Epileptic REVIEW ARTICLE

Encephalopathies

C O NT I N U U M A U D I O
I NT E RV I E W A V A I L AB L E
O NL I N E
By Shaun A. Hussain, MD, MS

ABSTRACT
PURPOSE OF REVIEW: This
article reviews the manifestations and treatment
of the epileptic encephalopathies, which are a heterogeneous group of
disorders characterized by both seizures and neurocognitive impairment. CITE AS:
CONTINUUM (MINNEAP MINN)
2018;24(1, CHILD NEUROLOGY):171–185.
RECENT FINDINGS: Next-generation (exome- and genome-based) sequencing
technologies are revolutionizing the identification of single-gene causes Address correspondence to
of epileptic encephalopathy but have only had a modest impact on Dr Shaun A. Hussain, University
of California Los Angeles,
patient-specific treatment decisions. The treatment of most forms of
Pediatric Neurology, 10833 Le
epileptic encephalopathy remains a particularly challenging endeavor, Conte Ave, Room 22–474, Los
with therapeutic decisions chiefly driven by the electroclinical syndrome Angeles, CA 90095–1752,
shussain@mednet.ucla.edu.
classification. Most antiseizure drugs are ineffective in the treatment
of these disorders, and treatments that are effective often entail RELATIONSHIP DISCLOSURE:
significant risk and cost. Dr Hussain serves on the board
of directors of the Child
Neurology Foundation and
SUMMARY: The epileptic encephalopathies continue to pose a major receives personal compensation
challenge in diagnosis and treatment, with most patients experiencing for serving on the advisory
boards of INSYS Therapeutics
very poor outcomes, although a significant minority of patients respond to, Inc, Mallinckrodt
or are even cured by, specific therapies. Pharmaceuticals, and UCB, Inc;
for serving as a consultant for
Eisai Inc; and for serving on the
speaker’s bureau of and as a
consultant for Mallinckrodt
INTRODUCTION Pharmaceuticals. Dr Hussain has
received research/grant support

T
he term epileptic encephalopathy refers to a heterogeneous group from Eisai Inc, GW
of epileptic disorders in which epileptic activity itself (ictal or Pharmaceuticals, INSYS
Therapeutics Inc, Lundbeck, and
interictal) impairs cognitive and behavioral function above and UCB, Inc. Dr Hussain has served
beyond what is expected from the underlying pathology alone.1 It on the editorial board of the
is important to note that the precise mechanisms underlying epileptic Journal of Pediatric Epilepsy and
received compensation for
encephalopathy are unknown, but they likely reflect widespread neuronal service as an expert medical
network dysfunction.2 The prognosis of these disorders is generally quite poor, witness in cases relevant to
but a significant minority of cases can be ameliorated and even cured by prompt pediatric epilepsy.

diagnosis and successful treatment. Although some overlap among these UNLABELED USE OF
syndromes exists, the identification of a specific electroclinical syndrome is PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
critically important, as it guides treatment and informs prognosis. Although
Dr Hussain discusses the
many specific structural, genetic, and metabolic causes for epileptic unlabeled/investigational use of
encephalopathy have been described, the identification of a specific etiology clobazam, ezogabine, felbamate,
prednisolone, topiramate, and
often proves elusive, despite tremendous advances in neuroimaging and genetic zonisamide for the treatment of
diagnostics. Furthermore, even in cases in which a specific diagnosis can be epileptic encephalopathy and
ascertained, the evaluation may be quite time-consuming and must not delay infantile spasms.

treatment. For this reason, these syndromes are distinguished based on age of © 2018 American Academy
onset, seizure type(s), and characteristic EEG patterns. This article describes the of Neurology.

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EPILEPTIC ENCEPHALOPATHIES

FIGURE 8-1
Suppression burst. Interictal suppression burst is typical of both early infantile epileptic
encephalopathy and early myoclonic encephalopathy and is reminiscent of burst suppression
that accompanies pharmacologic- or injury-induced encephalopathy. In suppression burst,
the bursts tend to be high voltage and irregular, in contrast to the well-formed epileptiform
discharges more typically encountered with burst suppression. Suppressions between the
bursts tend to be very low amplitude (less than 10 mV).

cardinal features of key syndromes within the spectrum of epileptic

encephalopathy and discusses abbreviated guides to treatment.

EARLY INFANTILE EPILEPTIC ENCEPHALOPATHY

Early infantile epileptic encephalopathy, also known as Ohtahara syndrome, is
among the epileptic encephalopathy syndromes with neonatal onset, often
beginning by 2 weeks of age.3 The seizure type classically associated with this
syndrome is a tonic spasm. These episodes are highly variable but typically
manifest with a paroxysmal jerk (usually with a duration of more than
250 milliseconds) followed by sustained tonic extensor posturing of the upper
and/or lower extremities, which lasts several seconds. These spasms typically
emerge in clusters and may occur hundreds of times per day. The electrographic
signature of these seizures is similarly heterogeneous but usually manifests with a
burst of chaotic, generalized, high-amplitude, mixed-frequency activity (often
with superimposed spikes, polyspikes, or paroxysmal fast activity) followed by
generalized voltage attenuation and often with the subsequent appearance of
diffuse low-voltage fast activity.4
The interictal EEG in early infantile epileptic encephalopathy is characterized
by a suppression-burst pattern (FIGURE 8-1). This pattern is characterized
by bursts of high-amplitude spikes and polyspikes that alternate with periods of
electrographic suppression and is often indistinguishable from the

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aforementioned ictal pattern. As is typical of many forms of epileptic encephalopathy, KEY POINTS
an incredible variety of structural and metabolic etiologies are associated with
● The term epileptic
early infantile epileptic encephalopathy (TABLE 8-1). Among the more common encephalopathy refers to
structural etiologies are hemimegalencephaly and cortical dysplasia. Myriad disorders in which epileptic
metabolic causes include nonketotic hyperglycinemia, pyridoxine dependency, activity threatens cognition
and a variety of disorders implicating the mitochondrial respiratory chain. above and beyond what
would be expected from
Similarly, genetic associations with early infantile epileptic encephalopathy are pathology alone.
numerous, with a list of single-gene mutations that is likely to grow substantially
as modern approaches to exome and genome sequencing are implemented on a ● Early infantile epileptic
wider scale. The vast structural, metabolic, and genetic heterogeneity of this encephalopathy is
interictally characterized by
disorder highlights its age specificity and lack of etiologic specificity.
the suppression-burst
The treatment of early infantile epileptic encephalopathy is overall quite pattern.
challenging, with limited data indicating modest efficacy of a variety of
antiepileptic drugs, as well as the ketogenic diet. Accordingly, the prognosis of ● Genetic associations with
early infantile epileptic encephalopathy is generally poor, with most patients all forms of epileptic
encephalopathy are
suffering adverse neurocognitive outcomes, early death, and transition to other numerous, with a list of
forms of epileptic encephalopathy such as infantile spasms and Lennox-Gastaut single-gene mutations that is
syndrome. However, in a minority of patients for whom etiology-specific likely to grow substantially as
treatment is available and promptly administered (eg, hemispherectomy for modern approaches to
exome and genome
hemimegalencephaly or pyridoxine for pyridoxine dependency), excellent sequencing are implemented
neurodevelopmental outcomes are possible. on a wider scale.

EARLY MYOCLONIC ENCEPHALOPATHY

Early myoclonic encephalopathy is frequently discussed in combination with
early infantile epileptic encephalopathy, and a debate exists as to whether these
syndromes are truly distinct entities. Like early infantile epileptic
encephalopathy, early myoclonic encephalopathy begins in the neonatal period.
The clinical presentation is most often heralded by fragmentary focal myoclonia
of the face or extremities, with seemingly random migration from one part of
the body to another.5 In short order, the syndrome’s ictal repertoire expands to

Key Clinical Features of Epileptic Encephalopathies TABLE 8-1

Subtype Age of Onset Etiology Interictal EEG Seizure Type(s)

Early infantile epileptic Neonatal Structural and genetic Suppression burst Tonic spasms
encephalopathy more than metabolic

Early myoclonic Neonatal Metabolic more than Suppression burst Myoclonic, focal seizures
encephalopathy structural and genetic

Epilepsy of infancy with Neonatal, Genetic, especially KCNT1 Nonspecific Focal seizures, status epilepticus
migrating focal seizures infancy
Infantile spasms 3 to 12 months Structural, genetic, Hypsarrhythmia Epileptic spasms
metabolic

Lennox-Gastaut 1 to 6 years Structural, genetic, Slow spike-wave Atypical absence, tonic, atonic,
syndrome metabolic myoclonic, epileptic spasms,
focal, generalized tonic-clonic

EEG = electroencephalogram.

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EPILEPTIC ENCEPHALOPATHIES

highly pharmacoresistant multifocal seizures, which frequently exhibit

concomitant autonomic phenomena such as apnea.6 The interictal EEG is
characterized by a suppression-burst pattern nearly identical to that observed in
early infantile epileptic encephalopathy (FIGURE 8-1). A transition to
hypsarrhythmia, with evolution of infantile spasms, is not infrequent. In
comparison to early infantile epileptic encephalopathy, early myoclonic
encephalopathy is more frequently attributed to inborn errors of metabolism
such as the various aminoacidopathies, especially nonketotic hyperglycinemia,
and less often linked to structural abnormalities such as cortical dysplasia.7 The
prognosis of early myoclonic encephalopathy is quite poor, and, as in early
infantile epileptic encephalopathy, this reflects a paucity of effective treatments.
Anecdotal reports support the use of a variety of antiepileptic drugs (AEDs) as
well as nonpharmacologic approaches such as the ketogenic diet.

EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURES

Epilepsy of infancy with migrating focal seizures (previously known as
malignant migrating partial seizures of infancy) is the form of epileptic
encephalopathy in which the electroclinical signature was most recently
elucidated.8 The age of onset is typically within the first few months of life.
Epilepsy of infancy with migrating focal seizures is characterized by focal
seizures with multiple topographic origins that migrate within and between
cerebral hemispheres, at times with each hemisphere exhibiting simultaneous
independent seizures.9 These seizures are typically quite prolonged, and they
often fulfill criteria for status epilepticus. The interictal EEG tends to be
nonspecifically abnormal, with prominent slowing, disorganization, and
multifocal independent epileptiform discharges, although not hypsarrhythmia.9
As in early infantile epileptic encephalopathy, only anecdotal reports suggest
limited success with a variety of AEDs, the ketogenic diet, and vagal
nerve stimulation.
Although most forms of epileptic encephalopathy exhibit highly diverse
genetic, metabolic, and structural etiologies, epilepsy of infancy with migrating
focal seizures appears to be somewhat more homogeneous. Most cases exhibit
normal or nonspecifically abnormal MRI features, and genetic characterization
appears to be more specific than other forms of epileptic encephalopathy.
Although individual cases of epilepsy of infancy with migrating focal seizures
have been linked to mutations in the SCN1A, SCN2A, PLCB1, TBC1D24, and
SLC25A22 genes, numerous subsequent reports with larger cohorts have now
implicated the KCNT110 gene, which codes for a voltage-gated potassium
channel subunit. KCNT1 mutations have thus emerged as the most frequent
cause of epilepsy of infancy with migrating focal seizures, and manipulation of
potassium currents is a prime target of emerging therapeutic approaches. At
present, given a lack of effective treatments, the prognosis of epilepsy of infancy
with migrating focal seizures is uniformly poor, with highly intractable seizures
and an unfortunately high incidence of early death.8

INFANTILE SPASMS
Infantile spasms were first described by Dr William J. West in a letter to the
editor of The Lancet in 1841,11 in which he described the syndrome’s key
manifestations in his own son. Infantile spasms usually begin later than early
infantile epileptic encephalopathy, early myoclonic encephalopathy, or epilepsy

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of infancy with migrating focal seizures, with onset most often between the ages KEY POINTS
of 3 and 12 months, although onset has been reported as late as childhood and
● Early myoclonic
even adulthood (in which case, it is more aptly termed epileptic spasms). The encephalopathy bears great
prognosis of infantile spasms is generally poor, with most children exhibiting resemblance to early
psychomotor retardation and intractable epilepsy. However, infantile spasms are infantile epileptic
a critical example of an epileptic encephalopathy in which prompt diagnosis and encephalopathy but is
more often caused by inborn
successful treatment can yield normal neurodevelopmental outcomes, at least in errors of metabolism.
cases where the underlying cause of infantile spasms does not threaten
development independent of seizures. Although infantile spasms have been ● The hallmark of epilepsy
associated with myriad structural, genetic, and metabolic entities, the exact of infancy with migrating
focal seizures is frequent,
pathogenesis of infantile spasms remains uncertain and probably depends on
long seizures with multifocal
etiology. In cases where an acquired cause of infantile spasms is identified (eg, origin and migration (as
hypoxic-ischemic encephalopathy, postnatal hemorrhage), the onset does not opposed to spread).
immediately follow the antecedent insult; instead, spasms begin several months
after acquired injury.12,13 As illustrated in CASE 8-1, this delay suggests a period of ● KCNT1 mutations have
emerged as the most
subclinical epileptogenesis and thus an opportunity to potentially prevent frequent cause of epilepsy
infantile spasms among infants at risk. Moreover, although many brain insults with migrating focal
carry some risk of infantile spasms, the majority of “at-risk” children do not seizures, and manipulation
actually develop infantile spasms. The precise genetic or environmental factors of potassium currents is a
prime target of emerging
shared by at-risk children who actually manifest infantile spasms remain therapeutic approaches.
unknown. The discovery of such factors could potentially allow for identification
of patients at highest risk and justify the use of high-risk preventive therapies ● Prompt diagnosis of
(eg, adrenocorticotropic hormone [ACTH]). infantile spasms is a critical
prerequisite for successful
The seizures (spasms) that characterize infantile spasms are highly variable in
treatment.
appearance, but they typically occur in clusters and often commence upon
awakening. Spasms have generally been described as flexor (forced anterior ● The seizures (spasms)
flexion of the neck and axial musculature, often with concomitant elevation and that characterize infantile
extension of the bilateral upper extremities), extensor (forced extension of the spasms are highly variable in
appearance, but they
head and neck), or mixed flexor/extensor.15 Individual spasms generally last typically occur in clusters
between 0.5 and 1.0 seconds and repeat every 5 to 30 seconds in clusters of and often commence upon
approximately 2 to 20 minutes.16 Patients with focal structural etiologies of awakening.
infantile spasms often exhibit asymmetric spasms, typically with head
● Although often a
movement away from the pathologic hemisphere and more vigorous dramatic interictal
extension/elevation of the contralateral arm.17 Needless to say, many variations abnormality, hypsarrhythmia
on this theme exist. is often relatively subtle or
The interictal EEG background pattern of hypsarrhythmia (FIGURE 8-2), absent; the absence of
hypsarrhythmia neither
which manifests with extremely high-voltage chaotic waveforms and
excludes the diagnosis of
superimposed multifocal epileptiform discharges, is often, but not always, seen infantile spasms nor
for some portion of the time in which infantile spasms are present.18 warrants less aggressive
Mirroring the variability of ictal spasms, multiple atypical or modified variants treatment.
of hypsarrhythmia have been described.19 However, the identification and
classification of hypsarrhythmia can be quite difficult, especially in borderline
cases,20 and patients without hypsarrhythmia have been described.21
Although treatment strategies vary greatly, two principal pharmacologic
approaches predominate. The first is hormonal therapy, including ACTH
(biological and synthetic depot preparations) and a variety of corticosteroid
agents (eg, prednisolone, prednisone, methylprednisolone, hydrocortisone).
Although most practice parameters tend to favor high-dose short-duration
regimens of ACTH,15 debate continues regarding the ideal dose and duration
of therapy.22 Furthermore, whereas ACTH is clearly favored over relatively

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EPILEPTIC ENCEPHALOPATHIES

CASE 8-1 A 12-month-old boy presented with developmental regression

experienced over the past month. He had stopped babbling, seemed less
interactive, and no longer reached toward his toys. His history was notable
for a ruptured arteriovenous malformation (arising from the anterior
division of the left middle cerebral artery) status post hematoma
evacuation and resection of the malformation at the age of 4 months. His
postoperative right hemiparesis had been improving. The boy’s parents
described recent clusters of head drops and concomitant upward eye
rolls, beginning at age 11 months. Each head drop lasted less than 1 second
and manifested with forceful anterior flexion of the neck as well as slight
elevation of the right arm. The clusters typically occurred daily upon first
morning awakening, with 15 to 25 head drops over 3 to 5 minutes.
A diagnosis of infantile spasms was confirmed by video-EEG. The
interictal record demonstrated abundant multifocal spikes (left more
than right) on an asymmetric, high-voltage (albeit less than 200 6V), and
disorganized background (higher voltage and more severe
disorganization was demonstrated over the left hemisphere). Each
head drop was accompanied by a symmetric and irregularly generalized
spike or sharp wave, immediately followed by diffuse relative
attenuation for 1 to 2 seconds afterward. Brain MRI demonstrated the
evolution of previously characterized structural injury, with marked
gliosis and atrophy throughout the distribution of the left middle
cerebral artery, with ex vacuo dilation of the left lateral ventricle.
The boy did not respond to sequential courses of prednisolone
(20 mg 3 times a day, approximately 6 mg/kg/d) and adrenocorticotropic
hormone (ACTH) (44 IU 2 times a day, approximately 150 IU/m2/d). Six
days after commencing vigabatrin with rapid titration to 750 mg 2 times
a day (approximately 100 mg/kg/d), the seizures stopped, and the
patient seemed to “wake up.” Repeat video-EEG after 2 weeks of
vigabatrin therapy demonstrated absence of epileptic spasms with
continued hemispheric asymmetry but marked reduction (normalization)
in voltage and visualization of the anterior-posterior gradient (organization)
over the right hemisphere. The vigabatrin was tapered off after 6 months,
and after 6 years, the boy maintained seizure freedom, and he was
socially and academically age appropriate. He exhibited incoordination
and weakness of the right hand but no other motor deficits.

COMMENT This patient presented with developmental regression and substantial

encephalopathy out of proportion to his left hemispheric pathology
(ie, epileptic encephalopathy), which is typical of infantile spasms. The
aforementioned aggressive treatment regimen was warranted despite the
absence of hypsarrhythmia (traditional voltage criteria were not met). Had
vigabatrin proven inefficacious, left hemispherectomy would have been
the author’s next step in management. With contemporary available data,
simultaneous vigabatrin and hormonal therapy may have been considered,
rather than sequential courses of treatment.14

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FIGURE 8-2
Hypsarrhythmia. Hypsarrhythmia is characterized by extraordinary high-voltage (nonepileptiform
slow waves with amplitude consistently more than 200 mV), abundant, multifocal or generalized
epileptiform discharges (which are often so frequent as to obscure the background EEG), and
disorganization (loss of the anterior-posterior voltage-frequency gradient in wakefulness).
Hypsarrhythmia is typical of infantile spasms, but not required for diagnosis.

lower-dose corticosteroid preparations,23 the presumed superiority of ACTH

has been challenged by several contemporary studies employing very high-dose
prednisolone.24,25 The exact mechanism of action of ACTH and corticosteroids in
the treatment of infantile spasms is unknown. Aside from the aforementioned
hormonal therapies, the main pharmacologic alternative is vigabatrin, an
irreversible inhibitor of g-aminobutyric acid (GABA) transaminase. Vigabatrin is
often used as a first-line treatment, especially outside the United States, although
it appears to be somewhat less effective than hormonal therapies,22 with a
possible exception being the treatment of infantile spasms associated with
tuberous sclerosis complex. Vigabatrin appears to be considerably more effective
in the treatment of infantile spasms associated with tuberous sclerosis complex in
comparison to infantile spasms associated with other etiologies,26 and a broad
consensus supports vigabatrin as the preferred initial therapy for treatment of
tuberous sclerosis complex–associated infantile spasms.15 Despite demonstrated
efficacy, the use of vigabatrin has been curtailed by fear of irreversible peripheral
vision loss as well as reversible and largely asymptomatic MRI signal changes
seen in the basal ganglia, thalami, brainstem tegmentum, and deep cerebellar
nuclei. However, the risk of vision loss—especially clinically meaningful
visual impairment—appears to be very low in infants,26 and the risk of
vigabatrin-associated MRI phenomena is reasonably low and dose-dependent.27
In addition to these pharmacologic approaches, resective surgery is commonly
undertaken among patients who are refractory to medical therapy and exhibit

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EPILEPTIC ENCEPHALOPATHIES

focal structural etiologies such as cortical dysplasia.28 Limited data support the
use of the ketogenic diet29 or treatment with a variety of drugs,
including topiramate and zonisamide.

LENNOX-GASTAUT SYNDROME
Lennox-Gastaut syndrome is the most common form of epileptic encephalopathy,
in part because of inconsistent, nonspecific, and rather inclusive diagnostic
criteria. As in other forms of epileptic encephalopathy, reported etiologies
8are incredibly varied, perhaps more so than any other form of epileptic
encephalopathy, including a substantial minority of patients for whom a specific
cause is unknown despite extensive diagnostic queries.30 Most definitions of
Lennox-Gastaut syndrome require (1) multiple seizure types, (2) cognitive
impairment, and (3) the interictal EEG pattern termed slow spike wave (typically
1.0 Hz to 2.5 Hz, usually generalized and occasionally multifocal) (FIGURE 8-3).31
Among children with Lennox-Gastaut syndrome, the most commonly
reported seizures include atypical absence seizures, tonic seizures (often or
exclusively occurring during sleep), and drop seizures (classically referring to
atonic seizures but inclusive of tonic, myoclonic, or generalized tonic-clonic
seizures in some classification schemes). Age of onset is usually later than the
forms of epileptic encephalopathy described above and typically occurs between
the ages of 1 and 6 years.31 Although Lennox-Gastaut syndrome may arise in an
otherwise healthy child, Lennox-Gastaut syndrome often begins as an evolution
from infantile spasms or other forms of epileptic encephalopathy and reflects a
significant degree of shared pathogenesis among these disorders.

FIGURE 8-3
Slow spike wave. Generalized slow (1 Hz to 2.5 Hz) spike wave is typically encountered
as an interictal phenomenon accompanying Lennox-Gastaut syndrome, especially in sleep.
It is also observed as an ictal electrographic pattern during atypical absence seizures.

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 The developmental prognosis of Lennox-Gastaut syndrome is quite poor KEY POINTS
and, based on the majority of definitions requiring cognitive impairment as a
● The age of onset of
diagnostic criterion, is essentially a foregone conclusion.32 The principal goals of Lennox-Gastaut syndrome is
treatment are seizure control and, to a much more limited extent, improvement usually later than other
of cognition. Among the seizure types that define Lennox-Gastaut syndrome, forms of epileptic
drop seizures often prove most difficult to control, and they impart encephalopathy and
typically occurs between
disproportionately large morbidity given the potential for traumatic injury to the the ages of 1 and 6 years.
face, jaw, teeth, and brain. As such, the elimination of drop seizures is a critical
goal in management. Although complete seizure freedom is rarely achieved in ● Drop seizures are a
the management of Lennox-Gastaut syndrome, substantial improvement in common manifestation of
Lennox-Gastaut syndrome
seizure burden is frequently accomplished with a variety of AEDs. Efficacy has
and pose disproportionate
been demonstrated with topiramate,33 valproic acid,34 felbamate,35 lamotrigine,36 harm given the potential for
benzodiazepines (especially clonazepam37), and rufinamide.38 Of particular note physical injury.
is the specific effectiveness of clobazam and rufinamide to combat drop seizures.
In addition to AEDs, considerable support exists for adjunct therapies including ● Reports of seemingly
miraculous success
the ketogenic diet, focal surgical resection when appropriate, corpus accompanying the use of
callosotomy, and vagal nerve stimulation, with the latter two particularly useful cannabidiol-enriched
for atonic seizures. Among investigational therapies in clinical trials for cannabis extracts for
Lennox-Gastaut syndrome, considerable excitement and debate is focused on treatment of seizures in
Lennox-Gastaut syndrome
cannabidiol, including both pure pharmaceutical preparations and have been balanced by
cannabidiol-enriched cannabis extracts (“medical marijuana”).39 Reports of concerns of reporting bias
seemingly miraculous success accompanying the use of cannabidiol-enriched and the possibility that the
cannabis extracts40 have been balanced by concerns of reporting bias41 and the perception of favorable
efficacy is confounded by
possibility that favorable efficacy—even in clinical trials—is confounded by drug interaction with
drug interaction with clobazam.42 The results of ongoing clinical trials are clobazam.
highly anticipated.
● Landau-Kleffner
LANDAU-KLEFFNER SYNDROME AND THE SYNDROME OF CONTINUOUS syndrome and the syndrome
of continuous spike and
SPIKE AND WAVE IN SLOW SLEEP wave in sleep exhibit similar
Landau-Kleffner syndrome and the syndrome of continuous spike and wave in EEG patterns but clearly
slow sleep (CSWS) are often discussed together based on similar nocturnal distinct phenotypes.
interictal electrographic features, but the associated clinical phenotypes are
● Electrical status
completely distinct (TABLE 8-2). Typically, a child with Landau-Kleffner epilepticus in slow sleep is
syndrome presents at school age with rapidly progressive linguistic deterioration frequently missed on routine
(specifically, acquired auditory agnosia) with preservation of other cognitive EEGs, as activation of
domains.43 A history of self-limited or easily controlled seizures is common, but epileptiform discharges
occurs most often in
some children presenting with Landau-Kleffner syndrome have no history of slow-wave sleep.
epilepsy whatsoever.44 In stark contrast, children and adolescents with CSWS
typically have long-standing and severe epilepsy as well as global neurocognitive
impairment.45 In fact, most cases of CSWS are identified coincidentally during
the evaluation of sleep/overnight EEG in patients with highly intractable
epilepsy. The awake EEG in patients with Landau-Kleffner syndrome tends to be
either normal or minimally abnormal, with occasional epileptiform discharges
and perhaps mild background slowing. In contrast, the awake EEG in patients
with CSWS tends to be markedly abnormal, with severe background slowing and
frequent multifocal epileptiform discharges. The key electrographic signature of
both Landau-Kleffner syndrome and CSWS is a dramatic activation of interictal
discharges in sleep, especially slow-wave sleep. The occasional to frequent
discharges seen in wakefulness are activated in sleep and consume the background
EEG. This interictal pattern was thus termed electrical status epilepticus in slow sleep

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EPILEPTIC ENCEPHALOPATHIES

(ESES), and in its original description was defined as a spike-wave burden of

at least 85%, meaning that greater than 85% of the EEG during slow-wave sleep is
occupied by epileptiform discharges (FIGURE 8-4).46
Practically speaking, a spike-wave index can be defined by sampling
slow-wave sleep and calculating the percentage of 1-second epochs that contain
an epileptiform discharge. Needless to say, several challenges arise in the
implementation of this quantification approach.45–47 Although it is clear that
these dramatically activated EEG patterns are a potential marker of severe
linguistic or global neurocognitive dysfunction, it has not been established that
an increasing spike-wave index is associated with increased cognitive
impairment. Furthermore, contemporary descriptions of ESES suggest that
spike-wave indexes smaller than 85% may be clinically significant.48
The treatment of ESES is largely guided by small cohort studies, but several
treatment strategies are noteworthy.49–51 In the case of Landau-Kleffner
syndrome, dramatic language deterioration can be followed by equally dramatic
recovery of language with accompanying normalization of the sleep EEG.
The two mainstays of therapy are benzodiazepines (especially diazepam49 or
clobazam50) and high-dose corticosteroids.51 As illustrated in CASE 8-2, the
author favors an oral diazepam challenge (1 mg/kg at bedtime, maximum
dose 20 mg), administered with continuous EEG monitoring as well as
cardiorespiratory telemetry.52 The author has observed several patients with
substantial clinical and electrographic recovery after even a single dose, although
treatment failures and relapses certainly can occur.53 The author typically
continues relatively high-dose diazepam (approximately 0.25 mg/kg/d to
0.5 mg/kg/d) for several weeks or even months, depending on extended clinical
and electroencephalographic response. The most widely acknowledged therapy
for ESES is prednisone, with typical dosage in the range of 1 mg/kg/d to

TABLE 8-2 Characteristics of Syndromes Associated With Electrical Status Epilepticus

in Slow Sleep

Age of Comorbid Presenting

Syndrome Onset Etiology Epilepsy Features Response to Treatment Prognosis

Landau-Kleffner 5 to Unknown Mild, focal/ Acquired auditory Favorable clinical and Favorable
syndrome 12 years multifocal agnosia electrographic response
seizures (ie, resolution of electrical
status epilepticus in slow
sleep)
Syndrome of After Genetic/ Severe, Usually identified Poor clinical response Clinical response not
continuous 1 year structural/ highly in setting of severe and variable electrographic well established and
spike and wave metabolic variable epilepsy/cognitive response variable electrographic
in slow sleep impairment response

Autistic 1 to Unknown Highly Autistic regression Poor Unknown

regression with 2 years variable
epileptiform
EEG

EEG = electroencephalogram.

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FIGURE 8-4
Electrical status epilepticus in slow sleep. Electrical status epilepticus in slow sleep is the interictal
EEG pattern associated with multiple clinical syndromes, including Landau-Kleffner syndrome,
the syndrome of continuous spike and wave in slow sleep, and autistic regression with epileptiform
EEG. The key feature is sleep activation (ie, nearly continuous epileptiform discharges during sleep)
in contrast to occasional or rare epileptiform discharges observed during wakefulness. In this
sample, the spike-wave index is 93%, as 14 of 15 seconds contain a spike. Discharges may be
focal, generalized, or both and are often bicentral or bitemporal in topographic distribution.

2 mg/kg/d.51 The author tends to favor prednisone, for patients who fail
benzodiazepine therapy, as the risks and side effect burden of long-term
corticosteroid therapy are substantial.
In contrast to other forms of epileptic encephalopathy, the prognosis of
Landau-Kleffner syndrome is generally favorable, as reflected in the brisk
clinical and electrographic recovery that usually accompanies treatment.
Unfortunately, although children with CSWS often exhibit modest or even
dramatic electrographic improvement (diminished spike-wave index),
substantial neurocognitive improvement has not been reported widely. It
may be that the neurocognitive impairment accompanying CSWS is too
long-standing and hard wired to be remedied by presently available
treatments.54 In addition, the spectrum of syndromes associated with ESES
includes not only Landau-Kleffner syndrome and CSWS but also a related
syndrome in which cognitive impairment is dominated by autistic features
(autistic regression with epileptiform EEG)45 as well as rare cases of rolandic
epilepsy, in which the burden of seizures and nocturnal spike wave is
especially high (malignant rolandic epilepsy).55 Whereas patients with
malignant rolandic epilepsy, similar to Landau-Kleffner syndrome, tend to
respond favorably to the aforementioned treatments, children with autistic
regression with epileptiform EEG unfortunately exhibit an unsatisfying
response to therapy reminiscent of CSWS. Finally, it should be noted that

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EPILEPTIC ENCEPHALOPATHIES

CASE 8-2 A 9-year-old girl presented for a second opinion with a 3-year history of
occasional focal seizures and a 2-year history of insidious cognitive
deterioration with school failure, requiring a transition to a special-needs
classroom and social withdrawal. Prior to the onset of seizures, the
patient had been a precocious and socially adept student who enjoyed
school and excelled in all academic disciplines. At the onset of seizures,
which were brief left temporal-onset focal seizures with alteration of
consciousness and without secondary generalization occurring
exclusively during the day, a routine EEG in wakefulness and drowsiness
demonstrated occasional left centrotemporal spikes. MRI of the brain
was normal. After institution of treatment with levetiracetam and, later,
clobazam, her seizures were controlled, but cognitive deterioration
continued to progress. Once freedom from seizures was achieved, the
child’s parents had been told nothing could be done.
Upon seeking this second opinion 2 years later, an overnight EEG
demonstrated a pattern similar to FIGURE 8-4. Occasional left
centrotemporal spikes in wakefulness were dramatically activated in
sleep with a spike-wave index of greater than 90%, satisfying criteria for
electrical status epilepticus in slow sleep (ESES). A diazepam challenge
and titration of clobazam did not improve symptoms of encephalopathy
and did not impact the burden of spikes on repeat EEG. A subsequent
course of corticosteroids (prednisone 20 mg 2 times a day, approximately
1 mg/kg/d) accompanied near resolution of interictal spikes, and her parents
reported modest improvement in verbal comprehension and speech
fluency. Friends and teachers not familiar with the recent diagnostic
revelations and treatment did not identify a substantial change in cognition
or behavior. Although the burden of spikes remained much improved on
EEG, the patient did not make any substantive improvement with sequential
courses of other antiepileptic drugs and IV immunoglobulin (IVIg).

COMMENT This patient’s presentation is reminiscent of Landau-Kleffner syndrome,

although with a somewhat higher burden of seizures and with a relatively
slow cognitive decline. This contrasts with the typically precipitous acquired
auditory agnosia of Landau-Kleffner syndrome. Although linguistic dysfunction
was apparent, her neuropsychological performance implicated broader
dysfunction. The social dysfunction may either be a direct feature of the
epileptic encephalopathy or it may reflect anxiety and depression, which
accompanied academic decline and disintegration of her social life. This
case is an illustration of lost opportunity. It is possible that a clinical
response (neuropsychological functioning) would have been meaningful
had ESES been discovered at the onset of cognitive decline and been
followed immediately by appropriate treatment. As in this case, ESES is
frequently missed on routine outpatient EEGs, as activation of epileptiform
discharges occurs most often in slow-wave sleep.

182 FEBRUARY 2018

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there are rare reports of ESES accompanying focal structural lesions such as KEY POINT
cortical dysplasia or tumor, which have responded quite favorably to
● Although uncommon in
surgical resection.56 epileptic encephalopathy,
meaningful response, or
even a cure, requires prompt
CONCLUSION diagnosis and treatment.
Epileptic encephalopathy encompasses a very broad range of disorders with
diverse etiology, highly variable age of onset, and heterogeneous response to
therapy. Although prognosis is generally poor, even dismal, for children with the
earliest onset of epileptic encephalopathy, important exceptions occur. Across all
forms of epileptic encephalopathy, any chance of meaningful improvement, with
respect to both seizures and neurocognitive outcomes, critically depends upon
prompt electroclinical diagnosis followed by expeditious and appropriate
therapy. Epileptic encephalopathy remains a challenging focal point of ongoing
clinical, translational, and basic research. A tremendous need exists for salient
animal models to facilitate the identification of novel treatments. Until such
therapies are available, the clinical identification and appropriate application of
existing therapies remains an essential first step.

ACKNOWLEDGMENT
This work was supported by the Elsie and Isaac Fogelman Endowment and the
Milken Family Foundation.

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