There is no
medical consensus about what to do with people who have subclinical
epileptiform discharges (SEDs) on their EEG. That is people who do not have
seizures but have an abnormal EEG. There is evidence to support the use of
anti-epileptic drugs (AEDs) in such people.
About 5% of
the general population have SEDs, but a far higher number of people with autism
have SEDs.
You are more
likely to detect epileptiform activity depending on which test you use. Magnetoencephalography
(MEG) detects the most abnormalities, followed by a sleep EEG and then an EEG
with a subject wide awake.
It had been thought that epileptiform activity (SEDs) was more common in regressive autism, but
that is no longer thought to be the case. It even briefly had a name, Autistic
Epileptiform Regression (AER). Subsequent studies indicate that regression is
not relevant to subclinical
epileptiform discharges (SEDs).
Estimates of
prevalence still vary dramatically from Dr Chez at 60% to others believing it
is 20-30%.
Epileptiform
activity without seizures does also occur in about 5% of neurotypical people.
Dr Chez and
some others believe in treating epileptiform activity with anti-epileptic drugs
(AEDs), with valproate being the popular choice. Some neurologists believe in
leaving SEDs untreated.
Personally I
would consider minor epileptiform activity in autism as pre-epilepsy. We know
that about 30% of those with more severe autism will develop epilepsy and we
know that in many cases when they start to receive AEDs their autism tends to
moderate.
We know that
an excitatory/inhibitory (E/I) imbalance is at the core of many types of autism
and we should not be surprised that brains in an excitatory state produce odd
electrical activity; rather we should be expecting it.
There are
different types of possible E/I imbalance in the brain and there are very many
different biological mechanisms that can trigger seizures. So nothing is simple
and exceptions may be more likely than valid generalizations. So we should not
be surprised that in one child valproate normalized their EEG, while in another
it makes it worse.
In this post
we review the far from conclusive literature.
I think that
everything should be done to avoid the first seizure in a child with autism,
for some people this may possible using bumetanide, but for others very likely
entirely different therapy will be needed. The first seizure seems to lower the
threshold at which further seizures may occur.
Valproate appears
to be the preferred AED, but in some people it can actually make epileptiform
activity worse. In some people the Modified Atkins Diet (MAD) has normalized epileptiform
activity, this is not a surprise given that this diet and the more complex
ketogenic diet are successfully used to treat epilepsy.
If an AED
can normalize the EEG result and at the same time improve behavior or
cognition, it would seem a good choice.
It would be
interesting if the Bumetanide researchers carried out a before and after sleep
EEG in their autism clinical trials, along with the IQ test that I suggested to
them a long time ago.
Autism Spectrum Disorders (ASD) are an
etiologically and clinically heterogeneous group of neurodevelopmental
disorders. The pathophysiology of ASD remains largely unknown. One essential
and well-documented observation is high comorbidity between ASD and epilepsy.
Electroencephalography (EEG) is the most widely used tool to detect epileptic
brain activity. The EEG signal is characterized by a high temporal resolution
(on the order of milliseconds) allowing for precise temporal examination of
cortical activity. This review addresses the main EEG findings derived from
both the standard or qualitative (visually inspected) EEG and the quantitative
(computer analyzed) EEG during resting state in individuals with ASD. The bulk
of the evidence supports significant connectivity disturbances in ASD that are
possibly widespread with two specific aspects: over-connectivity in the local
networks and under-connectivity in the long-distance networks. Furthermore, the
review suggested that disruptions appear more severe in later developing parts
of the brain (e.g., prefrontal cortex). Based on available information, from
both the qualitative and quantitative EEG literature, we postulate a
preliminary hypothesis that increased cortical excitability may contribute to
the significant overlap between ASD and epilepsy and may be contributing to the
connectivity deviations noted. As the presence of a focal epileptic discharge
is a clear indication of such hyperexcitability, we conclude that the presence
of epileptic discharges is a potential biomarker at least for a subgroup of
ASD.
Finally, it is not known whether currently available seizure
medications are effective in normalizing hyperexcitable brain tissue that has
not yet become capable of inducing seizures. Scattered reports suggest that a
few of these medications may have some efficacy in this regards but further
research is needed to examine these efficacies, particularly in newly diagnosed
ASD patients.
Predictive Value of Isolated Epileptiform Discharges for a Favorable Therapeutic Response to Antiepileptic Drugs in Nonepileptic Psychiatric Patients
Summary: The
efficacy of antiepileptic drugs (AEDs) in treating behavioral symptoms in
nonepileptic psychiatric patients with abnormal EEGs is currently unknown.
Although isolated epileptiform discharges have been reported in many
psychiatric conditions, they are most commonly observed in patients with
aggression, panic, or autistic spectrum disorders. The literature search was
guided by 3 criteria: (1) studies had patients who did not experience seizures,
(2) patients had EEGs, and (3) an AED was administered. Most important finding
is that the number of
“controlled” studies was extremely small. Overall, most reports suggest
that the use of an AED can be associated with clinical and, at times, improved
EEG abnormalities. Additionally, six controlled studies were found for other
psychiatric disorders, such as learning disabilities with similar results.
Overall, the use of
anticonvulsants to treat nonepileptic psychiatric patients needs further
controlled studies to better define indications, adequate EEG work-up,
best AED to be used, and optimal durations of treatment attempts.
What does
the Simons Foundation have to say? They are funding a clinical trial.
Spence and her collaborator, Greg Barnes at Vanderbilt Medical
Center in Nashville, plan to test whether an anticonvulsant medication
(valproic acid, also known as divalproex sodium or Depakote) can be used to
treat children with autism and epileptiform EEGs. The researchers aim to
recruit 30 participants between 4 and 8 years old who have been diagnosed with
an autism spectrum disorder and who do not have epilepsy or metabolic
disorders.
The views of
the US National Institute of Mental Health:-
Autism is a neurodevelopmental disorder of unknown
etiology characterized by social and communication deficits and the presence of
restricted interests/repetitive behaviors. Higher rates of epilepsy have long
been reported, but prevalence estimates vary from as little as 5% to as much as
46%. This variation is probably the result of sample characteristics that
increase epilepsy risk such as sample ascertainment, lower IQ, the inclusion of
patients with non-idiopathic autism, age, and gender. However, critical review of
the literature reveals that the rate in idiopathic cases with normal IQ is
still significantly above the population risk suggesting that autism itself is
associated with an increased risk of epilepsy. Recently there has been interest
in the occurrence of epileptiform electroencephalograms (EEGs) even in the
absence of epilepsy. Rates as high as 60% have been reported and some
investigators propose that these abnormalities may play a causal role in the
autism phenotype. While this phenomenon is still not well understood and risk
factors have yet to be determined, the treatment implications are increasingly
important. We review the recent literature to elucidate possible risk factors
for both epilepsy and epileptiform EEGs. We then review existing data and discuss
controversies surrounding treatment of EEG abnormalities.
The now
disputed AER subgroup:-
Autistic
regression is a well known condition that occurs in one third of children with
pervasive developmental disorders, who, after normal development in the first
year of life, undergo a global regression during the second year that
encompasses language, social skills and play. In a portion of these subjects,
epileptiform abnormalities are present with or without seizures, resembling, in
some respects, other epileptiform regressions of language and behaviour such as
Landau-Kleffner syndrome. In these cases, for a more accurate definition of the
clinical entity, the term autistic epileptifom regression has been suggested.
As in other
epileptic syndromes with regression, the relationships between EEG
abnormalities, language and behaviour, in autism, are still unclear. We
describe two cases of autistic epileptiform regression selected from a larger
group of children with autistic spectrum disorders, with the aim of discussing
the clinical features of the condition, the therapeutic approach and the
outcome.
Dr Chez has a long
involvement and his findings have evolved:-
In 1999:-
Background. 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.
Objective. 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.
Design. 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.
Results. 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.
Conclusions. 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 significant improvement in language and autistic
features. autism, pervasive developmental disorder–not otherwise
specified, epilepsy, magnetoencephalography, Landau-Kleffner syndrome.
2004
Epileptiform activity in sleep has been described even in the absence of
clinical seizures in 43–68% of patients with autistic spectrum disorders
(ASDs). Genetic factors may play a significant role in the frequency of
epilepsy, yet the frequency in normal age-matched controls is unknown. We
studied overnight ambulatory electroencephalograms (EEGs) in 12 nonepileptic,
nonautistic children with a sibling with both ASDs and an abnormal EEG. EEG
studies were read and described independently by two pediatric epileptologists;
10 were normal studies and 2 were abnormal. The occurrence of abnormal EEGs in
our sample (16.6%) was lower than the reported occurrence in children with
ASDs. Further, the two abnormal EEGs were of types typically found in childhood
and were different from those found in the ASD-affected siblings. The lack of
similarity between sibling EEGs suggests that genetic factors alone do not
explain the higher frequency of EEG abnormalities reported in ASDs.
2006:
Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to2005.
Abstract
Autism spectrum disorders (ASDs)
affect 1 in 166 births. Although electroencephalogram (EEG) abnormalities and
clinical seizures may play a role in ASDs, the exact frequency of EEG
abnormalities in an ASD population that has not had clinical seizures or prior
abnormal EEGs is unknown. There is no current consensus on whether treatment of
EEG abnormalities may influence development. This retrospective review of 24-hour ambulatory digital
EEG data collected from 889 ASD patients presenting between 1996 and 2005 (with
no known genetic conditions, brain malformations, prior medications, or
clinical seizures) shows that 540 of 889 (60.7%) subjects had abnormal EEG
epileptiform activity in sleep with no difference based on clinical regression.
The most frequent sites of epileptiform abnormalities were localized over the
right temporal region. Of 176
patients treated with valproic acid, 80 normalized on EEG and 30 more showed
EEG improvement compared with the first EEG (average of 10.1 months to repeat
EEG).
An easy to read
two page review paper:
Many authors focused their research on the relationship
between EEG abnormalities and autistic regression. Our analysis included only
studies that involved autistic children with and without regression, i.e.
clinically non-selected samples. We excluded studies involving only children
with regression, or only children with EEG abnormalities. A summary of our
findings is presented in Table 1.
A large majority of the studies (7 of 9 studies) did not
find any significant relationship between EEG abnormalities and autistic
regression. Only two studies were positive [10,11].
Of all the studies, Tuchman & Rapin [10]
had the largest sample (585 children) but only part of the sample (392
children) had EEGs available (i.e. sleep EEGs; only sleep EEGs were performed
in this study). Readers of the Tuchman & Rapin [10]
study should note that the overall rate of epilepsy in the autistic sample was
quite low (11%), as was the rate of epileptiform EEG abnormalities in
non-epileptic autistic patients (15%). In comparison, other studies listed in
our summary gave higher rates of epileptiform abnormalities in non-epileptic
autistic children, 19% [12],
22% [13],
and 24% [14].
The overall rate of epileptiform EEG abnormalities in the whole sample (21%)
was also very low, where other comparable studies were in the range of 28 - 48%
[5,11,14-17].
What about Keppra (Levetiracetam) ? Here we have a clinical trial
Subclinical epileptiform discharges (SEDs) are
common in pediatric patients with autism spectrum disorder (ASD), but the
effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This
physician-blinded, prospective, randomized controlled trial investigated an
association between the anticonvulsant drug levetiracetam and SEDs in children
with ASD.
Methods
A total of 70
children with ASD (4–6 years) and SEDs identified by electroencephalogram were
randomly divided into two equal groups to receive either levetiracetam and
educational training (treatment group) or educational training only (control).
At baseline and after 6 months treatment, the following scales were used to
assess each individual’s behavioral and cognitive functions: the Chinese
version of the Psychoeducational Profile – third edition (PEP-3), Childhood
Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour
electroencephalogram was recorded on admission (baseline) and at follow-up. The
degree of satisfaction of each patient was also evaluated.
Results
Relative to
baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were
significantly improved in both the treatment and control groups. At the 6-month
follow-up, the PEP-3 scores of the treatment group were significantly higher
than those of the control, whereas the CARS and ABC scores were significantly
lower, and the rate of electroencephalographic normalization was significantly
higher in the treatment group.
Conclusion
Levetiracetam appears to be effective for
controlling SEDs in pediatric patients with ASD and was also associated with
improved behavioral and cognitive functions.
Levetiracetam
Levetiracetam
(LEV) is a broad-spectrum antiepileptic agent that has been used effectively
for a variety of seizure types in adults and children, and for different
psychiatric disorders.39,40
LEV does not have a direct effect on GABA
receptor-mediated responses. In vitro findings reveal that LEV behaves as a
modulator of GABA type A and of the glycine receptors, suppressing the
inhibitory effect of other negative modulators (beta-carbolines and zinc). LEV
inhibits the ability of zinc and beta-carbolines to interrupt chloride influx,
an effect that enhances chloride ion influx at the GABA type A receptor
complex.
And Lamictal (Lamotrigine)?
This study
is in general autism, not autism with epileptiform activity:-
In
autism, glutamate may be increased or its receptors up-regulated as part of an
excitotoxic process that damages neural networks and subsequently contributes
to behavioral and cognitive deficits seen in the disorder. This was a
double-blind, placebo-controlled, parallel group study of lamotrigine, an agent
that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11
years (M = 5.8) with a primary diagnosis of autistic disorder received either
placebo or lamotrigine twice daily. In children on lamotrigine, the drug was
titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per
day. This dose was then maintained for 4 weeks. Following maintenance
evaluations, the drug was tapered down over 2 weeks. The trial ended with a
4-week drug-free period. Outcome measures included improvements in severity and
behavioral features of autistic disorder (stereotypies, lethargy, irritability,
hyperactivity, emotional reciprocity, sharing pleasures) and improvements in
language and communication, socialization, and daily living skills noted after
12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in
improvements between lamotrigine or placebo groups on the Autism Behavior
Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior
scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably
due to expectations of benefits
Conclusion
What would be nice to know is whether
epileptiform activity is a precursor to seizures, in the way that atopic
dermatitis is often a precursor to developing asthma. Perhaps by treating
epileptiform activity, some people could avoid ever developing epilepsy.
As I have pointed out before, I think
that treating the E/I imbalance in autism with Bumetanide may well reduce the
likelihood of later developing epilepsy.
In people with epileptiform activity
but no seizures, treatment with AEDs can often normalize this activity within a
few years. Does the possible autism
benefit correlate with this normalization? Or do you need to maintain the AED
treatment even after the epileptiform activity has gone?
Do some people with autism, but no
epileptiform activity, also demonstrate behavioral improvement on AEDs? I
suspect some might, but it will depend on the AED.
Since medicine does not fully
understand how most AEDs work and there are very many types of epilepsy, we
cannot really expect concrete answers.
AEDs help many people with seizures,
but a substantial number of people have seizures that do not respond to standard
AEDs. Matching the AED to the person with seizures is more art than science and
I would call it trial and error.
I did write a post a long time ago on
the benefit of low dose AEDs in people with autism, but without seizures. Given the many and varied effects of AEDs, it
is not surprising that some people benefit.
The side effects of AEDs vary widely
and some look more suitable than others for people that do not actually have
seizures.
You might think based on the currently
understanding of how Keppra works, it would not be helpful in someone that
responds to Bumetanide. But anecdotally
people do respond to both, so most likely Keppra’s mode of action is not quite
what we think it is.
So just like a neurologist applies
trial and error to find an effective therapy for his patients, the same method
can be applied to those with autism.
Clearly some people with autism do
benefit from Valproate, others from Keppra and others from Lamotrigine. In my
autism Polypill there is a little Potassium Bromide, the original AED from the
19th century.
If your neurologist does not want to treat your child's sub-clinical epileptiform activity, suggest he or she reads the literature and the very recent clinical trial using Keppra. It is not guaranteed to improve autism, but you have a pretty good chance that one AED will help.
If your neurologist does not want to treat your child's sub-clinical epileptiform activity, suggest he or she reads the literature and the very recent clinical trial using Keppra. It is not guaranteed to improve autism, but you have a pretty good chance that one AED will help.