Making Sense of Abnormal EEGs in Autism

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. 

EEG changes associated with autistic spectrum disorders 

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. 

Treating autism and epileptic discharges with valproic acid 

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:-  

The Role of Epilepsy and Epileptiform EEGs in Autism Spectrum Disorders

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 epileptiform regression

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:- 

Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders. 

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

Frequency of EEG abnormalities in age-matched siblings of autistic children with abnormal sleep EEG patterns

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: 

EEG Abnormalities in Autism: What is the Significance 

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

Levetiracetam is associated with decrease in subclinical epileptiform discharges and improved cognitive functions in pediatric patients with autism spectrum disorder 

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 as an alternative therapy for Tourette syndrome 

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:- 

Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial 

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 19^th 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.