Author’s Accepted Manuscript

Cognitive and Social Outcomes of Epileptic

Encephalopathies

Katherine C. Nickels, Elaine C. Wirrell

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PII: S1071-9091(17)30119-5
DOI: http://dx.doi.org/10.1016/j.spen.2017.10.001
Reference: YSPEN682
To appear in: Seminars in Pediatric Neurology
Cite this article as: Katherine C. Nickels and Elaine C. Wirrell, Cognitive and
Social Outcomes of Epileptic Encephalopathies, Seminars in Pediatric
Neurology, http://dx.doi.org/10.1016/j.spen.2017.10.001
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Cognitive and Social Outcomes of Epileptic Encephalopathies

Authors:

1. Katherine C Nickels MD, Associate Professor, Divisions of Child and Adolescent Neurology and
Epilepsy, Department of Neurology, Mayo Clinic, Rochester MN

2. Elaine C Wirrell MD, Professor and Director of Pediatric Epilepsy, Divisions of Child and
Adolescent Neurology and Epilepsy, Department of Neurology, Mayo Clinic, Rochester MN

Mailing Address:

Dr. E Wirrell

Child and Adolescent Neurology, Mayo Clinic

200 First St SW

Rochester MN 55905

Ph (507)266-0774

Fax (507)284-0727

Email: wirrell.elaine@mayo.edu

Disclosure of Interests:

The authors have no commercial, proprietary of financial interest in any product or companies described
in this article.
Abstract

The term “epileptic encephalopathy” denotes a disorder in which seizures or frequent interictal
discharges exacerbate neurocognitive dysfunction beyond what would be expected on the basis of
underlying etiology. However, many underlying causes of epileptic encephalopathy also result in
neurocognitive deficits, and it can be challenging to discern to what extent these deficits can be
improved with better seizure control. Additionally, as seizures in these conditions are typically
refractory, children are often exposed to high doses of multiple antiepileptic drugs which further
exacerbate these co-morbidities. This review will summarize the neurocognitive and social outcomes in
children with various epileptic encephalopathies. Prompt, accurate diagnosis of epilepsy syndrome and
etiology allows selection of optimal therapy to maximize seizure control, limiting the impact of ongoing
seizures and frequent epileptiform abnormalities on the developing brain. Furthermore, mandatory
screening for co-morbidities allows early recognition and focused therapy for these commonly-
associated conditions to maximize neurocognitive outcome.

Definition of “Epileptic Encephalopathy”?

The term “epileptic encephalopathy” is used to denote a situation in which seizures or frequent
interictal discharges exacerbate neurocognitive dysfunction beyond what would be expected on the
basis of underlying etiology 1. This concept is most relevant to intractable epilepsies which start early in
life.

Causes of Neurocognitive Deficits in the Epileptic Encephalopathies

Neurocognitive deficits seen in children with epileptic encephalopathies are likely multifactorial and
determining the degree of additional adverse developmental impact resulting from seizures and
epileptiform discharges can be very challenging.

One of the main contributors to neurocognitive deficit is underlying etiology2. There is evidence from
both animal and human data that individuals predisposed to epilepsy have increased rates of
comorbidities, even prior to onset of the first seizure 3, 4. The epileptic encephalopathies are often
associated with etiologies that are highly correlated with premorbid intellectual disability, which is often
profound, even in the absence of severe seizures. Diffuse, neurocognitive dysfunction may result from
processes that are generalized, diffuse, or multifocal. Although focal processes tend to affect more
specific cognitive functions, in the developing brain these result in more diffuse functional change and
dysfunction, presumably through involvement of neuronal networks5.

Genetic causes have been increasingly recognized as important etiologies for epileptic encephalopathies
and may result in neurocognitive impairment via a number of mechanisms including ion channel
dysfunction (i.e. SCN1A, SCN2A, SCN8A , GRIN2A) or abnormal cortical development (i.e. ARX, LIS1, TSC
and other mTORopathies).
Structural brain abnormalities are subdivided into congenital (i.e. malformations of cortical
development) or acquired lesions. The resultant neurocognitive disability depends on the extent of the
abnormality, the specific location, and for acquired lesions, the age of insult. Generalized or diffuse
insults are typically associated with more global and severe impairment than very focal ones. An isolated
focal lesion usually has much less developmental consequences when sustained early in infancy,
compared to in later childhood or adolescence, due to brain plasticity.

Metabolic disorders result in neurocognitive dysfunction due to toxic effects of excessive accumulation
of specific metabolites, decreased inhibition, energy failure or neuronal dysfunction associated with
structural changes. For some select disorders, effective targeted therapies are available which markedly
mitigate or prevent cognitive sequelae.

Frequent seizures and interictal discharges may also exacerbate neurocognitive dysfunction. Although
the concept of “epileptic encephalopathy” has been debated 2, many children show a clear association
between onset of frequent seizures and/or epileptiform abnormalities on EEG and cognitive decline.
This decline is most evident in cases in which prominent slowing of the EEG background is also seen,
such as hypsarrhythmia, electrical status epilepticus in slow sleep, or generalized slow spike-wave
discharges (Figures 1 and 2). Arousal is mediated by increased activation of cholinergic nuclei in the
brainstem, which terminates thalamic hyperpolarization, and results in cortical depolarization with
desynchronization of the EEG. Encephalopathy in children with severe epilepsy and persistent, excessive
background slowing may be caused by insufficient depolarization or excessive, inappropriate
hyperpolarization of the thalamus or cortex, resulting in a cortex that is “asleep” during periods of
wakefulness, with alterations in intracortical synapses affecting a critical period of cognitive
development 6.

Seizures early in life result in structural brain changes, including spine loss in pyramidal cells of the CA3
region of the hippocampus, and impaired neurogenesis and synaptic reorganization in rodent models 7, 8.
Epileptic activity, even if focal, can disrupt metabolism in both affected and connected cortical regions,
resulting in widespread dysfunction 9-11. Interictal spikes which occur at critical periods in the learning
task have been shown to disrupt memory and performance 7, 12. If very frequent, they may inhibit action
potential firing in the hippocampus and result in impaired central processing speed, short-term memory,
and visuomotor integration in children 13.

As epileptic encephalopathies are typically notoriously refractory to therapy, many children are treated
with multiple antiepileptic agents, often at high doses, in an attempt to reduce seizure burden.
However, these agents may also adversely impact on development. Phenobarbital, phenytoin and
lamotrigine can cause neuronal apoptosis in neonatal rats 14, although such changes have not been
proven in humans. Many antiepileptic drugs such as phenobarbital 15, valproic acid 16, topiramate 17 and
zonisamide are also associated with cognitive impairment.
Cognitive and Social Outcomes of Specific Epileptic Encephalopathies

1. Early Myoclonic Encephalopathy and Ohtahara syndrome

Early myoclonic encephalopathy (EME) and Ohtahara syndrome present in early infancy, often during
the neonatal period with a suppression-burst pattern on EEG18. Fragmentary myoclonus is most
prominent in EME, although both focal and tonic seizures as well as spasms often evolve over time19-21.
In Ohtahara syndrome, seizure types include tonic spasms and focal seizures19, 22, 23.

While the cause of EME is unknown in up to 50% of infants, inborn errors of metabolism have been
reported. Brain malformations are more likely to be associated with Ohtahara syndrome 21.

Unfortunately, the prognosis for EME and Ohtahara syndrome is poor with profound intellectual
disability and a 50% mortality rate in the first one to two years 22, 23. Children who survive typically have
pharmacoresistant epilepsy and severe intellectual disability, often evolving to West syndrome in
infancy and some developing Lennox-Gastaut syndrome in childhood 23. Particularly for Ohtahara
syndrome, it is critical to determine whether there is a surgically-amenable, structural cause, as
disconnection or resection of the epileptogenic lesion can lead to seizure resolution and dramatically
increases the likelihood of a more favorable cognitive outcome 24.

2. Epilepsy in Infancy with Migrating Focal Seizures (EIMFS)

EIMFS presents in previously healthy children, typically within the first 6 months of life with exceedingly
frequent, multifocal seizures and an interictal EEG which demonstrates background slowing and
multifocal epileptiform discharges that are maximal over the temporal and rolandic regions22, 25. The
ictal EEG shows focal onset of seizures that shift from one lobe or hemisphere to the other, often with
one seizure beginning before another completely ends 22. Genetic mutations are the most frequent
etiology 20, 26-28.

This syndrome is refractory to treatment. The expected outcome is poor, with developmental
regression and subsequent profound intellectual disability25. Most children have acquired microcephaly,
cortical visual impairment, and language is typically absent. Mortality is high during early childhood,
typically due to respiratory failure 22, 25. However, one study reported a less severe outcome in young
children, and suggested more profound delays may become apparent over time 29.

While there is no known treatment for EIMFS, response to potassium bromide, stiripentol,
levetiracetam, benzodiazepines, rufinamide, ketogenic diet, and cannabidiol used in variable
combinations has been reported in small case series 30-33. However, correlation between improved
seizure control and developmental outcome is inconsistent 31, 34.
3. West Syndrome

West syndrome is the most common epileptic encephalopathy presenting in the first year of life, with an
estimated incidence of approximately 1 in 2500 live births 35. This entity is characterized by a triad of
epileptic spasms, hypsarrhythmia on EEG, and developmental delay or regression. An underlying
etiology is found in approximately two thirds of cases 36.

Long-term follow-up studies have documented that only one third of patients achieve sustained seizure
freedom 37, 38. Approximately one third of cases evolve to Lennox-Gastaut syndrome 38 and most of the
remaining cases have intractable focal or multifocal epilepsy.

Developmental prognosis is often poor and patients have higher rates of premature mortality. In a large
Finnish study of 214 infants with clinical spasms and an EEG showing either hypsarrhythmia or modified
hypsarrhythmia followed into adulthood (mean 25.6 years) or until death, the mortality rate was 31%,
with 10% of children dying prior to 3 years of age and 19% prior to 10 years of age 37. All but one patient
who died had intellectual disability, and infection was the leading cause of death. Another study showed
a similar mortality rate of 24%, but noted that none of deaths were directly seizure-related, but rather
due to the underlying neurological disability38.

Pre-existing developmental delay is common, and developmental stagnation or regression frequently

occurs with spasm onset. Ultimately 70-90% of cases are intellectually disabled, often in the moderate
to profound range 37. Furthermore, there is a higher risk of specific learning disorders, even amongst
children who test in the normal range. Elevated rates of autism spectrum disorders are also seen in
children with a history of infantile spasms, ranging from 9-35% 39-41.

As adults, most patients remain dependent on others, with only 14% capable of living independently,
14% independent for most basic activities but incapable of living independently, and 73% dependent on
others for nearly all activities of daily living 42. However, even those who were deemed capable to some
degree of independent living, a significant minority had psychiatric or behavioral concerns, or were
socially isolated.

Several factors play a role in predicting intellectual and social outcomes in children with West syndrome.
One of the most predictive factors of intellectual function is the underlying etiology - those with a
known cause (symptomatic spasms) have poorer outcomes than those in whom no cause is found
(cryptogenic spasms). In the long-term follow-up study of Riikonen, intellectual outcome was normal in
35% of those with cryptogenic spasms versus only 13% with symptomatic spasms 37. In a study of 57
consecutive cases of West syndrome from the Hospital for Sick children, all of whom underwent
developmental assessment using the Griffith Mental Development Scale administered a mean of 37.7
months after spasm onset, the mean developmental quotient was significantly higher in the cryptogenic
group (mean 71.2 +/- 24.2) than the symptomatic group (mean 48.3 +/- 24.5) 43. Of 109 infants with
West Syndrome identified in Los Angeles between 1990-2008 and followed for a mean of 5.4 years,
cognitive outcome was normal in 21% of cryptogenic cases versus only 8% of symptomatic ones
(p=0.047) 44. Finally, in the recent UKISS study, in which infants completed the Vineland Adaptive
Behavior Scales (VABS) at a mean age of 4.2 years, better development outcome was seen in cases
without an identified etiology in both hormonal-treated (median VABS composite score: 96 if unknown
etiology versus 45 if known etiology) and vigabatrin-treated groups (median VABS composite score: 63 if
unknown etiology versus 50 if known etiology) 45.

Specific type of etiology is also important. While structural etiologies are the most common cause for
spasms 36, outcome depends very much on the type of etiology. In cases with diffuse cortical
malformations (such as lissencephaly) or severe perinatal brain injury (such as diffuse hypoxic-ischemic
insults), intractable seizures often persist and intellectual disability is typically profound. While tuberous
sclerosis was previously associated with poorer outcome, vigabatrin has been remarkably effective 46
and resulted in improved cognitive outcomes 47. Similarly, the increased use of resective epilepsy
surgery has significantly improved cognitive and seizure outcomes for children with focal lesions, such as
cortical dysplasia, with the best outcomes seen with earlier surgery 48, 49. Between 0.6-13% of children
with Down syndrome develop infantile spasms 50, making it the most common genetic etiology seen in
cohorts of infants with West syndrome 36, 51. While these children have better outcomes overall than
other symptomatic causes 50, the impact of spasms is not benign. In a study comparing
neurodevelopment in children with Down syndrome using the Bayley Scales of Infant and Toddler
Development, children with co-morbid spasms scored approximately 20 points lower in cognitive,
motor, and language domains than whose without seizures 52. There are increasing numbers of genetic
etiologies identified for spasms 53, many of which are correlated with profound development delays,
including ARX, CDKL5, FOXG1 and STXBP1.

Symptomatic etiology is also a major risk factor for the development of autism in children with West
syndrome 54.

Another very significant predictor is preceding developmental delay or neurological abnormalities which
pre-date onset of spasms. Children with these risk factors are at significantly higher risk of poorer
seizure control and cognitive function 55.

There is also evidence that greater delay to diagnosis and initiation of effective therapy correlates with
poorer developmental outcome. This factor was addressed in the large United Kingdom Infantile Spasm
Study, which prospectively followed infants with newly-diagnosed spasms, recording date of spasm
onset and initiation of treatment and developmental outcome at 4 years of age 56. Lead time to
treatment was categorized into five categories, ranging from less than 8 days to greater than two
months. Each increase in category of lead time duration was associated with a 3.9 decrease in Vineland
Adaptive Behavior Scale score. This finding was most marked in children without an identified etiology.

Data from surgical series also support better outcomes with earlier intervention, showing higher
Vineland scores with younger age at surgery 48 and shorter duration of epilepsy 49. Thus, prompt
diagnosis and initiation of effective therapy are critical to maximize developmental outcome (Figure 1).
Other factors that correlate with better developmental outcome include older age at spasm onset,
favorable response to the first antiepileptic medication 44 and normal EEG following resolution of
hypsarrhythmia 57. Both temporal or frontotemporal focal discharges 39, 54 and bilateral temporal
hypometabolism on PET 58 are associated with higher rates of autism spectrum disorders.

4. Dravet Syndrome

Dravet syndrome presents in previously healthy infants with prolonged hemiconvulsive seizures, often
triggered by fever, in the first year of life. Over time, other seizure types emerge including myoclonic,
atypical absences, and obtundation status. Refractory seizures persist in the majority of cases but by
young adulthood, most patients have brief, generalized convulsions as their sole seizure type, which
more commonly occur nocturnally 59. Over 80% of cases are due to mutations in SCN1A. However,
mutations in this gene have also been associated with genetic epilepsy with febrile seizures plus (GEFS+)
as well as a range of other, often severe, phenotypes. These mutations result in loss of function in
voltage-gated sodium channels, and it is hypothesized that the increased epileptogenicity is the result of
reduction of sodium currents in inhibitory interneurons in the cortex 60.

Dravet syndrome is associated with elevated mortality rates of 15.8 per 1000 person-years 61. Long-term
follow-up studies have documented that 14.3-20.8% of patients die by early adulthood, with mortality
due to status epilepticus and its consequences in younger patients, and sudden unexpected death in
epilepsy in older children and young adults 59 62, 63.

Development is often said to be normal at epilepsy onset, although one prospective study which
enrolled infants with two or more focal or prolonged febrile seizures before 14 months of age noted
early impaired visual function in those who progressed to Dravet syndrome 64. Over time, variable
degrees of disability are noted with obvious delays typically evident by the late preschool years 65.
Decline in developmental quotients are steepest during the first four years, following which there is a
milder decrease 64. In most cases, true regression does not occur, but the decline is “due to the rising
discrepancy between the steady mental age and the increasing chronological age” 66, 67. Initial deficits
involve the visual dorsal pathway, which includes extrastriate visuomotor areas, extending from
occipital to parietal and frontal regions, which involve processing spatial information and visual control
of actions 64 67, 68. Language is also affected, and preferentially affects phonological skills (repetition,
phonological and morpho-syntactic accuracy), articulation and verbal planning, with lesser impact on
receptive and semantic (word and sentence comprehension) language skills 64, 69 70. Young adults with
Dravet syndrome also have imprecise articulation, abnormal nasal resonance, voice and pitch, and
prosody errors 71.

Occasionally developmental regression can occur following a prolonged convulsive seizure. “Autistic
traits” and hyperactivity have also been reported 72.
By adulthood, the majority of patients have significant disability 59, 62, 73-75 (Table 1). While most patients
are ambulatory, ataxia, pyramidal signs and crouch gait are frequent. Kyphoscoliosis develops in a
significant minority. Intellectual disability is typically in the moderate to severe range, and
communication is limited. Overall, only a small minority are able to live independently – the majority
need considerable support.

Several factors have been found to correlate with poorer intellectual outcomes, including higher
frequency of convulsive seizures in adulthood 73 and lack of occipital alpha activity on EEG in adulthood
62, 73
. While “borderland” forms of Dravet syndrome (those without myoclonic or atypical absence
seizures) were associated with improved cognitive outcome in one study 73, another study found no
correlation between phenotype and outcome 74.

Several possible mechanisms may lead to cognitive impairment 76. There is abundant literature on the
potential detrimental impact of recurrent status epilepticus on the developing brain 77. However, the
impact of prolonged seizures on ultimate outcome of persons with Dravet syndrome is less clear.
Imaging studies have shown low rates of mesial temporal sclerosis and, while cerebral or cerebellar
atrophy often is seen over time, these changes have not been found to correlate with frequency of
status epilepticus 78. Furthermore, neuropathological studies in adults with Dravet syndrome have
shown remarkable preservation of neurons and interneurons in the neocortex and hippocampi 75.

Although the literature is sparse, there is little correlation between intellectual outcome and any
epilepsy data, excepting for early onset atypical absences79, myoclonic seizures67, 79 and focal seizures67,
all of which predicted a more adverse outcome.

It is well-recognized that sodium channel agents exacerbate seizures in Dravet syndrome 80 but no study
has examined the duration of use of such agents with cognitive outcome.

5. Myoclonic-atonic epilepsy (MAE)

Myoclonic-atonic epilepsy presents in previously developmentally normal preschoolers with generalized

tonic-clonic seizures, followed by development of myoclonic-atonic, myoclonic and atypical absence
seizures, as well as non-convulsive status epilepticus. Seizure frequency is high, often multiple per day,
and falls due to seizures are common. Seizures are accompanied by developmental plateauing or
regression in some patients 81, 82.

Unlike many early-onset epileptic encephalopathies, the long term seizure and cognitive outcomes of
MAE are quite variable. In the majority of patients, seizures spontaneously remit and normal cognitive
abilities can be seen 82, 83. Approximately 30-45% will have some degree of intellectual disability or
cognitive impairment. Hyperkinetic and aggressive behavior can also be seen. Although cognitive and
behavioral abnormalities are mild in the majority, impairment persists after seizures remit 82, 84.

While the course is unpredictable, features that have previously been associated with a more severe
course include earlier age at onset, frequent episodes of nonconvulsive status epilepticus, frequent falls,
nocturnal tonic seizures, as well as frequent epileptiform discharges and continued background slowing
on EEG 81-84. However, the presence of any of these features is not always associated with poor
outcome. Effective, early treatment may improve long term outcome, although this is not yet certain.

6. Lennox-Gastaut syndrome

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that presents in early childhood,
between ages 1-8 years 85 with multiple seizure semiologies including tonic, atonic, generalized tonic
clonic, myoclonic, focal, and atypical absence seizures. Development prior to seizure onset is often
abnormal, and up to two thirds of patients have a prior history of West syndrome. Seizures are
pharmacoresistant and are concurrent with developmental plateauing or regression 21, 86. Furthermore,
cognitive and behavioral comorbidities are common.

During the initial years of the disease, in addition to developmental plateau, children are noted to have
hyperkinetic behavior, poor impulse control, and poor sense of danger. Later, psychomotor slowing can
be seen87, 88. Aggressive and hyperactive behaviors can be particularly challenging84. Injury due to
seizures, especially drop attacks, is common and difficulty to avoid87. Over time, cognition can be
expected to improve in only a minority of children89. Additional cognitive slowing and other side effects
of medication can be seen, but are difficult to identify due to the patient’s intellectual disability and
difficulties with communication90.

For most children with LGS, the long-term outcome is poor. Most continue to have seizures, in spite of
treatment, and up to 80% have daily seizures. Mortality is associated in 5-17%, with up to half dying of
complications of their seizures85. Cognitive outcome is similarly poor. Even though approximately half of
children have some degree of intellectual disability at onset, 95% will have cognitive impairment by
adulthood84. Even if seizure control is obtained, the cognitive and behavioral difficulties persist91. Thus, it
is important to have appropriate goals for treatment in LGS. Complete seizure freedom is unlikely, so
trying to decrease the most debilitating seizures is likely a more realistic option. It is also important to
avoid over-medicating these patients, as the cognitive and behavioral side effects of medications can
lead to reduced quality of life. However, reducing seizure burden can also improve alertness and
behavior92.

While the prognosis of LGS is typically severe, there may be milder phenotypes, depending on etiology.
Overall, less than 10% of patients with LGS will have borderline or normal cognition. However, in a
retrospective study of patients with LGS with three or more years of follow-up, 33% of patients with
unknown etiology had borderline or normal range cognition93.

Although focal structural etiologies are uncommon, in such cases, resective surgery might be a
treatment option. In surgically treated patients, seizure improvement was associated with
improvement in cognition, behavior, and quality of life 94. For those who are not resection candidates,
the ketogenic diet may afford seizure reduction95. However, it is not clear whether seizure reduction
was associated with cognitive improvement.
It is imperative to differentiate LGS from MAE, given the significantly better outcome of MAE.
Intellectual disability prior to seizure onset, drop attacks without a preceding myoclonic component,
frequent tonic seizures, and early EEGs demonstrating moderate to severe slowing of the background
are all suggestive of LGS, rather than MAE 85.

7. Continuous spike-wave in slow-wave sleep (CSWS) and Landau Kleffner syndrome (LKS)

CSWS and LKS most commonly present in late preschool to early school age children with
developmental regression and an EEG showing electrical status epilepticus in sleep (ESES) (Figure 3).
Premorbid developmental delay or focal neurologic abnormalities such as hemiplegia are seen in up to
one third of children with CSWS, in distinction to children with LKS who are developmentally normal
prior to onset.

Children with CSWS typically present with regression of skills and intellectual deterioration96, Expressive
language and nonverbal communication deficits are common96, 97. Language content is affected, as well
as abstraction and temporospatial organization. Memory impairment also occurs. Behavior disorders
can be challenging, including hyperactivity, aggression, emotional lability and poor interpersonal skills.
Motor dyspraxia, dystonia, and ataxia have also been reported 97, 98.

In LKS, regression is typically isolated to receptive language also known as acquired epileptic aphasia or
acquired epileptic agnosia 97, 99. Nonverbal skills are typically spared98. Abnormal language development
and behavior disturbances can predate the onset of regression, but then additional loss of skills occurs
slowly or acutely100. Furthermore, some children can present with regression without seizures.
Additional symptoms include hyperkinesia, irritability, inattentiveness and impulsivity, as well as
autistic-like behavior 97.

In both of these syndromes, effective therapy targeting the ESES can markedly improve development101
97, 102, 103
. However, relapse is common. EEG improvement with resolution of ESES, often corresponding
with significant improvement in seizures occurs by early to mid-adolescence.

Several studies have evaluated long-term outcome in children with CSWS/LKS. Although most show
improved cognitive function in the majority of children over time98, 104, 105, normalization of intellectual
function is uncommon. Liukkonen et al. followed 32 children with ESES over three years or longer, and
pre-morbid cognitive level was regained in only 32% of cases105. Long-term studies into adulthood have
demonstrated continued deficits that impact abilities to function independently as adults98, 100. Of 29
children followed for a mean of 12 years, only 27.5% completely recovered language function100.
Language recovery only occurred with significant EEG improvement or normalization, however a normal
EEG did not guarantee a favorable outcome.

Risk factors for poorer neuropsychological outcome include underlying etiology, atypical features,
longer duration of ESES with high discharge rates, pharmacoresistance, developmental delay at time of
diagnosis, and preexisting neurological conditions 99, 105, 106. In a large study of 117 children with CSWS, a
normal outcome at follow-up was only seen in those with normal neuroimaging and no known
etiology96. In this study, nearly 30%, all of whom had a known cause for their CSWS, had no
improvement. Regarding duration of ESES, baseline cognitive function is regained in 50% of children
who have resolution of ESES after 2-13 months versus none in whom this abnormal EEG pattern persists
beyond 18 months106.

Conclusions

Epileptic encephalopathies are typically associated with cognitive and psychosocial comorbidities,
including intellectual disability, learning disorders, attention deficit-hyperactivity disorder and autism
spectrum disorder, and several approaches are needed to limit the impact of these comorbidities (Table
2).

Optimizing seizure control in a timely manner is essential to maximize neurocognitive outcome.

Frequent seizures can affect the child’s ability to learn during the ictal and post-ictal period. However,
anti-seizure medications can be associated with sedation and cognitive slowing, which may worsen the
encephalopathy. Therefore, it is essential to strike a balance between seizure control and avoiding over-
medication. Proper identification of epilepsy syndrome is crucial. As previously mentioned, some of the
epileptic encephalopathies can be exacerbated by specific medications, such as phenytoin in Dravet
syndrome and carbamazepine in CSWS/LKS. The use of inappropriate or contraindicated medications
can worsen the underlying encephalopathy, even if seizures may initially respond. Furthermore, while
the majority of epileptic encephalopathies are resistant to treatment, those with focal seizures or
identifiable focal structural pathology may be surgical candidates. Early surgical intervention can, not
only lead to seizure freedom, but also can potentially avoid the formation of abnormal neuronal
networks, leading to improved cognitive outcome. The ketogenic diet can also be remarkable effective
in some early onset epilepsies.

Given the high prevalence of neurocognitive comorbidities in children with epilepsy, screening for these
conditions is mandatory. Intellectual disability and learning disorders should be recognized early,
preferably through formal neuropsychometric testing, to allow for adequate academic support.
Attention deficit disorder is more common in children with epilepsy compared to the general
population, although often is under-recognized. Additionally, there is often hesitancy to treat children
with epilepsy and comorbid attention deficit disorder with psychostimulants, although there is no
evidence to support seizure exacerbation due to these agents. Similarly, autism spectrum disorder in
children with epilepsy should be addressed, rather than assuming the symptoms will resolve once the
seizures improve 96

Therefore, while epileptic encephalopathies often are refractory to treatment and have poor
neuropsychological outcome, improved precision diagnosis of electroclinical syndrome and etiology,
appropriate medication- and non-medication treatment when warranted, and avoidance of over-
medication can potentially ameliorate the outcome. Furthermore, early identification of
neurodevelopmental comorbidities and pursuing appropriate academic support, therapies, and
pharmacologic treatment can also help to maximize learning and psychosocial development.
Table 1: Long-term outcome in Dravet Syndrome in Adulthood

Study N mean age Neurological findings Intellectual function Living

in years arrangement

(range)

Jansen et al. 14 26 (18-47) Motor impairment – 71% Severe disability – 43% Needing considerable

2006 -cerebellar signs – 29% Moderate disability – 36% support – 72%

-pyramidal signs – 43% Mild disability – 14% Supervised community

-extrapyramidal signs – 29% Low average – 7% accommodation – 14%

Lived independently

but unemployed – 14%

Akiyama et al. 31 24 (18-43) Language: 3% could live

2010 -23% nonverbal independently but

-29% only a few words developed psychosis

-29% primitive conversation

-16% simple conversation

and some reading ability

-3% mild impairment

Genton et al. 24 24.8 (20-50) Ataxia – 37.5% Language assessed in 21 Totally dependent –

2011 Dysarthria – 33% cases: 54%

Tremor – 29% -14% nonverbal Partly dependent - 33%

Impaired gait – 29% -19% noncommunicative Independent with some

Orthopedic issues (kyphosis, language external support -

foot abnormalities) – 29% -33% minimal 12.5%

communicative language

-33% poor but

communicative language
 Autistic or psychotic

personality disorder in 25%

Catarino et al. 22 39 (20-66) Kyphoscoliosis – 27% Severe disability – 82% Residential care - 73%

2011 Cerebellar signs – 23% Moderate disability – 18% At home with support –

Pyramidal signs – 32% 27%

Extrapyramidal signs – 18%

Dysphagia – 23% - began at

th
or after 4 decade and

required G tube

Takayama et 64 30 (19-45) Bedridden – 6% Severe disability – 77% Institutionalized – 27%

al. 2014 Ataxic gait – 47% Moderate disability – 19% Lives independently –

Hemiplegia from prolonged Mild disability – 5% 3%

status – 6%
Table 2: Interventions to Maximize Cognitive Outcome

Maximizing Seizure Control in a Timely Manner

 Avoid over-medication

o Ensure families understand the importance of compliance to avoid seizure breakthrough

and resultant increases in medication dose

o Space medications evenly throughout the day

 Recognize and diagnose specific electroclinical syndrome and etiology, when possible

o Understand recommended and contraindicated AEDs for that syndrome

o Identify potential surgical candidates

 Seek alternative therapies, such as surgery or dietary therapy, once pharmaco-resistance has

been established

Identify comorbidities with neuropsychological testing and screening

 Obtain academic support and therapies, when appropriate

 Treat ADHD
Figure 1.

A 3 year old boy presented with a 6 month history of intractable epileptic spasms, language regression,
poor eye contact and limited social reciprocity. He had HSV encephalitis at 15 months of age, and had a
single prolonged seizure at that time. He underwent right temporal resection at 43 months of age and
has been seizure-free since. Repeat neuropsychological testing done 10 months after surgery showed
resolution of autistic features and marked improvement in language skills.

Prior to resection, the EEG showed very frequent, high-amplitude, multifocal discharges which were
maximal in the right temporal region. Epileptic spasms were recorded with generalized discharge
(Figure 1A).

Following right temporal resection, the EEG showed a normal background activity. Rare right temporal
sharp waves were noted in sleep (Figure 1B).

Pre-operative coronal FLAIR MRI (Figure 1C) shows encephalomalacia of the right mesial temporal lobe
involving the uncus and hippocampus

Figure 2

A 3 year old girl with Myoclonic Atonic Epilepsy experienced daily seizures unresponsive to 3
antiepileptic medications. She was initiated on a ketogenic diet with marked improvement, becoming
seizure-free within two weeks. With onset of seizures, she became withdrawn and her development
declined. With seizure resolution, she resumed developmental progress and one year later, was
medication-free on the ketogenic diet and was developmentally appropriate for age.

Just prior to ketogenic diet onset, her EEG shows diffuse slowing with generalized slow spike-and-wave
discharges at 2-2.5 Hz (Figure 2A).

Four months after initiation of the diet, the EEG is much improved, showing mild background slowing
but no epileptiform discharges (Figure 2B).

Figure 3

A previously healthy 5 year old boy developed nocturnal seizures and was started on carbamazepine.
Seizures persisted and he developed language and behavioral regression.

His EEG showed bitemporal epileptiform discharges in wakefulness (Figure 3A) which became
continuous and bisynchronous in sleep, in keeping with electrical status epilepticus in sleep (Figure 3B).

Following discontinuation of carbamazepine, and initiation of acetazolamide, seizures and

developmental regression resolved and his EEG normalized in wakefulness (Figure 3C) and sleep (Figure
3D).
References

1. 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. Apr 2010;51(4):676-685.
2. Korff CM, Brunklaus A, Zuberi SM. Epileptic activity is a surrogate for an underlying etiology and
stopping the activity has a limited impact on developmental outcome. Epilepsia. Oct
2015;56(10):1477-1481.
3. Austin JK, Perkins SM, Johnson CS, et al. Behavior problems in children at time of first recognized
seizure and changes over the following 3 years. Epilepsy Behav. Aug 2011;21(4):373-381.
4. Racine RJ, Steingart M, McIntyre DC. Development of kindling-prone and kindling-resistant rats:
selective breeding and electrophysiological studies. Epilepsy Res. Jul 1999;35(3):183-195.
5. Hermann BP, Seidenberg M, Bell B. The neurodevelopmental impact of childhood onset
temporal lobe epilepsy on brain structure and function and the risk of progressive cognitive
effects. Prog Brain Res. 2002;135:429-438.
6. Lado FA, Rubboli G, Capovilla G, Avanzini G, Moshe SL. Pathophysiology of epileptic
encephalopathies. Epilepsia. Nov 2013;54 Suppl 8:6-13.
7. Chapman KE, Specchio N, Shinnar S, Holmes GL. Seizing control of epileptic activity can improve
outcome. Epilepsia. Oct 2015;56(10):1482-1485.
8. Henderson AK, Galic MA, Fouad K, Dyck RH, Pittman QJ, Teskey GC. Larger cortical motor maps
after seizures. Eur J Neurosci. Aug 2011;34(4):615-621.
9. Kumar A, Semah F, Chugani HT, Theodore WH. Epilepsy diagnosis: positron emission
tomography. Handb Clin Neurol. 2012;107:409-424.
10. Pan JW, Williamson A, Cavus I, et al. Neurometabolism in human epilepsy. Epilepsia. 2008;49
Suppl 3:31-41.
11. De Tiege X, Goldman S, Van Bogaert P. Insights into the pathophysiology of psychomotor
regression in CSWS syndromes from FDG-PET and EEG-fMRI. Epilepsia. Aug 2009;50 Suppl 7:47-
50.
12. Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition
in rats. Ann Neurol. Feb 2010;67(2):250-257.
13. Ebus S, Arends J, Hendriksen J, et al. Cognitive effects of interictal epileptiform discharges in
children. Eur J Paediatr Neurol. Nov 2012;16(6):697-706.
14. Forcelli PA, Janssen MJ, Vicini S, Gale K. Neonatal exposure to antiepileptic drugs disrupts
striatal synaptic development. Ann Neurol. Sep 2012;72(3):363-372.
15. Loring DW, Meador KJ. Cognitive side effects of antiepileptic drugs in children. Neurology. Mar
23 2004;62(6):872-877.
16. Glauser TA, Cnaan A, Shinnar S, et al. Ethosuximide, valproic acid, and lamotrigine in childhood
absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia. Jan 2013;54(1):141-
155.
17. Martin R, Kuzniecky R, Ho S, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine
in healthy young adults. Neurology. Jan 15 1999;52(2):321-327.
18. Yamamoto H, Okumura A, Fukuda M. Epilepsies and epileptic syndromes starting in the neonatal
period. Brain Dev. Mar 2011;33(3):213-220.
19. Beal JC, Cherian K, Moshe SL. Early-onset epileptic encephalopathies: Ohtahara syndrome and
early myoclonic encephalopathy. Pediatr Neurol. Nov 2012;47(5):317-323.
20. Dhamija R, Wirrell E, Falcao G, Kirmani S, Wong-Kisiel LC. Novel de novo SCN2A mutation in a
child with migrating focal seizures of infancy. Pediatr Neurol. Dec 2013;49(6):486-488.
21. Khan S, Al Baradie R. Epileptic encephalopathies: an overview. Epilepsy Res Treat.
2012;2012:403592.
22. Wong-Kisiel LC, Nickels K. Electroencephalogram of age-dependent epileptic encephalopathies
in infancy and early childhood. Epilepsy Res Treat. 2013;2013:743203.
23. Yamatogi Y, Ohtahara S. Early-infantile epileptic encephalopathy with suppression-bursts,
Ohtahara syndrome; its overview referring to our 16 cases. Brain Dev. Jan 2002;24(1):13-23.
24. Malik SI, Galliani CA, Hernandez AW, Donahue DJ. Epilepsy surgery for early infantile epileptic
encephalopathy (ohtahara syndrome). J Child Neurol. Dec 2013;28(12):1607-1617.
25. Coppola G. Malignant migrating partial seizures in infancy: an epilepsy syndrome of unknown
etiology. Epilepsia. May 2009;50 Suppl 5:49-51.
26. Ishii A, Shioda M, Okumura A, et al. A recurrent KCNT1 mutation in two sporadic cases with
malignant migrating partial seizures in infancy. Gene. Dec 01 2013;531(2):467-471.
27. Ohba C, Kato M, Takahashi S, et al. Early onset epileptic encephalopathy caused by de novo
SCN8A mutations. Epilepsia. Jul 2014;55(7):994-1000.
28. Poduri A, Chopra SS, Neilan EG, et al. Homozygous PLCB1 deletion associated with malignant
migrating partial seizures in infancy. Epilepsia. Aug 2012;53(8):e146-150.
29. Marsh E, Melamed SE, Barron T, Clancy RR. Migrating partial seizures in infancy: expanding the
phenotype of a rare seizure syndrome. Epilepsia. Apr 2005;46(4):568-572.
30. Djuric M, Kravljanac R, Kovacevic G, Martic J. The efficacy of bromides, stiripentol and
levetiracetam in two patients with malignant migrating partial seizures in infancy. Epileptic
Disord. Mar 2011;13(1):22-26.
31. Merdariu D, Delanoe C, Mahfoufi N, Bellavoine V, Auvin S. Malignant migrating partial seizures
of infancy controlled by stiripentol and clonazepam. Brain Dev. Feb 2013;35(2):177-180.
32. Saade D, Joshi C. Pure cannabidiol in the treatment of malignant migrating partial seizures in
infancy: a case report. Pediatr Neurol. May 2015;52(5):544-547.
33. Vendrame M, Poduri A, Loddenkemper T, Kluger G, Coppola G, Kothare SV. Treatment of
malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic
Disord. Mar 2011;13(1):18-21.
34. Unver O, Incecik F, Dundar H, Komur M, Unver A, Okuyaz C. Potassium bromide for treatment of
malignant migrating partial seizures in infancy. Pediatr Neurol. Nov 2013;49(5):355-357.
35. Riikonen R, Donner M. Incidence and aetiology of infantile spasms from 1960 to 1976: a
population study in Finland. Dev Med Child Neurol. Jun 1979;21(3):333-343.
36. Wirrell EC, Shellhaas RA, Joshi C, Keator C, Kumar S, Mitchell WG. How should children with
West syndrome be efficiently and accurately investigated? Results from the National Infantile
Spasms Consortium. Epilepsia. Apr 2015;56(4):617-625.
37. Riikonen R. Long-term otucome of West syndrome: a study of adults with a history of infantile
spasms. Epilepsia. Apr 1996;37(4):367-372.
38. Camfield P, Camfield C. Long-term prognosis for symptomatic (secondarily) generalized
epilepsies: a population-based study. Epilepsia. Jun 2007;48(6):1128-1132.
39. Riikonen R, Amnell G. Psychiatric disorders in children with earlier infantile spasms. Dev Med
Child Neurol. Dec 1981;23(6):747-760.
40. Sidenvall R, Eeg-Olofsson O. Epidemiology of infantile spasms in Sweden. Epilepsia. Jun
1995;36(6):572-574.
41. Saemundsen E, Ludvigsson P, Rafnsson V. Autism spectrum disorders in children with a history
of infantile spasms: a population-based study. J Child Neurol. Sep 2007;22(9):1102-1107.
42. Camfield C, Camfield P. Twenty years after childhood-onset symptomatic generalized epilepsy
the social outcome is usually dependency or death: a population-based study. Dev Med Child
Neurol. Nov 2008;50(11):859-863.
43. Koo B, Hwang PA, Logan WJ. Infantile spasms: outcome and prognostic factors of cryptogenic
and symptomatic groups. Neurology. Nov 1993;43(11):2322-2327.
44. Partikian A, Mitchell WG. Neurodevelopmental and epilepsy outcomes in a North American
cohort of patients with infantile spasms. J Child Neurol. Apr 2010;25(4):423-428.
45. Darke K, Edwards SW, Hancock E, et al. Developmental and epilepsy outcomes at age 4 years in
the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre
randomised trial. Arch Dis Child. May 2010;95(5):382-386.
46. Chiron C, Dumas C, Jambaque I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and
hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res. Jan 1997;26(2):389-
395.
47. Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P. Long-term neurological outcome
in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav. Dec
2011;22(4):735-739.
48. Asarnow RF, LoPresti C, Guthrie D, et al. Developmental outcomes in children receiving
resection surgery for medically intractable infantile spasms. Dev Med Child Neurol. Jul
1997;39(7):430-440.
49. Jonas R, Asarnow RF, LoPresti C, et al. Surgery for symptomatic infant-onset epileptic
encephalopathy with and without infantile spasms. Neurology. Feb 22 2005;64(4):746-750.
50. Arya R, Kabra M, Gulati S. Epilepsy in children with Down syndrome. Epileptic Disord. Mar
2011;13(1):1-7.
51. Osborne JP, Lux AL, Edwards SW, et al. The underlying etiology of infantile spasms (West
syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on
contemporary causes and their classification. Epilepsia. Oct 2010;51(10):2168-2174.
52. Tapp S, Anderson T, Visootsak J. Neurodevelopmental outcomes in children with Down
syndrome and infantile spasms. J Pediatr Neurol. Jun 2015;13(2):74-77.
53. Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms.
Pediatr Neurol. Dec 2011;45(6):355-367.
54. Bitton JY, Demos M, Elkouby K, et al. Does treatment have an impact on incidence and risk
factors for autism spectrum disorders in children with infantile spasms? Epilepsia. Jun
2015;56(6):856-863.
55. Appleton RE. West syndrome: long-term prognosis and social aspects. Brain Dev. Nov
2001;23(7):688-691.
56. O'Callaghan FJ, Lux AL, Darke K, et al. The effect of lead time to treatment and of age of onset on
developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom
Infantile Spasms Study. Epilepsia. Jul 2011;52(7):1359-1364.
57. Riikonen R. Long-term outcome of patients with West syndrome. Brain Dev. Nov
2001;23(7):683-687.
58. Chugani HT, Da Silva E, Chugani DC. Infantile spasms: III. Prognostic implications of bitemporal
hypometabolism on positron emission tomography. Ann Neurol. May 1996;39(5):643-649.
59. Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia. Apr
2011;52 Suppl 2:44-49.
60. Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol. Jun 01 2010;588(Pt
11):1849-1859.
61. Cooper MS, McIntosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res. Dec
2016;128:43-47.
62. Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y. A long-term follow-up study of Dravet
syndrome up to adulthood. Epilepsia. Jun 2010;51(6):1043-1052.
63. Oguni H, Hayashi K, Awaya Y, Fukuyama Y, Osawa M. Severe myoclonic epilepsy in infants--a
review based on the Tokyo Women's Medical University series of 84 cases. Brain Dev. Nov
2001;23(7):736-748.
64. Battaglia D, Ricci D, Chieffo D, Guzzetta F. Outlining a core neuropsychological phenotype for
Dravet syndrome. Epilepsy Res. Feb 2016;120:91-97.
65. Wirrell EC, Laux L, Donner EJ, et al. Optimizing the Diagnosis and Management of Dravet
Syndrome: Recommendations from a North American Consensus Panel. Pediatr Neurol.
2017;68:18-34.
66. Ragona F, Brazzo D, De Giorgi I, et al. Dravet syndrome: early clinical manifestations and
cognitive outcome in 37 Italian patients. Brain Dev. Jan 2010;32(1):71-77.
67. Nabbout R, Chemaly N, Chipaux M, et al. Encephalopathy in children with Dravet syndrome is
not a pure consequence of epilepsy. Orphanet J Rare Dis. Nov 13 2013;8:176.
68. Chieffo D, Battaglia D, Lettori D, et al. Neuropsychological development in children with Dravet
syndrome. Epilepsy Res. Jun 2011;95(1-2):86-93.
69. Villeneuve N, Laguitton V, Viellard M, et al. Cognitive and adaptive evaluation of 21 consecutive
patients with Dravet syndrome. Epilepsy Behav. Feb 2014;31:143-148.
70. Chieffo D, Battaglia D, Lucibello S, et al. Disorders of early language development in Dravet
syndrome. Epilepsy Behav. Jan 2016;54:30-33.
71. Turner SJ, Brown A, Arpone M, Anderson V, Morgan AT, Scheffer IE. Dysarthria and broader
motor speech deficits in Dravet syndrome. Neurology. Feb 01 2017.
72. Wolff M, Casse-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome):
natural history and neuropsychological findings. Epilepsia. 2006;47 Suppl 2:45-48.
73. Takayama R, Fujiwara T, Shigematsu H, et al. Long-term course of Dravet syndrome: a study
from an epilepsy center in Japan. Epilepsia. Apr 2014;55(4):528-538.
74. Jansen FE, Sadleir LG, Harkin LA, et al. Severe myoclonic epilepsy of infancy (Dravet syndrome):
recognition and diagnosis in adults. Neurology. Dec 26 2006;67(12):2224-2226.
75. Catarino CB, Liu JY, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence
from long-term course and neuropathology. Brain. Oct 2011;134(Pt 10):2982-3010.
76. Guerrini R, Falchi M. Dravet syndrome and SCN1A gene mutation related-epilepsies: cognitive
impairment and its determinants. Dev Med Child Neurol. Apr 2011;53 Suppl 2:11-15.
77. Wasterlain CG, Fujikawa DG, Penix L, Sankar R. Pathophysiological mechanisms of brain damage
from status epilepticus. Epilepsia. 1993;34 Suppl 1:S37-53.
78. Striano P, Mancardi MM, Biancheri R, et al. Brain MRI findings in severe myoclonic epilepsy in
infancy and genotype-phenotype correlations. Epilepsia. Jun 2007;48(6):1092-1096.
79. Ragona F, Granata T, Dalla Bernardina B, et al. Cognitive development in Dravet syndrome: a
retrospective, multicenter study of 26 patients. Epilepsia. Feb 2011;52(2):386-392.
80. Wallace A, Wirrell E, Kenney-Jung DL. Pharmacotherapy for Dravet Syndrome. Paediatr Drugs.
Jun 2016;18(3):197-208.
81. Doose H. Myoclonic-astatic epilepsy. Epilepsy Res Suppl. 1992;6:163-168.
82. Guerrini R, Aicardi J. Epileptic encephalopathies with myoclonic seizures in infants and children
(severe myoclonic epilepsy and myoclonic-astatic epilepsy). J Clin Neurophysiol. Nov-Dec
2003;20(6):449-461.
83. Caraballo RH, Flesler S, Pasteris MC, Lopez Avaria MF, Fortini S, Vilte C. Myoclonic epilepsy in
infancy: an electroclinical study and long-term follow-up of 38 patients. Epilepsia. Sep
2013;54(9):1605-1612.
84. Nickels KC, Zaccariello MJ, Hamiwka LD, Wirrell EC. Cognitive and neurodevelopmental
comorbidities in paediatric epilepsy. Nat Rev Neurol. Aug 2016;12(8):465-476.
85. VanStraten AF, Ng YT. Update on the management of Lennox-Gastaut syndrome. Pediatr Neurol.
Sep 2012;47(3):153-161.
86. Ferlazzo E, Nikanorova M, Italiano D, et al. Lennox-Gastaut syndrome in adulthood: clinical and
EEG features. Epilepsy Res. May 2010;89(2-3):271-277.
87. Camfield P, Camfield C. Epileptic syndromes in childhood: clinical features, outcomes, and
treatment. Epilepsia. 2002;43 Suppl 3:27-32.
88. Dulac O. Epileptic encephalopathy. Epilepsia. 2001;42 Suppl 3:23-26.
89. Rathaur BP, Garg RK, Malhotra HS, et al. Lennox-Gastaut Syndrome: A Prospective Follow-up
Study. J Neurosci Rural Pract. Apr-Jun 2017;8(2):225-227.
90. Camfield PR. Definition and natural history of Lennox-Gastaut syndrome. Epilepsia. Aug 2011;52
Suppl 5:3-9.
91. Kerr M, Kluger G, Philip S. Evolution and management of Lennox-Gastaut syndrome through
adolescence and into adulthood: are seizures always the primary issue? Epileptic Disord. May
2011;13 Suppl 1:S15-26.
92. Montouris GD. Rational approach to treatment options for Lennox-Gastaut syndrome. Epilepsia.
Aug 2011;52 Suppl 5:10-20.
93. Goldsmith IL, Zupanc ML, Buchhalter JR. Long-term seizure outcome in 74 patients with Lennox-
Gastaut syndrome: effects of incorporating MRI head imaging in defining the cryptogenic
subgroup. Epilepsia. Apr 2000;41(4):395-399.
94. Liu SY, An N, Fang X, et al. Surgical treatment of patients with Lennox-Gastaut syndrome
phenotype. ScientificWorldJournal. 2012;2012:614263.
95. Lemmon ME, Terao NN, Ng YT, Reisig W, Rubenstein JE, Kossoff EH. Efficacy of the ketogenic
diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and
summary of the literature. Dev Med Child Neurol. May 2012;54(5):464-468.
96. Caraballo RH, Veggiotti P, Kaltenmeier MC, et al. Encephalopathy with status epilepticus during
sleep or continuous spikes and waves during slow sleep syndrome: a multicenter, long-term
follow-up study of 117 patients. Epilepsy Res. Jul 2013;105(1-2):164-173.
97. Nickels K, Wirrell E. Electrical status epilepticus in sleep. Semin Pediatr Neurol. Jun
2008;15(2):50-60.
98. Praline J, Hommet C, Barthez MA, et al. Outcome at adulthood of the continuous spike-waves
during slow sleep and Landau-Kleffner syndromes. Epilepsia. Nov 2003;44(11):1434-1440.
99. Hughes JR. A review of the relationships between Landau-Kleffner syndrome, electrical status
epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy Behav. Feb
2011;20(2):247-253.
100. Caraballo RH, Cejas N, Chamorro N, Kaltenmeier MC, Fortini S, Soprano AM. Landau-Kleffner
syndrome: a study of 29 patients. Seizure. Feb 2014;23(2):98-104.
101. De Negri M, Baglietto MG, Battaglia FM, Gaggero R, Pessagno A, Recanati L. Treatment of
electrical status epilepticus by short diazepam (DZP) cycles after DZP rectal bolus test. Brain Dev.
Sep-Oct 1995;17(5):330-333.
102. Sinclair DB, Snyder TJ. Corticosteroids for the treatment of Landau-kleffner syndrome and
continuous spike-wave discharge during sleep. Pediatr Neurol. May 2005;32(5):300-306.
103. Fine AL, Wirrell EC, Wong-Kisiel LC, Nickels KC. Acetazolamide for electrical status epilepticus in
slow-wave sleep. Epilepsia. Sep 2015;56(9):e134-138.
104. van den Munckhof B, van Dee V, Sagi L, et al. Treatment of electrical status epilepticus in sleep:
A pooled analysis of 575 cases. Epilepsia. Nov 2015;56(11):1738-1746.
105. Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granstrom ML. Long-term outcome
of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome.
Epilepsia. Oct 2010;51(10):2023-2032.
106. Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and
medical treatment of children with electrical status epilepticus in sleep (ESES). Epilepsia. Jun
2009;50(6):1517-1524.