Childhood Epilepsy: Developmental & Neuropsychiatric Connections

Arthur Partikian, MDAssistant Professor of Pediatrics & Neurology

Director, Division of Child NeurologyLAC + 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, population-

based 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

– Many epileptic syndromes are specific to childhood

– Many forms of childhood onset epilepsies resolve by adolescence or adulthood

Berg et al. Newly diagnosed epilepsy in children: presentation and diagnosis. Epilepsia 40:445–452. 1999

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)

– 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

• 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:

– 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 treatmentafter 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 2-year 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 syndromesNeonatal period• Benign familial neonatal seizures (BFNS)• Early myoclonic encephalopathy (EME)• Ohtahara syndromeInfancy• Migrating partial seizures of infancy• West syndrome• Myoclonic epilepsy in infancy (MEI)• Benign infantile seizures• Dravet syndrome• Myoclonic encephalopathy in nonprogressive disordersChildhood• Febrile seizures plus (FS+) (can start in infancy)• Early onset benign childhood occipital epilepsy

(Panayiotopoulos type)• Epilepsy with myoclonic astatic seizures• Benign childhood epilepsy with centrotemporal spikes

(BCECTS)• Autosomal-dominant nocturnal frontal lobe epilepsy

(ADNFLE)

• Late onset childhood occipital epilepsy (Gastaut type)• Epilepsy with myoclonic absences• Lennox-Gastaut syndrome• Epileptic encephalopathy with continuous spike-and-

wave during sleep (CSWS) including: Landau-Kleffner syndrome (LKS)

• Childhood absence epilepsy (CAE)

Adolescence - Adult• Juvenile absence epilepsy (JAE)• Juvenile myoclonic epilepsy (JME)• Progressive myoclonus epilepsies (PME)• Autosomal dominant partial epilepsy with auditory

features (ADPEAF)• Other familial temporal lobe epilepsies• Epilepsy with generalized tonic-clonic seizures aloneLess Specific Age Relationship –• Familial focal epilepsy with variable foci (childhood to

adult)• Reflex epilepsies

Report of the Commission on Classification andTerminology: Update and Recommendations at www.ilae-epilepsy.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:– 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

Dark lines- patients with no risk factorsDashed lines- any risk factor

Berg et al. Pediatrics. 114(3). 2004

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

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