ArticlePDF Available
AUTISM SCIENCE DIGEST: THE JOURNAL OF AUTISMONE  
Elias Tembenis
 
4
  5
A CONSENSUS STATEMENT
FROM THE ELIAS TEMBENIS
SEIZURES THINK TANKS
SHORT TITLE: SEIZURES IN AUTISM SPEC TRU M DISORDER
Abbreviations: ASD: autism spectrum disorder; EEG: electroencephalogram;
GABA: gamma-aminobutyric acid; SEDs: subclinical electrical discharges.
Keywords: Autism spectrum disorder; seizures; epilepsy; prevalence; subclinical electrical discharges;
excitatory-to-inhibitory cortical balance; genetic syndrome; metabolic disorders; treatment
Conict of Interest: e authors have no conicts of interest to declare
Financial Disclosures: e authors have no nancial disclosures to declare
Please send all correspondence to: Dr. Richard E. Frye, M.D., Ph.D., Slot 512-41B, Room R4025,
13 Children’s Way, Little Rock, AR 72202, USA, Phone: 501-364-4662; Fax: 501-364-1648,
E-mail: REFrye@uams.edu.
Authors’ Contribution: To develop this summary, we held the Elias Tembenis Seizures ink Tanks at the
AutismOne meeting in Chicago in May of 2009 and 2010 and at the Autism Canada meeting in Toronto,
Canada in October of 2009. ese think tanks included scientists and clinicians with expertise in seizures
related to ASD. e participants represented a wide variety of researchers and practitioners who treat
ASD. e participants from the initial think tank in May of 2009 provided the basis for the content of the
information within this supplement. Individuals in the following two think tanks (October 2009 and May
2010) provided suggestions for the developed document. Individual participants who provided written text
for the supplement or contributed in the editing of the document are recognized as authors.
By Richard E. Frye, M.D., Ph.D., Arkansas Childrens Hospital Research Institute, Little Rock,
AR; Manuel Casanova, M.D., University of Louisville, Louisville, KY; Gregory L Brown, M.D.
and Victoria Martin, R.N., Autism Recovery and Comprehensive Health Medical Center,
Franklin, WI; Stephen Edelson, Ph.D., Autism Research Institute, San Diego, CA; Robert Coben,
Ph.D., New York University Brain Research Lab, New York, NY; Jerey Lewine, Ph.D., MIND
Research Network, Albuquerque, NM; Daniel Rossignol, M.D., Rossignol Medical Center,
Irvine, CA; Derrick MacFabe, M.D., University of Western Ontario, London, Ontario, Canada;
John Slattery, B.S., Arkansas Childrens Hospital Research Institute, Little Rock, AR; and James B.
Adams, Ph.D., Arizona State University, Tempe, AZ.
AUTISM SCIENCE DIGEST: THE JOURNAL OF AUTISMONE  
MANUEL CASANOVA, MD, completed
his residency in neurology and then did a
fellowship in neuropathology at Johns Hopkins
Hospital. During his stay at Johns Hopkins, he
was in charge of pediatric neuropathology.
Dr. Casanova spent several years as Deput y
Medical Examiner for Washington, DC,
gaining valuable experience in the post-mortem
examination of SIDS and child abuse cases.
His expertise was recognized by honorary
appointments as a scientific expert for the Armed
Forces Institute of Pathology and as a professorial
lecturer for the Department of Forensic Science
at George Washington University. Dr. Casanova
helped establish two of the most successful brain
banks in this country. He is well published in a
multitude of postmortem techniques. His interest
shifted toward the study of abnormalities of
cortical circuitry. His most recent studies have
investigated the presence of abnormalities of
minicolumnar organization and lateralization
in the brains of patients who exhibit language
disturbances, including autism, Asperger’s
syndrome, and dyslexia.
RICHARD FRYE, MD, PHD, is the Director
of Autism Research at Arkansas Children’s
Hospital Research Institute and the Director of
the Autism Multispecialty Clinic at Arkansas
Children’s Hospital. He is a well-recognized
expert in the diagnosis and treatment of ASD
and other neurodevelopmental disorders. Dr.
Frye is fellowship trained in behavioral neurology
and psychology and has clinical expertise in
the assessment, diagnosis, and treatment of
children with ASD. He is the author of over 100
peer-reviewed articles and book chapters on
neurological disorders. Over the past two years,
Dr. Frye has completed three clinical studies
related to ASD, including an open-label trial
examining the metabolic and behavioral effects
of tetrahydrobiopterin, a clinical study of the
metabolic and genetic characteristics of children
with ASD and mitochondrial disease, and a
clinical study on the prevalence of the folate
receptor alpha autoantibody in children with ASD
as well as the response to leucovorin treatment
in ASD children with the folate receptor alpha
autoantibody.
JAMES B. ADAMS, PhD, is a father of a
daughter with autism, who was diagnosed in
1994, and that is what led him to eventually shift
much of his research emphasis to autism. His
research focuses on the medical causes of autism
and how to treat it, including addressing nutrition,
toxic metals, gut bacteria, and seizures, and he
is widely published. He is currently a President’s
Professor at Arizona State University, where he
directs the ASU Autism/Asperger’s Research
Program. He is the president of the Autism
Society of Greater Phoenix and the president and
founder of the Autism Conferences of America.
Prof. Adams has won multiple awards. He served
on the board of directors of the Autism Research
Institute and continues to serve as the co-leader
of ARI’s science advisory committee.
GREGORY L BROWN, MD VICTORIA MARTIN, RN STEPHEN EDELSON, PhD ROBERT COBEN, PhD
JEFFREY LEWINE, PhD DANIEL ROSSIGNOL, MD DERRICK MACFA BE, MD JOHN SLATTERY, BS
6 
 
1. INTRODUCTION
The prevalence of autism spectrum disorders (ASD) is high with recent
Center for Disease Control studies estimating the prevalence at 1
in 881. Although ASD is a behaviorally defined disorder, children
with ASD often suffer from comorbid medical conditions, including
abnormalities in the peripheral nervous, musculoskeletal, endocrine,
gastrointestinal, immune, detoxification, redox regulation systems
and mitochondrial function.2,3 It is not known whether these medical
abnormalities are part of the etiological processes that cause ASD
or whether they arise as a consequence of other pathological
processes that arise after the development of ASD. Regardless, it is
crucial to understand these comorbid medical abnormalities in order
to optimally manage children with ASD and assist them toward a
pathway that promotes developing more typical cognitive function.
Seizures are the most prevalent neurological disorder associated
with ASD4. To provide insight and knowledge about this subject,
we held three Elias Tembenis Seizures Think Tanks that included
practitioners who treat children with ASD and seizure disorders with
both traditional and non-traditional treatments for ASD. The first Elias
Tembenis Seizures Think Tank was held at the AutismOne meeting
in Chicago in May of 2009. Work continued on this project during
similar think tanks held at Autism Canada in Toronto in October 2009
and AutismOne in Chicago in May 2010. The think tanks included
a wide variety of scientists and clinicians with expertise in ASD and
seizures. The summary points below represent the major agreed upon
conclusions of the think tanks. These conclusions were based on the
most valid, evidence-based information available on seizures and
epilepsy in ASD.
2. SUMMARY POINTS
Summary point 1, Prevalence: Seizures are a significant concern
and are relatively common in individuals with ASD. While 1-2% of
children in the general population develop epilepsy, the prevalence of
epilepsy in ASD is much higher with estimates varying widely from 5%
to 38%.5-9 Some individuals with ASD develop seizures in childhood,
some at puberty, and some at adulthood. Although the prevalence
of seizures by age is not well studied, recent studies suggest the risk
of seizure into adulthood remains high. Seizures are associated with
increased mortality and morbidity in individuals with ASD10 and are
the leading cause of mortality in adults with ASD.11 Certain subgroups
of individuals with ASD have a higher risk for developing seizures
and epilepsy; these subgroups include individuals with comorbid
intellectual disabilities, single gene defects, or brain malformations.5
Summary point 2, Subclinical Electrical Discharges:
Electroencephalographic (EEG) subclinical electrical discharges
(SEDs), not necessarily associated with clinical seizures, appear to
be very prevalent in individuals with ASD. The prevalence of these
abnormalities is high in ASD, varying from 30%12 to 61%13 in studies
that have used long-term EEG monitoring and varying from 82%14
to 100%15 in studies that have used magnetoencephalography
(MEG). Studies using non-ASD populations have shown that SEDs
are associated with cognitive and behavioral abnormalities, and
controlled studies have shown improvement in cognition and behavior
with anti-epileptic drug (AED) treatment of SEDs in children with
epilepsy.16,17 Thus, the authors believe there is evidence to support
the notion that SEDs could contribute to the cognitive and behavioral
SEIZURES IN AUTISM
SPECTRUM DISORDER
Although autism spectrum disorder (ASD) is a behaviorally dened disorder, research shows that
ASD is associated with neurological, genetic, gastrointestinal, and other medical abnormalities. In
this article, we discuss the most prevalent neurological abnormality aecting children with ASD --
seizures. To provide insight and knowledge about this subject, we held three Elias Tembenis Seizures
ink Tanks that included practitioners who treat children with ASD and seizure disorders using
both traditional and non-traditional treatments. is article outlines the summary points of the
major agreed upon conclusions of the think tanks. ese conclusions were based on the most valid,
evidence-based information available on seizures and epilepsy in ASD.
While 1-2% of children in the general population develop epilepsy, the prevalence of
epilepsy in ASD is much higher with estimates varying widely from 5% to 38%.
7
AUTISM SCIENCE DIGEST: THE JOURNAL OF AUTISMONE  
morbidity associated with ASD and, thus, deserve careful study in the
future.
Summary point 3, Pathophysiological processes: Many
pathophysiological processes are related to both ASD and seizures,
and the majority of these pathophysiological processes act through
altering the excitatory-to-inhibitory balance of the cortex. Many
single gene defects and metabolic disorders change this excitatory-
to-inhibitory balance by altering γ-aminobutyric acid (GABA) or
glutamate neurotransmission. The neuropathology associated with
ASD has also demonstrated defects in GABA neurotransmission at the
cortical level, potentially leading to an elevation in the excitatory-to-
inhibitory balance of the cortex, thereby resulting in seizures. Other
pathological processes such as vitamin and mineral deficiencies,
oxidative stress, and immune abnormalities may contribute to the
development of seizures, but the exact mechanisms by which they
might cause seizures requires further study.
Summary point 4, EEG Assessment: Subtle symptoms of seizures
are very difficult to differentiate from abnormal behaviors commonly
associated with ASD. Some individuals with ASD may not have any
clear or subtle symptoms of seizures despite having SEDs.18 Thus, it
is reasonable to consider a screening EEG in children with ASD in
order to detect subtle seizure activity and/or SEDs. An extended
overnight EEG should be strongly considered as a screening test
since (1) routine 1-2 hour studies are very often unsuccessful due to
patient agitation or the need for sedative medications for electrode
placement and (2) several seizure syndromes associated with autistic
regression require a prolonged recording of sleep.
Summary point 5, Systematic Workup: Since specific genetic and
metabolic syndromes are associated with both ASD and seizures,
children with ASD and comorbid seizures or SEDs should have a
systematic workup for these known syndromes. A chromosomal
microarray with testing for fragile X and Rett syndrome in boys and
girls, respectively, should be highly considered as initial genetic testing.
Genetic testing for tuberous sclerosis complex as well as Angelman,
Prader–Willi, velocardiofacial, Smith-Lemli-Opitz syndromes should be
conducted as indicated based on specific dysmorphological findings.
Several metabolic syndromes that have been suggested to have a high
prevalence in ASD such as mitochondrial dysfunction and cerebral
folate deficiency can also be associated with seizures and should be
highly considered in children with ASD and seizures. Other metabolic
disorders that are considered rare, such as succinic semialdehyde
dehydrogenase deficiency, adenylosuccinate lyase deficiency,
creatine metabolism disorder, phenylketonuria, pyridoxine dependent
and responsive seizures, and urea cycle disorder, are associated
with both seizures and ASD; such disorders should be considered if
supporting clinical characteristics exist.
Summary point 6, Seizure Treatments: Traditional treatments
for seizures and epilepsy have not been well studied in the ASD
population. Since children with ASD may be sensitive to cognitive and
behavioral adverse effects of treatments, it is wise to carefully consider
the safety profile of treatments. One large survey study investigated
the perceived effect of many different types of treatments for seizures
in individuals with ASD.19 In this study, specific antiepileptic drugs
(AEDs) and non-AED treatments were rated as improving seizures.
AEDs, including lamotrigine, levetiracetam, valproic acid, and
ethosuximide were rated as improving seizures and not negatively
affecting mood and behavior as much as other AEDs. Non-AED
therapy, including the ketogenic diet and Atkin’s diet, were rated
as improving seizures and positively affecting other important
clinical factors such as mood and behavior. In addition, adverse
effects of specific AEDs may be minimized by co-treatment with
specific vitamins. For example, carnitine can help with valproic acid
metabolism, and pyridoxine can mitigate adverse behavioral effects
of levetiracetam. Overall, it was found that research on treatment for
seizures in children with ASD is needed.
Summary point 7, Treatment of Subclinical Electrical Discharges:
Several controlled studies have shown improvement in cognitive
function and behavior with AED treatment of SEDs in children with
epilepsy. Studies have demonstrated improvement in SEDs in children
with ASD using AED treatment, but, unfortunately, there are no studies
focusing on the behavioral or cognitive effects of AED treatment of
SEDs in children with ASD. Given the excellent safety profile of newer
AEDs, the authors believe that the risk/benefit ratio is reasonable to
consider in the treatment of SEDs in a careful and controlled fashion
with close follow-up and frequent clinical reevaluation. It is likely that
SEDs work in concert with underlying neuropathology to exacerbate
ASD symptoms; thus, although AED treatment may improve ASD
symptoms, it is not likely that AED treatment of SEDs will result in
complete resolution of ASD symptoms.
Summary point 8, Alternative Seizure Treatments: Some
alternative treatments commonly prescribed to children with ASD,
such as vitamin supplementation, may, theoretically, have a positive
influence on some of the pathological processes known to cause
seizures in ASD. However, empirical evidence for efficacy for the
great majority of these treatments is lacking. Thus, certain treatments
that have excellent safety profiles may be worth considering for
treating seizures in ASD. However, for safety reasons, such treatment
should be used as an adjunct or add-on therapy with standard
therapies when treating clinical seizures.
Summary point 9, Future Research: There are several areas that
are ripe for future research efforts. These include 1) further defining
the pathophysiological causes of seizures in ASD, particularly with
respect to the pathophysiology that may cause both behavioral
and cognitive aspects of ASD as well as seizures, 2) evaluation
of the tolerability, safety, and efficacy of standard and alternative
treatments for seizures, 3) the natural history of seizures and epilepsy
in children with ASD, particularly with respect to the influence of
hormonal fluctuations during adolescence, and 4) investigation into
the significance and treatments of SEDs. Dietary manipulations and
transcranial magnetic stimulation are particular treatments that were
felt to be promising and deserving of more study.
Dietary manipulations and transcranial magnetic stimulation are particular
treatments that were felt to be promising and deserving of more study.
8
 
3. HIGHLIGHTS (SUMMARY FOR PARENTS)
Incidence of Epilepsy: Epilepsy and seizures are significantly
more common in children, adolescents, and adults with autism. The
incidence of developing seizures appears to continue to increase
into adulthood, so it is important to be aware of seizure symptoms in
individuals with ASD regardless of age.
Causes of Epilepsy: The causes of most seizures are unknown, but
many medical abnormalities associated with ASD, including genetic
and metabolic disorders, are associated with brain hyperexcitability,
a state that is likely to predispose an individual with ASD to have
seizures. Thus, patients with ASD and epilepsy should undergo a
comprehensive genetic and metabolic workup for underlying causes.
Subclinical Electrical Discharges: Seizure-like activity has
been reported to occur with a high prevalence in individuals
with ASD even if they do not have obvious seizures. It is very
possible that these abnormal electrical discharges may interfere
with attention, cognition, and learning. Thus, we recommend an
overnight electroencephalograph for all patients with autism due
to the high prevalence of these abnormalities and the inability
to adequately detect symptoms of these abnormalities during a
clinical evaluation. In addition, several clinical studies support
treating subclinical electrical discharges. Thus, a treatment trial
is reasonable if subclinical electrical discharges are found on
electroencephalogram.
Seizure Treatments: Certain specific treatments, including specific
antiepileptic drugs (lamotrigine, levetiracetam, valproic acid, and
ethosuximide) and diets (ketogenic diet, modified Atkin’s diet),
appear to be rated as improving seizures without significant adverse
effects. Other nutritional supplements and non-traditional treatments
may also be beneficial but have not been studied. Thus, in patients
with epilepsy and seizures, non-traditional treatments should be used
as add-on therapy rather than primary therapy at this point.
Future research: More research is needed on the causes of
seizures, with a focus on metabolic abnormalities. Also, more
research is needed on new treatments, including dietary treatments
and possibly transcranial magnetic stimulation.
Participant Speciality May Oct May
2009 2009 2010
Rich ard Frye, MD, PhD Child a nd Behaviora l Neurology
Derric k MacFabe, MD Neurolog y, Neurophysiology
Paul Hard y, MD Child Neurology
James Ad ams, PhD Biochemistry
Manuel C asanova, M D Neuropathology
Jerey Lew ine, PhD Neuropsyc hology, Neurophysiology
Maya Shet reat-Klein, MD Child Neurology
Tapan Audhya , PhD Vitami n Supplementati on
Gregor y Brown, MD Alter native Medicine
Vicki Mar tin, R N Al ternative Medicine
Rob Coben , PhD Neuropsyc hology, Neurophysiology
Harr y Schneider, M D Neuroimaging
Dan Ros signol, MD Fami ly Medicine
eohar is eoharides , PhD Pharmacolog y, Internal Med icine, Biochem istry, Immunology
Mart ha Herbert , MD, PhD Child Neurology
Stephen Ed elson, PhD Alternati ve Medicine
Sey yed Hossein Fatem i, MD, PhD Psychiat ry, Cell Biolog y and Neuroanatomy
Cindy L . Grin, DSH-P, DIHom Homeopathy
Lindy l Lanha m, DSH-P, HD Homeopathy
Jon Poling , MD, PhD Neurolog y, Neurophysiology
All an Sosin, MD Alter native Medicine
Aris to Vojdani , PhD Immunology
Willia m Walsh, Ph D Biochemistry
Haru mi Jyonouchi, M D Allergy/Immunology
Georgia D avis, MD Neurolog y, Psychiatr y, Pathology
Jerey Brad street, MD Alter native Medicine
Sarge nt Goodchild Biofeedback
Nancy Mu llan, M D Psychiatrist
Natal ie King Wilson , DO Chiropractor
Danie l Barth, Ph D Elect rophysiology, Neuroimmunology
Dan Pavel, M D Neuroim aging , Nuclear Medicine
Alexa nder Rotenberg , MD, PhD Child Neu rology, Neurophysiology
Evdokia A gnostou, PhD Psychologist 
Appendix A: Participants of the Elias Tembenis Seizures Think Tanks
Attended S pecic Meeting
Did Not Attend S pecic Meeting
9
AUTISM SCIENCE DIGEST: THE JOURNAL OF AUTISMONE  
1. Prevalence of autism spectrum disorders - Autism and Developmental Disabilities
Monitoring Network, United St ates, 200 6. MMWR Sur veill Summ. Dec 18
2009 ;58(10):1-20. PMCID:
2. Xue M, Bri macombe M, Chaaban J, Zimmerman- Bier B, Wagner GC. Autism spectrum
disorde rs: concurrent clinical disorders. J Child Neurol. Jan 2008;23 (1):6-13. PMCID:
3. Rossignol DA, Frye RE. A review of research trends in physi ological abnormaliti es
in autism spectrum d isorders: immune dysreg ulation, inflammation, oxidative stress,
mitochondrial dys function and environmental toxicant exposures. Mol Psychiatry. 2012.
PMCID:
4. Tuchman R, Cu ccaro M. Epilepsy and Autism: Neurodevelopmental Perspective. Current
neurology and neuroscience repor ts. Mar 22. PMCI D:
5. Tuchman R, Rapin I. Epilepsy in autism. Lancet neurology. Oct 2002;1(6):352- 358.
PMCID:
6. Deykin E Y, MacMahon B. The incidence of seizures among children with autistic
symptoms. The American journal of psychiatry. Oct 1979;136(10):1310-1312. PMCID:
7. Volkmar FR , Nelson DS. Seizure disorders in autism. Journal of the A merican Ac ademy
of Child and Adolescen t Psychiatr y. Jan 1990 ;29(1):127-129. PMCID:
8. Danielsson S, Gillb erg IC, Billstedt E, Gillberg C, Olsson I . Epilepsy in young adults with
autism : a prospective p opulation-based follow-up study of 120 individuals diagnosed in
childhood. Epilepsia. Jun 200 5;46 (6):918-923. PMCID:
9. Hara H. Autism and epil epsy: a retros pective follow-up study. Brain & development. Sep
2007;29 (8): 486- 490. PMCID :
10. Picket t J, Xiu E, Tuchman R, Dawson G, Lajo nchere C. Mor tality in Individuals With
Autism, With and Without Epilepsy. J Child Neurol. A pr 6. PMCID:
11. Shavelle RM, Strauss DJ, Pickett J. Causes of death in autism. Journal of autism and
develop mental disorders. Dec 20 01;31(6): 569-576. PMCID:
12. McVicar KA, B allaban -Gil K, Rap in I, Moshe SL, Shinnar S. Epileptiform EEG
abnorm alities in children with language regres sion. Neurology. Jul 12 2005; 65(1):129-
131. PMCID:
13. Chez MG, Chang M, Krasne V, Coughlan C, Komins ky M, Schwar tz A. Freque ncy
of epileptiform EEG abnormalities in a sequential screening of autistic patients wi th no
known cl inical epilepsy from 1996 to 20 05. Epilepsy Behav. Feb 2006;8 (1):267-271.
PMCID:
14. Lewine JD, Andrews R, Chez M, Patil AA , Devinsky O, Smith M, Kanner A , Davis
JT, Funke M, Jones G, Chong B, Provencal S, Weisend M, Lee RR, Orris on WW, Jr.
Magnetoencephalographic pat terns of epileptiform activity in children with regressive
autism s pectrum disorders. Pediatrics. Sep 1999;104(3 P t 1):405 -418. PMCID :
15. Munoz-Yunta JA, Ortiz T, Palau-Baduell M, Martin-Munoz L, Salvado -Salvad o B,
Valls- Santasusana A, Perich -Alsina J, Cristobal I, Fernandez A , Maestu F, Durste ler C.
Magnetoencephalographic pat tern of epileptiform ac tivity in children with early-onset
autism s pectrum disorders. Clin Neurophysiol. Mar 2008 ;119(3) :626-634. PMCID :
16. Pressler RM, Robinson RO, Wilson GA, B innie CD. Treatme nt of interictal epilept iform
discharges can improve behavior in children with behavioral problems and epilepsy.
The Jour nal of pediatrics. Jan 2005;146(1):112-117. PMCID:
17. Marston D, Besag F, Binnie CD, Fowler M. Effects of trans itory cognitive impairment on
psychosocial func tioning of children with ep ilepsy: a therapeutic trial. Developmental
medicine and child neurology. Jul 1993;35(7): 574-581. PMCID :
18. Frye RE, Butler I, Strickland D, Castillo E, Papanicolaou A. Electroencephalogram
discharges in atypical cognitive development. J Child Neurol. in press. PMC ID:
19. Frye RE, Sreenivasula S, Adams JB. Traditional and non- traditional treatments for autism
spect rum disorder w ith seizures: an on- line survey. BMC Pediatr. 2011(11):37. PMCID:
REFERENCES
ACKNOWLEDGEMENTS
We would like to thank Autism One conference director Teri Arranga for organizing the Elias Tembenis Seizures Think Tanks; Kirkman
Laboratories, Enzymedica, and Apothecure for funding the 2009 and 2010 think tank meetings; and Harry and Gina Tembenis for their
inspiration. The motivation for organizing this think talk arose from the unfortunate passing of Elias Tembenis, a promising young man with a
refractory seizure disorder, who was recovering from autism at the time that a seizure took his life. We would also like to thank Timothy D. Folsom
and Teri J. Reutiman and the Elias Tembenis Seizures Think Tank participants (listed in Appendix A).
10
... 63 These conditions include mitochondrial dysfunction, 64-67 inflammation, 68 oxidative stress, 68 environmental toxicant exposures, 68 and seizures. 69 A great deal of information has been learned about autism since my children were diagnosed. Every day, more and more studies concerning autism are appearing in the literature. ...
Article
Full-text available
I remember the first time I heard the word “autistic.” I was 10 years old, and my mom mentioned that someone had a child who was autistic. I was confused because I mistook her description as “artistic.” In April 2001, our first child, Isaiah, was born. My wife, Lanier, was concerned that he had autism at about 11 months of age, but I did not recognize his obvious problems, even though he was not responding to his name, was obsessed with spinning objects, and did not play with toys appropriately. He also had no language, did not walk until 18 months, and had significant gastrointestinal (GI) problems including severe reflux requiring medication and chronic diarrhea. At 19 months of age, Isaiah was diagnosed with autistic disorder.
... Second, we considered treatments associated with metabolic and genetic disorders that are commonly found in children with ASD and seizures. Third, we considered novel treatments obtained from two sources: (a) a panel of experts who regularly treat children with ASD and who attended at least one of the three Elias Tembenis Seizure Think Tanks (13), and (b) recent surveys of novel treatments used by parents in children with ASD and seizures and in the general ASD population (10,11). ...
Article
Full-text available
Despite the fact that seizures are commonly associated with autism spectrum disorder (ASD), the effectiveness of treatments for seizures has not been well studied in individuals with ASD. This manuscript reviews both traditional and novel treatments for seizures associated with ASD. Studies were selected by systematically searching major electronic databases and by a panel of experts that treat ASD individuals. Only a few anti-epileptic drugs (AEDs) have undergone carefully controlled trials in ASD, but these trials examined outcomes other than seizures. Several lines of evidence point to valproate, lamotrigine and levetiracetam as the most effective and tolerable AEDs for individuals with ASD. Limited evidence supports the use of traditional non-AED treatments, such as the ketogenic and modified Atkins diet, multiple subpial transections and immunomodulation and neurofeedback treatments. Although specific treatments may be more appropriate for specific genetic and metabolic syndromes associated with ASD and seizures, there are few studies which have documented the effectiveness of treatments for seizures for specific syndromes. Limited evidence supports L-carnitine, multivitamins and N-acetyl-L-cysteine in mitochondrial disease and dysfunction, folinic acid in cerebral folate abnormalities and early treatment with vigabatrin in tuberous sclerosis complex. Finally, there is limited evidence for a number of novel treatments, particularly magnesium with pyridoxine, omega-3 fatty acids, the gluten-free casein-free diet and transcranial magnetic simulation. Zinc and L-carnosine are potential novel treatments supported by basic research but not clinical studies. This review demonstrates the wide variety of treatments used to treat seizures in individuals with ASD as well as the striking lack of clinical trials performed to support the use these treatments. Additional studies concerning these treatments for controlling seizures in individuals with ASD are warranted.
Article
Full-text available
Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures ('four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics ('four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006-2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.
Article
Full-text available
Despite the high prevalence of seizure, epilepsy and abnormal electroencephalograms in individuals with autism spectrum disorder (ASD), there is little information regarding the relative effectiveness of treatments for seizures in the ASD population. In order to determine the effectiveness of traditional and non-traditional treatments for improving seizures and influencing other clinical factor relevant to ASD, we developed a comprehensive on-line seizure survey. Announcements (by email and websites) by ASD support groups asked parents of children with ASD to complete the on-line surveys. Survey responders choose one of two surveys to complete: a survey about treatments for individuals with ASD and clinical or subclinical seizures or abnormal electroencephalograms, or a control survey for individuals with ASD without clinical or subclinical seizures or abnormal electroencephalograms. Survey responders rated the perceived effect of traditional antiepileptic drug (AED), non-AED seizure treatments and non-traditional ASD treatments on seizures and other clinical factors (sleep, communication, behavior, attention and mood), and listed up to three treatment side effects. Responses were obtained concerning 733 children with seizures and 290 controls. In general, AEDs were perceived to improve seizures but worsened other clinical factors for children with clinical seizure. Valproic acid, lamotrigine, levetiracetam and ethosuximide were perceived to improve seizures the most and worsen other clinical factors the least out of all AEDs in children with clinical seizures. Traditional non-AED seizure and non-traditional treatments, as a group, were perceived to improve other clinical factors and seizures but the perceived improvement in seizures was significantly less than that reported for AEDs. Certain traditional non-AED treatments, particularly the ketogenic diet, were perceived to improve both seizures and other clinical factors.For ASD individuals with reported subclinical seizures, other clinical factors were reported to be worsened by AEDs and improved by non-AED traditional seizure and non-traditional treatments. The rate of side effects was reportedly higher for AEDs compared to traditional non-AED treatments. Although this survey-based method only provides information regarding parental perceptions of effectiveness, this information may be helpful for selecting seizure treatments in individuals with ASD.
Article
Full-text available
To investigate the significance of electroencephalogram (EEG) discharges and their treatment, we retrospectively reviewed the charts of 22 children with atypical cognitive development that did not respond to standard educational therapy and demonstrated discharges on EEG. Most children demonstrated no obvious symptoms of seizures, and developmental regression and/or fluctuations were uncommon. The majority of children demonstrated a language and attention disorder and autism symptomatology and had multifocal discharges on EEGs. Of the 20 patients treated with antiepileptic medications, 70% demonstrated definite improvement within 1 clinic visit. This study suggests that children with EEG discharges and developmental cognitive disorders demonstrate a unique pattern of symptomatology and discharges on EEG. This study suggests that children with developmental cognitive disorders that do not respond to standard therapy may benefit from screening with an EEG and a trial of antiepileptic mediation if discharges are detected.
Article
Full-text available
One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism. To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS. Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder-not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients. The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases. This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significa
Article
Previous studies show higher mortality rates among individuals with autism than the general population. Comorbidity with epilepsy is an assumed, often ill-defined factor in the increased mortality rates of individuals with autism. Data from the Autism Tissue Program, a tissue donation program established to support biomedical research on autism, show that approximately one-third of its brain donors with autism also had epilepsy. Analysis of new data from the California State Department of Developmental Services is consistent with past reports showing that there is a higher than expected rate of mortality in individuals with autism and epilepsy than autism alone. Accurate, complete and accessible records on cause of death are necessary not just for brain research, but also for understanding risk factors that contribute to early death in individuals with autism spectrum disorders. Various national health care and state developmental disability agency initiatives to reduce risk of mortality are described.
Epilepsy and autism coexist in up to 20% of children with either disorder. Current studies suggest that a frequent co-occurring condition in epilepsy and autism is intellectual disability, which shows a very high prevalence in those with both autism and epilepsy. In addition, these recent studies suggest that early-onset seizures may index a group of infants at high risk for developing autism, usually with associated intellectual deficits. In this review we discuss recent advances in the conceptualization of shared anatomical and molecular mechanisms that may account for the coexistence of epilepsy, autism, and intellectual disability. A major contribution to our improved understanding of the relationship among these three phenotypes is the discovery of multiple genomic variants that cut across them as well as other neurobehavioral phenotypes. As these discoveries continue they are very likely to elucidate causal mechanisms for the various phenotypes and pinpoint biologic pathways that may be amenable to therapeutic interventions for this group of neurodevelopmental disorders.
Article
The authors examined 183 children with autistic symptoms and found that the age-specific incidence rates of seizures in this sample were between 3 and 28 times the rates for children in the general population. The subjects classified as totally autistic were at high risk of developing seizure from early childhood well into adolescence, but especially so at puberty. The partially autistic children had an increased risk of seizures only up to age 10. The authors suggest that the high incidence of seizures at puberty observed in this study may be specific to children with total autistic symptomatology and may represent a distinct pathological process associated with autism.
Article
The authors report a trial of the use of anti-epileptic medication to treat possible cognitive deficits due to subclinical epileptiform EEG discharges in 10 children with psychosocial and educational problems associated with epilepsy. Medication intended to suppress the EEG discharges was added to the children's existing drug regime. In all instances, epileptiform activity, assessed by 24-hour periods of ambulatory monitoring, was reduced on active medication compared with placebo. In general, there was improvement of psychosocial function on active treatment: eight children improved, there was no change in one and one deteriorated. No psychosocial deterioration attributable to adverse effects of the medication was detected in those completing the trial. Despite possible confounding factors, the findings are in accordance with the view that subclinical EEG discharges can impair psychosocial function, which may be ameliorated by anti-epileptic medication.
Article
The objective of this study was to determine which causes of death are more frequent in persons with autism, and by how much, compared with the general population. Subjects were 13,111 ambulatory Californians with autism, followed between 1983 and 1997. The units of study were person-years, each linked to the subject's age, sex, and cause of death (if any) for the specific year. Observed numbers of cause-specific deaths were compared with numbers expected according to general population mortality rates. Standardized mortality rates (SMRs) were computed for each mental retardation level. Elevated death rates were observed for several causes, including seizures and accidents such as suffocation and drowning; elevated mortality due to respiratory disease was observed among persons with severe mental retardation. Overall, excess mortality was especially marked for persons with severe mental retardation, but life expectancy is reduced even for persons who are fully ambulatory and who have only mild mental retardation.
Article
It is generally agreed that children should be treated for epilepsy only if they have clinical seizures. The aim of this study was to examine whether suppressing interictal discharges can affect behavior in children with epilepsy. In a double-blinded, placebo-controlled, crossover study, 61 children with well-controlled or mild epilepsy were randomly assigned to add-on therapy with either lamotrigine followed by placebo or placebo followed by lamotrigine. Ambulatory electroencephalographic recordings and behavioral scales were performed during baseline and at the end of placebo and drug phases. The primary hypothesis to be tested was that behavioral scales would improve specifically in patients with a reduction of electroencephalographic discharges during active drug treatment. Global rating of behavior significantly improved only in patients who showed a significant reduction in either frequency ( P < .05) or duration of discharges ( P < .05) during active treatment but not in patients with without a significant change in discharge rate. This improvement was mainly seen in patients with partial epilepsy ( P < .005). Our data suggest that suppressing interictal discharges can improve behavior in children with epilepsy and behavioral problems, particularly partial epilepsy. Focal discharges may be involved in the underlying mechanisms of behavioral problems in epilepsy.