this can be associated with auras or other specific signs.
This is followed by the ictal phase (ictal is a term derived
from the Latin word ‘ictus’ meaning ‘blow’ or ‘stroke’, and
refers to the seizure event), which is the time from the first
symptom to the end of the seizure, and lastly the post ictal
(recovery) phase. People who suffer from epilepsy have
a predisposition to recurrent seizures, and epilepsy can
have significant cognitive and psychological consequences.
Epileptic patients can have a high frequency of depression
and have a higher risk of suicide than the general population. Certain patterns of psychosis are associated with epilepsy. Psychotic disorders are classified as ictal, if they are an
expression of the seizure activity; postictal, when they occur
within a week of a seizure; and interictal, when they occur
independently of seizures. Interictal psychosis may also be
an unwanted effect of the anti-epileptic therapy. Epilepsy
can be associated with lethality, direct effects (e.g. falls, road
traffic accidents, drowning) or indirect effects (psychiatric
complications, adverse effects of medication). Sudden unexpected death in epilepsy (SUDEP) affects ∼1:1000 epilepsy
patients.
Epilepsy can be linked to a variety of primary causes,
such as brain tumours or meningitis, and metabolic
abnormalities such as hypoglycaemia and uraemia (Table
13.1). Some types of seizure are induced by very ordi-
nary sensory stimuli, such as flashing lights, flickering
fluorescent lights, computer or television screens, and
strobe lighting. Other types are triggered by sleep deprivation or intense stress. However, most cases of epilepsy
have no immediately obvious cause and require a more
extensive investigation. In previous classifications, they
were termed idiopathic or cryptogenic (i.e. a cause is
suspected but not proven). The category of cryptogenic
epilepsies is diminishing due to progress in the understanding of various aetiological aspects of epilepsies.
Overall, the aetiology of epilepsies can be structural,
infectious, immune, genetic, metabolic or unknown. An
epilepsy or seizure type can belong to more than one of
these aetiological subgroups.
Diagnostic investigations of epilepsy
Table 13.1 Some causes and predisposing factors of epilepsy
Metabolic disturbances (especially electrolyte imbalances and
uraemia)
Hypoxia
Chronic alcohol abuse (seizures either during heavy drinking or
during withdrawal)
Some neuroactive drugs (either in overdose or at normal levels in
susceptible patients)
Drug withdrawal states (especially phenobarbitone and
benzodiazepines)
Strokes (haemorrhagic or ischaemic)
Aneurysms
Perinatal trauma and anoxia
Central nervous system infection (meningitis, encephalitis, cerebral
abscess)
Traumatic brain injury
Family history
Intrauterine infections (e.g. rubella)
Developmental abnormalities
Craniotomy
Degenerative brain disorders
Brain tumours
Table 13.2 Examples of childhood epileptic syndromes
Age of
Syndrome
Benign neonatal
familial convulsions
Benign Rolandic
epilepsy
Childhood absence
epilepsy (CAE)
Juvenile absence
epilepsy
Juvenile myoclonic
epilepsy (Janz
syndrome)
Infantile spasms
(West’s syndrome)
onset Features
Days to 2
months
3–13 years Focal seizures with secondary
3–12 years Many absences
7–17 years Fewer absences than with CAE
10–20
years
3–7
months
Generalized or focal, tonic or
clonic seizures
generalization
Convulsions rare
Convulsions common
Myoclonic jerks on waking
Generalized tonic–clonic
seizures
Occasional absences
Flexor spasms, tonic and
atonic seizures, progressive
mental handicap
A patient with suspected epilepsy requires a complete
neurological examination. The diagnosis of epilepsy
is primarily clinical. The definition of epilepsy is: (1) a
patient with two or more unprovoked seizures >24 hours
apart, (2) a patient with an unprovoked seizure who has
>60% risk of another seizure over the following 10 years
or (3) a patient with one or more seizures in the context of
a specific epilepsy syndrome.
276 SYSTEMS OF THE BODY
A detailed history is essential, and eyewitness reports
on the presentation of the seizure are very valuable.
Some patients may experience an aura before a seizure, that is, a peculiar sensation or symptom, such as
strange smells or unpleasant taste, epigastric pressure or
a general feeling of déjà vu (i.e. even if the environment
is new, it feels familiar, as though they have been there
13
before). If an aura precedes the attack, its description can
help identify a possible focus of functional or structural
abnormality in the brain.
When diagnosing epilepsy, it is important to first
make sure that there is no confusion with conditions that
produce similar clinical signs such as syncope, transient
ischaemic attacks (TIAs), hypoglycaemia, migraine or
pseudoseizures (also called psychogenic non-epileptic
seizures, where there is no objective evidence of brain
electrical abnormalities). Once the diagnosis of epilepsy
is confirmed, it is important to obtain additional information and determine possible causes. In an adult with
no previous history of epilepsy, it is important to carry
out brain imaging to exclude the possibility of a tumour
or other mass- filling lesion as the cause of the seizures.
Establishing whether there is a family history of epilepsy
is also important, for its link to a possible genetic cause
(Box 13.2).
Electroencephalography and
magnetoencephalography
Electroencephalography and magnetoencephalography are
based on the generation of electrical and magnetic fields
as a consequence of the electrical activity of neurons. An
electroencephalogram (EEG) is a non-invasive method of
measuring the surface electrical activity of the brain. When
cortical neurons are active, the electrical currents that flow
across the neuronal cell membranes also set up extracellular currents that flow through the extracellular space.
Recordings of these currents can be made at sites distant
from where the currents are generated. In the case of an
EEG, these currents are measured by electrodes placed on
the scalp. The changes in electrical potential measured by
the EEG are the summated ionic currents produced by the
large numbers of neurons found under the electrodes in
the cortex (Box 13.3). These scalp electrodes are positioned
using a conductive gel or paste according to a standard pattern specified by an international system, and the potential difference is measured between pairs of electrodes.
The major sites of placement of electrodes on the scalp are
shown in Fig. 13.2. Electrodes can also be embedded in a
mesh, forming a cap, which can be fitted on the patient’s
head. Most commercially available array head nets are
equipped with 64, 128 or 256 electrodes. Some are customizable, hence the optimal number of electrodes can be chosen for a particular clinical or research aim.
While the largest signal generated by neurons is the
action potential, it is a very short- lasting event and,
EPILEPSY
Box
13.2
There is a strong correlation between epilepsy and family history, with approximately 30% of patients having a close relative with epilepsy. At present, there are more than 500 genes
associated with epilepsy, and this list is likely to grow. The
genetic abnormalities seen in epilepsy include single mutations, copy number variations, microdeletions and microduplications. Mutations can occur in protein- coding exons and
also in non-coding regions. For most epileptic syndromes,
the mode of inheritance is complex. For example, common
forms of idiopathic epilepsy, such as juvenile myoclonic epilepsy or juvenile and childhood absence epilepsy (see Table
13.2), do not follow a simple Mendelian mode of inheritance.
Identification of the genes mutated in idiopathic epilepsies shows that these forms of epilepsy are most often channelopathies; that is, they are due to mutations in voltage- or
ligand- gated ion channels (e.g. cholinergic nicotinic receptors, Na+, K+ and Ca2+ channels, and GABAA receptors). These
mutations ultimately lead to altered neuronal excitability.
genetics in epilepsy is represented by the developmental and
epileptic encephalopathies (DEE), which are complex conditions associated with mutations in more than 60 genes. DEE
are a heterogeneous group of rare neurodevelopmental disorders characterized by (1) early- onset seizures that are often
intractable, (2) EEG abnormalities, (3) developmental delay
or regression and (4) in some cases, early death. An example
of DEE is Dravet syndrome (DS). DS is characterized by febrile
seizures within the first year of life in an otherwise healthy
Genetics of epilepsy
The strongest example that illustrates the importance of
child, evolving into a combination of intractable febrile and
afebrile seizures, with developmental arrest or regression
in the following years. More than 80% of DS patients carry
a de novo mutation of the SCN1A gene, encoding Naᵥ1.1
(the voltage- gated sodium channel type I α subunit). Other
clinical epilepsy presentations associated with mutations in
SNC1A include: generalized epilepsy with febrile seizures
plus (GEFS+), severe myoclonic epilepsy borderline (SMEB),
intractable childhood epilepsy with generalized tonic- clonic
seizures (ICE- GTC) and infantile partial seizures with variable
foci. It has been hypothesized that NaV1.1 mutations lead to
reduced sodium currents and subsequent hyperexcitability in
neural networks, that are linked to a GABAergic deficit.
Focal epilepsy (more than 60% of all epilepsy presentations), which is common in adults, is associated with a variety
of mutations in genes encoding ion channels and also genes
involved in cell growth pathways such as the mechanistic target of rapamycin (mTOR) - linked pathways. mTOR regulates
cell proliferation, autophagy and apoptosis, and is involved in
multiple signalling pathways. Brain somatic mutations in the
genes encoding mTOR components have been linked to focal
cortical dysplasia, which is often seen in focal epilepsies.
Determining a genetic cause in an individual with epilepsy
may be a key step towards a better and more personalized
clinical management of the patient. It may lead to the avoidance of therapeutic errors, such as using sodium channel
blockers in DS, and the consideration to use stiripentol—a
compound which enhances GABAergic activity.
277THE NERVOUS SYSTEM
13
Nose
Left ear Right ear
EPILEPSY
Box
13.3
The cerebral neocortex has six distinct layers, with layer 1
lying just beneath the pia mater, and layer 6 just above
the white matter (see Fig 15.6). Within these layers, there
is a relatively similar arrangement of the different cell
types throughout the brain, although the thickness of
the layers varies in the different functional regions of the
cortex. Cortical networks are composed of glutamatergic
excitatory projection neurons and local GABAergic inhibitory interneurons that modulate signal flow. Although
they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly
heterogeneous, forming functional classes based on their
morphological, electrophysiological and molecular features, as well as connectivity and in vivo patterns of activity. The cells with the largest cell bodies in the cortex are
the pyramidal cells, which are found in layers 2, 3 and 5,
oriented with the apex of their long dendrites running
upwards towards the brain surface. From their base, long
axons descend through deeper layers and leave the cortex. Areas rich in pyramidal cells are mainly output layers.
The cortex also contains non-pyramidal cells, which are
usually smaller and have no specific orientation of their
dendrites. Their axons terminate locally, in the same layer
or immediate vicinity. Non-pyramidal cells are involved
primarily in receiving inputs from thalamic and other
afferents, and in the local processing of information. As
pyramidal cells are orientated with their dendrites at right
angles to the cortical surface, when they are active, the
potentials generated in the extracellular fluid give the
largest signal at the brain surface.
Cerebral cortical neurons and the
generation of electrical signals
unless action potentials occur simultaneously, they
cannot summate to produce a large enough extracellular electrical potential to be measured by the scalp
electrodes. Therefore, most of the electrical activity
measured in an EEG comes from the summation of
postsynaptic potentials. Although these are smaller
than action potentials, they are much slower in their
development and can therefore summate. Electrical
activity recorded by electrodes placed on the scalp or
surface of the brain mostly reflects summation of excitatory and inhibitory postsynaptic potentials in apical
dendrites of pyramidal neurons in the superficial layers of the cortex. Quite large areas of cortex, in the order
of a few square centimetres, have to be activated synchronously to generate enough potential for changes to
be registered by scalp electrodes. The direction of the
waves recorded by the EEG electrodes depends both
on whether the postsynaptic potential is excitatory or
inhibitory and on the depth of the activity within the
cortex. Within the cortex, much of the activity is usually
contained within individual local areas, with outputs to
distant areas, allowing for extensive parallel and serial
processing of sensory and motor information. When the
activity of several groups of neurons is synchronized, a
seizure can occur.
Invasive EEG can be used in selected cases. It might
be offered to a patient with no underlying structural
pathology identified on neuroimaging, but in whom
other investigations have generated a suspicion as to
the location of an epileptogenic region. It utilizes cortical depth electrodes (inserted surgically under stereotactic magnetic resonance imaging [MRI] guidance)
and subdural electrodes (strips or grids, which require
craniotomy for placement). Cortical stimulation can
be performed with either type of electrode. Electrode
selection and placement is determined by the location of the epileptogenic zone. In general, wider areas
of cortex are covered by subdural electrodes, whereas
depth electrodes are more suitable for suspected deep
lying foci.
FP1
F7
F3
FZ
Fig. 13.2 Standard placement of EEG leads. The letters and numbers
correspond to specific anatomical positions. C, Central; F, frontal; O,
occipital; P, parietal; T, temporal.
T3
C3
CZ
P3
T5
PZ
O1
278 SYSTEMS OF THE BODY
FP2
F4
C4
P4
O2
Normal EEG patterns
A clinician uses an EEG to obtain information about
F8
electrical brain activity. Although the EEG pattern
of every individual is unique, there are several common patterns that can be related to specific brain states.
T4
The EEG shows characteristic patterns when a person
is alert, drowsy or asleep. The amplitude of the EEG
waves depends on the synchronicity in the activity of the
T6
underlying neuronal circuits. A frequency that is too high
or too low, is indicative of impaired cortical function. In
addition, the presence of unusual waveforms, such as
sharp spikes, spike- and- wave potentials or unusually
slow waves, indicates a brain lesion and may explain the
emergence of seizures.
Fig. 13.3A shows the normal EEG in the awake state.
It consists of a set of parallel recordings obtained from