Childhood Epilepsy: Developmental
& Neuropsychiatric Connections
Arthur Partikian, MD
Assistant Professor of Pediatrics & Neurology
Director, Division of Child Neurology
LAC + USC Medical Center
Disclosures
I have received unrestricted educational funds
from Questcor Pharmaceuticals, Inc. for
research pertaining to adverse events
associated with treatment of infantile spasms.
I have no further conflicts of interest to
disclose.
Objectives
• Discuss diagnosis, classification, &
epidemiology of childhood epilepsy
• Review evidence for behavioral and
psychiatric problems associated with
childhood epilepsy
• Discuss unique impact of epileptic
encephalopathies on development
Seizures Defined
• Seizure: unpredictable but stereotyped spell arising from
paroxysmal depolarization shift in a group of cortical
neurons
– May or may not involve alteration in consciousness
– Epileptiform discharges may start focally or involve both
hemispheres at the onset
• Epilepsy = 2 or more unprovoked seizures in an individual
▪ Incidence of first unprovoked seizures is b/w 25,000-40,000
annually
▪ This is ~33% greater than the incidence of epilepsy,
reflecting the proportion of first seizures that do not recur
▪ Seizures are frightening, unpredictable, paroxysmal events
Epidemiological Data
• More than 3 million
in North America
have epilepsy
• 5-10/10,000
prevalence
• More common than
Parkinson dz and MS
combined
ILAE Report: Epilepsy in North America. Epilepsia, 47(10):1700–1722, 2006
Etiology
• In a prospective, populationbased cohort in Connecticut
from 1990s, majority found to
be “normal” children
– 30% idiopathic syndromes
– 52% cryptogenic
– 18% Remote symptomatic
• 7% presumed intrauterine
insults, 2% perinatal stroke or
hypoxia, 3% brain
malformation, 1% intracranial
infxn, 1% tumor, 2%
neurocutaneous, 1%
chromosomal abnormality, 1%
autisms, 1%
neurodegenerative
Berg et al. Newly diagnosed epilepsy in children:
presentation and diagnosis. Epilepsia 40:445–452. 1999
– Many epileptic
syndromes are
specific to childhood
– Many forms of
childhood onset
epilepsies resolve by
adolescence or
adulthood
First of all, you’ve got to
make the diagnosis of a seizure!
Seizures 101
• It’s all about HISTORY, HISTORY, HISTORY
• Rule out other paroxysmal events:
Breathholding spells, syncope with clonic
jerks, benign sleep myoclonus, tics, dystonia,
excessive startle responses, hyperventilation,
migraine, and parasomnias, arrythmias
Seizures 101
• Prodrome: vague, subjective “feelings” preceding a seizure
• Symptoms during seizure (ictal)
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Aura: subjective sensations
Behavior or mood changes
Vocal: cry or gasp, dysarthria vs aphasia
Motor: head or eye turning, eye deviation, posturing, jerking, stiffening,
automatisms (purposeless repetitive movements)
– Respiration: Change in breathing pattern, apnea, cyanosis
– Autonomic: Pupillary dilation, change in RR or HR, incontinence, pallor,
vomiting
– AMS
• Symptoms following seizure (postictal):
– amnesia, confusion, lethargy, sleepiness, headaches, myalgias, Todd’s paresis,
N/E
• Abnormal posturing does not equate with seizure activity
Past Medical Hx affects risk of seizure
recurrence
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•
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Perinatal factors
Consanguinity and miscarriages
Developmental screen
Chronic medical conditions
Medication/toxin exposures
h/o CNS surgery, trauma, or infection
Family history
Social history
Role of EEG in the Evaluation of the first
Seizure
• Helps determine seizure type, epilepsy syndrome, and risk of
recurrence
• Optimal timing is unclear. Beware of transient postictal
slowing in first 24-48 hrs. Outpatient EEG is a reasonable
choice.
• Repeating an EEG up to 4 times may significantly increase
yield of epileptiform abnormalities with ~30% on 1st, ~40% on
2nd, ~50% on 3rd, and ~55% on 4th (Salinsky et al. 1987)
• Abnormal EEG does not mean that a seizure took place; a
normal EEG does not r/o epilepsy
What is an EEG anyway?
•
Method of recording voltage differences between groups of cortical
neurons at the scalp surface  PDS
Elements of an EEG:
•
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–
–
–
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Frequency of wavelength
Voltage
Waveform morphology
Regulation of frequency and voltage
Manner of occurrence (random, serial, continuous)
Locus
Reactivity (with eye opening, mental calculation, hypocapnia produced by
hyperventilation, sensory stimulation, movement, affective state, visual
scanning, etc)
Interhemispheric coherence: Symmetry of voltage and frequency vs.
Synchrony of specific waveform and bursts.
EEG Montage
Epileptiform EEG
• EEG with focal slowing or epileptiform activity is predictive of
seizure recurrence, especially in otherwise normal children
• EEG is recommended for neurodiagnostic evaluation as a
standard.
EEG with PLED’s
EEG of a 65-year-old patient with Herpes simplex encephalitis, showing
periodic epileptiform discharges occurring over the right temporal region
every 1 to 2 seconds.
EEG with Focal Slowing
EEG of a 43-year-old patient with right temporal glioma, showing
polymorphic delta activity and low-amplitude spike discharges (*)
over the right temporal region
Summary of Recommendations for Seizure
Evaluation
• Obtain accurate eye-witness history and
conduct basic neurologic exam
• Obtain EEG to predict risk of recurrence and to
classify sz type and epilepsy syndrome. EEG
not necessarily urgent.
• LP, laboratory tests, and neuroimaging as
needed to elucidate etiology and for
management
Hirtz et al. Practice Parameter: Evaluating a First Non-febrile
Seizure in Chidlren. Neurology. 2000. 55: 616-623
So why not start treatment
after a single seizure?
How likely is a second seizure?
 The majority of recurrences occur early
How likely are multiple recurrences?
• In one study of 407 children followed for > 10
years, 46% had 1+ recurrence, 19% with 4 or +
seizures, and only 10% with 10 or + seizures.
→ Majority of children who present with a
single seizure have favorable long term
outcomes. Medically refractory epilepsy is the
exception, not the rule.
Are there factors that increase the
recurrence risk? . . . YES!
• Underlying etiology
– “remote symptomatic” (without immediate cause
but with a prior identifiable major brain insult
such as severe trauma or MR/CP) recurrence risk
>50%, 30-50% for idiopathic/cryptogenic
• Abnormal EEG
– Epileptiform discharges and focal slowing
How effective is treatment in
prevention of recurrences?
→ only one randomized pediatric study (#41 above) with small sample
size and wide ranging confidence intervals
Does treatment with AED after a first
seizure change the long-term prognosis for
remission?
• Two studies provide no evidence of a
difference when treatment is started after first
versus second seizure in achieving a 1-or 2year seizure remission
• Remember: Antiepileptic drugs do not
prevent epilepsy; they are mostly
anticonvulsants designed to prevent more
seizures.
To Treat or Not to Treat: Current
Recommendations
1. Treatment with AED is not indicated for the
prevention of the development of epilepsy.
2. Treatment with AED may be considered in
circumstances where the benefits of reducing
the risk of a second seizure outweigh the risks
of pharmacologic and psychosocial side
effects.
Hirtz et al. Practice Parameter: treatment of the child with
first unprovoked seizure. Neurology. 2003. 60: 166-175
ILAE Classification: work in progress
• Electroclinical syndromes: complex of clinical features, signs and
symptoms that together define a distinctive, recognizable clinical
disorder.
• Clinically distinctive constellations: “diagnostically meaningful
forms of epilepsy and may have implications for clinical treatment,
particularly surgery.”
– Hypothalamic hamartoma with gelastic seizures
– Mesial Temporal Lobe Epilepsy (with hippocampal sclerosis)
– Rasmussen “syndrome”
• Epilepsies secondary to specific structural or metabolic lesions or
conditions
– “epilepsy with focal seizures secondary to focal cortical dysplasia in the
temporal lobe.”
• Epilepsies of unknown cause
• Conditions with epileptic seizures not diagnosed as a form of
epilepsy per se.
Benign neonatal seizures (BNS)
Febrile seizures (FS)
Report of the Commission on Classification and
Terminology: Update and Recommendations at
www.ilae-epilepsy.org
Electro-clinical syndromes
Neonatal period
•
Benign familial neonatal seizures (BFNS)
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Early myoclonic encephalopathy (EME)
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Ohtahara syndrome
Infancy
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Migrating partial seizures of infancy
•
West syndrome
•
Myoclonic epilepsy in infancy (MEI)
•
Benign infantile seizures
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Dravet syndrome
•
Myoclonic encephalopathy in nonprogressive disorders
Childhood
•
Febrile seizures plus (FS+) (can start in infancy)
•
Early onset benign childhood occipital epilepsy
(Panayiotopoulos type)
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Epilepsy with myoclonic astatic seizures
•
Benign childhood epilepsy with centrotemporal spikes
(BCECTS)
•
Autosomal-dominant nocturnal frontal lobe epilepsy
(ADNFLE)
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•
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•
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Late onset childhood occipital epilepsy (Gastaut type)
Epilepsy with myoclonic absences
Lennox-Gastaut syndrome
Epileptic encephalopathy with continuous spike-andwave during sleep (CSWS) including: Landau-Kleffner
syndrome (LKS)
Childhood absence epilepsy (CAE)
Adolescence - Adult
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Juvenile absence epilepsy (JAE)
•
Juvenile myoclonic epilepsy (JME)
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Progressive myoclonus epilepsies (PME)
•
Autosomal dominant partial epilepsy with auditory
features (ADPEAF)
•
Other familial temporal lobe epilepsies
•
Epilepsy with generalized tonic-clonic seizures alone
Less Specific Age Relationship –
•
Familial focal epilepsy with variable foci (childhood to
adult)
•
Reflex epilepsies
Report of the Commission on Classification and
Terminology: Update and Recommendations at www.ilaeepilepsy.org
Behavioral & Psychiatric Comorbidities
• Behavioral disturbance 4.8 times higher than
general population of children and 2.5 times
higher than in children with non-CNS chronic dz
• More attention/thought/social problems
• More internalizing problems (WD, somatic
complaints, anxiety, depression)
• In general, higher rate of psychopathology in
children with epilepsy and intellectual or
neurological disabilities
Illness-related variables and
Psychopathology
• Sz frequency and control: more problems with less sz
control, but need to control for other factors
• Type of epilepsy: inconsistent evidence except for
encephalopathic epilepsies
• Age of onset and duration of illness: high rate of
autisms with IS
• AEDs: depression (phenobarb, primidone, VPA), mania
(felbamate), psychosis (TPM, LEV, ZNS, vigabatrin),
irritability/agression/hyperactivity (multiple agents),
impaired word retrieval/cognitive slowing (TPM)
Psychosocial variables effecting
Psychopathology
• Family stress model
• Stressors: unpredictability of szs and its treatement,
fear of dying, changes in family dynamics, fitting in,
marital distress
• Adaptive resources: socioeconomic status & family
mastery
• Perceptions
• Coping
• Family adjustment
→ family variables more strongly a/w child behavrio
problems than illness-related variables
Austin & Caplan. Epilepsia. 48(9): 1639-1651, 2007
Neurocognitive findings
• Memory deficits especially with temporal lobe
seizures
• Mental processing speed slowed by epilepsy
itself, AED, comorbidies such as sleep dysfxn
• Studies plagued by lack of adequate controls,
various illness and psychosocial factors
Neuropsychological status at seizure
onset in children
• 282 children (ages 6-14 years, IQ >70) with
first recognized unprovoked sz versus control
group of 147 healthy siblings
• Neuropsychological battery w/in 6 mo: testing
language, processing speed, attention/
executive/construction, verbal memory and
learning, academic achievement
• Deficit defined as 1.3 SD below sibling norm
(10th percentile)
Fastenau et al. Neurology. 73(7), August 18,2009
Neuropsychological status at seizure
onset in children: Results
• 27% of children with one sz and 40% of those
with risk factors had NP deficits at or near sz
onset
• Factors that individually double odds of NP
deficits:
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Single seizure
Symptomatic/cryptogenic etiology
CAES
Epileptiform activity on initial EEG
Use of any AEDs
Neuropsychological status at seizure
onset in children
• NP deficits might emerge concomitantly with
sz onset but exert their influence on academic
achievement cumulatively over time
• Window for educational intervention before
academic underachievement translates to
vocational problems in adulthood
What about epilepsy and adaptive
behavior?
• Prospective, community-based study of newly
diagnosed epilepsy (N of 172)
• Children younger than 3 years at initial onset of
epilepsy
• Parents completed Vineland Adaptive Behavior
Scales at entry and once thereafter for up to 3
years
– (VABS: age specific, composite & domain specific
scores for communication, daily living skills,
socialization, and motor skills)
Longitudinal assessment
of Adaptive Behavior
Risk factors: remote
symptomatic etiology,
epileptic encephalopathy,
intractable seizures
Children without above risk
factors are able to reach and
sustain adaptive behaviors
appropriate for age
Berg et al. Pediatrics. 114(3). 2004
Dark lines- patients with no risk factors
Dashed lines- any risk factor
Epileptic Encephalopathies: seizures
as the tip of the iceberg
• leads to severe cognitive and behavioral impairment
above and beyond what might be expected from the
underlying pathology (e.g. cortical malformation) alone
• Infantile spasms
– West Syndrome triad of spasms, hypsarrythmic EEG
background, & psychomotor regression
– Incidence of 1 per 2000-4000 live births
– Cognitive decline in infancy
• Other examples: Lennox-Gastaut, Dravet (SMEI),
Landau-Kleffner-CSWS, and Doose (M-AE) syndromes
CHLA Infantile Spasms Cohort Study of Outcomes
Epileptic Encephalopathies: Continuous spike-waves
during slow-wave sleep vs. Landau-Kleffner
CSWS
• EEG: Spike wave index of
>50% to >85%, most diffuse
• Global cognitive decline,
motor disturbances
• More anterior brain
structures frontal dysfxn
• Atonic seizures
• Mean age of onset 4-8 years
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•
•
•
•
LKS
EEG: Spike wave index any
%,bitemporal/unilateral/diffuse
Receptive/mixed aphasia,
verbal agnosia
More posterior cortex (superior
temporal gyrus & perisylvian
cortex)  more language
dysfxn
Infrequent seizures
4-5 years onset
Marjan Scheltens-de Boer. Epilepsia. 50(Supp 7):13-17, 2009
Is autistic regression a form of
epileptic encephalopathy?
• Epilepsy present in 30% of autistic children,
higher rates with more intellectual dysfxn
• Prevalence of epileptiform abnormalities in
autism and no clinical h/o szs: 6-31%
• Autistic regression: regression of language
together with appearance of autistic behavior
before 24 mo of age. Reported by 1/3 of parents.
• Disintegrative disorder: late-onset autistic
regression, up to 77% epilepsy prevalence
Roberto Tuchman. Epilepsia. 50(Supp 7):18-20, 2009
Specific-language impairment
• Definition: language development
substantially below age level for no apparent
cause
– Excludes sensory deficit, neurologic, psychiatric, or
environmental disabling state
– 1.25 SD below mean (< 10th percentile)
– Difficulties interfere with academic/social
communication
– Expressive or receptive domains effected
Billard, Fluss, and Pinton. Epilepsia. 50(Supp 7):21-24, 2009
The Spectrum of
Epilepsy &
Language
Impairment
Epileptic interictal discharges (EIDs) found at higher rates in children
with language regression and receptive>expressive dysphasias
 VEEG and NP recordings have shown transient cognitive impairments
during EIDs: deficits on verbal tasks occurred with L-sided discharges
 EIDs and centrotemporal spikes may represent an “endophenotype”
inherited as a monogenic trait. Additional genetic and/or
environmental factors result in expression of actual clinical symptoms
Billard, Fluss, and Pinton. Epilepsia.
50(Supp 7):21-24, 2009
Rudolf et al. Epilepsia. 50 (Supp
7):25-28, 2009
Take home message
• Childhood epilepsy is common and distinct from
adult-onset epilepsy
• There exist guidelines for evaluation & treatment
of first unprovoked seizure in childhood
• Epilepsy is a neuropsychiatric disorder with subtle
but potentially important cognitive deficits
already present at disease onset
• Epileptic encephalopathies represent a malignant
phenotype of this neuropsychiatric,
developmentally-linked disorder