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P R O V I D I N G T H E L A T E S T I N E V I D E N C E - B A S E D
Pediatric Neurology
E X P R E S S
Managing Seizures in Children with
Developmental Disabilities
Based on data presented in the satellite symposium “Seizures in Children with Developmental Disabilities” held during
the 34th Annual Meeting of the Child Neurology Society, Wednesday, September 28, 2005, Los Angeles, California
This report was reviewed for medical and scientific accuracy by Kapila Seshadri, MD,
Associate Professor of Pediatrics, Director, Attention Deficit Disorder Program,
University of Medicine & Dentistry of New Jersey—Robert Wood Johnson Medical
School, New Brunswick, New Jersey
Expert Commentary
Shlomo Shinnar, MD, PhD, Professor of Neurology and Pediatrics; Hyman Climenko
Professor of Neuroscience Research; Director, Comprehensive Epilepsy Management
Center; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York
Epilepsy is the most prevalent major childhood neurological disorder,
affecting 0.5 to 1.0% of children up to 16 years of age.1 The prevalence
of epilepsy in developmentally-disabled children is significantly higher,
ranging from 30% to 50%.2 Moreover, seizures in developmentally-disabled
children are difficult to control,3.4 with increasing seizure incidence directly
proportional to the severity of the developmental disability.4 In addition to
epilepsy, children who are developmentally-disabled often have psychiatric
comorbidities. Approximately 60% of developmentally-disabled children
with epilepsy have at least one psychiatric diagnosis.5
Treatment goals for these patients include improved seizure control
and improved quality of life. Antiepileptic drug therapy is usually
recommended. Selection of therapy is based upon consideration of
efficacy for the patient seizure type and of adverse events and potential
drug interactions associated with antiepileptic drugs. Additionally,
comorbidities may significantly guide the antiepileptic drug of choice.
Thus, management of the developmentally-disabled child with epilepsy,
who may also have psychiatric comorbidities, presents a complex, clinical
challenge for physicians.
This Pediatric Neurology Express Report reviews data presented in
the satellite symposium, “Seizures in Children with Developmental
Disabilities”, held during the recent 34th Annual Meeting of the Child
Neurology Society that examined many of these issues. It is my hope
that the information reviewed in this report will assist you in the
management of your developmentally-disabled patients with epilepsy.
Epidemiology of Seizures in Children with
Developmental Disabilities
Approximately 30% of children with epilepsy have other developmental
disabilities, and conversely, epilepsy is more common in children who have
M E D I C I N E
R E P O R T™
developmental disabilities, according to Shlomo Shinnar, MD, PhD,
Professor of Neurology and Pediatrics; Hyman Climenko Professor of
Neuroscience Research; Director, Comprehensive Epilepsy Management
Center; Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx, New York.6 Moreover, children with developmental disabilities are
more likely to experience seizures, status epilepticus, and medically refrac-
tory epilepsy, and less likely to attain seizure remission, Dr. Shinnar advised.
Citing a retrospective evaluation of 1,946 children (<5 years of age)
referred to a child development center,7 Dr. Shinnar indicated that
significant risk factors for unprovoked seizures include cerebral palsy,
mental retardation, febrile seizures, and prematurity (Table 1).
Table 1. Risk Factors for Unprovoked Seizures (Multivariate Analysis).7
Cox Proportional Hazards Model
Risk Factor
Rate Ratio 95% CI P-value
Cerebral palsy 20.4 11.6–35.8 <.0001
Mental retardation 6.2 3.7–10.5 <.0001
Febrile seizures 4.3 2.3–7.8 <.0001
Prematurity 2.0 1.1–3.7 <.02
Cl = confidence interval.
Although there is an increased risk of seizures in children with multiple
severe disabilities, Dr. Shinnar acknowledged that many children with
epilepsy and developmental disabilities do attain remission, and many
of those can successfully discontinue medications. However, risk factors
that decrease the probability of remaining seizure-free following discon-
tinuation of antiepileptic drugs in children with remote symptomatic
epilepsy include age of onset >12 years, severe mental retardation,
atypical febrile seizures, and age of onset <2 years 8 (Table 2). Children with
none of these risk factors had approximately a 90% chance of remaining
seizure free at 5 years after discontinuation of antiepileptic drugs, while
children with 3 risk factors all had recurrent seizure before 3 years.
Dr. Shinnar commented that the management of developmentally-
disabled children with epilepsy can be clinically challenging and that
further studies are warranted to further assess antiepileptic treatment
options in this population.
Table 2. Risk Factors for Recurrent Seizures upon Discontinuation of phenobarbital, phenytoin, and tiagabine, Dr. Pellock noted. For infantile
Antiepileptic Drug Therapy in Children with Remote Symptomatic Seizures.8 spasms, tiagabine, topiramate, vigabatrin, and zonisamide may be
used. In addition, felbamate, lamotrigine, levetiracetam, topiramate,
Cox Proportional Hazards Model zonisamide, and valproate (divalproex) may be used for partial or
Risk Factor generalized seizures. Dr. Pellock also reviewed the antiepileptic drug
Rate Ratio 95% CI P-value recommendations from the National Institute for Health and Clinical
Age of onset >12 yrs 5.6 2.2–14.1 <.001 Excellence (NICE) 10 (Table 3).

Severe mental retardation 2.8 1.4–5.3 <.001 While the classic antiepileptic drugs (carbamazepine, phenobarbital,
phenytoin, primidone, and valproate) have similar efficacy in treating
Atypical febrile seizures 2.1 1.0–3.7 .04 partial and generalized tonic-clonic seizures,11 Dr. Pellock advised that
Absence seizures 0.4 0.2–0.9 .033 barbiturates have a substantial risk of behavioral adverse effects,
including hyperactivity, irritability, and lethargy. Cognitive and depressive
Age of onset < 2 yrs 1.9 0.97–3.8 .067
effects may also occur. These adverse effects could be particularly
problematic in developmentally-disabled children, Dr. Pellock noted.
Cl = confidence interval.
Once-daily extended-release formulations, such as extended-release
divalproex sodium, may offer a reduced incidence of adverse events.
Antiepileptic Treatment Options in Children Results of a pooled analysis indicate that conversion from divalproex
with Developmental Disabilities sodium to extended-release divalproex sodium was associated with
superior tolerability with less frequent tremor, weight gain, and
The goals of antiepileptic drug therapy in developmentally-disabled gastrointestinal complaints (all P<.001).12 Moreover, extended-release
children with epilepsy are to improve seizure control and improve divalproex sodium also yielded improved seizure control and greater
quality of life by increasing psychosocial functioning and maximizing improvement of psychiatric symptoms, and was greatly preferred by
participation in self-directed activities. Principles of drug treatment patients over the conventional divalproex sodium formulation. Newer
include attempts to minimize drug-
drug interactions, adverse events
Table 3. NICE Recommendations for Antiepileptic Drug Therapy.10
and exacerbation of other
conditions. For children with
developmental disabilities, side Seizure Type 1st-line Drugs 2nd-line Drugs Others Drugs to Avoid
effects should be monitored using Carbamazepinea Levetiracetam Acetazolamide Tiagabine
standardized approaches that do not Generalized Lamotrigineb Oxcarbazepinea Clonazepam Vigabatrin
rely on communication from the
patient. These include nonverbal
tonic-clonic Valproate* Phenobarbitala
a,b
cues, laboratory values, and Topiramate Phenytoina
monitoring seizure activity with Primidonea,c
attention to worsening, increased
Ethosuximide Clonazepam Carbamazepinea
frequency, or emergence of absence, b
myoclonic, or atonic events, Lamotrigine Topiramatea Gabapentin
according to John M. Pellock, MD, Absence Valproate* Oxcarbazepinea
Professor and Chairman, Division of Tiagabine
Child Neurology, Vice Chair, Vigabatrin
Department of Neurology, Virginia
Commonwealth University/Medical Valproate* Clonazepam Carbamazepinea
a,d
College of Virginia; Professor of (topiramate ) Lamotrigine Gabapentin
Neurology, Pediatrics and Pharmacy Myoclonic Levetiracetam Oxcarbazepinea
and Pharmaceutics, Virginia Topiramatea Tiagabine
Commonwealth University;
Vigabatrin
Richmond, Virginia.9
Lamotrigineb Clonazepam Acetazolamide Carbamazepinea
Dr. Pellock indicated that in order to
select an appropriate initial anti- Tonic Valproate* Levetiracetam Phenobarbitala Oxcarbazepinea
epileptic drug, the seizure type Topiramatea Phenytoina
must be correctly identified, as Primidonea,c
some antiepileptic drugs are more
Lamotrigineb Clonazepam Acetazolamide Carbamazepinea
effective for certain seizure types.
In contrast, some antiepileptic Atonic Valproate* Levetiracetam Phenobarbitala Oxcarbazepinea
drugs may exacerbate certain Topiramatea Primidonea,c Phenytoina
seizure types. For partial seizures,
antiepileptic drug options include * valproate is also known as divalproex sodium. ahepatic enzyme-inducing antiepileptic drug; bused as a first choice under circumstances
carbamazepine, gabapentin, as outlined in the NICE technology appraisal of newer antiepileptic drugs; cshould rarely be initiated – phenobarbital is preferred if
levetiracetam, oxcarbazepine, barbiturate is required; din children, for severe myoclonic epilepsy of infancy.

2
antiepileptic drugs such as felbamate, lamotrigine and topiramate may be
effective in reducing drop attacks that occur in Lennox-Gastaut
syndrome.13-15 In addition to antiepileptic drugs, Dr. Pellock pointed out
that vagus nerve stimulation may also decrease seizures from 34% to 90%
in Lennox-Gastaut syndrome.16
Dr. Pellock commented briefly on non-pharmacologic treatment options.
The ketogenic diet has a long history and is experiencing a resurgence
of interest. In a multicenter study of 51 children (ages 1–8 years) with
refractory epilepsy treated with the ketogenic diet for 12 months, 40%
had a >50% reduction in seizures, while 10% became seizure free.17
Surgical therapies include temporal lobe resection for mesial temporal
lobe epilepsy, focal resections for partial epilepsies due to resectable
structural lesions, and hemispherectomy for catastrophic secondary
epilepsies such as hemimegalencephaly, Rasmussen’s encephalitis, and
Sturge-Weber syndrome, Dr. Pellock noted.
Dr. Pellock summarized that current treatment strategies for children
with developmental disabilities include selection of an appropriate
antiepileptic drug for the seizure type, employing broad-spectrum
antiepileptic drugs for mixed or unknown seizure types, monotherapy
when possible, and avoiding antiepileptic drugs that exacerbate seizures.
Management of Comorbidities in Children with
Developmental Disabilities
Emphasizing the important role of diagnosing psychiatric conditions in
children with developmental disabilities and epilepsy, Jay Salpekar, MD,
Director, Outpatient Services, Department of Psychiatry and Behavioral
Sciences, Children's National Medical Center; Assistant Professor of
Psychiatry and Pediatrics, George Washington University School of
Medicine; Washington, DC, indicated that psychiatric, psychological, and
behavioral problems are over-represented in epilepsy.18 The rate of
psychiatric comorbidity in children with epilepsy is nearly 3-fold greater
than that found in diabetic children.19 According to Dr. Salpekar, the scope
of psychiatric comorbidities includes mood disorders (bipolar spectrum
and major depression), attention disorders (attention-deficit/hyperactivity
disorder [ADHD]), learning disorders, anxiety disorders (obsessive
compulsive syndrome, phobias), and psychosis.
Children with psychiatric disorders comorbid with developmental
disability and epilepsy are significantly impaired and difficult to treat.
Dr. Salpekar advised that the goal of therapy is to optimize antiepileptic
treatment and that monotherapy with broad-spectrum antiepileptic
drugs may address seizure, as well, as behavioral control. However,
polytherapy is the rule rather than the exception and low doses of
adjunctive antiepileptics drugs may lead to improved behavior.
When bipolar spectrum disorder is comorbid with epilepsy, patients
treated with carbamazepine, divalproex sodium, or lamotrigine
monotherapy have significantly improved psychiatric symptoms.18
Additionally, extended-release divalproex sodium offers convenient once-
daily dosing. Levetiracetam and oxcarbazepine may also be effective for
bipolar spectrum symptoms. Dr. Salpekar advised that appropriate target
symptoms for antiepileptic therapy directed at mood stabilization include
impulsivity, rage or explosive outbursts, mood lability, arousal
disturbance, and disinhibition.
Risperidone in children with autism and serious behavioral problems
may result in improvement,20 and divalproex sodium may also be useful
in autism spectrum disorders.21
3
When treating comorbidities, Dr. Salpekar advised clinicians to consider
the propensity for adjunctive therapies to induce or modify seizure
thresholds. For children with controlled seizures and ADHD, stimulants
(eg, methylphenidate, mixed amphetamine salts) do not appear to cause
breakthrough seizures. Antidepressants such as selective serotonin-
reuptake inhibitors (eg, fluoxetine, sertraline, paroxetine), trazodone and
nefazodone have a low risk of triggering seizures, while high-dose
bupropion has a greater risk. Antipsychotics such as haloperidol and
risperidone have a low risk of triggering seizures, while clozapine and
chlorpromazine have a higher risk, Dr. Salpekar noted.
In summarizing his presentation, Dr. Salpekar pointed out that the use of
any medication to treat developmentally-disabled children with epilepsy
may often result in paradoxical reactions.
Long-term Outcomes for Children with
Developmental Disabilities
Improved seizure control, fewer medication side effects, and less complex
therapeutic regimens should allow more successful community
placement of multi-handicapped children with epilepsy, advised
Theodore R. Sunder, MD, Professor of Psychiatry, Neurology and
Pediatrics, Southern Illinois University School of Medicine; Director,
Clinical Services, Division of Developmental Disabilities, Illinois
Department of Human Services; Springfield, Illinois.22 Furthermore,
while ‘optimal’ therapeutic goals include complete seizure control and no
adverse events, ‘reasonable’ goals include the best control of significant
epileptic events, reduction of polypharmacy, reduction of side effects,
improved safety, and improved quality of life, Dr. Sunder noted. Although
most states have shifted to community-based services for persons with
intellectual disability,23 Dr. Sunder pointed out that community
placement is adversely impacted by lower IQ, lower functional level, and
comorbidities such as epilepsy.
Dr. Sunder stated that in both children and adults with epilepsy,
quality of life is consistently lower than in peers. In persons with severe
intellectual disability, quality of life is rated only fair (43%) or poor (53%)
and related to functional and social impairment.24 Moreover, quality of
life improves with seizure control and is best with seizure remission.
Dr. Sunder observed that even patients with profound mental retardation
may show dramatic improvements in alertness and responsiveness due to
a reduction in polypharmacy or reduction in barbiturate dose.25
Dr. Sunder observed that the risk of injury doubles in children with
intellectual disability and maladaptive behaviors. Epilepsy increases the
age-based fracture rate from 15% without epilepsy to 26% when epilepsy
is comorbid.26 In addition, mortality risk doubles in mental retardation
with the presence of epilepsy, and the incidence of sudden death nearly
triples from 1.3 per 1000 person-years without epilepsy to 3.6 per 1,000
person-years in those with epilepsy.27
Effective treatment programs should integrate medical goals with
individual and team goals, include interdisciplinary communication,
identify a clear outcome goal, continually reassess the patient,
coordinate seizure control with other therapies, integrate seizure
calendars with other management areas, stay vigilant for medication side
effects, and consider alternative treatments early, summarized Dr. Sunder.
Potential outcomes of aggressive therapeutic programs include enhanced
functional level and quality of life, reduced injury, improved mortality
rate, and reduced cost of care.
 References
1. Shinnar S, Pellock JM. Update on the epidemiology and prognosis of
pediatric epilepsy. J Child Neurol. 2002;17(Suppl 1):S4-S17.
2. Sunder TR. Meeting the challenge of epilepsy in persons with multiple
handicaps. J Child Neurol. 1997;12(Suppl 1):S38-S43.
3. Alvarez N, Besag F, Iivanainen M. Use of antiepileptic drugs in
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4. Airaksinen EM, Natilainen R, Mononen T, et al. A population-
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5. Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in
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Disabilities. Presented as part of the satellite symposium, “Seizures in
Children with Developmental Disabilities” during the 34th Annual
Meeting of the Child Neurology Society, Wednesday, September 28,
2005, Los Angeles, California.
7. Nevo Y, Shinnar S, Samuel E, et al. Unprovoked seizures and
developmental disabilities: clinical characteristics of children referred to
a child development center. Pediatr Neurol. 1995;13:235-241.
8. Shinnar S, Berg AT, Moshe SL, et al. Discontinuing antiepileptic drugs in
children with epilepsy: a prospective study. Ann Neurol. 1994;35:534-545.
9. Pellock JM. Treatment of Epilepsy in Children with Developmental
Disabilities: Special Issues. Presented as part of the satellite symposium,
“Seizures in Children with Developmental Disabilities” during the
34th Annual Meeting of the Child Neurology Society, Wednesday,
September 28, 2005, Los Angeles, California.
10. National Institute for Health and Clinical Excellence Clinical Guideline.
CG20 The epilepsies - the diagnosis and management of the
epilepsies in adults and children in primary and secondary care.
Available at www.nice.org.uk/pdf/CG020NICEguideline.pdf.
Accessed October 16, 2005.
11. de Silva M, MacArdle B, McGowan M, et al. Randomised comparative
monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or
sodium valproate for newly diagnosed childhood epilepsy. Lancet.
1996;347:709-713.
12. Smith MC, Centorrino F, Welge JA, Collins MA. Clinical comparison of
extended-release divalproex versus delayed-release divalproex: pooled
data analyses from nine trials. Epilepsy Behav. 2004;5:746-751.
13. The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy
of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut
syndrome). N Engl J Med. 1993;328:29-33.
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P.O. Box 1709 . Newark . NJ . 07101-1709
Ph 973.972.4267 or 1.800.227.4852 . Fax 973.972.7128
Disclosures:
Shlomo Shinnar, MD, PhD: Grant/Research Support—GlaxoSmithKline, Xcel
Pharmaceuticals; Consultant and Speakers Bureau—Abbott Laboratories, Cephalon, Eisai,
Elan Pharmaceuticals, GlaxoSmithKline, MedPointe, Ovation, Schwarz Pharma,
UCB Pharma, Valeant, Xcel Pharmaceuticals.
Kapila Seshadri, MD: No relationships to disclose.
The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University
of Medicine & Dentistry of New Jersey; Millennium CME Institute, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or
suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions, assessment of possible contraindications or dangers in use, review of any
applicable manufacturer’s product information, and comparison with the recommendation of other authorities. This Pediatric Neurology Express Report™ was made possible through an
educational grant from Abbott Laboratories.
© 2005 Millennium CME Institute, Inc., and UMDNJ—Center for Continuing and Outreach Education
14. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P.
Lamotrigine for generalized seizures associated with the Lennox-Gastaut
syndrome. Lamictal Lennox-Gastaut Study Group. N Engl J Med.
1997;337:1807-1812.
15. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double-
blind, randomized trial of topiramate in Lennox-Gastaut syndrome.
Topiramate YL Study Group. Neurology. 1999;52:1882-1887.
16. Hosain S, Nikalov B, Harden C, Li M, Fraser R, Labar D. Vagus nerve
stimulation treatment for Lennox-Gastaut syndrome. J Child Neurol.
2000;15:509-512.
17. Vining EP, Freeman JM, Ballaban-Gil K, et al. A multicenter study of the
efficacy of the ketogenic diet. Arch Neurol. 1998;55:1433-1437.
18. Salpekar J. Management of Comorbidities in Children with
Developmental Disabilities and Seizures. Presented as part of the
satellite symposium, “Seizures in Children with Developmental
Disabilities” during the 34th Annual Meeting of the Child Neurology
Society, Wednesday, September 28, 2005, Los Angeles, California.
19. Hoare P. The development of psychiatric disorder among schoolchildren
with epilepsy. Dev Med Child Neurol. 1984;26:3-13.
20. McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism
and serious behavioral problems. N Engl J Med. 2002;347:314-321.
21. Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S.
An open trial of divalproex sodium in autism spectrum disorders.
J Clin Psychiatry. 2001;62:530-534.
22. Sunder TR. Long-term Outcomes for Children with Developmental
Disabilities and Epilepsy. Presented as part of the satellite symposium,
“Seizures in Children with Developmental Disabilities” during the 34th
Annual Meeting of the Child Neurology Society, Wednesday,
September 28, 2005, Los Angeles, California.
23. May D, Hogg J. Continuity and change in the use of residential services
by adults with intellectual disability: the Aberdeen cohort at mid-life.
J Intellect Disabil Res. 2000;44:68-80.
24. Beadle-Brown J, Murphy G, Wing L. Long-term outcome for people with
severe intellectual disabilities: impact of social impairment.
Am J Ment Retard. 2005;110:1-12.
25. Pellock JM, Hunt PA. A decade of modern epilepsy therapy in institu-
tionalized mentally retarded patients. Epilepsy Res. 1996;25:263-268.
26. Jancar J, Jancar MP. Age-related fractures in people with intellectual
disability and epilepsy. J Intellect Disabil Res. 1998;42:429-433.
27. McKee JR, Bodfish JW. Sudden unexpected death in epilepsy in adults
with mental retardation. Am J Ment Retard. 2000;105:229-235.
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