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.

The Clever Ketogenic Diet for some Autism

I have covered the Ketogenic Diet (KD) in earlier posts. 

There are more and more studies being published that apply the KD to mouse models of autism.

Calling the KD a diet does rather under sell it.  The classic therapeutic ketogenic diet was developed for treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective epilepsy drugs.

There are various exclusion diets put forward to treat different medical conditions; some are medically accepted but most are not, but that does not mean they do not benefit at least some people.

When it comes to the ketogenic diet (KD) the situation is completely different, this diet is supposed to be started in hospital and maintained under occasional medical guidance. The KD was developed as a medical therapy to treat pediatric epilepsy.  It is very restrictive which is why it is used mainly in children, since they usually will (eventually) eat what is put in front of them.

The KD was pioneered as a medical therapy by researchers at Johns Hopkins in the 1920s, over the years they have shown that most of the benefit of the KD can be achieved by the much less restrictive Modified Atkins Diet (MAD).  The first autism mouse study below suggests something similar “Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior”.

What about the KD in Autism?

Most people with autism, but without epilepsy, will struggle to get medical help to initiate the KD.  Much research in animal models points to the potential benefit of the KD.

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

·        Drug treatments are poorly effective against core symptoms of autism.

·        Ketogenic diets were tested in EL mice, a model of comorbid autism and epilepsy.

·        Sociability was improved and repetitive behaviors were reduced in female mice.

·        In males behavioral improvements were more limited.

·        Metabolic therapy may be especially beneficial in comorbid autism and epilepsy.

The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.

Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder

·        The BTBR mouse has lower movement thresholds and larger motor maps relative to control mice.

·        The high-fat low-carbohydrate ketogenic diet raised movement thresholds and reduced motor map size in BTBR mice.

·        The ketogenic diet normalizes movement thresholds and motor map size to control levels.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T + Itpr^tf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.

Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder

Background

Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBR^T + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile.

Findings

Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals.

Conclusions

Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.

Effect of a ketogenic diet on autism spectrum disorder: A systematic review

·        We evaluated, throughout a systematic review, the studies with a relationship between autism and ketogenic diet.

·        Studies points to effects of KD on behavioral symptoms in ASD through the improve score in Childhood Autism Rating Scale (CARS).

·        Reviewed studies suggest effects of KD especially in moderate and mild cases of autism.

·        KD in prenatal VPA exposed rodents, as well in BTBR and Mecp2 mice strains, caused attenuation of some autistic-like features.

Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.

Conclusion

Since very many parents do not want to use drugs to treat autism, it is surprising more people do not try the ketogenic diet (KD) or at least the KD-lite, which is the Modified Atkins Diet (MAD).

I think you have to be pretty rigid about the MAD, if you go MAD-lite you will likely achieve little; rather like thinking you have a Mediterranean diet because you buy the occasional bottle of olive oil.

Many children with epilepsy who started out on the KD continue in adulthood with the Modified Atkins Diet (MAD).

There is anecdotal evidence that people with mitochondrial disease benefit from the KD.

All in all, it is hard to argue that the KD/MAD should not be the first choice for those choosing to treat autism by diet. It really does have science and clinical study to support it.

In some people with autism it appears that when you eat is as important as what you eat.  There can be strange behaviors just after eating, presumably caused by a spike in blood sugar, or for others before breakfast. 

In regressive autism (AMD) Dr Kelley, from Johns Hopkins, wrote that:- 

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.  In some children, early morning symptoms can be a consequence of compromised mitochondrial function, whereas, in others, a normal rise in epinephrine consequent to a falling blood glucose level in the early morning hours can elicit agitation, ataxia, tremors, or difficulty waking.  In children who normally sleep more than 10 hours at night, significant mitochondrial destabilization can occur by the morning and be evident in biochemical tests, although this is less common in AMD than in other mitochondrial disorders.  When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period.  Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours.

I still find it rather odd that none of Dr Kelley's work on treating regressive autism has been published in any scientific or medical journal.  After all, he was a leading staff member at one of the world's leading hospitals.  He is no quack.  It is extremely wasteful of knowledge and clinical insights that could help improve the lives of something greater than 0.2% of the world's young children.  That is a lot of people.

Potassium Bromide for Intractable Epilepsy and perhaps some Autism

Potassium Bromide has been on my to do list ever since I read a case study about Ida, a girl with epilepsy and non-verbal autism being treated at London’s Great Ormond Street Hospital 150 years ago.  Of course, the doctor not did not use the term autism, but it was obviously present.  

What I took away was not the resolution of her seizures but her behavioral change and most importantly the initiation of age-appropriate play.

Later I read a Brazilian paper called “Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures”.

My first toe in the water in treating my son’s autism was to use Bumetanide.  That trial was successful and ever since I have looked at ways of increasing this bumetanide effect.

Bumetanide partially blocks the flow of chloride (Cl-) into neurons and over time lowers the concentration towards where it should be, in typical mature neurons.  This allows the neurotransmitter GABA to function as it should and brings back neurons into a less excitatory state and hence gives better cognitive function.

Other ideas to further lower the level of chloride included using the AE3 ion exchanger and so I proposed the possible use of Diamox.

It might also be possible to increase the expression of KCC2, the transporter that takes chloride out of neurons; this might be achieved using intranasal insulin or indeed IGF-1.

Yet another theoretical method might be to introduce bromide and allow it to compete with chloride.  We know that Br^– ions cross cellular membranes more quickly than Cl^–. So by adding bromide we should automatically reduce chloride concentration within neurons.

Medical use of Potassium Bromide

It is surprising how medicine varies so much by country.  One example is the continued use of potassium bromide (KBr) to treat childhood epilepsy in Germany, Austria and Japan.

It is currently used to treat severe forms of generalized tonic-clonic seizures, early-childhood-related Grand-Mal-seizures, and also severe myoclonic seizures during childhood.

KBr was the world’s first epilepsy drug and its use was pioneered by Sir Charles Locock in 1857.  It is still the first-line treatment for treating epilepsy in dogs, but no longer in humans.

Due to a very long half-life, it takes a month of use to reach a stable level, so in the earlier years it is likely that un-necessarily high doses (up to 6g per day) were used.  This led to side effects.  The modern dosage is 50 to 70 mg/kg in infants and toddlers, 30 to 50 mg/kg in school children and 20 to 30 mg/kg in adults.  Tolerability of bromide treatment is much improved.

It is possible to start therapy with a loading dosage to overcome the problem of the long half life, but I expect this just increases the chance of side effects.

My thought was that at a lower concentration than prevents seizures, bromide might still be effective in some autism that responds to bumetanide.  At such a dosage the side effects that occur in German epilepsy therapy might become trivial.

The main side effects are usually drowsiness (19%) and acneiform skin eruption (13%) at the 50mg/kg dosage.  I was thinking that at a quarter of this dose you might get the good without the bad.

If you have one of the many kids with autism and intractable epilepsy then you might as well follow the standard dosage and just accept the risk of some spots.  After all, the standard anti-epileptic drugs (AEDs) all have side effects and we are not just taking about spots.

Interestingly, while KBr does not interact directly with other AEDs, it is found in Germany that previously ineffective AEDs can become effective when the person is given KBr.  There are various theories to explain this.  As a result KBr look doubly useful for intractable epilepsy.  

Dravet Syndrome

KBr seems to be particularly effective in people with SCN1A-mutations suffering from Dravet syndrome.  You may recall that Professor Catterall trialed his low dose clonazepam therapy in the mouse model of Dravet syndrome.  German and Austrian clinicians have shown that KBr is highly effective in treating seizures in the human form of Dravet, while a Japanese retrospective analysis of 99 patients which found complete prevention of status epilepticus in 41.7% of patients receiving bromide.

Mode of Action

Nobody knows exactly why KBr is effective in epilepsy, but that also applies to many other AEDs.

The Brazilian view is:-

“bromide may exert antiepileptic activity not only because of its reinforcement of the Cl^– hyperpolarizing Nernst potential, but also because of its low affinity for the NKCC enzyme in comparison with Cl^– . In summary, bromide's antiepileptic effect may be divided into three parts: (1) compensation of Cl^– accumulation by means of its hyperpolarizing effect on chloride channels; (2) antagonism of chloride flow through the channels because of its competition with chloride; (3) low affinity for the NKCC enzyme”

That paper is:-

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

The German view is:-

“While the exact mode of action of bromide is still unknown, the most acceptable hypothesis besides an inhibition of carbonic anhydrase is stabilization of excitable membranes through hyperpolarization of neurons. Bromide crosses cellular membranes more quickly than chloride, enhancing

GABA-activated inhibitory postsynaptic potentials and leading to hyperpolarization. Not only GABA-activated chloride channels are more permeable to bromide, but also voltage dependent channels. Studies using combined rat hippocampus-entorhinal cortex slices showed that bromide reduced or even blocked low calcium and low magnesium induced recurrent discharges, including the low magnesium induced late recurrent discharges which do not respond to most clinically used anticonvulsants. This mechanism might explain why our patients who previously did not

improve with various other antiepileptic drugs responded to treatment with bromide.

The above is from one of many good German papers on KBr :-

Bromidein Patients with SCN1A-Mutations Manifesting as Dravet Syndrome

Intractable Epilepsy

About one-third of people with epilepsy will eventually develop intractable epilepsy. This means that standard anti-epileptic drugs (AEDs) do not work well, or at all, to control the seizures.

Intractable epilepsy can have a big effect on life. People with intractable epilepsy may have trouble at work or school. They may worry a lot about when their next seizure will come. They may also have injuries that result from their seizures.

In the case of the 30+% of people with strictly define autism (SDA) and epilepsy things can get particularly difficult and depend a great deal on where you live.

In the US some children with severe autism and recurring seizures can still be collected from home by the school bus and dropped back at the end of the day.  Not only do they have qualified nurses at school to deal with any seizures but even the bus has a nurse.

I was just reading about a teenage girl in the UK who no longer attends school at all because she may have a seizure.  The irony here is that the girl has been to the county’s top children’s hospital, Great Ormond Street.  Had she been there one hundred and fifty years ago she would have been prescribed KBr.  Had she attended a hospital in Innsbruck or Salzburg, Austria this year she would very likely also have been prescribed KBr.

The literature supporting the use of KBr is published in the English language and so there is no excuse for epilepsy experts not to be aware of it. Both the US and the UK have provisions in place where clinicians can apply to treat patients with non locally approved drugs.  So there is nothing to stop a neurologist or epileptologist in the US or UK from using KBr if he really wants to.  He just has some extra paperwork.  The simpler solution if you have intractable epilepsy might be to pay a visit to Germany, Austria or indeed Japan. Or you go see the vet.

Conclusion

This blog does not have many German/Austrian readers, in fact for a condition “invented” by Austrians (Kanner and Asperger) there is very little coming out of that part of the world nowadays.

German/Austrian parents would be the ones best placed to see the effect of KBr on intractable epilepsy and perhaps some autism.

Any readers that do try potassium bromide are very welcome to share their experiences.