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Statement of
Editorial Purpose
The Epilepsy Board Review Manual is a study
guide for trainees and practicing physicians
preparing for board examinations in epilepsy.
Each manual reviews a topic essential to the
current management of patients with epilepsy.
PUBLISHING STAFF
Bruce M. White
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Nature of Epileptic Seizures and Epilepsies . . . . 2
Classification of Seizures. . . . . . . . . . . . . . . . . . . 4
History, Examination, and Laboratory Tests. . . . 7
Classification of Epilepsies and Epileptic
Seizures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Specific Syndromes of Epilepsy. . . . . . . . . . . . . 10
Introduction
Epileptic seizures are among the most common
neurologic symptoms in all human populations.
Over 5% of Americans have at least one epileptic
seizure during their lifetimes.1 At any point in time,
1% to 2% of Americans have epilepsy. Cumulative
lifetime incidence of epilepsy exceeds 3%. These
statistics are similar across large human populations, although the incidence and prevalence of
epileptic seizures and epilepsies can be higher in
certain smaller groups (for example, in populations
exposed to military combat due to high rates of traumatic brain injury [TBI]).
This article is the first of a 6-part review of epilepsy
diagnosis and management. It provides an overview
of the pathophysiology of epileptic seizures and classification systems for seizure and epilepsy and summarizes key features of established types of epilepsies. Subsequent articles in this series will discuss the
techniques, interpretation, and applications of electroencephalography (EEG) and video-EEG (Part 2)
and structural and functional brain imaging (Parts 3
and 4). Part 5 focuses on selection, dosing, adverse
definitions
Seizures are defined as paroxysmal events of
transitory alteration in consciousness or other signs
or symptoms that can be due to brain dysfunction.
Epileptic seizures are seizure events that are caused
by excessive, abnormally synchronized, localized or
widely distributed neuronal electrical discharges3;
usually these electrophysiological correlates are
presumed by indirect evidence, although electrophysiological recordings sometimes are performed
during seizures. Nonepileptic seizures are seizure
events that are not caused by such electrocerebral
discharges. Nonepileptic seizures are sometimes
divided into categories of organic nonepileptic seizures, such as atypical syncope and parasomnias,
and psychogenic nonepileptic seizures, such as
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Figure 1. Paroxysmal depolarization shift (PDS). When a PDS occurs as an abnormally prolonged run of action potentials during sustained
membrane depolarization in a single neuron, as shown in the upper trace in B, the event is detectable only with microelectrodes; increased
glutamate concentration is associated with influx of cations initially, followed by increased GABA concentration with efflux of potassium.
When PDSs in a large number of neurons are synchronized for less than 200 ms, as shown in A, these electrical potentials may summate
as a spike-wave complex that is recorded with macroelectrodes, as shown in the lower trace in B. When sustained repetitive firing of PDSs
in a large number of neurons becomes synchronized for many seconds or longer, an electrographic seizure occurs, as shown in C. (Adapted
with permission from Holmes GL, Ben-Ari Y. Seizing hold of seizures. Nature Med 2003;9:9946.)
Figure 2. Genetic channelopathies in epilepsy. (A) Genetic channelopathies can support the occurrence of paroxysmal depolarization shifts (PDS) by altering the usual balance of Na+ and K+ ion conductance across neuronal membranes. Increased Na+
conductance (B, upper panel) creates a situation in which a single action potential initiates sustained depolarization as a PDS
(B, lower panel). Decreased K+ conductance (C, upper panel) also can predispose to PDS. (Adapted with permission from Chang
BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1261. Copyright 2003 Massachusetts Medical Society.)
In experimental models of partial epilepsies, intracortical mechanisms of synchronization operate during ictal discharges (Figure 4).8 There is
evidence that in certain epilepsies specific channelopathies operate to initiate PDSs in individual
neurons and produce seizures through normal
mechanisms of interneuronal synchronization,
while other epilepsies appear to require abnormal
interneuronal pathways to generate pathological
synchronization.
Experimental models of seizures and
epilepsy
Figure 3. Thalamocortical circuits in generalized epilepsies. Under normal conditions, brainstem monoaminergic projections synchronize
the thalamic reticular neurons into cycles of slow waves, and GABAergic projections of these neurons synchronize thalamocortical relay
neurons into cycles of slow waves, resulting in synchronized glutamatergic thalamocortical projections to widespread cortical areas that
generate the electroencephalography (EEG)-recorded slow waves of non-REM sleep and also sleep spindles. In generalized epilepsies,
repetitive paroxysmal depolarization shifts (PDSs) in thalamic reticular neurons synchronize PDSs in thalamocortical relay neurons, which
in turn synchronize PDSs in cortical neurons, thus generating EEG-recorded spike-wave discharges and sometimes absence seizures.
Presumably, a structurally normal complement of thalamic and cortical neurons and their pathways are able to generate spike-wave discharges and absence seizures due to genetically based dysfunction of channels, receptors, or other neurochemical elements. (Adapted with
permission from Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1259. Copyright 2003 Massachusetts Medical Society.)
Classification of seizures
Types of epileptic seizures
Figure 4. Epilepsy pathophysiology in mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis. Epileptic reorganization of the
hippocampal formation can be caused by a variety of insults that cause loss of vulnerable neurons in experimental models, but etiologic
insults only occasionally are evident in human TLE. This epileptic reorganization includes sprouting of mossy-fiber axons of dentate
granule cells; dentate granule cells project to CA3 neurons, and increased activity in mossy-fiber projections can support excessive
excitation of CA3 neurons. Thus, according to this hypothesis, normal excitatory inputs from the entorhinal cortical neurons to these
reorganized dentate granule cells induce excessive excitation of CA3 neurons in the setting of inadequate inhibition, to initiate sustained
repetitive firing in downstream CA1 neurons as a focal seizure with the potential to propagate more widely. Several experimental models
of TLE generate the same histopathological findings in the animal hippocampus that are observed in the human hippocampal sclerosis.
(Adapted with permission from Chang BS, Lowenstein DH. Epilepsy. N Engl J Med 2003;349:1262. Copyright 2003 Massachusetts
Medical Society.)
information regarding movements and responsiveness.) For example, when syncope is not preceded
by lightheadedness and postsyncopal confusion
occurs, other diagnoses must be entertained. Atypical presentations of syncope and incompletely observed parasomnias are among the most common
organic nonepileptic seizures.12,13
Psychogenic nonepileptic seizures (PNES) can
mimic essentially any type of epileptic seizure, as
6 Hospital Physician Board Review Manual
Adapted with permission from Berg AT, Berkovic SF, Brodie MJ, et al.
Revised terminology and concepts for organization of seizures and
epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:67685.
Convulsion
Hypopostural Event
Organic nonepileptic
event types
Rigors
Psychogenic nonepileptic
seizure types
Most frequently indicated
tests
Psychogenic convulsion
Generalized tonic
Generalized atonic
Generalized myoclonic
Infantile spasm
Syncope
Vertebrobasilar TIA
Cataplexy
Psychogenic swoon
EEG or video-EEG,
routine or prolonged
Brain MRI
(CT emergently)
ECG, routine or
prolonged
Tilt-table test
Brain MRI/MRA
Atypical arousal
Psychogenic stare or
catatonia
EEG or video-EEG,
routine or prolonged
Brain MRI
EEG or video-EEG,
routine or prolonged
Brain MRI
Polysomnography
CT = computed tomography; ECG = electrocardiography; EEG = electroencephalography; MRA = magnetic resonance angiography; MRI = magnetic
resonance imaging; TIA = transient ischemic attack.
Adapted with permission from Henry TR, Drury I. Non-epileptic seizures in temporal lobectomy candidates with medically refractory seizures.
Neurology 1997;48:137482
EEGs are common in many epilepsies, as are interictal focal and generalized slowing without spikes.
Video-EEG monitoring is highly valuable in diagnosis of paroxysmal events with impaired consciousness or with abnormal movements and behaviors.18
The EEG data can fully distinguish epileptic seizure
discharges (with phenomena specific to partialonset versus generalized-onset epileptic seizures),
pathological generalized slowing and depression of
electrocerebral activities (of syncope and organic
encephalopathies), onset of unconscious behaviors
during sleep (specific to REM-onset versus slowwave sleep onset), and absence of change from
waking or drowsy baseline EEG activities (in psychogenic events). The synchronized audio-video recordwww.turner-white.com
Adolescence Adult
Electroclinical Syndrome
Benign familial neonatal epilepsy (BFNE)
Early myoclonic encephalopathy (EME)
Early myoclonic encephalopathy (EME)
Epilepsy of infancy with migrating focal seizures
West syndrome
Myoclonic epilepsy in infancy (MEI)
Benign infantile epilepsy
Benign familial infantile epilepsy
Dravet syndrome
Myoclonic encephalopathy in nonprogressive disorders
Febrile seizures plus (FS+) (can start in infancy)
Panayiotopoulos syndrome
Epilepsy with myoclonic atonic (previously astatic) seizures
Benign epilepsy with centrotemporal spikes (BECTS)
Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE)
Late onset childhood occipital epilepsy (Gastaut type)
Epilepsy with myoclonic absences
Lennox-Gastaut syndrome
Epileptic encephalopathy with continuous spike-and-wave during
sleep (CSWS)
Landau-Kleffner syndrome (LKS)
Childhood absence epilepsy (CAE)
Juvenile absence epilepsy (JAE)
Juvenile myoclonic epilepsy (JME)
Epilepsy with generalized tonicclonic seizures alone
Progressive myoclonus epilepsies (PME)
Autosomal dominant epilepsy with auditory features (ADEAF)
Other familial temporal lobe epilepsies
Familial focal epilepsy with variable foci (childhood to adult)
Reflex epilepsies
Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS)
Rasmussen syndrome
Gelastic seizures with hypothalamic hamartoma
Hemiconvulsionhemiplegiaepilepsy
Adapted with permission from Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:67685.
Lennox-Gastaut syndrome, and is most often associated with brain structural abnormalities including unilateral or bilateral cerebral hypoplasia and
other developmental malformations. The prognosis
for neurocognitive development is grim.
Infancy
Childhood absence epilepsy (CAE) or pyknolepsy is the most widely recognized form of
epilepsy in childhood, but not the most common,
with a prevalence of less than 10% in children
with epilepsy.5867 Seizure onset is usually at 3 to 8
years of age in children with normal development.
Most have only absence (petit mal) seizures, often
occurring multiple times daily before treatment, but
some also rarely experience generalized tonicclonic (GTC) seizures. The interictal EEG is usually normal except for brief bursts of generalized
3-per-second spike-wave discharges, which are
provoked with photic stimulation and hyperventilation; often there is also occipital intermittent
rhythmic delta slowing. Generalized 3-per-second
spike-wave discharges usually last 10 to 20 seconds during the seizures. Brain imaging is generally considered unnecessary, as no lesional or
acquired epilepsies cause these types of seizures
with these EEG findings. Ethosuximide is usually
effective for absences, and valproate for both absences and GTC seizures. Seizures cease by the
teens in over 90% of patients, and those whose
seizures persist most often evolve into the juvenile
myoclonic epilepsy syndrome.
Lennox-Gastaut syndrome (LGS) begins at
Evolution into a GTC seizure may be immediately preceded by oculocephalic version. Typical
interictal EEG findings include unilateral or bilateral anterior temporal spikes or runs of intermittent
rhythmic delta activity (specific TLE discharges),
nonspecific focal temporal or generalized slowing, or a persistently normal interictal EEG. Typical
ictal discharges are focal frontotemporal rhythmic
discharges that can be sinusoidal or sharply contoured and evolve in field, frequency, and morphology, or similar discharges that are nonlocalizing
at onset and sometimes develop later temporal
maximum. Brian MRI can be normal or nonspecifically abnormal (with subcortical white matter signal
alterations, for example), but the classic signs are
unilateral or rarely bilateral hippocampal atrophy
and T2 signal increase. This syndrome is medically refractory in perhaps 50% of individuals, but
is more likely to be amenable to surgical resection
than are most other epilepsies.
Rasmussen syndrome is an electroclinical syndrome of epilepsia partialis continua with progressive atrophy of the affected cerebral hemisphere
and profound medication refractoriness.140144 Characteristic onset is in early to middle childhood,
but considerably later onset is recognized, as are
variants with aphasic or other focal seizures rather
than focal motor seizures. The clinical and EEG abnormalities are highly lateralized, with EEG slowing,
spikes and seizures continuing over months and
years, usually with limited response to tolerable or
intoxicating polypharmacy. Serial brain MRI shows
progressive atrophy of the affected hemisphere,
correlating with progressive hemiparesis. Brian tissue shows characteristic microglial proliferation
and nodularization, perivascular lymphocytic cuffing, and neuronal loss and gliosis in the affected
hemisphere. T-cell dysfunction and other lines of
evidence support various anti-inflammatory and
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