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Emerging and Less Common Viral Encephalitides - Chapter 91
Emerging and Less Common Viral Encephalitides - Chapter 91
2018 3:42PM
Chapter
Emerging and Less Common Central Nervous System
91 Viral Encephalitides
H. T. Chong and C. T. Tan
Nipah encephalitis
Hendra
encephalities
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herpesvirus 6, cause the unusual picture of a demyelinating with reactivity to external stimuli. Other EEG changes
encephalitis. included focal discharges, electrical status epilepticus, periodic
The occurrence of seizures and epilepsy are generally not lateralized epileptiform discharges (about 10% of patients),
well studied in viral encephalitides. Most infections cause focal burst suppression, generalized attenuation, and alpha coma
seizures with or without secondary generalized tonic–clonic in about 10% of patients. An EEG tracing that is non-reactive
seizures or myoclonic seizures. Little is known about the pre- to external stimuli carries a poorer prognosis [13,19,29].
dictive factors of seizures in most infections. In some instances, During convalescence, more than a third of patients have
for instance in Japanese B encephalitis, seizures carry a poor normal EEG and over half have only mild abnormalities, sig-
prognosis in terms of immediate outcome, but in most infec- nifying good recovery in the survivors. By 3–12 months after
tions, the presence of seizures does not influence the prognosis. the onset of illness, three-quarters of the patients have a normal
EEG recording. However, in patients with more severe infec-
Emerging Encephalitides tion, especially in situations where adequate medical facilities
are not accessible, mortality may be as high as 30% in those
Japanese Encephalitis Virus admitted, and half of the survivors have severe neurological
sequelae, which include motor deficits, fixed flexion deformi-
Japanese encephalitis virus is a flavivirus transmitted by mos-
ties of the limbs, cognitive deficits, and remote symptomatic
quitoes from birds and pigs to humans. It is found in East,
epilepsy in up to 20% [29].
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 West Nile Virus
annually, and thus is the most important viral encephalitis West Nile virus is a flavivirus closely related to the Kunjin virus
globally. The virus causes diffuse encephalitis, affecting the and, somewhat less closely, to the Japanese encephalitis virus.
midbrain, thalamus, and basal ganglia more severely [17,28]. First identified in Uganda in 1939, the reservoirs of West Nile
Only 1 in 250–1000 patients infected with the virus virus are birds and the vector Culex mosquitoes. Human and
becomes symptomatic. The infection ranges from mild, flu- other mammals are dead-end hosts. West Nile viral infection is
like illness, to fatal meningoencephalitis. In endemic areas, it endemic in Africa, the Mediterranean, and the Middle East.
is mainly a childhood disease, though visiting naive adults are Migratory birds are believed to be important in the long-
at particular risk of developing severe illness. After an incuba- distance spread of the virus. The first outbreaks outside the
tion period of 5–15 days, symptomatic patients present first endemic area occurred in Romania in 1996 and in the
with fever, headache, vomiting, seizure, and impaired con- Volgograd and Krasnodar regions of Russia in 1999, which
sciousness. Extrapyramidal signs such as mask-like face, tre- coincided with a major change in neurovirulence. In August
mor, rigidity, choreoathetosis, dystonia, dyskinesia, and the same year, the virus affected 62 patients in New York, and
generalized hypertonia are common, and so are brainstem by 2002, it had spread throughout the United States and
signs. Brain magnetic resonance imaging (MRI) is sensitive reached the Pacific coast.
and shows hyper-intensities in brainstem, cerebellum, basal In endemic areas, the infection is often asymptomatic.
“… or 1 in 150
ganglia, and even the cerebral region. Diagnosis is mainly by After an incubation period of 3–15 days, about 20% of patients
infections,
serology or polymerase chain reaction (PCR) in the acute present with flu-like illness with a non-pruritic roseolar or usually …”
stage. Effective vaccines are available, though treatment is maculopapular rash that lasts for about a week. Only about
mainly supportive [28]. 15% of patients, or 1 in 150, usually the elderly, develop central
Seizures occur in approximately 40–60% of patients, nervous system involvement. In non-endemic areas neurolo-
though the rate is as high as 80% in children. Of these patients, gical involvement is more common and more severe. Fever,
45–57% have generalized clonic or tonic–clonic seizures, headache, neck pain, myalgia, back pain, nausea, chills, and
18–43% have focal motor seizures, and up to 25% may have rigors are the commonest symptoms, while altered mental
status epilepticus. The seizure manifestations can be subtle, state, neck stiffness, parkinsonism (including tremor, rigidity,
especially in children, and include minimal clonic movements and bradykinesia), are common signs. Other clinical features
of the eyes, eyebrows, eyelids, mouth, or digits, with or without include brainstem involvement, optic neuritis, myelitis, acute
tonic eye movements, nystagmus, salivation, and irregular flaccid paralysis presumably from anterior horn cell involve-
breathing. Seizures are associated with focal weakness and ment, aseptic meningitis, and encephalitis. Cerebrospinal fluid
abnormalities on the electroencephalogram (EEG) and brain (CSF) analysis shows pleocytosis, often lymphocytic, with
computed tomography (CT) scan. Seizures also herald a poorer raised protein and normal sugar levels. Magnetic resonance
prognosis, being associated with higher mortality and poorer imaging of the brain shows bilateral hyperintense lesions in the
conscious state. This is especially the case in multiple or pro- basal ganglia, thalamus, and pons on T2-weighted images.
longed seizures or status epilepticus, probably because the Diagnosis is based on serologic testing of serum or CSF, or
seizures lead to raised intracranial pressure and a higher risk PCR analysis of CSF during the early part of the illness. There
of herniation syndrome [29]. is no specific antiviral therapy for West Nile infection.
Acutely, the EEG is abnormal in the vast majority of Treatment is mainly supportive. Long-term outcomes are
patients, though in a non-specific manner. More than 60% of often good, though persistent fatigue, myalgia, and cognitive
patients exhibit slow waves, usually of high amplitudes, often deficits have been reported.
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Seizures occur in 5–30% of patients with West Nile ence- Computed tomography scan of the brain is almost invari-
Delete the
phalitis, and often focal motor and present during the later part ably normal, while almost all patients have an abnormal
word “an”
of the illness. Rarely, non-convulsive status epilepticus MRI, showing widespread, focal, vasculitic-like lesions in
may occur. Electroencephalographic changes are often non- the subcortical and deep white matter. Nipah
specific, such as diffuse irregular slow waves, and even in immunoglobulin M (IgM) serology is positive in almost
patients with non-convulsive status epilepticus, the EEG may all patients by day 12 of the illness, and that of immuno-
show only polymorphic delta slow waves. Focal sharp waves globulin G (IgG) by day 26. In a non-randomized, histor-
are seen occasionally [8,26]. ical-controlled trial, ribavirin was found to reduce mortality
by about 30%, though supportive treatment is equally, if
Nipah Virus not more, important [5,9].
Seizures are common in patients with acute Nipah ence-
Nipah virus is a paramyxovirus endemic among the giant fruit
phalitis; about a quarter of the patients have generalized
bats (Pteropus species) in South and South-East Asia and in
tonic–clonic seizures and one-third to half have segmental
east African coastal regions. In 1998, it caused a fatal outbreak
myoclonus, involving the diaphragm, limbs, and facial mus-
of encephalitis among pig farmers in Malaysia, when pigs
cles. The myoclonus may be persistent over hours.
contracted the virus by consuming fruits partially eaten by
Interestingly, myoclonus was absent in the reports of Nipah
fruit bats. The disease continues to cause small annual out-
encephalitis in Bangladesh, though this could be due to report-
breaks in Bangladesh and north-east India, probably related to
ing bias.
the local practice of consuming raw, contaminated, date palm
During the acute phase of infection, more than 96% of
juice.
patients have an abnormal EEG and 88% have continuous
After an incubation period of about 2 weeks (range 1–32
diffuse slow waves with or without focal discharges. Focal
days), Nipah infection causes a severe encephalitis charac-
discharges are seen in about half of the patients and bitemporal
terized by sudden onset of fever, headache, giddiness, drow-
periodic complexes in a quarter. The periodic complexes are
siness, nausea, anorexia, vomiting, abdominal pain, cough,
stereotypical with single spike or sharp wave followed by a slow
focal neurological deficits, and seizures. Over the ensuing
wave of 200–250 ms, repeating irregularly every 1–2
1–2 weeks, the patient’s consciousness continues to deterio-
s (Fig. 91.2). Almost all patients with periodic complexes
rate. In the Malaysian outbreak, more than 60% of patients
were comatose in the initial Malaysian outbreak and none
required mechanical ventilatory support and mortality was
survived [3,9].
about 40%. Terminal events were often heralded by severe
During the acute illness, the focal discharges and the per-
hypertension, tachycardia, and hyperthermia, and then irre-
iodic complexes seen on EEG do not correlate with focal
versible shock. A previous history of diabetes mellitus,
neurological deficits, clinical seizures, or segmental myoclo-
brainstem signs, and positive CSF viral cultures were poor
nus, though the degree of slowing correlates with the severity
prognostic factors. Analysis of CSF shows features typical of
of illness [3].
viral encephalitis in 50–60% of patients with raised lym-
The mortality rates were 32–41% in the Malaysian out-
phocytes and protein levels, but normal sugar values.
breaks, and on average, as high as 73% in the Bangladesh
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Clinically, enterovirus 71 affects mainly children, and those disease to deteriorate within 48–72 hr after defervescence.
under 5 years of age are more severely affected. Enterovirus 71 Vascular leakage is evident by hemoconcentration, severe
infections may be asymptomatic, or it may cause diarrhea, thrombocytopenia (platelet count ≤ 105/µl), ascites, pleural
hand–foot–and–mouth disease, herpangina, myocarditis, effusion, hypoalbuminemia, or hypoproteinemia. This is
acute flaccid paralysis, Guillian–Barré syndrome, aseptic termed dengue hemorrhagic fever, and it is an indication of
meningitis, acute cerebellar ataxia, encephalitis, and rhomben- impending shock. Therefore, intensive observation and pro-
cephalitis; the last of which is associated with fatal pulmonary phylactic replenishment of lost intravascular fluid are indi-
edema and hemorrhage. Analysis of CSF shows increased cated. If not treated, the patient may progress into dengue
protein, normal sugar levels, and pleocytosis, often lymphocy- shock syndrome, which may be heralded by intense abdom-
tic, though in up to 40% it may be neutrophilic. Magnetic inal pain, persistent vomiting, restlessness, lethargy, or
“… which can
enhance in the
resonance imaging of the brain shows hyperintense lesions in hypothermia with sweating. Other uncommon, but often
acute phase of the the brainstem and spinal cord on T2-weighted images, which severe, manifestations of dengue infection include severe
illness.” can enhance in the acute illness. Diagnosis is by viral isolation hemorrhage, hepatic damage, cardiomyopathy, and encepha-
or PCR. There is no proven antiviral therapy for enterovirus lopathy/encephalitis. Diagnosis is by serologic testing. Since
71, though various agents have been tried, such as steroids and dengue virus is closely related to other flaviviruses, the ser-
intravenous immunoglobulin. Supportive care remains the ologic test may be falsely positive in Japanese encephalitis,
most important aspect of management. West Nile fever, or St. Louis encephalitis. Treatment is sup-
Among children with rhombencephalitis, 68–86% are portive, with particular attention to adequate fluid replace-
reported to exhibit myoclonic jerks, which can range from ment titrated against clinical findings and the patient’s
mild and intermittent jerks during sleep, or persistent jerks hematocrit.
during both sleeping and waking, and which may continue Neurological involvement in dengue infection is well docu-
after the patient recovers from the acute encephalitis. Other mented, though whether the virus causes an encephalopathy or
seizures and opsomyoclonus have been documented, though encephalitis is still debated. The incidence is low, and seen espe-
there are few details in the current literature. The EEG shows cially among pediatric patients. Patients with neurological invol-
bilateral central and parietal slow waves or sporadic sharp or vement present with confusion, altered conscious state, limb
spindle waves. weakness, and seizures. Approximately 10 to 15% of those with
The overall outlook is good; in children without pulmonary neurological involvement have seizures; commonly generalized
edema or hemorrhage, mortality is close to zero. The outlook tonic–clonic seizures, but occasionally myoclonic jerks. The EEG
for children with pulmonary edema and/or hemorrhage is often shows non-specific theta slow waves [11,18,19,23].
poor, however, with a mortality rate of about 80%. Among The overall mortality of dengue infection is low; however, if
the survivors, 5% or fewer have residual neurological deficits shock sets in, the mortality rate can rise to 12–44%. Among the
which include poor motor skills and lower IQ. Remote symp- patients with central nervous system involvement, mortality is
tomatic epilepsy is not documented in survivors of enterovirus approximately 30%; and another 20–30% of survivors have
71 infection [12]. long-term neurological deficits.
patients varies from 24% to 66%, and symptomatic disease is pet trade. Clinically, it causes fever and acute pustular rash.
more likely to result from primary infection than reactivation Among the 34 patients infected in the Midwestern United
of latent infection. Clinical features include fever, leukopenia, States outbreak, a 6-year-old girl developed acute encephalitis
rash, interstitial pneumonitis, and encephalitis, and in bone and seizures [25].
marrow transplant patients, bone marrow suppression.
In patients with reactivation of latent infection, including Other Uncommon Encephalitides
patients with human immunodeficiency virus infection,
human herpesvirus 6 infections often manifest as fever, though Rabies
encephalitis, including limbic encephalitis, and interstitial
Rabies, a rhabdovirus which is spread by the bites of infected
pneumonitis have been documented.
animals, is an important health problem worldwide. Although
In immunocompromised patients with human herpesvirus 6
only 15% of the bite victims develop rabies, worldwide there
encephalitis, common clinical features include confusion, altered
are more than 35,000 reported human cases annually, the
conscious states, headache, focal neurological deficits, and sei-
majority of which occur in India. Dogs are the primary vectors
zures, which occur in about 25% of patients. Findings with CT
in developing countries, while small terrestrial mammals and
and MRI scans are non-specific and the EEG may show focal
bats are the primary vectors in developed countries. After an
discharges. The gold standard of diagnosis is viral culture of
incubation period of 3 weeks to 2 months, the patient develops
peripheral mono-nuclear cells, while anti-complement immuno-
fever, flu-like symptoms, mood changes, and local pruritus,
fluorescence assay is an alternative. Serologic tests are not spe-
pain, and paresthesiae at the sites of bite. If the brainstem,
cific in detecting recent infection, as IgM may be produced in
limbic system, hypothalamus, and the autonomic center are
both primary and reactivation of latent infection. Treatment is
involved, the patient develops furious or agitated rabies, char-
largely supportive, though ganciclovir and foscarnet have been
acterized by hydrophobia, aerophobia, and episodes of gener-
tried. In transplant patients with human herpesvirus 6 encepha-
alized arousal associated with confusion, agitation, and
litis, mortality is in excess of 50%, though residual neurological
hyperesthesia punctuated by periods of lucidity. Death often
deficits are not common among the survivors [6,27].
ensues within a week. If the spinal cord is primarily involved,
the patient may develop weakness, paresthesiae, pain, and
Chandipura Virus muscle fasciculation, starting from the affected limb spreading
Chandipura virus is a rhabdovirus transmitted to humans by to the rest of the body, and eventually involving all the other
sandflies. Although the virus is found in both India and Africa, limbs as well as the bulbar and respiratory muscles.
so far only two possible outbreaks of human infections have Uncommonly, patients may present with subtle or focal sei-
been reported, and both in India – the first in Andhra Pradesh zures, which are easily missed. Vaccines are available for pre-
in 2003 with 329 patients, and the second in Gujarat state in and post-exposure prophylaxis and treatment. Treatment
2004 with 26 patients. Children, especially boys under 16 years involves thorough washing of the wounds with soap, water,
of age in rural areas, are more at risk of acquiring Chandipura and if available, virucidal agents. The standard vaccine is given
infections. Typically, the patients present with sudden onset of intramuscularly in five doses on days 0, 3, 7, and 14 into deltoid
fever, follow by vomiting, altered conscious state, diarrhea, or the anterolateral aspect of thigh, and passive immunization
focal neurological deficits, and meningismus. Seizures occur with human rabies immunoglobulin infiltrated around the
in over 80% of patients. Although the mortality ranges from wounds. Passive immunization is contraindicated if the patient
55.6 to 78.3%, and most deaths occur within 24 hr of onset of had been vaccinated and had documented adequate antibody
disease, residual neurological deficits are rare in children who response. The mortality of rabies in unvaccinated individuals is
recover. Diagnosis is made by viral culture or PCR of throat 100% [32].
swab, brain aspirate, or peripheral blood mononuclear cell co-
culture. Serologic tests are not helpful; in the two outbreaks in Tick-Borne Encephalitis
India, only 4.5–13% of patients had positive IgM and 65.
The three subtypes of tick-borne encephalitis virus (Far
3–97.7% had positive neutralizing antibodies. Serologic tests
Eastern, Siberian (previously known as Russian
are less sensitive among children. Because of this, the role of
spring–summer encephalitis), and Western European) are
Chandipura virus in these outbreaks is still debated, and
the commonest causes of encephalitis in Europe, accounting
Chandipura viral infection was proven in only 8.5–45% of
for 29–54% of encephalitis with a diagnosis and 10,000–20,000
patients in these two outbreaks. In all of the affected patients,
cases annually. The flavivirus is transmitted by the Ixodes and
CSF pleocytosis was not observed, and in the autopsy cases,
Haemaphysalis ticks, with rodents and wolves acting as reser-
brain parenchymal inflammation was not observed [2,22].
voirs and amplifying hosts. Shrews, hedgehogs, moles, and
other insectivores are additional hosts. The risk of acquiring
Monkeypox Virus the infection is, therefore, higher among men, especially
Monkeypox virus is an orthomyxovirus closely related to var- among farmers, hunters, forest workers, and those participat-
iola or smallpox virus. The virus causes outbreaks in central ing in outdoor leisure activities. The virus is found in a large
and western Africa and was brought into the United States in geographical area stretching from Scandinavia to Jilin in
2003 through the importation of infected Gambian rats for the northern China and Hokkaido, Japan.
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Humans are the dead-end host of the virus, and 70–95% of behavioral changes, are seen in about 2% of the patients with
infections are subclinical. In symptomatic patients, the virus central nervous system infection.
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.
St. Louis Encephalitis
After an interval of 8–133 days, 74–87% of patients suffer St. Louis encephalitis, caused by a flavivirus, is the second
from central nervous system involvement; half of these develop commonest cause of viral encephalitis in the United States.
meningoencephalitis, the other half meningitis, radiculitis, or It occurs primarily in the Ohio–Mississippi valley, but human
myelitis. Patients with meningoencephalitis have recurrence of infections have been documented in other regions from south-
fever, headache, altered consciousness, confusion, tremor, ern Canada to Argentina. The virus is transmitted by the Culex
ataxia, weakness, dysphasia, cranial nerve palsies, and, uncom- mosquito, the amplifying hosts are birds, and the virus spills
monly, seizures which are seen in 0.3–3.3% of patients. out of the zoonotic cycle when there is a sufficient number of
The EEG is abnormal in 77% of patients, but the changes of mosquitoes. This causes periodic outbreaks of human disease
diffuse and/or intermittent focal slow waves are non-specific. once every decade or so. Only 1 in 800 to 1 in 100,000 human
Magnetic resonance imaging of the brain shows abnormalities infections results in clinical illness and the elderly are most at
in the thalamus, cerebellum, brainstem, and caudate nucleus in risk; while 40% of symptomatic young patients suffer from
18% of patients. Mortality is low at 0.1–1.4%, though 26–46% mild aseptic meningitis only, 90% of the symptomatic elderly
of patients have residual symptoms, and up to 30% have sig- develop encephalitis. The onset of encephalitis can be abrupt or
nificant neurological deficits. Approximately 4–5% of patients slow, and the clinical features include fever, headache, dizzi-
develop focal motor status epilepticus partialis continua, ness, nausea, malaise, meningismus, seizures, confusion, tre-
known as Kozhevnikov epilepsy among Russian neurologists mor, ataxia, apathy, cranial nerve palsies, and urinary
[10]. The disease is more severe among the elderly, and mor- frequency, urgency, or retention. The patients often recover
tality is reportedly higher in far-eastern Russia, though it is not from the acute infection after a week or so, though 30–50%
known whether this is due to the strain of the virus or under- continue to have prolonged asthenia, insomnia, irritability,
reporting of milder cases. Diagnosis at the first stage is by PCR, depression, poor memory, headache, tremor, and even gait
and the second stage by serology. There is no definitive treat- and speech disturbance which can last up to 2 years.
ment though effective vaccines are available [15]. 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
LaCrosse Encephalitis substantia nigra edema in about 20% of patients. Diagnosis is
The commonest cause of encephalitis in the United States is by serologic test and treatment is supportive. A mosquito con-
caused by the Californian serogroup of bunyaviruses; and trol program has proven effective in breaking the cycle of
among this group of viruses, LaCrosse virus is responsible for transmission.
almost all infections. LaCrosse virus is transmitted by the Aedes Among patients with acute St. Louis encephalitis, general-
triseriatus mosquito with chipmunks and squirrels as the nat- ized tonic–clonic seizures occur in 30%, myoclonic jerks in
ural reservoirs and amplifying hosts. Occurring mainly in the about 10%, and status epilepticus in another 10%. The EEG
upper Midwestern states during summer months, the inci- shows diffuse slow waves in 70% of patients, bilateral periodic
dence of LaCrosse infection has been stable over the years with lateralized epileptiform discharges in 10%, and status epilepti-
“… to contract the 70–100 cases annually. More than 90% of the cases occur in cus in another 10%.
virus compared to
young people under 15 years of age, with males being twice as
females.”
likely to contract the virus compared with females. In endemic
areas, up to 18% of residents are seropositive. Western Equine Encephalitis
Probably only 1 in 1000 person infected with the virus Western equine encephalitis virus is an alphavirus, from the
becomes symptomatic, and in these patients, fever is near Togaviridae family. It is mainly transmitted by the Culex tar-
universal, three-quarters have headache, and half have menin- salis mosquito and its natural reservoirs are birds. In summer,
gismus. Other common features are seizures, an altered state of the mosquito switches its feeding pattern from birds to mam-
consciousness, focal neurological deficits, abdominal pain, mals, causing outbreaks in horses, mules, and humans.
cough, and sore throat. About 12% of patients become coma- Western equine encephalitis is limited to North America and
tose, though the outcome is usually good. the last human outbreak was reported in Colorado in 1988.
LaCrosse encephalitis is highly epileptogenic. About Since then, fewer than five sporadic cases have been reported
40–49% of patients with symptomatic infection develop acute annually.
symptomatic seizures and up to 20% of patients develop Only 1 in 100–2000 infections results in clinical disease,
remote symptomatic epilepsy, even after recovery from the which ranges from mild fever to aseptic meningitis and ence-
infection. Abnormal EEG findings were reported in up to phalitis. Infants are more likely to develop central nervous
75% of children 3–4 years after the infection. Apart from system infection and neurological sequelae. After an incuba-
epilepsy, the overall outcomes remain good; the mortality tion period of 5–10 days, those with encephalitis present with
rate is only 0.3 to 0.5%, and residual neurological deficits, sudden onset of fever, headache, nausea, vomiting, and
such as weakness, learning disabilities, cognitive deficits, and respiratory symptoms. After a few days, the patients develop
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Delete “an”
lethargy, an altered consciousness, meningismus, and vertigo. re-emerged in Central Africa and Indonesia in 2000–2004.
In infants less than 1 year of age, irritability, tremor, weakness, The A226V mutation in the E1 gycoprotein facilitated replica-
and focal or generalized seizures are common features. Long- tion in A. albopictus mosquitoes, causing re-emergence in the
term sequelae of Western equine encephalitis are mild and form of devastating epidemics in countries around the Indian
include fatigue, headache, and tremor, and the mortality rate is Ocean since 2005. In 2013, the virus spread to the Americas
3–4%. In children, severe neurological deficits are common with the first documented local transmission in the Caribbean.
and seen in 56% of infants younger than 1 month of age and Post-mortem histopathology showed focal perivascular lym-
10% in older infants. A quarter to a third of children with acute phocytic infiltration with microglial activation and foci of
symptomatic seizures will develop remote symptomatic epi- active demyelination without gliosis.
lepsy, sometimes up to 2 years after the acute illness. Diagnosis Clinical manifestations follow a short incubation period of
is by viral isolation or serologic test. Treatment is mainly 2–10 days, when 78–96% of patients become symptomatic, most
supportive as there is no specific antiviral agent available [16]. 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
Eastern Equine Encephalitis patients. Blood tests commonly show lymphopenia, thrombo-
Eastern equine virus causes the most lethal arboviral encepha- cytopenia, and in some, anemia, hypocalcaemia, and elevated
litis in the United States. It is an alphavirus from the family liver enzymes and creatinine kinase. Some develop relapse or
Togaviridae, and found almost exclusively along the Atlantic chronic polyarthralgia, and less commonly, musculoskeletal
and Gulf coasts of the United States, extending as far inland as pain, sensory symptoms, fever, fatigue, and headaches, lasting
Wisconsin, Indiana, and Michigan. The chief vector is Culiseta over a year in 20–66%. Atypical infection occurs in 0.1–0.3% of
melanura, a fastidious mosquito that breeds in a specific patients, with infants most at risk. Neurological involvement
microenvironment of dark, organic-rich water in peat soil presents in up to a quarter of atypical infections; generalized or
and which is strictly ornithophilic. Human infections occur focal onset seizures are seen in 12.5%, but as high as 80% of
when other less fastidious mosquitoes venture into this envir- pediatric infections, up to half of whom have status epilepticus.
onment. There are about five reported cases of Eastern equine In adults, seizures are more common in those with pre-existing
encephalitis a year in the United States. epilepsy or chronic illnesses. Intrapartum viremia leads to ver-
Almost all infections are symptomatic, which could manifest tical transmission in half of the neonates and causes severe
as either systemic infection or encephalitis. Young children are encephalopathy, with persistent disabilities in 20–44% of chil-
more susceptible to develop encephalitis with its subsequent dren, including epilepsy, cerebral palsy, and other focal deficits.
serious neurological deficits. Systemic infection begins abruptly MRI is abnormal in fewer than 20% of adults and shows
with high fever, followed by myalgia, arthralgia, and malaise, bilateral frontoparietal diffusion weighted image lesions.
and lasts 1–2 weeks, and recovery is mostly complete. In patients In neonates, the lesions are more widespread and evolve into
with encephalitis, headache, irritability, restlessness, drowsiness, vasogenic oedema, some ultimately into cavitation with gen-
anorexia, vomiting, diarrhea, seizure, and coma occur a few days eralized cerebral atrophy.
after the onset of systemic infection. Children may develop Diagnosis is established by serum or CSF serology (ELISA)
generalized or facial edema, weakness, tremor, muscular twitch- or rt-PCR. Treatment is supportive and a vaccine is under
ing, or dysautonomia. In fatal cases, death often occurs as active development. Overall, fatality is uncommon but
a result of either severe encephalitis or dysautonomia causing increased in the extremes of age and as high as 10% in atypical
myocardial insufficiency and respiratory failure, and usually infection.
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
Influenza Virus
successfully in humans, but it is not yet available for general use. Influenza viruses are single-strand negative RNA orthomyxo-
Eastern equine encephalitis is the most lethal arboviral viruses. Of the three subtypes, influenza C infection is subcli-
encephalitis in North America; the mortality rate ranges nical. Influenza A and B viruses cause seasonal epidemics of
between 30% and 75% and the majority of the survivors are mainly mild and self-limiting respiratory tract infection with
left with severe, disabling, and often progressive intellectual abrupt onset of fever, cough, rhinitis, sore throat, headaches,
and physical disabilities, which include personality disorders, myalgia, and lethargy. Global pandemics can occur when new
cranial nerve palsies, weakness, and remote symptomatic sei- subtype of viruses emerge through the process of antigenic
zures. The long-term outcome is even poorer; 9 years after shift in influenza A and antigenic drift in both influenza
infection, up to 90% of patients had died because of associated A and B viruses. Although uncommon and occurring at
neurological deficits, and only 3% had recovered [1,25]. 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-
Chikugunya Virus thy, and others include encephalitis lethargica, Reye’s syn-
Chikungunya virus is an arthropod-borne alphavirus trans- drome, stroke, acute disseminated encephalomyelitis,
mitted by Aedes aegypti mosquitoes. The virus causes unpre- transverse myelitis, Guillain–Barré syndrome, and other focal
dictable epidemics every 7–20 years in Africa and Asia and deficits. Most of these are more common in children.
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Seizure is the commonest neurological manifestation and is The incubation period of Zika infection is unknown,
seen in approximately 70% of children with neurological com- though likely to be less than a week. Only 20% of infections
plications. It occurs in four clinical settings. The vast majority are symptomatic, with 90% of these presenting with macu-
are febrile seizures, which occur in approximately 1 in 5 children lopapular rash, often pruritic, and over half with low-grade
hospitalized with seasonal influenza. The virus also causes sei- fever, arthralgia, and conjunctivitis. Other common symp-
zures in older children beyond the age of febrile convulsion, toms include headaches, myalgia, vomiting, swelling of the
recurrent seizures in epileptic patients, and seizure in the setting extremities, and hearing disturbances. Infection was asso-
of encephalopathy, including acute necrotizing encephalopathy. ciated with acute motor axonal variant of Guillain–Barré
Influenza virus causes significantly higher rates of febrile sei- syndrome, and probably myelitis and meningoencephalitis,
zures and repeated seizures compared to parainfluenza virus in the Pacific island outbreaks. In Brazil, 29% of infected
and adenovirus [4]. Both simple and complex febrile seizures pregnant women had fetal abnormalities on ultrasound, the
are seen. Investigations are mainly normal, though occasionally commonest of which was microcephaly, but also included
brain MRI shows increased T2 signal in hippocampus and absence of corpus callosum, cerebral atrophy, hydranence-
splenium or mild gyral swelling, and EEG shows diffuse slowing, phaly, gyral abnormalities, ventriculomegaly, calcification,
spike-and-waves discharges or burst suppression. hydrops fetalis, anhydramnios, intrauterine growth retar-
Encephalopathy is the second commonest neurological dation, and eye abnormality in 35%. Intellectual impair-
complication, and varies in severity from mild confusion to ment and epilepsy complicate some of these abnormalities.
coma. About 80% of patients are children and the condition The risk of microcephaly was highest at 95 in 10,000 cases if
appears to be more common and more severe in Japan for infection occurred during the first trimester, but remained
unknown reason(s). Seizures and disturbances in conscious elevated if infection occurred as late as 18 weeks of gesta-
state are the two commonest manifestations; other features tional age.
include hallucination, abnormal behavior, and upper motor Diagnosis is established by rt-PCR during the first week
neuron lesion signs. Investigations are usually normal, though of infection, and IgM captured ELISA (MAC-ELISA) subse-
CSF may show pleocytosis and/or raised protein, EEG diffuse quently. Viral RNA becomes undetectable a week after
slow waves, and MRI non-specific T2 hyperintensity in the symptom onset though PCR may be positive for up to 10
splenium or other areas, cerebral oedema or changes similar weeks in pregnant mothers of infected fetuses. Serology test
to posterior reversible encephalopathy and ADEM. is falsely positive with current infection of other flaviviruses,
Approximately 10–25% of children with encephalopathy suffer especially dengue, in which case plaque reduction neutrali-
“…other
from acute necrotizing encephalopathy, which presents with zation test (PRNT) may confirm the diagnosis. However,
flaviviral
rapid deterioration to coma within a few days and MRI show- PRNT is expensive, time consuming, involves handling of infection or
ing necrosis in bilateral thalami, cerebral white matter, cere- live virus, and may not be useful in patients who had pre- vaccination.”
bellum, and brainstem. Familial and recurrent cases are vious exposure to other flaviviral infection of vaccination.
associated with mutations in the RANBP2 gene. An effective vaccine is not yet available and treatment is
Almost all patients with febrile seizures recover comple- supportive. Multiple concurrent preventive and mosquito
tely. Prognosis of encephalopathy is significantly worse, with control measures are more important in outbreak manage-
mortality ranging from 20% to 40% and long-term sequelae ment [21].
from 30% to 60%. The prognosis of acute necrotizing ence-
phalopathy is the worst, though poorly documented outside
Japan. Murray Valley Encephalitis
Diagnosis is established by first performing a screening test Murray Valley encephalitis virus is a flavivirus found only in
on nasopharyngeal swab with monoclonal antibodies, Australia, Papua New Guinea, and perhaps the eastern islands
and confirmed by PCR and serotyping. Treatment is suppor- of Indonesia. The Culex mosquito, especially C. annulirostris, is
tive [7]. the vector, and wading birds its natural reservoir and host.
Horses, feral pigs, and cattle may act as additional reservoir or
Zika Virus amplifying hosts. Outbreaks of Murray Valley encephalitis
have been reported throughout Australia, and sporadic cases
Zika virus, first discovered in the Zika forest in Uganda, is an
occur annually, mainly in the Kimberly region of northern
arthropod-borne flavivirus with non-human primates as its
Western Australia and in the Northern Territory. Only 1 in
primary host. Apart from transmission by various species of
500–5000 infections is symptomatic though infection is more
Aedes mosquitoes, it is also transmitted vertically, through
common and severe in children and infants. Clinically, the
sexual intercourse, and possibly through blood transfusion
patients present with sudden onset of fever, headache, vomit-
and breast milk. It has caused sporadic cases in Southeast
ing, dizziness, weakness, brainstem signs, seizures, and myo-
Asia, and in 2005–2016, multiple outbreaks in the Pacific
clonus. Mortality ranges from 15% to 31% and half of the
islands, where it was associated with Guillain–Barré syndrome.
survivors have significant residual neurological deficits.
In early 2015, the virus spread to the Americas and caused
There is no specific antiviral therapy for Murray Valley ence-
a massive outbreak in Brazil, where an increased number of
phalitis [24].
neonates born with microcephaly was noted.
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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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www.cambridge.org
Information on this title: www.cambridge.org/9781108420754
DOI: 10.1017/9781108355209
© Cambridge University Press 2019
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published 2018
Printed in <country> by <printer>
A catalogue record for this publication is available from the British Library.
Library of Congress Cataloging-in-Publication Data
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)
Subjects: LCSH: Epilepsy – Etiology. | BISAC: MEDICAL / Neurology.
Classification: LCC RC372 .C38 2018 | DDC 616.85/3–dc23
LC record available at https://lccn.loc.gov/2018021686
ISBN 978-1-108-42075-4 Hardback
Cambridge University Press has no responsibility for the persistence or
accuracy of URLs for external or third-party internet websites referred to
in this publication and does not guarantee that any content on such
websites is, or will remain, accurate or appropriate.
...........................................................................................................
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
information provided by the manufacturer of any drugs or equipment
that they plan to use.
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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
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Contents
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
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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Foreword
The written history of epilepsy goes back 3000 years with accu- identifying an increasing number of “epilepsy genes” respon-
rate descriptions of epileptic phenomena appearing in the writ- sible for specific types of epilepsy, and further characterizing
ings of ancient Mesopotamia and the Indian Ayurvedic texts. genetic disorders associated with epilepsy, but also advancing
Although physicians of the Hippocratic school in Greece, about the concept of susceptibility genes, which will explain variable
400 BC, understood that epileptic seizures originated in the individual predispositions to develop certain forms of acquired
brain, as did Galen several hundred years later, epilepsy was epilepsies. Now, in the twenty-first century, we are poised to
generally viewed as a mysterious condition attributed to super- reap the benefits of these dramatic advances in our under-
natural causes, at least in the West, until the mid nineteenth standing of the causes of epilepsy.
century. At that time, the nascent disciplines of basic neu- Methodology for characterizing different types of epileptic
roscience and clinical neurology defined a variety of ictal man- seizures and the disorders associated with them, particularly
ifestations, including focal seizures and absences, and through electroclinical correlations, that is the association of
recognized them as part of a constellation of disorders referred particular behavioral ictal signs and symptoms with their
to as epilepsy. In particular, postmortem clinical pathological unique EEG correlates, led the International League Against
correlations not only revealed specific anatomic substrates for Epilepsy (ILAE) to propose international classifications for
different ictal manifestations, but led directly to concepts of epileptic seizures, and for the epilepsies in 1970. These have
localization of function within the human brain, and to surgical undergone several revisions, but the most recent version of
treatment for certain types of focal epilepsies. The development the International Classification of Epileptic Seizures was pro-
of radiology in the twentieth century further improved physi- posed in 1981, and the most recent International
cians’ abilities to identify “invisible” lesions as responsible for Classification of the Epilepsies was proposed in 1989. These
epileptic seizures in some patients, but it was application of the were purported to be purely phenomenological, because the
electroencephalogram (EEG), and the subsequent field of both authors felt there was, at the time, insufficient mechanistic
clinical and basic electrophysiology, that provided a means to information on which to base a classification on specific
begin classifying and characterizing different types of epileptic causes of epilepsy. Nevertheless, the inclusion of EEG char-
seizures and epilepsy syndromes, and investigating their under- acteristics permitted categorization of ictal phenomena in a
lying fundamental pathophysiological neuronal mechanisms. way that implied certain pathophysiologic differences, as well
The careful delineation of different types of ictal phenomena as anatomic substrates. For instance, generalized seizures
provided the basis for creating experimental animal models for were distinguished from focal seizures that appeared to ori-
both in vitro and in vivo electrophysiological and microanato- ginate in a part of one hemisphere. Epilepsies were classified
mical investigations of epilepsy. EEG localization of the epi- not only based on their characteristic associated seizure types,
leptogenic region greatly increased the application of surgical but also according to broad etiologic categories: idiopathic,
treatment for focal epilepsies, which also provided novel meaning epilepsy and nothing else, presumably primary
opportunities for parallel invasive in vitro and in vivo electro- genetic disorders; and symptomatic, meaning secondary to
physiological and microanatomical investigations in patients. some other disease process. In addition, diseases associated
Towards the end of the twentieth century, explosive advances with epilepsy were well described, and some epilepsy diseases
in three-dimensional neuroimaging, first with structural X-ray were recognized as conditions with a single known cause, but
computerized tomography (CT), then functional positron most of the defined epilepsy conditions were syndromes,
emission tomography (PET), and finally both structural and characterized by specific seizure types, and other clinical
functional high-resolution magnetic resonance imaging (MRI) features, such as age of onset, response to antiepileptic
provided intricate insights into the pathophysiologic mechan- drugs, and comorbidity. Using this approach, the vast major-
isms and anatomic substrates of epilepsy disorders in indivi- ity of accepted epilepsy syndromes are pediatric idiopathic
dual patients that could be used to create more informed conditions, while the majority of epilepsies that affect adults,
categorizations and classifications. These efforts were joined most of which are symptomatic, still defy a reasonable syn-
by the burgeoning field of neurogenetics, which not only is dromic classification.
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Foreword
For over a decade, the ILAE has attempted to revise the 1981 disease pathogenesis and this will change forever the founda-
and 1989 classifications, with multiple reports that have tions on which we base diagnosis and treatment of disease.
updated the list of epileptic seizure types and epilepsy syn- The developments in the molecular understanding of dis-
dromes. They now recognize certain seizure types as diagnostic ease are nowhere more evident than in neurological disease,
entities with associated therapeutic, prognostic, and etiologic particularly the epilepsies. These clinical syndromes, often
implications that can be used when a definitive syndrome or dramatic in their clinical characteristics, have been associated
disease diagnosis cannot be made. These deliberations provide with a range of taxonomies that have developed over many
a basis for a more scientific classification of epilepsy disorders centuries. The clinical characteristics of seizures and an under-
based on underlying genetic and pathophysiologic mechan- standing of the abnormal electrophysiology provided a frame-
isms, as well as anatomic substrates. Ironically, however, as work on which taxonomy could be based, but clearly could not
the chapters in this book clearly confirm, with the increasing address the fundamental issue of the underpinning events in
sophistication of our investigative methodology, the elucida- disease pathogenesis. That has had to wait until the past twenty
tion of distinctive epilepsy conditions as diagnostic entities has years when the tools available for characterizing both families
become more, rather than less, complicated. The old dichoto- and individual patients have gradually become available.
mies of idiopathic versus symptomatic, and generalized versus Initial progress in this field focused, as with other diseases,
focal, are artificial and often impossible to apply. Well-defined on Mendelian forms of epilepsy using family based studies.
classical syndromes, such as childhood absence epilepsy, are Although these studies revealed a range of interesting patho-
not as homogeneous as once believed. Some idiopathic child- physiological mechanisms, including a number of ion chan-
hood epilepsies, such as Dravet syndrome, are not benign, and nels, it has been clear that this describes only a portion of the
there appear to be several distinctly different forms of temporal epilepsy syndromes, many of which involve more complex
lobe epilepsy with hippocampal sclerosis. However, the causes genetics. These now are increasingly tractable with the new
of epilepsy discussed in this textbook represent a major effort tools for genetic association and these are beginning to reveal
to put flesh on the bones of what hopefully will ultimately non-channel molecules and pathways associated with neural
become a biologically based international classification of the excitability. Together, these techniques are providing a crucial
epilepsies. framework for redefining the epilepsies based on pathophy-
With the hundreds of textbooks that have been published on siology and, in turn, this will have a profound impact on our
epilepsy in the past decade or so, it is rather amazing that none ability to predict, diagnose, and, ultimately, treat disease. Anti-
have focused specifically on the causes of epilepsy. The editors convulsive therapy has been remarkably successful, given how
have undertaken this monumental task and succeeded in doc- little we know about the pathogenic mechanisms of the disease,
umenting the current state of knowledge concerning the so it is likely that future therapeutic interventions based on a
genetic and pathological substrates of disorders characterized clearer understanding of the relevant pathways will be even
by epileptic seizures, as well as the situations that provoke ictal more effective.
events. This comprehensive compendium will not only serve as Together, these advances have made epilepsy one of the
an important resource for rethinking the organization and most significant examples in medicine of the importance of
classification of epileptic phenomena and epilepsy syndromes genetic tools in clarifying pathophysiology and these disor-
and diseases, but will also provide a foundation for basic ders demonstrate clearly how powerful the change from pure
research attempting to identify the diverse pathophysiological phenotypic classification of disease to one based on patho-
mechanisms at the subcellular, cellular, and systems levels, that physiology can be. The authors of this important book have
are responsible for epileptogenesis and seizure generation. been able to bring together a wide range of scientific insight
Identification of these fundamental neuronal processes in and data on this topic into a single volume that covers the
turn will lead to novel and more effective approaches to treat- whole range of clinical syndromes. They demonstrate how
ment, cure, and prevention of epilepsy. powerful these new genetic tools have already been in defin-
Jerome Engel, Jr. ing pathways in disease and they also clearly demonstrate
Los Angeles, California that, together, their observations are likely to lead to a funda-
mental new classification of these diseases. Not only is this
Medicine is undergoing a remarkable transition as we move volume timely, given the recent exciting developments in this
from descriptions of disease and a taxonomy based on clinical field, but it also demonstrates the enormous influence that
characteristics to a more detailed and precise understanding of these key basic insights will have on the way we categorize
disease pathogenesis. This revolution has been driven by the and, ultimately, treat individuals with disease. Epilepsy and
adoption of a range of molecular tools and, more particularly, its associated syndromes give us a clear vision of what the
by the application of molecular genetics to medicine. These future of medicine is likely to look like.
approaches are providing us with insights, often for the first Professor Sir John Bell
time, of the pathways and precise events associated with University of Oxford, UK
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One of the major strides forward in the field of epilepsy in recent entirely new section comprising a series of chapters dealing
years has been a renewed emphasis on its causes. An epileptic with the clinical approaches to establishing cause in different
seizure, like a headache, is a symptom. It is a symptom further- situations in clinical practice. Sections III and IV cover the
more which is known to have numerous different potential genetic causes, and have been greatly expanded with new
causes, but in many cases, these have remained hidden or obscure chapters reflecting the rapid advances in this field. The sections
(κρυπτός kryptós, hidden). Our ability to uncover the underlying are divided into the genetic causes of the idiopathic (or ‘pure’)
causes of epilepsy have been greatly enhanced in the last few epilepsies and into those of the genetically-based symptomatic
decades by the advent of medical technologies, notably in neu- epilepsies. Section V comprises chapters on the non-genetic
roimaging, molecular genetics and molecular chemistry, and causes of epilepsy and many of these too have been extensively
these have allowed many new causal factors to be recognized. rewritten, with an emphasis placed on the clinical features and
In the preface of the first edition, we cited the famous statement prognosis. In Section VI, we cover the precipitating factors of
of Kinnear Wilson that to attempt to list all causes of epilepsy epileptic seizures, which we consider to be as much a ‘cause’ of
would be an act of supererogation. However, with modern devel- epilepsy as are the underlying conditions, and which empha-
opments, we believe that this view is over-pessimistic, and not- sise the multifactorial nature of causation in epilepsy. In
withstanding the conceptual issues that complicate the idea of Section VII, the causes of status epilepticus are covered,
causation many of which were first enumerated by Hughlings which are often different from the causes of other forms of
Jackson, a listing of causes is now feasible to an extent previously epilepsy.
not imagined. The identification of the cause of epilepsy is a key As with the first edition, the purpose of the book is to be a
element in patient-centered clinical management, and is now comprehensive reference work, a catalogue of all known causes
increasingly successfully achieved. Long gone is the time when of epilepsy, and above all a clinical tool for clinicians caring for
epilepsy was simply described by the characteristics of the seizure patients with epilepsy. The intended audience is both specia-
(the seizure type) and hopefully, too, less focus can now be placed lists and generalists, and we have asked our contributing
on the intellectually sterile activity of rejigging classification authors to follow a predetermined template to provide a con-
schemes and more on the pathophysiology of underlying causes. cise summary of knowledge about the clinical aspects of the
What is attempted in this book is to describe all the known causes condition in a form that is helpful in the both hospital and
of epilepsy in a way which is useful for clinical purposes and outpatient settings.
which can stimulate further research to identify cause-specific We are also enormously grateful to Nick Dunton and to Anna
therapies. We have tried to do this approaching the relationships Whiting, his successor, the Senior Commissioning Editors at
between epilepsy phenomenology and its specific causes in a Cambridge University Press. Both have guided the project since
manner that is informative for both the epilepsy experts, who its inception with extraordinary skill and expertise, and we are
need to understand more about the underlying pathophysiology, equally grateful to Charlotte Brisley who came to the project in
and for those clinicians who are instead experts of the causative its later stages as content manager and who has worked tirelessly
disorders but might not be particularly familial with the peculia- to make it a success. The quality of the book depends on the skill
rities that epilepsy adds to a given medical condition. and clarity of the authors of the individual chapters and we have
As far as we are aware, this is the first, and indeed only, been very fortunate in the high level of expertise and commit-
textbook to focus specifically on the causes of epilepsy. It is ment all have brought to the book. We are also very obliged to
nine years since the publication of the first edition, and during our colleagues, around the world, who have engaged in stimu-
this time, we have learned a great deal from our experience lating discussions with us, who have shared their ideas and
with the first edition and also especially from the explosion of knowledge about the causes of epilepsy and who have guided
new information about the genetic and molecular causes of us in our quest to make this textbook a useful contribution to
epilepsy. As a result, this edition is expanded and extensively clinical and experimental work in epilepsy.
rewritten. In Section I of this second edition, we have included Simon Shorvon, Renzo Guerrini, Steve Schachter
new chapters on the concept of cause in epilepsy and on the and Eugen Trinka (editors)
basic principles of causation in epilepsy. Section II is an
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The editors have exercised a heavy editorial blue pen, have contributions. We are also enormously grateful to Nicholas
tried to minimize overlap or repetition, and have asked the Dunton, the Senior Commissioning Editor at Cambridge
authors to follow where possible a pre-assigned template. Our University Press, who has guided the project since its
contributors have responded magnificently in our opinion, and inception with extraordinary skill and expertise, and with-
we extend our grateful thanks for their hard work and for their out whose assistance the book would not have made it to
time and effort. We would like to thank also Professor Jerome the shelves. We also thank Assistant Editor Joanna
(Pete) Engel and Professor Sir John Bell for graciously agreeing Chamberlin and Production Editor Caroline Brown for
to write the foreword to the book. Pete Engel is a famous leader their great efforts on behalf of the book. Finally, we
in the field of epilepsy and a prolific author, who has made major would like to thank all our colleagues around the world
contributions to many fields of epilepsy. Sir John Bell is President for their stimulating ideas and knowledge, which have
of the Academy of Medical Sciences and Regius Professor of informed and illuminated all the pages of this book.
Medicine at the University of Oxford, and a renowned medical Simon Shorvon, Renzo Guerrini, and Fred Andermann
geneticist. The book is indeed fortunate to have their
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