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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 Children’s 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 Children’s 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
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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%.
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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
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AUTISM SCIENCE DIGEST: THE JOURNAL OF AUTISMONE
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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).
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