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Chapter
Emerging and Less Common Central Nervous System

91 Viral Encephalitides
H. T. Chong and C. T. Tan

Introduction process of infection, the anatomic sites involved, the immune

and reparative responses elicited by the infection, and other host
Seizures are a common manifestation of encephalitis and the
factors. Most viral infections of the central nervous system cause
commonest cause of encephalitis is viral infection. There are
acute brain parenchymal inflammation with perivascular lym-
hundreds of viruses that affect human beings, and many can
phocytic and mononuclear cell cuffing and infiltration, with
cause encephalitis [31]. The overall incidence of viral encephali-
ballooning and death of neurons leading to subsequent gliosis.
tides is approximately 3.5–7.4 in 100,000 per year. The incidence
There are, however, significant differences among different
is higher among children; in children under 1 year of age, the
infections in terms of histopathological appearance and the
incidence is 22.5 in 100,000 per year, and that in children 1–5
specific anatomic sites involved. In herpes simplex encephalitis,
years of age is 15.2 in 100,000 per year [14]. Viruses that cause
for example, the inflammation may progress to necrosis and
human central nervous system infections can be divided into
hemorrhage; and homogenous eosinophilic intranuclear inclu-
three broad categories – the primary human viruses, the arthro-
sion bodies (Cowdry type A) are seen in about half of the
pod-borne viruses or arboviruses, and the zoonotic viruses.
patients. Herpes simplex virus has a predilection to affect the
The primary human viruses are important causes of encephalitis
temporal and frontal lobes, the cingulate gyrus, and the insular
worldwide, and the arboviruses affect large geographical areas
cortex. In rabies, intracytoplasmic inclusions, or Negri bodies,
often across continents. The zoonotic viruses, apart from rabies,
are seen in 80% of patients, and the virus tends to affect the
tend to be more localized (Fig. 91.1). Some of these viruses are
spinal cord, brainstem, hypothalamus, cerebellum, and hippo-
important because of the size of population involved, others
campus. Japanese encephalitis virus causes a non-specific par-
because they are emerging. The common causes of viral ence-
enchymal inflammation and has a propensity to affect the
phalitides associated with seizures are discussed elsewhere. This
various deep brain nuclei, such as the thalami, besides the
chapter focuses on the emerging and less common viruses that
brainstem and cerebellum. Tick-borne encephalitis virus first
cause encephalitis and seizures.
infects the Langerhans cells before invading the lymphoid and
reticuloendothelial system, and finally causes inflammation not
Overview just in the brain, but also in the spinal cord and leptomeninges.
In principle, any virus that causes encephalitis could potentially Other viruses result in different pathological changes.
cause seizures. Clinically, however, certain viral agents are more The Venezuelan and Eastern equine viruses, Nipah, and
likely to cause seizures while others only do so rarely. This is Hendra viruses cause widespread vasculitic changes and micro-
probably due to the differences in the underlying pathological vascular infarcts. Rarely, some viruses, such as the human

Fig. 91.1 Geographical distribution of emerging

and some less common viral encephalitides.

Nipah encephalitis

Hendra
encephalities

St Louis encephalitis Western equine encephalitis West Nile encephalitis

Murray Valley and

Japanese encephalitis LaCrosse encephalitis
Kunjin encephalitis

Tick-borne encephalitis Eastern equine encephalitis

® HT Chong

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herpesvirus 6, cause the unusual picture of a demyelinating
encephalitis.
The occurrence of seizures and epilepsy are generally not
well studied in viral encephalitides. Most infections cause focal
seizures with or without secondary generalized tonic–clonic
seizures or myoclonic seizures. Little is known about the pre-
dictive factors of seizures in most infections. In some instances,
for instance in Japanese B encephalitis, seizures carry a poor
prognosis in terms of immediate outcome, but in most infec-
tions, the presence of seizures does not influence the prognosis.
Emerging Encephalitides
Japanese Encephalitis Virus
Japanese encephalitis virus is a flavivirus transmitted by mos-
quitoes from birds and pigs to humans. It is found in East,
South, and South-East Asia from eastern Russia to the north-
ern tip of Australia, and from India to the Guam Islands.
It causes 20,000 to 50,000 infections and 15,000 deaths
annually, and thus is the most important viral encephalitis
globally. The virus causes diffuse encephalitis, affecting the
midbrain, thalamus, and basal ganglia more severely [17,28].
Only 1 in 250–1000 patients infected with the virus
becomes symptomatic. The infection ranges from mild, flu-
like illness, to fatal meningoencephalitis. In endemic areas, it
is mainly a childhood disease, though visiting naive adults are
at particular risk of developing severe illness. After an incuba-
tion period of 5–15 days, symptomatic patients present first
with fever, headache, vomiting, seizure, and impaired con-
sciousness. Extrapyramidal signs such as mask-like face, tre-
mor, rigidity, choreoathetosis, dystonia, dyskinesia, and
generalized hypertonia are common, and so are brainstem
signs. Brain magnetic resonance imaging (MRI) is sensitive
and shows hyper-intensities in brainstem, cerebellum, basal
ganglia, and even the cerebral region. Diagnosis is mainly by
serology or polymerase chain reaction (PCR) in the acute
stage. Effective vaccines are available, though treatment is
mainly supportive [28].
Seizures occur in approximately 40–60% of patients,
though the rate is as high as 80% in children. Of these patients,
45–57% have generalized clonic or tonic–clonic seizures,
18–43% have focal motor seizures, and up to 25% may have
status epilepticus. The seizure manifestations can be subtle,
especially in children, and include minimal clonic movements
of the eyes, eyebrows, eyelids, mouth, or digits, with or without
tonic eye movements, nystagmus, salivation, and irregular
breathing. Seizures are associated with focal weakness and
abnormalities on the electroencephalogram (EEG) and brain
computed tomography (CT) scan. Seizures also herald a poorer
prognosis, being associated with higher mortality and poorer
conscious state. This is especially the case in multiple or pro-
longed seizures or status epilepticus, probably because the
seizures lead to raised intracranial pressure and a higher risk
of herniation syndrome [29].
Acutely, the EEG is abnormal in the vast majority of
patients, though in a non-specific manner. More than 60% of
patients exhibit slow waves, usually of high amplitudes, often
Emerging and Less Common CNS Viral Encephalitides
with reactivity to external stimuli. Other EEG changes
included focal discharges, electrical status epilepticus, periodic
lateralized epileptiform discharges (about 10% of patients),
burst suppression, generalized attenuation, and alpha coma
in about 10% of patients. An EEG tracing that is non-reactive
to external stimuli carries a poorer prognosis [13,19,29].
During convalescence, more than a third of patients have
normal EEG and over half have only mild abnormalities, sig-
nifying good recovery in the survivors. By 3–12 months after
the onset of illness, three-quarters of the patients have a normal
EEG recording. However, in patients with more severe infec-
tion, especially in situations where adequate medical facilities
are not accessible, mortality may be as high as 30% in those
admitted, and half of the survivors have severe neurological
sequelae, which include motor deficits, fixed flexion deformi-
ties of the limbs, cognitive deficits, and remote symptomatic
epilepsy in up to 20% [29].
West Nile Virus
West Nile virus is a flavivirus closely related to the Kunjin virus
and, somewhat less closely, to the Japanese encephalitis virus.
First identified in Uganda in 1939, the reservoirs of West Nile
virus are birds and the vector Culex mosquitoes. Human and
other mammals are dead-end hosts. West Nile viral infection is
endemic in Africa, the Mediterranean, and the Middle East.
Migratory birds are believed to be important in the long-
distance spread of the virus. The first outbreaks outside the
endemic area occurred in Romania in 1996 and in the
Volgograd and Krasnodar regions of Russia in 1999, which
coincided with a major change in neurovirulence. In August
the same year, the virus affected 62 patients in New York, and
by 2002, it had spread throughout the United States and
reached the Pacific coast.
In endemic areas, the infection is often asymptomatic.
“… or 1 in 150
After an incubation period of 3–15 days, about 20% of patients
infections,
present with flu-like illness with a non-pruritic roseolar or usually …”
maculopapular rash that lasts for about a week. Only about
15% of patients, or 1 in 150, usually the elderly, develop central
nervous system involvement. In non-endemic areas neurolo-
gical involvement is more common and more severe. Fever,
headache, neck pain, myalgia, back pain, nausea, chills, and
rigors are the commonest symptoms, while altered mental
state, neck stiffness, parkinsonism (including tremor, rigidity,
and bradykinesia), are common signs. Other clinical features
include brainstem involvement, optic neuritis, myelitis, acute
flaccid paralysis presumably from anterior horn cell involve-
ment, aseptic meningitis, and encephalitis. Cerebrospinal fluid
(CSF) analysis shows pleocytosis, often lymphocytic, with
raised protein and normal sugar levels. Magnetic resonance
imaging of the brain shows bilateral hyperintense lesions in the
basal ganglia, thalamus, and pons on T2-weighted images.
Diagnosis is based on serologic testing of serum or CSF, or
PCR analysis of CSF during the early part of the illness. There
is no specific antiviral therapy for West Nile infection.
Treatment is mainly supportive. Long-term outcomes are
often good, though persistent fatigue, myalgia, and cognitive
deficits have been reported.
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H. T. Chong and C. T. Tan
Seizures occur in 5–30% of patients with West Nile ence-
phalitis, and often focal motor and present during the later part
of the illness. Rarely, non-convulsive status epilepticus
may occur. Electroencephalographic changes are often non-
specific, such as diffuse irregular slow waves, and even in
patients with non-convulsive status epilepticus, the EEG may
show only polymorphic delta slow waves. Focal sharp waves
are seen occasionally [8,26].
Nipah Virus
Nipah virus is a paramyxovirus endemic among the giant fruit
bats (Pteropus species) in South and South-East Asia and in
east African coastal regions. In 1998, it caused a fatal outbreak
of encephalitis among pig farmers in Malaysia, when pigs
contracted the virus by consuming fruits partially eaten by
fruit bats. The disease continues to cause small annual out-
breaks in Bangladesh and north-east India, probably related to
the local practice of consuming raw, contaminated, date palm
juice.
After an incubation period of about 2 weeks (range 1–32
days), Nipah infection causes a severe encephalitis charac-
terized by sudden onset of fever, headache, giddiness, drow-
siness, nausea, anorexia, vomiting, abdominal pain, cough,
focal neurological deficits, and seizures. Over the ensuing
1–2 weeks, the patient’s consciousness continues to deterio-
rate. In the Malaysian outbreak, more than 60% of patients
required mechanical ventilatory support and mortality was
about 40%. Terminal events were often heralded by severe
hypertension, tachycardia, and hyperthermia, and then irre-
versible shock. A previous history of diabetes mellitus,
brainstem signs, and positive CSF viral cultures were poor
prognostic factors. Analysis of CSF shows features typical of
viral encephalitis in 50–60% of patients with raised lym-
phocytes and protein levels, but normal sugar values.
668
Computed tomography scan of the brain is almost invari-
Delete the
ably normal, while almost all patients have an abnormal
word “an”
MRI, showing widespread, focal, vasculitic-like lesions in
the subcortical and deep white matter. Nipah
immunoglobulin M (IgM) serology is positive in almost
all patients by day 12 of the illness, and that of immuno-
globulin G (IgG) by day 26. In a non-randomized, histor-
ical-controlled trial, ribavirin was found to reduce mortality
by about 30%, though supportive treatment is equally, if
not more, important [5,9].
Seizures are common in patients with acute Nipah ence-
phalitis; about a quarter of the patients have generalized
tonic–clonic seizures and one-third to half have segmental
myoclonus, involving the diaphragm, limbs, and facial mus-
cles. The myoclonus may be persistent over hours.
Interestingly, myoclonus was absent in the reports of Nipah
encephalitis in Bangladesh, though this could be due to report-
ing bias.
During the acute phase of infection, more than 96% of
patients have an abnormal EEG and 88% have continuous
diffuse slow waves with or without focal discharges. Focal
discharges are seen in about half of the patients and bitemporal
periodic complexes in a quarter. The periodic complexes are
stereotypical with single spike or sharp wave followed by a slow
wave of 200–250 ms, repeating irregularly every 1–2
s (Fig. 91.2). Almost all patients with periodic complexes
were comatose in the initial Malaysian outbreak and none
survived [3,9].
During the acute illness, the focal discharges and the per-
iodic complexes seen on EEG do not correlate with focal
neurological deficits, clinical seizures, or segmental myoclo-
nus, though the degree of slowing correlates with the severity
of illness [3].
The mortality rates were 32–41% in the Malaysian out-
breaks, and on average, as high as 73% in the Bangladesh
Fig. 91.2 (A) Bitemporal periodic complexes in
Nipah encephalitis; (B) the same patient 2 days later,
who died on the same day. (Reproduced from
Chew et al. [3]with kind permission.)
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outbreaks. About half of the Malaysian patients recovered
totally and of the rest, 15–30% recovered with residual neuro-
logical deficits. The incidence of late unprovoked seizures was
2.2% in an 8-year study of 137 patients in Malaysia – higher
among those who relapsed (4.0%) than the patients who had
only acute Nipah encephalitis (1.8%) [20]. During convales-
Delete “a”
cence and recovery, more than half of the patients had
a normal EEG. About 24% had intermittent diffuse slow
waves, 18% intermittent focal slow waves, and 6% showed
focal slow waves and focal discharges [3].
Relapsed Nipah Encephalitis
In up to 10% of symptomatic and 3.4% of patients with asympto-
matic infection, Nipah virus infection may cause a relapse of
encephalitis 4 years or more after the initial acute infection.
“… half have
neurological These patients present with recurrence of fever, headache, focal
deficits on neurological deficits, and seizures. Brain MRI shows diffuse gray
recovery. There matter involvement suggesting neuronal invasion by the virus.
is no treatment
Mortality is as high as 18%, and half have residual neurological
of proven value
for relapses.” deficits. There is no treatment of proven value for the relapse.
Seizures are seen in approximately half of the patients with
“… the a relapse, mainly focal motor or generalized tonic–clonic.
patients with Segmental myoclonus, prominent during acute infection, has
relapses, mainly not been seen in relapsing patients.
“
The EEG shows continuous diffuse slow waves with focal
Delete preponderance and frontal or temporal discharges.
“preponderance The ominous bitemporal periodic complexes in acute infection
and” are not seen in relapse patients. The EEG is abnormal in almost
all patients with clinical cerebral involvement, and the later-
ality of EEG changes corresponds with MRI changes. Focal
discharges on EEG do not predict mortality or the occurrence
of clinical seizures [30]. Late unprovoked seizures were docu-
mented in about 4.0% of patients in relapse in the Malaysian
series [20].
Emerging and Less Common CNS Viral Encephalitides
Fig. 91.2 (Cont.)
Hendra Virus
Hendra virus is a paramyxovirus closely related to the Nipah.
Like Nipah virus, its natural reservoirs and hosts are the pter-
opid bats. It was first discovered in Queensland, Australia, in
1994, when it caused infection in horses and encephalitis in
horse-handlers. Sporadic cases of human infections are still
reported, though the transmissions from bats to horses and
from horses to humans are not efficient. In symptomatic
patients, fever, flu-like symptoms, myalgia, headache, and ver-
tigo occur after a short incubation period of 6–12 days.
Mortality is approximately 50%. In a report of four patients,
two recovered with no residual neurological deficit; one had
relapse Hendra encephalitis 13 months after the initial acute
infection. She presented with focal neurological deficits,
altered conscious state, and seizures, and ultimately died [33].
Enterovirus 71
Enteroviruses are small, single RNA stranded, non-enveloped,
viruses that belong to the family of Picornaviridae. There are
more than 60 different serotypes of enteroviruses, and humans
are the only host. They are mostly transmitted by fecal–oral
route or by respiratory droplets. Transmission is facilitated
during warm weather; therefore, the incidence of infection is
high in warm countries all year round. A few serotypes pre-
dominate in a particular locality, and these cause cyclical out-
breaks depending on a variety of factors, including the
availability of new, susceptible hosts; usually young children.
Some serotypes are more likely to cause central nervous system
infection, and among these, enterovirus 71 is probably the
most important as it has caused large, multiple outbreaks in
the United States, Europe, Australia, and East and South-East
Asia since its discovery in California in 1969. The largest out-
break occurred in Taiwan in 1998 when the virus caused
a massive epidemic affecting over a million people.
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H. T. Chong and C. T. Tan
Clinically, enterovirus 71 affects mainly children, and those
under 5 years of age are more severely affected. Enterovirus 71
infections may be asymptomatic, or it may cause diarrhea,
hand–foot–and–mouth disease, herpangina, myocarditis,
acute flaccid paralysis, Guillian–Barré syndrome, aseptic
meningitis, acute cerebellar ataxia, encephalitis, and rhomben-
cephalitis; the last of which is associated with fatal pulmonary
edema and hemorrhage. Analysis of CSF shows increased
protein, normal sugar levels, and pleocytosis, often lymphocy-
tic, though in up to 40% it may be neutrophilic. Magnetic
“… which can
enhance in the
resonance imaging of the brain shows hyperintense lesions in
acute phase of the the brainstem and spinal cord on T2-weighted images, which
illness.” can enhance in the acute illness. Diagnosis is by viral isolation
or PCR. There is no proven antiviral therapy for enterovirus
71, though various agents have been tried, such as steroids and
intravenous immunoglobulin. Supportive care remains the
most important aspect of management.
Among children with rhombencephalitis, 68–86% are
reported to exhibit myoclonic jerks, which can range from
mild and intermittent jerks during sleep, or persistent jerks
during both sleeping and waking, and which may continue
after the patient recovers from the acute encephalitis. Other
seizures and opsomyoclonus have been documented, though
there are few details in the current literature. The EEG shows
bilateral central and parietal slow waves or sporadic sharp or
spindle waves.
The overall outlook is good; in children without pulmonary
edema or hemorrhage, mortality is close to zero. The outlook
for children with pulmonary edema and/or hemorrhage is
poor, however, with a mortality rate of about 80%. Among
the survivors, 5% or fewer have residual neurological deficits
which include poor motor skills and lower IQ. Remote symp-
tomatic epilepsy is not documented in survivors of enterovirus
71 infection [12].
Dengue
Dengue virus, a flavivirus, causes one of the most important
viral infections in humans, affecting over 50 million indivi-
duals yearly, with 500,000 hospital admissions. The virus is
pandemic in South and South-East Asia and South America, as
well as affecting northern Australia and sub-Saharan Africa.
In recent years, outbreaks have been recorded in Hawaii, Cuba,
and Singapore.
The incubation period of dengue infection ranges from 3
to 14 days. The infection is asymptomatic in the majority of
patients, especially among children. In symptomatic patients,
“… The rash may it often causes sudden rise of high fever, headache, retro-
be florid, and may ocular pain, myalgia, arthralgia, backache, nausea, anorexia,
even become vomiting, and a non-pruritic macular or petechial rash.
confluent …” The rash may be florid, or may even become confluent,
with associated flushing around the face, neck, and chest
and islands of pale, normal skin. Leukopenia and thrombo-
cytopenia are common, and so are bruises on the skin and
subcutaneous bleeding after venipuncture. The febrile period
lasts a week or less. However, thrombocytopenia and vascu-
lar leakage may worsen suddenly, and hemorrhagic compli-
cations and shock arise rapidly. There is a tendency for the
670
disease to deteriorate within 48–72 hr after defervescence.
Vascular leakage is evident by hemoconcentration, severe
thrombocytopenia (platelet count ≤ 105/µl), ascites, pleural
effusion, hypoalbuminemia, or hypoproteinemia. This is
termed dengue hemorrhagic fever, and it is an indication of
impending shock. Therefore, intensive observation and pro-
phylactic replenishment of lost intravascular fluid are indi-
cated. If not treated, the patient may progress into dengue
shock syndrome, which may be heralded by intense abdom-
inal pain, persistent vomiting, restlessness, lethargy, or
hypothermia with sweating. Other uncommon, but often
severe, manifestations of dengue infection include severe
hemorrhage, hepatic damage, cardiomyopathy, and encepha-
lopathy/encephalitis. Diagnosis is by serologic testing. Since
dengue virus is closely related to other flaviviruses, the ser-
ologic test may be falsely positive in Japanese encephalitis,
West Nile fever, or St. Louis encephalitis. Treatment is sup-
portive, with particular attention to adequate fluid replace-
ment titrated against clinical findings and the patient’s
hematocrit.
Neurological involvement in dengue infection is well docu-
mented, though whether the virus causes an encephalopathy or
encephalitis is still debated. The incidence is low, and seen espe-
cially among pediatric patients. Patients with neurological invol-
vement present with confusion, altered conscious state, limb
weakness, and seizures. Approximately 10 to 15% of those with
neurological involvement have seizures; commonly generalized
tonic–clonic seizures, but occasionally myoclonic jerks. The EEG
often shows non-specific theta slow waves [11,18,19,23].
The overall mortality of dengue infection is low; however, if
shock sets in, the mortality rate can rise to 12–44%. Among the
patients with central nervous system involvement, mortality is
approximately 30%; and another 20–30% of survivors have
long-term neurological deficits.
Human Herpesvirus 6
Human herpesvirus 6 is a beta-herpesvirus, a DNA virus clo-
sely related to the cytomegalovirus and human herpesvirus 7.
Humans are the primary and perhaps the only host. The mode
of transmission is not clear, though the virus is secreted in
saliva and urine. About 77–90% of children become seroposi-
tive by age 2 years and it has been reported to cause outbreaks
in daycare centers in Brazil. The primary infection is sympto-
matic in 93% of children, and the symptoms include fever,
irritability, rhinorrhea, cough, diarrhea, and rash. The typical
roseolar rash (roseola infantum, exanthema subitum, or sixth
disease) is seen in only 23% of children. About 10% of patients
with a primary infection may suffer from febrile seizures.
Uncommonly, focal demyelinating encephalitis may occur in
young children. Primary infection in immunocompetent
adults or older children is rare, and may result in infectious
mononucleosis-like illness, with fever, lymphadenopathy,
hepatitis, or encephalitis. Generally, the outcome of uncom-
plicated primary infection is excellent.
Immunocompromised hosts are more susceptible to
human herpesvirus 6 infections, either from primary or reac-
tivation of latent infection. The rate of infection in transplant
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patients varies from 24% to 66%, and symptomatic disease is
more likely to result from primary infection than reactivation
of latent infection. Clinical features include fever, leukopenia,
rash, interstitial pneumonitis, and encephalitis, and in bone
marrow transplant patients, bone marrow suppression.
In patients with reactivation of latent infection, including
patients with human immunodeficiency virus infection,
human herpesvirus 6 infections often manifest as fever, though
encephalitis, including limbic encephalitis, and interstitial
pneumonitis have been documented.
In immunocompromised patients with human herpesvirus 6
encephalitis, common clinical features include confusion, altered
conscious states, headache, focal neurological deficits, and sei-
zures, which occur in about 25% of patients. Findings with CT
and MRI scans are non-specific and the EEG may show focal
discharges. The gold standard of diagnosis is viral culture of
peripheral mono-nuclear cells, while anti-complement immuno-
fluorescence assay is an alternative. Serologic tests are not spe-
cific in detecting recent infection, as IgM may be produced in
both primary and reactivation of latent infection. Treatment is
largely supportive, though ganciclovir and foscarnet have been
tried. In transplant patients with human herpesvirus 6 encepha-
litis, mortality is in excess of 50%, though residual neurological
deficits are not common among the survivors [6,27].
Chandipura Virus
Chandipura virus is a rhabdovirus transmitted to humans by
sandflies. Although the virus is found in both India and Africa,
so far only two possible outbreaks of human infections have
been reported, and both in India – the first in Andhra Pradesh
in 2003 with 329 patients, and the second in Gujarat state in
2004 with 26 patients. Children, especially boys under 16 years
of age in rural areas, are more at risk of acquiring Chandipura
infections. Typically, the patients present with sudden onset of
fever, follow by vomiting, altered conscious state, diarrhea,
focal neurological deficits, and meningismus. Seizures occur
in over 80% of patients. Although the mortality ranges from
55.6 to 78.3%, and most deaths occur within 24 hr of onset of
disease, residual neurological deficits are rare in children who
recover. Diagnosis is made by viral culture or PCR of throat
swab, brain aspirate, or peripheral blood mononuclear cell co-
culture. Serologic tests are not helpful; in the two outbreaks in
India, only 4.5–13% of patients had positive IgM and 65.
3–97.7% had positive neutralizing antibodies. Serologic tests
are less sensitive among children. Because of this, the role of
Chandipura virus in these outbreaks is still debated, and
Chandipura viral infection was proven in only 8.5–45% of
patients in these two outbreaks. In all of the affected patients,
CSF pleocytosis was not observed, and in the autopsy cases,
brain parenchymal inflammation was not observed [2,22].
Monkeypox Virus
Monkeypox virus is an orthomyxovirus closely related to var-
iola or smallpox virus. The virus causes outbreaks in central
and western Africa and was brought into the United States in
2003 through the importation of infected Gambian rats for the
Emerging and Less Common CNS Viral Encephalitides
pet trade. Clinically, it causes fever and acute pustular rash.
Among the 34 patients infected in the Midwestern United
States outbreak, a 6-year-old girl developed acute encephalitis
and seizures [25].
Other Uncommon Encephalitides
Rabies
Rabies, a rhabdovirus which is spread by the bites of infected
animals, is an important health problem worldwide. Although
only 15% of the bite victims develop rabies, worldwide there
are more than 35,000 reported human cases annually, the
majority of which occur in India. Dogs are the primary vectors
in developing countries, while small terrestrial mammals and
bats are the primary vectors in developed countries. After an
incubation period of 3 weeks to 2 months, the patient develops
fever, flu-like symptoms, mood changes, and local pruritus,
pain, and paresthesiae at the sites of bite. If the brainstem,
limbic system, hypothalamus, and the autonomic center are
involved, the patient develops furious or agitated rabies, char-
acterized by hydrophobia, aerophobia, and episodes of gener-
alized arousal associated with confusion, agitation, and
hyperesthesia punctuated by periods of lucidity. Death often
ensues within a week. If the spinal cord is primarily involved,
the patient may develop weakness, paresthesiae, pain, and
muscle fasciculation, starting from the affected limb spreading
to the rest of the body, and eventually involving all the other
limbs as well as the bulbar and respiratory muscles.
Uncommonly, patients may present with subtle or focal sei-
zures, which are easily missed. Vaccines are available for pre-
and post-exposure prophylaxis and treatment. Treatment
involves thorough washing of the wounds with soap, water,
and if available, virucidal agents. The standard vaccine is given
intramuscularly in five doses on days 0, 3, 7, and 14 into deltoid
or the anterolateral aspect of thigh, and passive immunization
with human rabies immunoglobulin infiltrated around the
wounds. Passive immunization is contraindicated if the patient
had been vaccinated and had documented adequate antibody
response. The mortality of rabies in unvaccinated individuals is
100% [32].
Tick-Borne Encephalitis
The three subtypes of tick-borne encephalitis virus (Far
Eastern, Siberian (previously known as Russian
spring–summer encephalitis), and Western European) are
the commonest causes of encephalitis in Europe, accounting
for 29–54% of encephalitis with a diagnosis and 10,000–20,000
cases annually. The flavivirus is transmitted by the Ixodes and
Haemaphysalis ticks, with rodents and wolves acting as reser-
voirs and amplifying hosts. Shrews, hedgehogs, moles, and
other insectivores are additional hosts. The risk of acquiring
the infection is, therefore, higher among men, especially
among farmers, hunters, forest workers, and those participat-
ing in outdoor leisure activities. The virus is found in a large
geographical area stretching from Scandinavia to Jilin in
northern China and Hokkaido, Japan.
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H. T. Chong and C. T. Tan

“… to contract the
virus compared to
females.”
Humans are the dead-end host of the virus, and 70–95% of
infections are subclinical. In symptomatic patients, the virus
causes a biphasic illness after an incubation period of 4–28
days. The first, viremic, phase lasts 4–18 days, and the patients
complain of fever, myalgias, nausea, fatigue, and headache.
After an interval of 8–133 days, 74–87% of patients suffer
from central nervous system involvement; half of these develop
meningoencephalitis, the other half meningitis, radiculitis, or
myelitis. Patients with meningoencephalitis have recurrence of
fever, headache, altered consciousness, confusion, tremor,
ataxia, weakness, dysphasia, cranial nerve palsies, and, uncom-
monly, seizures which are seen in 0.3–3.3% of patients.
The EEG is abnormal in 77% of patients, but the changes of
diffuse and/or intermittent focal slow waves are non-specific.
Magnetic resonance imaging of the brain shows abnormalities
in the thalamus, cerebellum, brainstem, and caudate nucleus in
18% of patients. Mortality is low at 0.1–1.4%, though 26–46%
of patients have residual symptoms, and up to 30% have sig-
nificant neurological deficits. Approximately 4–5% of patients
develop focal motor status epilepticus partialis continua,
known as Kozhevnikov epilepsy among Russian neurologists
[10]. The disease is more severe among the elderly, and mor-
tality is reportedly higher in far-eastern Russia, though it is not
known whether this is due to the strain of the virus or under-
reporting of milder cases. Diagnosis at the first stage is by PCR,
and the second stage by serology. There is no definitive treat-
ment though effective vaccines are available [15].
LaCrosse Encephalitis
The commonest cause of encephalitis in the United States is
caused by the Californian serogroup of bunyaviruses; and
among this group of viruses, LaCrosse virus is responsible for
almost all infections. LaCrosse virus is transmitted by the Aedes
triseriatus mosquito with chipmunks and squirrels as the nat-
ural reservoirs and amplifying hosts. Occurring mainly in the
upper Midwestern states during summer months, the inci-
dence of LaCrosse infection has been stable over the years with
70–100 cases annually. More than 90% of the cases occur in
young people under 15 years of age, with males being twice as
likely to contract the virus compared with females. In endemic
areas, up to 18% of residents are seropositive.
Probably only 1 in 1000 person infected with the virus
becomes symptomatic, and in these patients, fever is near
universal, three-quarters have headache, and half have menin-
gismus. Other common features are seizures, an altered state of
consciousness, focal neurological deficits, abdominal pain,
cough, and sore throat. About 12% of patients become coma-
tose, though the outcome is usually good.
LaCrosse encephalitis is highly epileptogenic. About
40–49% of patients with symptomatic infection develop acute
symptomatic seizures and up to 20% of patients develop
remote symptomatic epilepsy, even after recovery from the
infection. Abnormal EEG findings were reported in up to
75% of children 3–4 years after the infection. Apart from
epilepsy, the overall outcomes remain good; the mortality
rate is only 0.3 to 0.5%, and residual neurological deficits,
such as weakness, learning disabilities, cognitive deficits, and
behavioral changes, are seen in about 2% of the patients with
central nervous system infection.
St. Louis Encephalitis
St. Louis encephalitis, caused by a flavivirus, is the second
commonest cause of viral encephalitis in the United States.
It occurs primarily in the Ohio–Mississippi valley, but human
infections have been documented in other regions from south-
ern Canada to Argentina. The virus is transmitted by the Culex
mosquito, the amplifying hosts are birds, and the virus spills
out of the zoonotic cycle when there is a sufficient number of
mosquitoes. This causes periodic outbreaks of human disease
once every decade or so. Only 1 in 800 to 1 in 100,000 human
infections results in clinical illness and the elderly are most at
risk; while 40% of symptomatic young patients suffer from
mild aseptic meningitis only, 90% of the symptomatic elderly
develop encephalitis. The onset of encephalitis can be abrupt or
slow, and the clinical features include fever, headache, dizzi-
ness, nausea, malaise, meningismus, seizures, confusion, tre-
mor, ataxia, apathy, cranial nerve palsies, and urinary
frequency, urgency, or retention. The patients often recover
from the acute infection after a week or so, though 30–50%
continue to have prolonged asthenia, insomnia, irritability,
depression, poor memory, headache, tremor, and even gait
and speech disturbance which can last up to 2 years.
The mortality rate is 5–20% though it can be as high as 70%
in those aged 75 years and above. Analysis of CSF shows raised
protein and pleocytosis, and MRI T2-weighted images show
substantia nigra edema in about 20% of patients. Diagnosis is
by serologic test and treatment is supportive. A mosquito con-
trol program has proven effective in breaking the cycle of
transmission.
Among patients with acute St. Louis encephalitis, general-
ized tonic–clonic seizures occur in 30%, myoclonic jerks in
about 10%, and status epilepticus in another 10%. The EEG
shows diffuse slow waves in 70% of patients, bilateral periodic
lateralized epileptiform discharges in 10%, and status epilepti-
cus in another 10%.
Western Equine Encephalitis
Western equine encephalitis virus is an alphavirus, from the
Togaviridae family. It is mainly transmitted by the Culex tar-
salis mosquito and its natural reservoirs are birds. In summer,
the mosquito switches its feeding pattern from birds to mam-
mals, causing outbreaks in horses, mules, and humans.
Western equine encephalitis is limited to North America and
the last human outbreak was reported in Colorado in 1988.
Since then, fewer than five sporadic cases have been reported
annually.
Only 1 in 100–2000 infections results in clinical disease,
which ranges from mild fever to aseptic meningitis and ence-
phalitis. Infants are more likely to develop central nervous
system infection and neurological sequelae. After an incuba-
tion period of 5–10 days, those with encephalitis present with
sudden onset of fever, headache, nausea, vomiting, and
respiratory symptoms. After a few days, the patients develop

672
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Delete “an”
lethargy, an altered consciousness, meningismus, and vertigo.
In infants less than 1 year of age, irritability, tremor, weakness,
and focal or generalized seizures are common features. Long-
term sequelae of Western equine encephalitis are mild and
include fatigue, headache, and tremor, and the mortality rate is
3–4%. In children, severe neurological deficits are common
and seen in 56% of infants younger than 1 month of age and
10% in older infants. A quarter to a third of children with acute
symptomatic seizures will develop remote symptomatic epi-
lepsy, sometimes up to 2 years after the acute illness. Diagnosis
is by viral isolation or serologic test. Treatment is mainly
supportive as there is no specific antiviral agent available [16].
Eastern Equine Encephalitis
Eastern equine virus causes the most lethal arboviral encepha-
litis in the United States. It is an alphavirus from the family
Togaviridae, and found almost exclusively along the Atlantic
and Gulf coasts of the United States, extending as far inland as
Wisconsin, Indiana, and Michigan. The chief vector is Culiseta
melanura, a fastidious mosquito that breeds in a specific
microenvironment of dark, organic-rich water in peat soil
and which is strictly ornithophilic. Human infections occur
when other less fastidious mosquitoes venture into this envir-
onment. There are about five reported cases of Eastern equine
encephalitis a year in the United States.
Almost all infections are symptomatic, which could manifest
as either systemic infection or encephalitis. Young children are
more susceptible to develop encephalitis with its subsequent
serious neurological deficits. Systemic infection begins abruptly
with high fever, followed by myalgia, arthralgia, and malaise,
and lasts 1–2 weeks, and recovery is mostly complete. In patients
with encephalitis, headache, irritability, restlessness, drowsiness,
anorexia, vomiting, diarrhea, seizure, and coma occur a few days
after the onset of systemic infection. Children may develop
generalized or facial edema, weakness, tremor, muscular twitch-
ing, or dysautonomia. In fatal cases, death often occurs as
a result of either severe encephalitis or dysautonomia causing
myocardial insufficiency and respiratory failure, and usually
occurs 2–10 days after the onset of symptoms. Diagnosis is by
serologic testing and treatment is largely supportive. A vaccine
for Eastern equine encephalitis has been developed and used
successfully in humans, but it is not yet available for general use.
Eastern equine encephalitis is the most lethal arboviral
encephalitis in North America; the mortality rate ranges
between 30% and 75% and the majority of the survivors are
left with severe, disabling, and often progressive intellectual
and physical disabilities, which include personality disorders,
cranial nerve palsies, weakness, and remote symptomatic sei-
zures. The long-term outcome is even poorer; 9 years after
infection, up to 90% of patients had died because of associated
neurological deficits, and only 3% had recovered [1,25].
Chikugunya Virus
Chikungunya virus is an arthropod-borne alphavirus trans-
mitted by Aedes aegypti mosquitoes. The virus causes unpre-
dictable epidemics every 7–20 years in Africa and Asia and
Emerging and Less Common CNS Viral Encephalitides
re-emerged in Central Africa and Indonesia in 2000–2004.
The A226V mutation in the E1 gycoprotein facilitated replica-
tion in A. albopictus mosquitoes, causing re-emergence in the
form of devastating epidemics in countries around the Indian
Ocean since 2005. In 2013, the virus spread to the Americas
with the first documented local transmission in the Caribbean.
Post-mortem histopathology showed focal perivascular lym-
phocytic infiltration with microglial activation and foci of
active demyelination without gliosis.
Clinical manifestations follow a short incubation period of
2–10 days, when 78–96% of patients become symptomatic, most
with abrupt onset of high fever, fatigue, headaches, polyarthral-
gia, back pain, abdominal pain, nausea, vomiting, and diarrhea,
follow by maculopapular rash 2–5 days later in half of the
patients. Blood tests commonly show lymphopenia, thrombo-
cytopenia, and in some, anemia, hypocalcaemia, and elevated
liver enzymes and creatinine kinase. Some develop relapse or
chronic polyarthralgia, and less commonly, musculoskeletal
pain, sensory symptoms, fever, fatigue, and headaches, lasting
over a year in 20–66%. Atypical infection occurs in 0.1–0.3% of
patients, with infants most at risk. Neurological involvement
presents in up to a quarter of atypical infections; generalized or
focal onset seizures are seen in 12.5%, but as high as 80% of
pediatric infections, up to half of whom have status epilepticus.
In adults, seizures are more common in those with pre-existing
epilepsy or chronic illnesses. Intrapartum viremia leads to ver-
tical transmission in half of the neonates and causes severe
encephalopathy, with persistent disabilities in 20–44% of chil-
dren, including epilepsy, cerebral palsy, and other focal deficits.
MRI is abnormal in fewer than 20% of adults and shows
bilateral frontoparietal diffusion weighted image lesions.
In neonates, the lesions are more widespread and evolve into
vasogenic oedema, some ultimately into cavitation with gen-
eralized cerebral atrophy.
Diagnosis is established by serum or CSF serology (ELISA)
or rt-PCR. Treatment is supportive and a vaccine is under
active development. Overall, fatality is uncommon but
increased in the extremes of age and as high as 10% in atypical
infection.
Influenza Virus
Influenza viruses are single-strand negative RNA orthomyxo-
viruses. Of the three subtypes, influenza C infection is subcli-
nical. Influenza A and B viruses cause seasonal epidemics of
mainly mild and self-limiting respiratory tract infection with
abrupt onset of fever, cough, rhinitis, sore throat, headaches,
myalgia, and lethargy. Global pandemics can occur when new
subtype of viruses emerge through the process of antigenic
shift in influenza A and antigenic drift in both influenza
A and B viruses. Although uncommon and occurring at
a rate of only 1–4/100,000 person-years, associated neurologi-
cal involvement has been recognized for over a century.
The commonest manifestations are seizures and encephalopa-
thy, and others include encephalitis lethargica, Reye’s syn-
drome, stroke, acute disseminated encephalomyelitis,
transverse myelitis, Guillain–Barré syndrome, and other focal
deficits. Most of these are more common in children.
673
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H. T. Chong and C. T. Tan
Seizure is the commonest neurological manifestation and is
seen in approximately 70% of children with neurological com-
plications. It occurs in four clinical settings. The vast majority
are febrile seizures, which occur in approximately 1 in 5 children
hospitalized with seasonal influenza. The virus also causes sei-
zures in older children beyond the age of febrile convulsion,
recurrent seizures in epileptic patients, and seizure in the setting
of encephalopathy, including acute necrotizing encephalopathy.
Influenza virus causes significantly higher rates of febrile sei-
zures and repeated seizures compared to parainfluenza virus
and adenovirus [4]. Both simple and complex febrile seizures
are seen. Investigations are mainly normal, though occasionally
brain MRI shows increased T2 signal in hippocampus and
splenium or mild gyral swelling, and EEG shows diffuse slowing,
spike-and-waves discharges or burst suppression.
Encephalopathy is the second commonest neurological
complication, and varies in severity from mild confusion to
coma. About 80% of patients are children and the condition
appears to be more common and more severe in Japan for
unknown reason(s). Seizures and disturbances in conscious
state are the two commonest manifestations; other features
include hallucination, abnormal behavior, and upper motor
neuron lesion signs. Investigations are usually normal, though
CSF may show pleocytosis and/or raised protein, EEG diffuse
slow waves, and MRI non-specific T2 hyperintensity in the
splenium or other areas, cerebral oedema or changes similar
to posterior reversible encephalopathy and ADEM.
Approximately 10–25% of children with encephalopathy suffer
from acute necrotizing encephalopathy, which presents with
rapid deterioration to coma within a few days and MRI show-
ing necrosis in bilateral thalami, cerebral white matter, cere-
bellum, and brainstem. Familial and recurrent cases are
associated with mutations in the RANBP2 gene.
Almost all patients with febrile seizures recover comple-
tely. Prognosis of encephalopathy is significantly worse, with
mortality ranging from 20% to 40% and long-term sequelae
from 30% to 60%. The prognosis of acute necrotizing ence-
phalopathy is the worst, though poorly documented outside
Japan.
Diagnosis is established by first performing a screening test
on nasopharyngeal swab with monoclonal antibodies,
and confirmed by PCR and serotyping. Treatment is suppor-
tive [7].
Zika Virus
Zika virus, first discovered in the Zika forest in Uganda, is an
arthropod-borne flavivirus with non-human primates as its
primary host. Apart from transmission by various species of
Aedes mosquitoes, it is also transmitted vertically, through
sexual intercourse, and possibly through blood transfusion
and breast milk. It has caused sporadic cases in Southeast
Asia, and in 2005–2016, multiple outbreaks in the Pacific
islands, where it was associated with Guillain–Barré syndrome.
In early 2015, the virus spread to the Americas and caused
a massive outbreak in Brazil, where an increased number of
neonates born with microcephaly was noted.
674
The incubation period of Zika infection is unknown,
though likely to be less than a week. Only 20% of infections
are symptomatic, with 90% of these presenting with macu-
lopapular rash, often pruritic, and over half with low-grade
fever, arthralgia, and conjunctivitis. Other common symp-
toms include headaches, myalgia, vomiting, swelling of the
extremities, and hearing disturbances. Infection was asso-
ciated with acute motor axonal variant of Guillain–Barré
syndrome, and probably myelitis and meningoencephalitis,
in the Pacific island outbreaks. In Brazil, 29% of infected
pregnant women had fetal abnormalities on ultrasound, the
commonest of which was microcephaly, but also included
absence of corpus callosum, cerebral atrophy, hydranence-
phaly, gyral abnormalities, ventriculomegaly, calcification,
hydrops fetalis, anhydramnios, intrauterine growth retar-
dation, and eye abnormality in 35%. Intellectual impair-
ment and epilepsy complicate some of these abnormalities.
The risk of microcephaly was highest at 95 in 10,000 cases if
infection occurred during the first trimester, but remained
elevated if infection occurred as late as 18 weeks of gesta-
tional age.
Diagnosis is established by rt-PCR during the first week
of infection, and IgM captured ELISA (MAC-ELISA) subse-
quently. Viral RNA becomes undetectable a week after
symptom onset though PCR may be positive for up to 10
weeks in pregnant mothers of infected fetuses. Serology test
is falsely positive with current infection of other flaviviruses,
especially dengue, in which case plaque reduction neutrali-
“…other
zation test (PRNT) may confirm the diagnosis. However,
flaviviral
PRNT is expensive, time consuming, involves handling of infection or
live virus, and may not be useful in patients who had pre- vaccination.”
vious exposure to other flaviviral infection of vaccination.
An effective vaccine is not yet available and treatment is
supportive. Multiple concurrent preventive and mosquito
control measures are more important in outbreak manage-
ment [21].
Murray Valley Encephalitis
Murray Valley encephalitis virus is a flavivirus found only in
Australia, Papua New Guinea, and perhaps the eastern islands
of Indonesia. The Culex mosquito, especially C. annulirostris, is
the vector, and wading birds its natural reservoir and host.
Horses, feral pigs, and cattle may act as additional reservoir or
amplifying hosts. Outbreaks of Murray Valley encephalitis
have been reported throughout Australia, and sporadic cases
occur annually, mainly in the Kimberly region of northern
Western Australia and in the Northern Territory. Only 1 in
500–5000 infections is symptomatic though infection is more
common and severe in children and infants. Clinically, the
patients present with sudden onset of fever, headache, vomit-
ing, dizziness, weakness, brainstem signs, seizures, and myo-
clonus. Mortality ranges from 15% to 31% and half of the
survivors have significant residual neurological deficits.
There is no specific antiviral therapy for Murray Valley ence-
phalitis [24].
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Emerging and Less Common CNS Viral Encephalitides

Summary exposure and places travelled are important steps to diag-

nosis. Ready access to the pattern of geographical distribu-
Viral encephalitis is an important, albeit less common, cause
tion of various viruses is helpful (see Figure 91.1). Even
of symptomatic seizure and epilepsy. Presentations are var-
more challenging are the emerging and newly emerged
ied, nonspecific and may mimic other conditions such as
viruses, given the changes in the virulence, and hence clin-
autoimmune encephalitis in human herpesvirus 6 limbic
ical presentation, and the relative lack of documented infor-
encephalitis, and systemic vasculitis in Nipah infection.
mation of such infections. Although treatment is mostly
Routine investigations, including CSF analysis, EEG and
supportive, prognosis, and in some viruses, successful pre-
MRI, though provide some clues, are often not specific,
vention of large scale outbreaks depend on correct identifi-
and the diagnosis challenging especially among returning
cation the infectious agents.
travelers. A high index of suspicion with detail history of

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The Causes of Epilepsy

Common and Uncommon Causes in Adults and
Children
SECOND EDITION
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C:/ITOOLS/WMS/CUP-NEW/14526440/WORKINGFOLDER/SHORVON/9781108420754PRE.3D iii [1–24] 6.9.2018 8:05AM

The Causes of Epilepsy

Common and Uncommon Causes in Adults and
Children
Second Edition

Edited by
Simon Shorvon
UCL Institute of Neurology

Renzo Guerrini
University of Florence

Steven Schachter
Harvard Medical School, Boston

Eugen Trinka
Paracelsus Medical University, Salzburg
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Names: Shorvon, S. D. (Simon D.) editor.
Title: The causes of epilepsy : diagnosis and investigation / edited by
Simon Shorvon, UCL Institute of Neurology [and three others].
Description: Second edition. | Cambridge, United Kingdom ; New York,
NY : Cambridge University Press, 2018.
Identifiers: LCCN 2018021686 | ISBN 9781108420754 (hardback)
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Every effort has been made in preparing this book to provide accurate and
up-to-date information that is in accord with accepted standards and
practice at the time of publication. Although case histories are drawn
from actual cases, every effort has been made to disguise the identities of
the individuals involved. Nevertheless, the authors, editors, and
publishers can make no warranties that the information contained herein
is totally free from error, not least because clinical standards are
constantly changing through research and regulation. The authors,
editors, and publishers therefore disclaim all liability for direct or
consequential damages resulting from the use of material contained in
this book. Readers are strongly advised to pay careful attention to
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Contents
List of Contributors x
Foreword xix
Preface to the Second Edition xxi
Preface to the First Edition – an Act of Supererogation? xxii

Section I Introduction 12 Approach to the Diagnosis of Epilepsy Syndromes

with Multiple Causes 103
1 Concept of Causation in Epilepsy 1 Patrick Van Bogaert
Simon Shorvon
13 Approach to the Diagnosis of Causation in Epilepsy
2 Epileptogenesis in Idiopathic Epilepsy 8 in Adults 112
Snezana Maljevic and Holger Lerche Michael R. Sperling
3 An Introduction to Epilepsy Genetics 24
Arjune Sen and Michael R. Johnson
Section III Idiopathic Epilepsies
4 Epileptogenesis in Symptomatic Epilepsy 35
14 Idiopathic Generalized Epilepsies 121
Andreas Schulze-Bonhage
Carla Marini and Renzo Guerrini
5 Animal Models of Causation of Epilepsy 46
15 Benign Partial Epilepsies of Childhood 134
Massimo Mantegazza
Roberto H. Caraballo and Natalio Fejerman

Section II Approaches to the Clinical Section IV Symptomatic Epilepsies of Genetic

Investigation and Diagnosis of Cause or Developmental Origin
6 Approach to the Diagnosis of Neonatal Seizures 53
(a) Single Gene Disorders and Inborn Errors of
Elissa Yozawitz and Ronit Pressler Metabolism
7 Approach to the Genetic Diagnosis of Epileptic 16 Benign Familial Neonatal Epilepsy (BFNE) 143
Encephalopathies and Developmental Jelena Radic, Ronit Pressler and J Helen Cross
Encephalopathies with Epilepsy of Early
17 Sleep-Related Hypermotor Epilepsy (SHE) 147
Childhood 60
Paolo Tinuper and Francesca Bisulli
Renzo Guerrini, Davide Mei and Simon Shorvon
18 Genetic Epilepsy with Febrile Seizures Plus
8 Approach to the Diagnosis Of Childhood-Onset
(GEFS+) 154
Epilepsy Associated with Developmental Delay 69
Iris Unterberger and Julia Höfler
Sarah Aylett
19 Dravet Syndrome and Other SCN1A
9 Approach to the Diagnosis of Cortical
Disorders 158
Developmental Disorders and their Clinical
Carla Marini and Renzo Guerrini
Genetics 76
William Dobyns and Nataliya Di Donato 20 Familial Lateral Temporal Lobe Epilepsy 166
Roberto Michelucci and Carlo Nobile
10 Approach to the Diagnosis of the Inborn Errors of
Metabolism Associated with Epilepsy and their 21 Familial Focal Epilepsy with Variable Foci 171
Clinical Genetics 86 Chantal Depondt
Richard E. Frye and Stephen G. Kahler
22 PCDH19 Mutations Related Epilepsy: Phenotype
11 Approach to the Diagnosis of Epilepsy Presenting and Genotype 175
with Myoclonus 95 Carla Marini and Renzo Guerrini
Aidan Neligan and Simon Shorvon

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Contents

23 CDKL5 Encephalopathy 188 43 Hyperinsulinism–Hyperammonemia and Biotin

Celina von Stülpnagel and Gerhard Kluger Pathway Defects 309
Isabelle Gourfinkel-An and Vincent Navarro
24 KCNQ2 Encephalopathy 193
Tiziana Pisano and Renzo Guerrini 44 Other Single-Gene Disorders 312
Mario Mastrangelo and Vincenzo Leuzzi
25 FOXG1 Encephalopathy 196
Nicola Specchio and Nicola Pietrafusa (b) Progressive Myoclonic Epilepsies
45 Unverricht–Lundborg Disease (or Progressive
26 STXBP1 Encephalopathy 202 Myoclonus Epilepsy Type 1) 326
Mitsuhiro Kato Reetta Kälviäinen and Anna-Elina Lehesjoki
27 Rett Syndrome 206 46 Dentatorubral-Pallidoluysian Atrophy;
Andreea Nissenkorn and Bruria Ben Zeev DRPLA 330
28 Epilepsy and GLUT1 DS 212 Kiyoshi Egawa and Yukitoshi Takahashi
Cigdem I. Akman and Darryl C. De Vivo 47 Lafora Body Disease 336
29 Other Rare Single-Gene Disorders Causing Epileptic Berge A. Minassian and Pasquale Striano
Encephalopathy 219 48 Epilepsies in Mitochondrial
Rima Nabbout Cytopathies 342
30 Mitochondrial Epilepsies 225 Laurence A. Bindoff and Bernt A. Engelsen
Shamima Rahman 49 Neuronal Ceroid Lipofuscinoses 352
31 Lysosomal Disorders and Epilepsy 234 Ruth E. Williams
Mirella Filocamo, Elena Procopio and Amelia 50 Sialidosis 359
Morrone Silvana Franceschetti and Laura Canafoglia
32 Peroxisomal Disorders and Epilepsy 250 51 Progressive Myoclonic Epilepsies: Other Rarer
Hendrik Rosewich and Jutta Gärtner Causes 364
33 Menkes’ Disease 255 Helle Hjalgrim and Reetta Kälviäinen
Alberto Verrotti and Chiara Mazzocchetti (c) Neurocutaneous Syndromes
34 Neuroacanthocytosis 259 52 Tuberous Sclerosis Complex 369
Anna C. Jansen and Ruth H. Walker Anna M. Larson, Catherine J. Chu and Elizabeth A.
Thiele
35 Organic Acid and Amino Acid Metabolism
Disorders 263 53 Neurofibromatosis 378
Elena Procopio, Alice Donati and Renzo Guerrini Patrick Adjei

36 Porphyrias 274 54 Sturge–Weber Syndrome 382

Saba Harrach and Joshua Ewen Alexis Arzimanoglou and Simon Shorvon

37 Pyridoxine-Dependent Epilepsy 281 55 Other Neurocutaneous Syndromes 389

Sidney M. Gospe Jr. Gerhard Kurlemann

38 Fatty Acid Oxidation Disorders 288 (d) Epilepsies Associated with Chromosomal
Andrea L. Gropman Abnormalities
56 Copy Number Variations Causing Epilepsy 398
39 GABA Syndromes 292 Antonietta Coppola and Pasquale Striano
Phillip L. Pearl and K. Michael Gibson
57 MECP2 Duplication Syndrome 406
40 Disorders of Creatine Metabolism and Epilepsy 296 Maria Paola Canevini and Aglaia Vignoli
Carmen Fons and Jaume Campistol
58 Down Syndrome 411
41 Epilepsy Caused by Congenital Disorders of Nadia Bahi-Buisson and Monika Eisermann
Glycosylation 300
Rita Barone and Agata Fiumara 59 Fragile X Syndrome 419
Ryan E. Gill and Carl E. Stafstrom
42 Urea Cycle Disorders 305
Nicholas Ah Mew, Debra S. Regier and Marshall L. 60 4p Deletion (Wolf–Hirschhorn) Syndrome 427
Summar Agatino Battaglia

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Contents

61 Inverted Duplicated Chromosome 15 (Isodicentric (b) Epilepsies Associated with Cerebral Tumours
Chromosome 15) 431 78 Epilepsy Associated with Glioma 561
Agatino Battaglia Markus Hutterer and Anette Leibetseder
62 Ring Chromosome 20 435 79 Epilepsy Associated with Ganglioglioma,
Geneviève Bernard, Laurence Gauquelin and Dysembryoplastic Neuroepithelial Tumor, and
Frederick Andermann Related Tumors 570
Ingmar Blümcke
63 Ring Chromosome 14 and Other Rare Ring
Chromosomal Disorders 439 80 Hypothalamic Hamartoma and Gelastic
Federico Vigevano and Marina Trivisano Epilepsy 581
Charuta Joshi and Angus Wilfong
64 Angelman Syndrome 444
Karine Pelc and Bernard Dan 81 Epilepsy Associated with Meningioma 585
Bartosz T. Grobelny and Howard L. Weiner
(e) Epilepsies Associated with Developmental Anomalies
of Cerebral Structure 82 Metastatic Disease 589
65 Hemimegalencephaly 448 Rolando F. Del Maestro, Abdulrahman Sabbagh,
Alissa M. D’Gama and Annapurna Poduri Ahmed Lary and Marie-Christine Guiot
66 Focal Cortical Dysplasia 455 (c) Epilepsies Associated with Cerebral Infection
Renzo Guerrini, Carmen Barba and Michael 83 Epilepsy Associated with Viral Encephalitis 597
Duchowny Johann Sellner and Eugen Trinka
67 Agyria–pachygyria band spectrum 466 84 Bacterial Meningitis and Focal Suppurative
Elena Parrini and Renzo Guerrini Intracranial Infections in Children 607
Thom O’Neill and Richard F. M. Chin
68 Corpus Callosum and Epilepsies 475
Gerhard Bauer and Iris Unterberger 85 Bacterial Meningitis and Pyogenic Abscess in
Adults 616
69 Polymicrogyria and Schizencephaly 480
Lina Nashef and Fahmida A. Chowdhury
Renzo Guerrini and Carmen Barba
86 Epilepsy Associated with Malaria 628
70 Periventricular Nodular Heterotopia 492
Charles R. J. C. Newton
Giorgi Kuchukhidze and Eugen Trinka
87 Epilepsy Associated with Neurocysticercosis 632
71 Microcephaly 497
Hector H. Garcia
M. Elizabeth Ross
88 Other Parasitic Diseases 638
72 Arachnoid Cysts 508
Manish Modi and Gagandeep Singh
Gianpiero Tamburrini and F. Bianchi
89 Epilepsy Associated with Tuberculosis 647
73 Disorders Associated with Tubulinopathies and
Nadir E. Bharucha and Roberta H. Raven
mTORopathies 513
Peter Crino 90 HIV and Seizures 656
Parthasarathy Satishchandra and Sanjib Sinha
91 Emerging and Less Common Central Nervous System
Section V Symptomatic Epilepsies of Acquired Viral Encephalitides 666
Origin H. T. Chong and C. T. Tan
(a) Epilepsies Associated with Cerebral Trauma (d) Epilepsies Associated with Cerebrovascular Disease
74 Epilepsy Associated with Head Injury 521 92 Epilepsy Associated with Intracerebral
Simon Shorvon and Eugen Trinka Hemorrhage 676
75 ‘De Novo’ Epilepsy after Neurosurgery 535 Raimund Helbok and Alois J. Schiefecker
Charles E. Polkey 93 Epilepsy Associated with Subarachnoid
Hemorrhage 685
76 Epilepsy after epilepsy surgery 540
Raimund Helbok, Alois J. Schiefecker and Ronny
Andre Palmini, Eliseu Paglioli and Taiane Pigozzo
Beer
77 Epilepsy after Abusive Head Trauma 551
94 Epilepsy and Cerebrovascular Disease 693
Alessio De Ciantis and Renzo Guerrini
Uma Menon and R. Eugene Ramsay

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Contents

95 Epilepsy Associated with Arteriovenous

Malformations 702
Section VI Provoking Factors and Provoked
Abdulrahman Y Alturki, Ajith Thomas and Epilepsies: Reflex Seizures
Christopher S. Ogilvy 110 Fever as a Precipitating Factor for Epileptic
96 Epilepsy Associated with Cavernous Seizures 805
Malformations 708 Martin Holtkamp and Pawel Fidzinski
Andrew C. Vivas and Fernando L. Vale 111 The Menstrual Cycle and Catamenial Epilepsy 811
97 Epilepsy Associated with Other Vascular Andrew G. Herzog
Disorders 714 112 Sleep and Epilepsy 821
Erik Taubøll and Leif Gjerstad Erik K. St. Louis
(e) Epilepsies Associated with Cerebral Immunological 113 Electrolyte and Sugar Disturbances 830
Disorders
Simon D. Shorvon and Bindu Menon
98 Rasmussen’s Encephalitis and Related
Conditions 721 114 Drug-Induced Seizures 839
Antonio Gambardella and Frederick Andermann Francesco Brigo and Eugen Trinka
99 Epilepsy Associated with Systemic Lupus 115 Recreational and Illicit Drugs Causing Seizures and
Erythematosus and Other Collagen Vascular Epilepsy 848
Diseases 727 Steven V. Pacia and Thomas Boes
Anna Rosati, Andrea Taddio and Rolando Cimaz
116 Alcohol- and Toxin-Induced Seizures 852
100 Epilepsy Associated with Inflammatory and Adam Strzelczyk and Felix Rosenow
Immunological Diseases of the Central Nervous
System 735 117 Visual Stimuli, Photosensitivity and Photosensitive
Epilepsy 863
Tiziana Granata and Annamaria Vezzani
Dorothée Kasteleijn-Nolst Trenité, Laura
101 Epilepsy in Multiple Sclerosis and Other Acquired Cantonetti and Pasquale Parisi
Demyelinating Diseases 749
118 Startle-Induced and Other Sensory-Induced
Mark Manford and Sybil Stacpoole
Epilepsy 872
102 Immune-Mediated Epilepsy 757 Takashi Matsudaira and Yushi Inoue
Christian G. Bien
119 Primary Reading Epilepsy 878
(f) Epilepsies Associated with Other Cerebral Disorders Matthias J. Koepp
103 Hippocampal Sclerosis 763
120 Auditory-Induced Epilepsy 882
Fernando Cendes and Márcia Elisabete Morita
Carlo Di Bonaventure
104 Epilepsy Associated with Psychiatric
Disorders 772 121 Seizures Induced by Eating, a Rare but Special Form
of Reflex Epilepsy 888
Marco Mula
Dorothée Kasteleijn-Nolst Trenité
105 Hydrocephalus and Porencephaly 777
122 Hot Water Epilepsy 890
Pierangelo Veggiotti and Federica Teutonico
Parthasarathy Satishchandra, SanjibSinha and
106 Epilepsy Associated with Alzheimer’s Disease and Anuranjan Anand
Other Adult Neurodegenrative Disorders 783
123 Reflex Epilepsy with Higher-Level Processing 898
Francesco Brigo and Raffaele Nardone
Peter Wolf
107 Epilepsy Associated with Eclampsia and the
Posterior Reversible Encephalopathy
Syndrome 790 Section VII Status Epilepticus
Page Pennell and Mary O’Neal
124 The Causes of Status Epilepticus in Children 905
108 Cerebral Palsy 794 Anna Rosati and Renzo Guerrini
Sameer M. Zuberi and Andreas Brunklaus
125 The Common Causes of Convulsive Status
109 Seizures and Epilepsy Associated with Pertussis and Epilepticus in Adults 915
Other Vaccinations 801 Francesco Brigo and Eugen Trinka
Simon D. Shorvon

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126 Uncommon Causes of Status Epilepticus 939 128 The Causes of Epilepsia Partialis Continua 963
Aidan Neligan and Simon D. Shorvon Attila Rácz and Christian E. Elger
127 Causes of Nonconvulsive Status Epilepticus in
Adults 948
Francesco Brigo and Eugen Trinka
Index 970

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Contributors

Rita Barone
Patrick Adjei
Child Neurology and Psychiatry Unit, Department of Clinical
Department of Medicine and Therapeutics, School of Medicine
and Experimental Medicine, University of Catania, Catania,
and Dentistry, College of health Sciences, University of Ghana,
Italy
Legon, Accra, Ghana
Agatino Battaglia
Nicholas Ah Mew
Division of Medical Genetics, Department of Pediatrics,
Rare Disease Institute, Children’s National Medical Center,
University of South Dakota, Sanford School of Medicine, Sioux
Washington, DC, USA
Falls, SD, USA
Cigdem I. Akman
Gerhard Bauer
Department of Neurology, Division of Pediatric Neurology
Department of Neurology, Innsbruck Medical University,
Columbia University College of Physicians and Surgeons, New
Innsbruck, Austria
York, NY, USA
Ronny Beer
Abdulrahman Y. Alturki
Department of Neurology, Neurocritical Care Unit, Medical
Endovascular and Operative Neurovascular Surgery,
University of Innsbruck, Innsbruck, Austria
BIDMC Neurosurgery & Brain Aneurysm Institute. Harvard
Medical School, Boston, MA, USA Geneviève Bernard
Anuranjan Anand Pediatric Neurologist and Fellow in Neurogenetics, CHUM
and Saint-Justine’s Hospital, Montreal, Québec, Canada
Molecular Biology and Genetics unit, JNCASR, Bangalore,
India Nadir E. Bharucha
Frederick Andermann Departments of Neurology and Neuroepidemiology, Bombay
Hospital Institute of Medical Science, Mumbai, India
Institute of Neurology, Department of Medical and Surgical
Sciences, University Magna Graecia, Catanzaro, Italy F. Bianchi
Alexis Arzimanoglou Pediatric Neurosurgery, Institute of Neurosurgery, Catholic
University Medical School, Rome, Italy
Department of Epilepsy, Sleep and Pediatric Neurophysiology,
University Hospitals of Lyon (HCL) and Hôpital, Femme Mère Christian G. Bien
Enfant, Lyon, France Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld,
Sarah Aylett Germany
Neurosciences, Great Ormond Street Hospital NHS Laurence A. Bindoff
Foundation Trust and Clinical Neurosciences UCL Department of Clinical Medicine (K1), University of Bergen,
Great Ormond Street Institute of Child Health, Bergen, Norway
London UK
Francesca Bisulli
Nadia Bahi-Buisson Department of Neurological Sciences, University of Bologna,
Pediatric Neurology, Necker Enfants Malades University Bologna, Italy
Hospital, APHP, Paris, France
Ingmar Blümcke
Carmen Barba Department of Neuropathology, University Hospital Erlangen,
Neuroscience Department, Children’s Hospital A. Meyer- Erlangen, Germany
University of Florence, Florence, Italy

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List of Contributors

Thomas Boes J Helen Cross

NYU Comprehensive Epilepsy Center, New York, NY, USA UCL-Great Ormond Street Institute of Child Health, London,
UK
Francesco Brigo
Department of Neurology, Franz Tappeiner Hospital, Merano, Bernard Dan
Italy Université Libre de Bruxelles (ULB), Brussels, Belgium
Andreas Brunklaus Alessio De Ciantis
Fraser of Allander Neurosciences Unit, Royal Hospital for Department of Neuroscience, Anna Meyer Children’s
Children, Glasgow, UK Hospital, University of Florence, Florence, Italy
Jaume Campistol Chantal Depondt
Pediatric Neurology Department, Sant Joan de Déu Hospital, Department of Neurology, Hôpital Erasme, Université Libre de
Barcelona University, Barcelona, Spain Bruxelles, Brussels, Belgium
Laura Canafoglia Rolando F. Del Maestro
Neurophysiopathology, IRCCS Foundation C. Besta Neurosurgical Simulation Research and Training Centre,
Neurological Institute, Milan, Italy Department of Neurology and Neurosurgery, McGill
University, Montreal, Quebec, Canada
Maria Paola Canevini
Department of Health Sciences, Università degli Studi di Darryl C. De Vivo
Milano, Milan, Italy Department of Neurology, Division of Pediatric Neurology
Columbia University College of Physicians and Surgeons, New
Laura Cantonetti York, NY, USA
Bambino Gesù Children Hospital, Palidoro, Rome, Italy
Alissa M. D’Gama
Roberto H. Caraballo Division of Genetics and Genomics, Boston
Department of Neurology, Hospital Nacional de Pediatria, Children’s Hospital, Harvard Medical School, Boston, MA,
“Prof. Dr. Juan P. Garrhan,” Buenos Aires, Argentina USA
Fernando Cendes Carlo Di Bonaventure
Department of Neurology, University of Campinas – Epilepsy Unit, Department of Neurological Sciences, “La
UNICAMP, Campinas, SP, Brazil Sapienza” University of Rome, Rome, Italy
Richard F. M. Chin Nataliya Di Donato
Royal Hospital for Sick Children, Edinburgh, UK Institute for Clinical Genetics, TU Dresden, Dresden,
Department of
Neurology, H. T. Chong Germany
Western
Division of Neurology, Faculty of Medicine, University of William Dobyns
Health,
Melbourne, Malaya, Kuala Lumpur, Malaysia Departments of Neurology and Pediatrics, Center for
Australia
Fahmida A. Chowdhury Integrative Brian Research, Seattle Children’s Research
Institute, Seattle, WA, USA
King’s College Hospital, London, UK
Alice Donati
Catherine J. Chu
Pediatric Neurology and Metabolic Units Neuroscience
Department of Neurology, Programs in Pediatric Epilepsy and
Department, Children’s Hospital A. Meyer-University of
Neurophysiology, Massachusetts General Hospital, MA, USA
Florence, Florence, Italy
Rolando Cimaz
Michael Duchowny
Rheumatology Unit, Anna Meyer Children’s Hospital,
Neuroscience Program and the Comprehensive Epilepsy
Department of Pediatrics, University of Florence, Florence,
Center, Miami Children’s Hospital, FL, USA
Italy
Kiyoshi Egawa
Antonietta Coppola
Pediatric Department, Hokkaido University Graduate School
Epilepsy Centre, Neurology Department Of Neurology,
of Medicine, Hokkaido, Japan
Reproductive and Odontostomalogy, Federico II University,
Naples, Italy Monika Eisermann
Peter Crino Department of Clinical Neurophysiology, Necker
Enfants Malades Hospital, Université Paris Descartes, Paris,
Department of Neurology, University of Maryland School of
France
Medicine, MD, USA

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List of Contributors

Christian E. Elger Leif Gjerstad

Department of Epileptology, University of Bonn Medical Department of Neurology, Oslo University Hospital –
Center, Bonn, Germany Rikshospitalet, Oslo, Norway
Bernt A. Engelsen K. Michael Gibson
Department of Clinical Medicine (K1), University of Bergen, Division of Experimental and Systems Pharmacology, College
Bergen, Norway of Pharmacy, Washington State University, Spokane, WA,
USA
Joshua Ewen
Kennedy Krieger Institute, Baltimore, MD, Ryan E. Gill
USA Department of Neurology and Developmental Medicine,
Kennedy Krieger Institute, Johns Hopkins University School of
Natalio Fejerman Medicine, Baltimore, MD, USA
Department of Neurology, Hospital Nacional de Pediatria,
“Prof. Dr. Juan P. Garrhan,” Buenos Aires, Argentina Isabelle Gourfinkel-An
AP-HP, Epilepsy unit, Pitié-Salpêtrière Hospital and
Pawel Fidzinski Sorbonne University, UPMC University Paris, Paris,
Epilepsy-Center Berlin-Brandenburg, Department of France
Neurology, Charité – Universitätsmedizin Berlin, Berlin,
Germany Sidney M. Gospe Jr.
Division of Pediatric Neurology, University of Washington,
Mirella Filocamo Seattle, WA, USA
Centro di Diagnostica Genetica e Biochimica delle Malattie
Metaboliche, Istituto G. Gaslini, Genova, Italy Tiziana Granata
Department of Pediatric Neuroscience,
Agata Fiumara IRCCS-Fondazione Istituto Neurologico “C.Besta”, Milano,
Regional Referral Center for Metabolic Diseases, Pediatric Italy
Clinic, Department of Clinical and Experimental Medicine –
University of Catania, Catania, Italy Bartosz T. Grobelny
Department of Neurosurgery, NYU Langone Medical Center,
Carmen Fons New York, NY, USA
Pediatric Neurology Department, Sant Joan de Déu Hospital,
Barcelona University, Barcelona, Spain Andrea L. Gropman
Division of Neurogenetics and Neurodevelopmental
Silvana Franceschetti Disabilities, Children’s National Health System
Neurophysiopathology, IRCCS Foundation C. Besta
Neurological Institute, Milan, Italy The George Washington University of the Health Sciences,
Washington, DC, USA
Richard E. Frye
Barrow Neurological Institute, Phoenix Children’s Hospital, Renzo Guerrini
Phoenix, AZ, USA Children’s Hospital A. Meyer-University of Florence, Firenze,
Italy
Antonio Gambardella
Institute of Neurology, Department of Medical and Surgical Marie-Christine Guiot
Sciences, University Magna Graecia Catanzaro, Catanzaro, Department of Neuropathology, Montreal Neurological
Italy Institute and Hospital, McGill University, Montreal, Quebec,
Canada
Hector H. Garcia
Cysticercosis Unit, Instituto Nacional de Ciencias Saba Harrach
Neurologicas, Lima, Peru Psychiatry Department, Kaiser Franz Josef Spital Wien,
Vienna, Austria
Jutta Gärtner
Department of Pediatrics and Adolescent Medicine, Division Raimund Helbok
of Pediatric Neurology, University Medical Center Göttingen, Department of Neurology, Neurocritical Care Unit, Medical
Göttingen, Germany University of Innsbruck, Innsbruck, Austria

Laurence Gauquelin Andrew G. Herzog

Department of Neurology and Neurosurgery, McGill Harvard Neuroendocrine Unit, Beth Israel Deaconess Medical
University, Montreal, Canada Center, Boston, MA, USA

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List of Contributors

Helle Hjalgrim Giorgi Kuchukhidze

Danish Epilepsy Centre Filadelfia, University of Southern Department of Neurology, Christian Doppler Klinik,
Denmark, Dianalund, Denmark Paracelsus Medical University of Salzburg, Salzburg, Austria
Julia Höfler Gerhard Kurlemann
Department of Neurology, Paracelsus Medical University, Department of Neuropediatrics, University Children’s
Salzburg, Austria Hospital Münster, Albert, Münster, Germany
Martin Holtkamp Anna M. Larson
Epilepsy-Center Berlin-Brandenburg, Department of Department of Neurology, Programs in Pediatric Epilepsy
Neurology, Charité – Universitätsmedizin Berlin, Berlin, and Neurophysiology, Massachusetts General Hospital, MA,
Germany USA
Markus Hutterer Ahmed Lary
Neurooncology Working Group, Department of Neurology 1 – Neurosciences Department, International Medical Center,
Neuromed Campus, Kepler University Hospital Linz, Linz, Jeddah, Makkah Region, Saudi Arabia
Austria
Anna-Elina Lehesjoki
Yushi Inoue Folkhälsan Research Center and Medicum, University of
Shizuoka Institute of Epilepsy and Neurological Disorders, Helsinki, Helsinki Finland
Aoi-ku, Shizuoka, Japan
Anette Leibetseder
Anna C. Jansen Neurooncology Working Group, Department of Neurology 1 –
Pediatric Neurology Unit, Department of Pediatrics, UZ Neuromed Campus, Kepler University Hospital Linz, Linz,
Brussel, Brussels, Belgium Austria
Michael R. Johnson Holger Lerche
Division of Brain Sciences, Imperial College London, London, Department of Neurology and Epileptology, Hertie Institute
UK for Clinical Brain Research, University of Tübingen, Tübingen,
Germany
Charuta Joshi
Childrens Hospital Colorado, Epilepsy Team, Aurora, CO, Vincenzo Leuzzi
USA Department of Pediatrics, Child Neurology and Psychiatry,
“Sapienza” University of Rome, Rome, Italy
Stephen G. Kahler
Arkansas Children’s Research Institute, Little Rock, AR, USA Snezana Maljevic
The Florey Institute of Neuroscience and Mental Health,
Reetta Kälviäinen Melbourne, Australia
Epilepsy Center/Neurocenter, Kuopio University Hospital and
Institute of Clinical Medicine, University of Eastern Finland, Mark Manford
Kuopio, Finland University of Cambridge, Cambridge University NHS
Foundation Trust, Cambridge, UK
Dorothée Kasteleijn-Nolst Trenité
University of Utrecht, Utrecht, The Netherlands Massimo Mantegazza
Institute of Molecular and Cellular Pharmacology (IPMC),
Mitsuhiro Kato University Côte d’Azur and CNRS UMR7275, Provence-
Department of Pediatrics, Showa University School of Alpes-Côte d’Azur, France
Medicine, Tokyo, Japan
Carla Marini
Gerhard Kluger Paediatric Neurology Unit and Laboratories, Children’s
Schön Klinik Vogtareuth, Department of Neuropaediatrics Hospital A. Meyer, Florence, Italy
and Neurological Rehabilitation, Epilepsy Centre for Children
and Adolescents, Day clinic for Neuropaediatrics, Vogtareuth, Mario Mastrangelo
Germany Department of Pediatrics, Child Neurology and Psychiatry,
“Sapienza” University of Rome, Rome, Italy
Matthias J. Koepp
Department of Clinical and Experimental Epilepsy, UCL Takashi Matsudaira
Institute of Neurology, London, UK Shizuoka Institute of Epilepsy and Neurological Disorders,
Aoi-ku, Shizuoka, Japan

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List of Contributors

Chiara Mazzocchetti Charles R. J. C. Newton

Department of Pediatrics, University of L’Aquila, Laquila, University of Oxford, Oxford, UK
Italy
Andreea Nissenkorn
Davide Mei Service for Rare Disorders, Edmond and Lilly Safra Children
Children’s Hospital A. Meyer-University of Florence, Firenze, Hospital, Chaim Sheba Medical Center, Tel Ha Shomer, Israel
Italy
Carlo Nobile
Bindu Menon Department of Biomedical Sciences, University of Padua,
Department of Neurology, Narayana Medical College and Padova, Italy
Superspeciality Hospital, Nellore, Andhra Pradesh, India
Christopher S. Ogilvy
Uma Menon Harvard Medical School, BIDMC Brain Aneurysm Institute,
International Center for Epilepsy, Ochsner Medical Center, Endovascular and Operative Neurovascular Surgery, Boston,
New Orleans, LA, USA MA, USA
Roberto Michelucci Mary O’Neal
IRCCS-Institute of Neurological Sciences of Bologna, Unit of Brigham and Women’s Hospital, Harvard Medical School,
Neurology, Bellaria Hospital, Bologna, Italy Boston, MA, USA
Berge A. Minassian Thom O’Neill
Program in Genetics and Genome Biology and Division of Royal Hospital for Sick Children, Edinburgh, UK
Neurology, Department of Paediatrics, The Hospital for
Sick Children and the University of Toronto, Toronto, Steven V. Pacia
Canada NYU School of Medicine, NYU Comprehensive Epilepsy
Center, New York, NY, USA
Amelia Morrone
Paediatric Neurology Unit and Laboratories, Meyer Children’s Andre Palmini
Hospital, Firenze, Italy Neurology Service and School of Medicine, Hospital São Lucas,
Pontifícia Universidade Católica do Rio Grande do Sul
Manish Modi (PUCRS), Porto Alegre, RS, Brazil
Department of Neurology, Postgraduate Institute of Medical
Education & re-search, Chandigarh, India Eliseu Paglioli
Neurology Service and School of Medicine, Hospital São Lucas,
Márcia Elisabete Morita Pontifícia Universidade Católica do Rio Grande do Sul
Department of Neurology, University of Campinas – (PUCRS), Porto Alegre, RS, Brazil
UNICAMP, Campinas, SP, Brazil
Elena Parrini
Marco Mula Pediatric Neurology, Neurogenetics and Neurobiology Unit
Atkinson Morley Regional Neuroscience Centre, St George’s and Laboratories, Neuroscience Department, A Meyer
University Hospitals NHS Foundation Trust, London, UK Children’s Hospital, University of Florence, Florence, Italy
Rima Nabbout Pasquale Parisi
Department of Pediatric Neurology, Necker Enfants Malades NESMOS Department, Faculty of Medicine & Psychology,
Hospital, Paris Descartes University, Paris, France “Sapienza” University of Rome, Rome, Italy
Raffaele Nardone Phillip L. Pearl
Department of Neurology, Franz Tappeiner Hospital, Merano, Dept Neurology, Boston Children’s Hospital, Harvard Medical
Italy School, Boston, MA, USA
Lina Nashef Karine Pelc
King’s College Hospital, London, UK Université Libre de Bruxelles (ULB), Brussels, Belgium
Vincent Navarro Page Pennell
AP-HP, Epilepsy unit, Pitié-Salpêtrière Hospital and Sorbonne Brigham and Women’s Hospital, Harvard Medical School,
University, UPMC University of Paris, Paris, France Boston, MA, USA
Aidan Neligan Nicola Pietrafusa
UCL Institute of Neurology, University College London, Department of Neuroscience, Bambino Gesù Children’s
London, UK Hospital, IRCCS, Rome, Italy

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List of Contributors

Taiane Pigozzo Hendrik Rosewich

Neurology Service and School of Medicine, Hospital São Lucas, Department of Pediatrics and Adolescent Medicine, Division
Pontifícia Universidade Católica do Rio Grande do Sul of Pediatric Neurology, University Medical Center Göttingen,
(PUCRS), Porto Alegre, RS, Brazil Göttingen, Germany
Tiziana Pisano M. Elizabeth Ross
Paediatric Neurology Unit and Laboratories, Children’s Laboratory of Neurogenetics and Development, Weill Medical
Hospital A. Meyer, Florence, Italy College of Cornell University, New York, NY, USA
Annapurna Poduri Abdulrahman Sabbagh
Epilepsy Genetics Program, F.M. Kirby Neurobiology Center, Division of Neurosurgery, Department of Surgery, Faculty of
Department of Neurology, Harvard Medical School, Boston, Medicine and Clinical Skill and Simulation Center, King
MA, USA Abdulaziz University, Jeddah, Saudi Arabia
Charles E. Polkey ParthasarathySatishchandra
Department of Clinical Neurosciences, Institute of Psychiatry, Department of Neurology, NIMHANS, Bangalore, India
King’s College, London, UK
Alois J. Schiefecker
Ronit Pressler Department of Neurology, Neurocritical Care Unit, Medical
UCL-Great Ormond Street Institute of Child Health, London, University of Innsbruck, Innsbruck, Austria
UK
Andreas Schulze-Bonhage
Elena Procopio Epilepsy Department, University Hospital Freiburg, Freiburg,
Metabolic and Muscular Unit, Meyer Children’s Hospital, Germany
Firenze, Italy
Johann Sellner
Attila Rácz Department of Neurology, Christian Doppler Medical
Department of Epileptology, University of Bonn Medical Center, Paracelsus Medical University Austria, Slazberg,
Center, Bonn, Germany Austria
Jelena Radic Arjune Sen
UCL-Great Ormond Street Institute of Child Health, London, Oxford Epilepsy Research Group, University of Oxford,
UK Oxford, UK
Shamima Rahman Simon Shorvon
Mitochondrial Research Group, UCL Great Ormond Street UCL Institute of Neurology, London, UK
Institute of Child Health, London, UK
Gagandeep Singh
R. Eugene Ramsay Department of Neurology, Dayanand Medical College,
International Center for Epilepsy, University of Miami School Ludhiana, India
of Medicine, Miami, FL, USA
Sanjib Sinha
Roberta H. Raven Dept of Neurology, NIMHANS, Bangalore, India
Department of Neuroepidemiology, Bombay Hospital
Institute of Medical Science, Mumbai, India Nicola Specchio
Department of Neuroscience, Bambino Gesù Children’s
Debra S. Regier Hospital, IRCCS, Rome, Italy
Rare Disease Institute, Children’s National Medical Center,
Washington, DC, USA Michael R. Sperling
Department of Neurology, Thomas Jefferson University,
Anna Rosati Philadelphia, PA, USA
Pediatric Neurology Unit, Neuroscience Excellence Center,
Anna Meyer Chldren’s Hospital, University of Florence, Sybil Stacpoole
Florence, Italy Peterborough and Stamford NHS Foundation Trust and
University of Cambridge, Cambridge University NHS
Felix Rosenow Foundation Trust, Cambridge, UK
Epilepsy Center Frankfurt Rhine-Main, Center of
Neurology and Neurosurgery, J.W. Goethe-University Carl E. Stafstrom
Frankfurt, Frankfurt am Main, Germany Division of Pediatric Neurology, Johns Hopkins University
School of Medicine, Baltimore, MD, USA

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List of Contributors

Erik K. St. Louis Marina Trivisano

Mayo Center for Sleep Medicine, Departments of
Neurology and Medicine, Mayo Clinic, Rochester, MN,
USA
Pasquale Striano
Pediatric Neurology and Muscular Diseases Unit,
Department of Neurosciences, Rehabilitation,
Ophthalmology, Genetics, Maternal and Child Health,
University of Genoa, ‘G. Gaslini’ Institute, Genova,
Italy
Research Fellow Neurology Unit – Bambino Gesù Children’s
Hospital Piazza San Onofrio, Rome, Italy
Iris Unterberger
Department of Neurology, Innsbruck Medical University,
Innsbruck, Austria
Fernando L. Vale
Department of Neurological Surgery and Brain Repair,
University of South Florida, Tampa, FL, USA

Adam Strzelczyk Patrick Van Bogaert

Epilepsy Center Frankfurt Rhine-Main, Center of Neurology Department of Pediatric Neurology, CHU d’Angers, and
and Neurosurgery, J.W. Goethe-University Frankfurt, Laboratoire Angevin de Recherche en Ingénierie des Systèmes
Frankfurt am Main, Germany (LARIS), Université d’Angers, Angers, France

Marshall L. Summar Pierangelo Veggiotti

Rare Disease Institute, Children’s National Medical Center, Department of Child Neurology and Psychiatry, “C. Mondino”
Washington, DC, USA Foundation, University of Pavia, Pavia, Italy

Andrea Taddio Alberto Verrotti

Institute for Maternal and Child Health IRCCS “Burlo Department of Pediatrics, University of L’Aquila, Aquila, Italy
Garofolo” and University of Trieste, Trieste, Italy Annamaria Vezzani
Yukitoshi Takahashi Department of Neuroscience, IRCCS-Istituto di Ricerche
National Epilepsy Center, Shizuoka Institute of Epilepsy and Farmacologiche “Mario Negri”, Milano, Italy
Neurological Disorder, Shizuoka, Japan Federico Vigevano
Gianpiero Tamburrini Director of Neuroscience Department, Bambino Gesù
Pediatric Neurosurgery, Institute of Neurosurgery, Catholic Children’s Hospital Piazza San Onofrio, Rome, Italy
University Medical School, Rome, Italy Aglaia Vignoli
C. T. Tan Department of Health Sciences, Università degli Studi di
Division of Neurology, Faculty of Medicine, University of Milano, Milan, Italy
Malaya, Kuala Lumpur, Malaysia Andrew C. Vivas
Erik Taubøll Department of Neurological Surgery and Brain Repair,
Department of Neurology, Oslo University Hospital – University of South Florida, Tampa, FL, Italy
Rikshospitalet, Oslo, Norway Celina von Stülpnagel
Federica Teutonico Institute for Rehabilitation, Transition and Palliation of
Department of Child Neurology and Psychiatry, “C. Mondino” Neurologically Ill Children at the Paracelsus Medical
Foundation, University of Pavia, Italy University Salzburg, Salzburg, Austria

Elizabeth A. Thiele Ruth H. Walker

Herscot Center for Tuberous Sclerosis Complex, Boston, MA, Department of Neurology, James J. Peters Veterans Affairs
USA Medical Center, Bronx, New York, NY, USA

Ajith Thomas Howard L. Weiner

Harvard Medical School, BIDMC Brain Aneurysm Institute, Division of Pediatric Neurosurgery, Department of Surgery,
Boston, MA, USA Texas Children’s Hospital, Department of Neurosurgery,
Baylor College of Medicine, Houston, TX, USA
Paolo Tinuper
Department of Neurological Sciences, University of Bologna, Angus Wilfong
Bologna, Italy BARROW Neurological Institute at Phoenix Children’s
Hospital, Phoenix, AZ, USA
Eugen Trinka
Department of Neurology, Christian Doppler Klinik, Ruth E. Williams
Paracelsus Medical University of Salzburg, Salzberg, Evelina London Children’s Hospital, Guy’s and St Thomas’
Austria NHS Foundation Trust, London, UK

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List of Contributors

Peter Wolf Bruria Ben Zeev

Danish Epilepsy Centre, Dianalund, Denmark Pediatric Neurology Unit and Israeli Rett Centre, Edmond and
Lilly Safra Children Hospital, Chaim Sheba Medical Center,
Elissa Yozawitz Tel Ha Shomer, Israel
Saul R. Korey Department of Neurology,
Department of Pediatrics, Albert Einstein College of Sameer M. Zuberi
Medicine and Montefior Medical Center, New York, Fraser of Allander Neurosciences Unit, Royal Hospital for
NY, USA Children, Glasgow, UK

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Foreword
The written history of epilepsy goes back 3000 years with accu-
rate descriptions of epileptic phenomena appearing in the writ-
ings of ancient Mesopotamia and the Indian Ayurvedic texts.
Although physicians of the Hippocratic school in Greece, about
400 BC, understood that epileptic seizures originated in the
brain, as did Galen several hundred years later, epilepsy was
generally viewed as a mysterious condition attributed to super-
natural causes, at least in the West, until the mid nineteenth
century. At that time, the nascent disciplines of basic neu-
roscience and clinical neurology defined a variety of ictal man-
ifestations, including focal seizures and absences, and
recognized them as part of a constellation of disorders referred
to as epilepsy. In particular, postmortem clinical pathological
correlations not only revealed specific anatomic substrates for
different ictal manifestations, but led directly to concepts of
localization of function within the human brain, and to surgical
treatment for certain types of focal epilepsies. The development
of radiology in the twentieth century further improved physi-
cians’ abilities to identify “invisible” lesions as responsible for
epileptic seizures in some patients, but it was application of the
electroencephalogram (EEG), and the subsequent field of both
clinical and basic electrophysiology, that provided a means to
begin classifying and characterizing different types of epileptic
seizures and epilepsy syndromes, and investigating their under-
lying fundamental pathophysiological neuronal mechanisms.
The careful delineation of different types of ictal phenomena
provided the basis for creating experimental animal models for
both in vitro and in vivo electrophysiological and microanato-
mical investigations of epilepsy. EEG localization of the epi-
leptogenic region greatly increased the application of surgical
treatment for focal epilepsies, which also provided novel
opportunities for parallel invasive in vitro and in vivo electro-
physiological and microanatomical investigations in patients.
Towards the end of the twentieth century, explosive advances
in three-dimensional neuroimaging, first with structural X-ray
computerized tomography (CT), then functional positron
emission tomography (PET), and finally both structural and
functional high-resolution magnetic resonance imaging (MRI)
provided intricate insights into the pathophysiologic mechan-
isms and anatomic substrates of epilepsy disorders in indivi-
dual patients that could be used to create more informed
categorizations and classifications. These efforts were joined
by the burgeoning field of neurogenetics, which not only is
identifying an increasing number of “epilepsy genes” respon-
sible for specific types of epilepsy, and further characterizing
genetic disorders associated with epilepsy, but also advancing
the concept of susceptibility genes, which will explain variable
individual predispositions to develop certain forms of acquired
epilepsies. Now, in the twenty-first century, we are poised to
reap the benefits of these dramatic advances in our under-
standing of the causes of epilepsy.
Methodology for characterizing different types of epileptic
seizures and the disorders associated with them, particularly
through electroclinical correlations, that is the association of
particular behavioral ictal signs and symptoms with their
unique EEG correlates, led the International League Against
Epilepsy (ILAE) to propose international classifications for
epileptic seizures, and for the epilepsies in 1970. These have
undergone several revisions, but the most recent version of
the International Classification of Epileptic Seizures was pro-
posed in 1981, and the most recent International
Classification of the Epilepsies was proposed in 1989. These
were purported to be purely phenomenological, because the
authors felt there was, at the time, insufficient mechanistic
information on which to base a classification on specific
causes of epilepsy. Nevertheless, the inclusion of EEG char-
acteristics permitted categorization of ictal phenomena in a
way that implied certain pathophysiologic differences, as well
as anatomic substrates. For instance, generalized seizures
were distinguished from focal seizures that appeared to ori-
ginate in a part of one hemisphere. Epilepsies were classified
not only based on their characteristic associated seizure types,
but also according to broad etiologic categories: idiopathic,
meaning epilepsy and nothing else, presumably primary
genetic disorders; and symptomatic, meaning secondary to
some other disease process. In addition, diseases associated
with epilepsy were well described, and some epilepsy diseases
were recognized as conditions with a single known cause, but
most of the defined epilepsy conditions were syndromes,
characterized by specific seizure types, and other clinical
features, such as age of onset, response to antiepileptic
drugs, and comorbidity. Using this approach, the vast major-
ity of accepted epilepsy syndromes are pediatric idiopathic
conditions, while the majority of epilepsies that affect adults,
most of which are symptomatic, still defy a reasonable syn-
dromic classification.
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Foreword
For over a decade, the ILAE has attempted to revise the 1981
and 1989 classifications, with multiple reports that have
updated the list of epileptic seizure types and epilepsy syn-
dromes. They now recognize certain seizure types as diagnostic
entities with associated therapeutic, prognostic, and etiologic
implications that can be used when a definitive syndrome or
disease diagnosis cannot be made. These deliberations provide
a basis for a more scientific classification of epilepsy disorders
based on underlying genetic and pathophysiologic mechan-
isms, as well as anatomic substrates. Ironically, however, as
the chapters in this book clearly confirm, with the increasing
sophistication of our investigative methodology, the elucida-
tion of distinctive epilepsy conditions as diagnostic entities has
become more, rather than less, complicated. The old dichoto-
mies of idiopathic versus symptomatic, and generalized versus
focal, are artificial and often impossible to apply. Well-defined
classical syndromes, such as childhood absence epilepsy, are
not as homogeneous as once believed. Some idiopathic child-
hood epilepsies, such as Dravet syndrome, are not benign, and
there appear to be several distinctly different forms of temporal
lobe epilepsy with hippocampal sclerosis. However, the causes
of epilepsy discussed in this textbook represent a major effort
to put flesh on the bones of what hopefully will ultimately
become a biologically based international classification of the
epilepsies.
With the hundreds of textbooks that have been published on
epilepsy in the past decade or so, it is rather amazing that none
have focused specifically on the causes of epilepsy. The editors
have undertaken this monumental task and succeeded in doc-
umenting the current state of knowledge concerning the
genetic and pathological substrates of disorders characterized
by epileptic seizures, as well as the situations that provoke ictal
events. This comprehensive compendium will not only serve as
an important resource for rethinking the organization and
classification of epileptic phenomena and epilepsy syndromes
and diseases, but will also provide a foundation for basic
research attempting to identify the diverse pathophysiological
mechanisms at the subcellular, cellular, and systems levels, that
are responsible for epileptogenesis and seizure generation.
Identification of these fundamental neuronal processes in
turn will lead to novel and more effective approaches to treat-
ment, cure, and prevention of epilepsy.
Jerome Engel, Jr.
Los Angeles, California
Medicine is undergoing a remarkable transition as we move
from descriptions of disease and a taxonomy based on clinical
characteristics to a more detailed and precise understanding of
disease pathogenesis. This revolution has been driven by the
adoption of a range of molecular tools and, more particularly,
by the application of molecular genetics to medicine. These
approaches are providing us with insights, often for the first
time, of the pathways and precise events associated with
xx
disease pathogenesis and this will change forever the founda-
tions on which we base diagnosis and treatment of disease.
The developments in the molecular understanding of dis-
ease are nowhere more evident than in neurological disease,
particularly the epilepsies. These clinical syndromes, often
dramatic in their clinical characteristics, have been associated
with a range of taxonomies that have developed over many
centuries. The clinical characteristics of seizures and an under-
standing of the abnormal electrophysiology provided a frame-
work on which taxonomy could be based, but clearly could not
address the fundamental issue of the underpinning events in
disease pathogenesis. That has had to wait until the past twenty
years when the tools available for characterizing both families
and individual patients have gradually become available.
Initial progress in this field focused, as with other diseases,
on Mendelian forms of epilepsy using family based studies.
Although these studies revealed a range of interesting patho-
physiological mechanisms, including a number of ion chan-
nels, it has been clear that this describes only a portion of the
epilepsy syndromes, many of which involve more complex
genetics. These now are increasingly tractable with the new
tools for genetic association and these are beginning to reveal
non-channel molecules and pathways associated with neural
excitability. Together, these techniques are providing a crucial
framework for redefining the epilepsies based on pathophy-
siology and, in turn, this will have a profound impact on our
ability to predict, diagnose, and, ultimately, treat disease. Anti-
convulsive therapy has been remarkably successful, given how
little we know about the pathogenic mechanisms of the disease,
so it is likely that future therapeutic interventions based on a
clearer understanding of the relevant pathways will be even
more effective.
Together, these advances have made epilepsy one of the
most significant examples in medicine of the importance of
genetic tools in clarifying pathophysiology and these disor-
ders demonstrate clearly how powerful the change from pure
phenotypic classification of disease to one based on patho-
physiology can be. The authors of this important book have
been able to bring together a wide range of scientific insight
and data on this topic into a single volume that covers the
whole range of clinical syndromes. They demonstrate how
powerful these new genetic tools have already been in defin-
ing pathways in disease and they also clearly demonstrate
that, together, their observations are likely to lead to a funda-
mental new classification of these diseases. Not only is this
volume timely, given the recent exciting developments in this
field, but it also demonstrates the enormous influence that
these key basic insights will have on the way we categorize
and, ultimately, treat individuals with disease. Epilepsy and
its associated syndromes give us a clear vision of what the
future of medicine is likely to look like.
Professor Sir John Bell
University of Oxford, UK
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Preface to the Second Edition
One of the major strides forward in the field of epilepsy in recent
years has been a renewed emphasis on its causes. An epileptic
seizure, like a headache, is a symptom. It is a symptom further-
more which is known to have numerous different potential
causes, but in many cases, these have remained hidden or obscure
(κρυπτός kryptós, hidden). Our ability to uncover the underlying
causes of epilepsy have been greatly enhanced in the last few
decades by the advent of medical technologies, notably in neu-
roimaging, molecular genetics and molecular chemistry, and
these have allowed many new causal factors to be recognized.
In the preface of the first edition, we cited the famous statement
of Kinnear Wilson that to attempt to list all causes of epilepsy
would be an act of supererogation. However, with modern devel-
opments, we believe that this view is over-pessimistic, and not-
withstanding the conceptual issues that complicate the idea of
causation many of which were first enumerated by Hughlings
Jackson, a listing of causes is now feasible to an extent previously
not imagined. The identification of the cause of epilepsy is a key
element in patient-centered clinical management, and is now
increasingly successfully achieved. Long gone is the time when
epilepsy was simply described by the characteristics of the seizure
(the seizure type) and hopefully, too, less focus can now be placed
on the intellectually sterile activity of rejigging classification
schemes and more on the pathophysiology of underlying causes.
What is attempted in this book is to describe all the known causes
of epilepsy in a way which is useful for clinical purposes and
which can stimulate further research to identify cause-specific
therapies. We have tried to do this approaching the relationships
between epilepsy phenomenology and its specific causes in a
manner that is informative for both the epilepsy experts, who
need to understand more about the underlying pathophysiology,
and for those clinicians who are instead experts of the causative
disorders but might not be particularly familial with the peculia-
rities that epilepsy adds to a given medical condition.
As far as we are aware, this is the first, and indeed only,
textbook to focus specifically on the causes of epilepsy. It is
nine years since the publication of the first edition, and during
this time, we have learned a great deal from our experience
with the first edition and also especially from the explosion of
new information about the genetic and molecular causes of
epilepsy. As a result, this edition is expanded and extensively
rewritten. In Section I of this second edition, we have included
new chapters on the concept of cause in epilepsy and on the
basic principles of causation in epilepsy. Section II is an
entirely new section comprising a series of chapters dealing
with the clinical approaches to establishing cause in different
situations in clinical practice. Sections III and IV cover the
genetic causes, and have been greatly expanded with new
chapters reflecting the rapid advances in this field. The sections
are divided into the genetic causes of the idiopathic (or ‘pure’)
epilepsies and into those of the genetically-based symptomatic
epilepsies. Section V comprises chapters on the non-genetic
causes of epilepsy and many of these too have been extensively
rewritten, with an emphasis placed on the clinical features and
prognosis. In Section VI, we cover the precipitating factors of
epileptic seizures, which we consider to be as much a ‘cause’ of
epilepsy as are the underlying conditions, and which empha-
sise the multifactorial nature of causation in epilepsy. In
Section VII, the causes of status epilepticus are covered,
which are often different from the causes of other forms of
epilepsy.
As with the first edition, the purpose of the book is to be a
comprehensive reference work, a catalogue of all known causes
of epilepsy, and above all a clinical tool for clinicians caring for
patients with epilepsy. The intended audience is both specia-
lists and generalists, and we have asked our contributing
authors to follow a predetermined template to provide a con-
cise summary of knowledge about the clinical aspects of the
condition in a form that is helpful in the both hospital and
outpatient settings.
We are also enormously grateful to Nick Dunton and to Anna
Whiting, his successor, the Senior Commissioning Editors at
Cambridge University Press. Both have guided the project since
its inception with extraordinary skill and expertise, and we are
equally grateful to Charlotte Brisley who came to the project in
its later stages as content manager and who has worked tirelessly
to make it a success. The quality of the book depends on the skill
and clarity of the authors of the individual chapters and we have
been very fortunate in the high level of expertise and commit-
ment all have brought to the book. We are also very obliged to
our colleagues, around the world, who have engaged in stimu-
lating discussions with us, who have shared their ideas and
knowledge about the causes of epilepsy and who have guided
us in our quest to make this textbook a useful contribution to
clinical and experimental work in epilepsy.
Simon Shorvon, Renzo Guerrini, Steve Schachter
and Eugen Trinka (editors)
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Preface to the First Edition – an Act of Supererogation?

classification schemes, based as they are largely on clinical

An inquiring mind must return again and again to the problem
semiology and electroencephalography, and it is interesting
of origin or cause…. physicians have dug away at diverse etiolo-
to muse on what form the epilepsy classification might have
gic theories or facts; physical or psychic; general or individual;
taken if MRI scanning had preceded EEG as a clinical investi-
genetic or acquired; fundamental or contributory. When a crime
gatory tool.
is committed, everyone in the vicinity is suspect. William Lennox,
We thus open this book with, in Chapter 2, the presentation
Epilepsy and Related Conditions, 1960
of a draft etiological classification which goes some way we
Thus Lennox opened his chapter on “The diverse sources of
hope to filling the nosological void. The main part of the book
seizures,” and indeed he devoted a great many pages of his
is organized according to this classificatory scheme. We have
famous book to the question of etiology. Yet, 50 years later,
divided the etiologies into four categories: idiopathic epilep-
causation is an aspect of epilepsy now somewhat neglected in
sies, symptomatic epilepsies, cryptogenic epilepsies, and pro-
the scientific literature on epilepsy, in the classification of
voked epilepsies, and these are defined in Chapter 2. In doing
epilepsy, and in the conceptualization of epilepsy at a clinical
so, of course, we recognize, as Lennox, and many before him,
and experimental level. It was to go some way to remedying
frequently reiterated, that epilepsy is in the great majority of
this deficiency that this book was conceived.
cases multifactorial, and frequently has a developmental basis
Kinnier Wilson in 1940 wrote that the listing of all causes of
with therefore a temporal dimension. The epilepsy is often the
epilepsy would be an act of supererogation, but the editors of this
result of both genetic and acquired influences and also influ-
book beg to differ. This is the first book ever published, as far as
enced by provoking factors, and assignment in such cases to
we know, which is devoted to the topic of causation in epilepsy,
any single etiology is therefore to an extent arbitrary.
and we have attempted within its 800 pages to catalog the known
The approach to the problem of etiology between 1860 and
causes of epilepsy, and corral these into a single tome.
1960 forms the subject of the historical introduction (Chapter
Such an attempt is only possible because of the great
1) which ends with Lennox’s work, and this is included as we
advances made in imaging, molecular biology, and molecular
believe it is important to understand the evolution of concepts
genetics in the last 40 years or so, and we believe that progress
of causation within its historical context.
has now been sufficient to permit at least a stab at a compre-
In subsequent chapters, we have asked the authors to con-
hensive listing of causation. The literature on epilepsy has
sider their topic in a consistent fashion, dealing with the
rapidly increased in recent years. Kinnier Wilson noted that
phenomenon of epilepsy in each etiology, including its epide-
the index catalogue of the US Surgeon-General’s office (1925)
miology, clinical features, and prognosis, and any specific
contained about 3000 titles and the “Gruhle’s review for the
aspects of investigation or treatment.
years 1910–1920 deals with some 1000 articles.” In the last 10-
The purpose of the book is to be a comprehensive reference
year period, a search on PubMed® using the keyword epilepsy
work, a catalog of all the important causes of epilepsy, and a
produces more than 37 000 references, many of which deal at
clinical tool for all clinicians dealing with patients with epilepsy. It
least tangentially with etiology. It is this literature-base which
is aimed at specialists and the interested generalist and it is hoped
we have asked our contributors to summarize in the various
provides a distillation of knowledge in a form that is helpful in the
chapters of this volume.
clinical setting. We hope too that it will act as a clinical guide to
One striking omission has been the absence of any detailed
scientists probing the dark interior of the subject.
consideration of etiology in the standard classifications of
We have attempted to take a worldwide perspective, and have
epilepsy. This is partly because at the time that these schemes
included chapters on the causes of epilepsy that are rare in the
were being devised neither modern investigatory imaging
West but common in other parts of the world. To match the
methods nor modern molecular biology were available – and
worldwide spread of the conditions considered here, we have a
the ascertainment of “cause” in life was often simply not
distinguished faculty with a similar global reach, and the book
possible. Although it was fully recognized that epilepsy was
has 165 contributors from 21 countries and all continents many
often “a symptom” of neurological disease, the underlying
of whom are the leaders in their fields.
cause of the symptom was completely absent from the current

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The editors have exercised a heavy editorial blue pen, have
tried to minimize overlap or repetition, and have asked the
authors to follow where possible a pre-assigned template. Our
contributors have responded magnificently in our opinion, and
we extend our grateful thanks for their hard work and for their
time and effort. We would like to thank also Professor Jerome
(Pete) Engel and Professor Sir John Bell for graciously agreeing
to write the foreword to the book. Pete Engel is a famous leader
in the field of epilepsy and a prolific author, who has made major
contributions to many fields of epilepsy. Sir John Bell is President
of the Academy of Medical Sciences and Regius Professor of
Medicine at the University of Oxford, and a renowned medical
geneticist. The book is indeed fortunate to have their
Preface to the Second Edition
contributions. We are also enormously grateful to Nicholas
Dunton, the Senior Commissioning Editor at Cambridge
University Press, who has guided the project since its
inception with extraordinary skill and expertise, and with-
out whose assistance the book would not have made it to
the shelves. We also thank Assistant Editor Joanna
Chamberlin and Production Editor Caroline Brown for
their great efforts on behalf of the book. Finally, we
would like to thank all our colleagues around the world
for their stimulating ideas and knowledge, which have
informed and illuminated all the pages of this book.
Simon Shorvon, Renzo Guerrini, and Fred Andermann
xxiii
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