Thursday, 28 September 2017

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. 

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.  

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.


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.


Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to2005. 


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.


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.


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.


Levetiracetam appears to be effective for controlling SEDs in pediatric patients with ASD and was also associated with improved behavioral and cognitive functions. 


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


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.


  1. Great post Peter,I could say that my son´s subclinical epilepsy, started to do its harm when he was a baby and cried all afternoons in his crib, without an apparent reason with much feeling. He talked and sang until he was 2, then the regression was such that I can remember that day, he standed in a corner, holding his hands to the ears and stopped talking, but he never lost his smile.His MEG showed accute generalized epileptiform activity in the fronto temporal region,prevailing the slow delata wave. My neurologist didn´t hesitate in giving valproat and at the age of 2 and half,the rehabilitation took place and he started to come back. Keppra could be interesting for my son,you know his profile. Valentina

    1. Valentina, maybe your son is an example of the Autistic Epileptiform Regression (AER) mentioned in the post, which experts no longer see as a subgroup. Maybe they are wrong.

      Ask your neurologist about Keppra. The AEDs are all different and neurologists do know to swap from one to the other and which ones you can take at the same.

    2. Peter, I also think this is a very interesting post. Would that make sense to follow children with untreated SEDs over a period of time to see if seizures are overrepresented in that group compared to some controls or data from general population? How many of them would be needed? I think I know a place where no child with SEDs gets treatment, what about a retrospective study?

      Valentina, I’ll answer your recent question here: Valproate without Bumetanide cleared EEG in my son, but did not improve cognition and sensory suffering, then Bumetanide without Valproate helped for both and improved awake EEG (slowing), but epileptiform pattern during sleep worsened again. On Bumetanide+Diamox both awake and sleep EEG improved to borderline normal, with no more SEDs.
      All in all, complicated ;-)

    3. Agnieszka,sure it´s complicated, how old was your son when he started to take valproate and for how long did he take it? My son is a clear case of Autistic Epileptiform Regession,it isn´t so common within the spectrum. May be that is why Valproate was a lifesaver for him.Y would like to try Keppra, it seems ideal for my son. Valentina

    4. I would stay away from Keppra. Read about 'Keppra rage'. Last neurologist I visited said that other neurologists who prescribe Keppra are crazy.
      My son also had abnormal EEG (spikes), and we normalized it with Trileptal and Lamictal. Abnormal EEG can be an indicator of Landau Kleffner syndrome. LKS is diagnosed when 'continuous spike-wave' is observed during 85% of 'slow sleep'. Children who develop LKS (typaclly between ages 2 and 8) show dramatic regression in language, eye contact, self-care, etc. Luckily, the prognosis is more positive than in autism case. Valproic acid and corticosteroids are the first line of defense against LKS. Not all AED's are created equal. Some actually can actually cause LKS and associated regression: The problem with Valproic acid is that it reduces cognition. It is a known fact, and almost every article I have read agrees on that. The only other medication that would treat LKS without cognitive side effects is Lamictal.

    5. Anonymous, thankyou, my son´s case is rare, could be a case of autism that mimicks LKS. As his regression started very early, at the age of almost 3, he didn´t have time to advanced language development. Before the regression he spoke single words and sang the first words of the star song, ¨litlle star where are you, in middle tongue and nothing more. He called me mother later, after valproate.I know that in a small child, LkS could be devastating, because the language is blocked in the middle of the process.Only 10% of children with LKS regress before 3 years.The neurologist report said acute fronto temporal assimetry with prevalence of delta slow wave and later hyperlexia, extraordinary reading ability at the age of 5. Valentina

    6. Agnieszka, I think if you could collect a large sample using data from several years, perhaps a few hundred children, and you found that say 60% of those with untreated SEDs and moderate to severe autism went on to develop epilepsy, you would have something that could not be ignored.

      Nobody can agree on the prevalence of epilepsy in autism, because autism is too vague a word. It clearly is more common in more severe autism.

      If the data on SEDs was from Poland, you could use some prevalence of epilepsy in autism in Poland as the control, which will probably be higher than in the US. I assume autism is a more strict diagnosis in Poland.

      You could look at the EEG records of all people with autism and compare the later incidence of epilepsy in those with SEDs to those without SEDs. People going for EEG would have a bias towards those with some suspected electrical activity. So you would have to be careful how you interpreted the data.

    7. Agnieszka, how did you choose Diamox?
      As my daughter has epileptiform activity and I am waiting for Bumetanide later this year I should really ask the neurologist for something in the time in between. I have to admit that I am scared stiff for a first seizure to happen before we get any help...
      Magnesium threonate seems to take away some of my daughters daily staring spells, in the same way as Ponstan (but weakly). Is it possible that Verapamil could do something for epilepsy-tendencies?
      Any other Magnesium form that would be even better?

    8. Ling,

      I tried Diamox mainly for severe migraine control.

      Diamox affects chloride neuronal regulation and has been successfully used in "sporadic hemiplegic migraine" - a condition that is sometimes associated with CACNA1A dysfunction. I could see other symptoms related to CACNA1A dysfunction in my son (paroxysmal tonic upgaze).
      There are anecdotal reports of autism improvement on Diamox.
      All enough for me to try.

      Also look at this paper:
      "Acetazolamide for electrical status epilepticus in slow-wave sleep."

      It is about LKS, discussed here above. Seems like Diamox can be a very promising option in LKS/ESES. ESES is sometimes diagnosed in children with autism.
      Frankly, I am not sure if my son's EEG was ever properly evaluated for ESES, it is not easy even for neurologists in many cases. For me reading EEG is "dark art" - to quote Paul Whiteley... Anyway, can you share more details about your daughter's EEG result description? Maybe it can point to some decision.

      Verapamil was trialled in epilepsy with some success as far as I remember, but did not improve EEG in my son though.

    9. Could you post your experience with Diamox. What changes did it bring? Have you tried Bumetanide? And if so, do you see more response from Diamox than Bumetanide?

    10. Anonymous, when I used Diamox my son had already been on Bumetanide for more than a year. Before, at age of 5 he regressed in cognitive abilities to the point he was not able to learn any new skill for more than a year. Bumetanide changed this.

      I used Diamox without Bumetanide only for a short time and felt like the effects are better when both drugs are used together. Diamox brought further improvement in cognition, language use, social interactions and possibly motor control. It was effective in migraine control, unfortunately only for few months. While on Diamox my son developed significant speech disfluency, but it seems to be related to other issues.

    11. Thank you for your answer Agnieszka!
      At the moment I do not have any more information than that there were abnormalities in my daughters EEG, I don't even know if it was only when she was sleeping or also when she was awake. We'll probably get an over-night EEG later this year and hopefully I can get a more detailed description from that. I do not suspect CACNA1A dysfunction, but other CACNA1x-dysfunctions.
      Now that I know we have a chance on bumetanide, I'll focus on verapamil and will put together a new stack of papers on that. If you have any good ones beside those in the request for verapamil-post, please share!


    12. Ling, are you looking for papers to convince your doctor to prescribe verapamil or for other purpose? Do you need more papers on calcium channel blockers and ASD or CCBs and mast cell activation?

      While there are many more papers within basic science realm, your doctor could be concerned about safety of verapamil use in children. If so, papers on pediatric migraine/cluster headache treatment would be of help. Verapamil dose used in pediatric migraines is higher than most people use in autism. Let me know if you need references.

      Also, not from papers, but from personal experience: when my son had already been on verapamil we met a neurologist with outstanding knowledge and interest in channelopathies. For this doctor verapamil response was one of the most important clinical clues to suspect calcium channelopathy in my son. Other two were symptoms characteristics. Thinking this way and with good safety profile of verapamil, CCB response test should be a routine part of channelopathy diagnostics in autism - as there are no straight-forward lab test to confirm this. Just as mast cell stabilizers response is one of three MCAS diagnostic criteria. Of course currently it is rather in my imagination than in reality, but why not discuss this with neurologist.

  2. Hi Peter, I've been searching about Greek mountain tea and found these:

    GABAA receptor modulation by terpenoids from sideritis extracts

    This one is for Alzheimer's

    and this one as triple monoamine reuptake inhibitor

  3. Hi Peter

    Do you know if Bumex/Diamox and Clonzapham increase GABA-a?

    I am unable to find how they work in the same manner,one used for kidney issue and the other being used for anxiety.


    1. SB, these drugs do affect GABAa receptors, they will change what happens these receptors are activated. Bumex and, to an extent, Diamox lower the level of chloride inside neurons, this makes GABA more inhibitory. A tiny dose of clonazepam increases the effect of the alpha3 subunit of GABAa receptors, which again makes GABA more inhibitory.

      To read about these effects you will need to read the scientific papers, otherwise you will just read about what these drugs are normally prescribed for. Bumex is a diuretic, but it is much more than that.

  4. Hello Peter,

    I have a really silly question to ask but would still appreciate if you answer. The burinex which I had ordered last year has an expiry date mentioned as sep,2017. I wanted to do a quick one month retrial as reordering is a cumbersome process and I cant even find the site from where I had revieved my bumetanide. Although it seems that most drugs do retain their potency long after an expiry date I would be happy with a second opinion.

    1. I don't suppose one month is going to make a difference. Some drugs do degrade and produce harmful substances, rather than lose potency. The temperature at which you store drugs will also affect how long they last.

    2. At least in the United States, drug expiration dates are kind of a scandal in the sense of how many drugs of perfectly viable efficacy get tossed out to the degree a reasonable mind would conclude Medicare is just a giant money-laundering scheme, meanwhile many millions of people without means would benefit from unused medications (this would drive down prices which of course big pharma and its corrupt cronies in Congress would never allow it).

      The vast majority of drugs never really have their potency, efficacy, and safety tested, instead you just have some arbitrary date thrown on that has no scientific basis and may even be applied for the purpose of forcing health case providers to buy more drugs than they need due to very arbitrary expiration rules.

      To think of how much money is literally flushed down the toilet in Medicare payments is pretty mind-boggling as the amount is literally the GDP of countries which can barely feed their own people and who would benefit greatly from unused drugs that are obviously safe and viable far longer than the expiration date actually says.

      While some drugs have chemicals that degrade rapidly to environmental exposures such as heat or oxygen (such as NAC), the vast majority of drugs are going to last for just about forever because unless their chemistry is disturbed somehow, it is not like they are going to radioactively decay or anything silly like that. You put a pile of salt in a cave somewhere with a controlled climate and come back to it in a million years from now and it will still be there as salt. This common sense eludes a lot of people when it comes to drug expiration dates.

      That does not mean that there are not many drugs which will degrade from exposure to heat, light, or oxygen but the expiration dates are almost always severely exaggerated and often chosen not for scientific reasons, but rather for the purpose of the company which sells them placing a date of "planned obsolescence" to keep their stock price high and their executives rich.

      As for Bumetanide itself, I am aware of no reasoning or study done on its long-term efficacy/safety or at least any scientific guidelines for making assumptions to how long it will last. I have not looked myself, but I suspect like for almost all drugs, this kind of study was never actually done because it is not required in any meaningful way by the FDA and is just a waste of resources from the perspective of a company looking to push pills as fast as they can. On top of that, the company can claim they just put some arbitrary date on the packaging because they wanted to be plausibly "on the safe side" for legal reasons (the United States is the most litigious country in the world) when in reality they have no idea if the safe side is a week from now or else when the sun burns out of hydrogen and becomes a red giant.

  5. Hi Peter,
    Do you think if Bumex and Didmox did not work,there is hardly any chance that Clonapham will work since all the three target gaba-a? The reason I ask is because it was very easy to get Bumes/Diamox but Clonazepam is another story.
    Not sure if it is worth the trouble

    1. Bumex/bumatanide may not work in some people because it may not lower chloride sufficiently. Many kinds of inflammation actually increase chloride within neurons, so you have to first reduce any inflammation, which could range from allergy to juvenile arthritis to leukaemia flare-ups.

      If you have no inflammatory condition and bumex/bumetanide at 1g or 2g once a day has no effect then you are not a responder and likely have normal levels of chloride inside neurons.

      I would still try low dose clonazepam, because it may still help people with normal levels of chloride. It works in a different way.

      Clonazepam may be hard to get hold of, but at low doses it looks like one of the safest autism interventions.

  6. Have you seen the Nernest equation for membrane potential? The ionic composition of the nervous system can affect membrane potential or the voltage of the signals transmitted. The highly fluoridated water, I was forced to drink as a child, made it agonizingly painful just to be touched.

  7. Peter, there was a trial of Ivermectin as adjuvant in the treatment of refractory epilepsy with surprisingly good results.
    Not exactly "on topic" but I thought it was worth mentioning.

    Ivermectin as an adjunct in the treatment of refractory epilepsy

    "RESULTS. Progressively, patients entered into crisis control, at the end of the programmed follow-up period, the total percentage of crisis reduction was 97%, of which 57% did not return to crisis from the beginning of treatment, all patients being free of crisis according to International League Against Epilepsy criteria. CONCLUSION. Ivermectin has been useful as an adjuvant, achieving a significant decrease in seizures in this group of drug resistant patients."

    Full article free, but in spanish.


    1. Jane, very interesting. In particular, because they have used it long term, which some have suggested is not possible.

    2. Interesting indeed. I wish it got translated into English.

      I had a quick look, ivermecitin acts on purinergic receptors amongst others - only one type it seems, P2X4

      Also affects nicotinic alpha receptors, but this is probably its most relevant mode of action:

      "Ivermectin binds with high affinity to glutamate-gated chloride channels which occur in invertebrate nerve and muscle cells, causing an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell. Hyperpolarization results in paralsysis and death of the parasite either directly or by causing the worms to starve. (Consult 2005) At least one study, however, seems to suggest a depolarizing rather than hyperpolarizing role for Ivermectin on the glutamate-gated chloride channel... However, in either case, the end result is the deactivation of the channel by manipulation of chloride levels."

  8. Here is an interesting paper on hypertension that may be relevant to autism in terms of the ideas it brings to the table:

    Press Release:


    Essentially the gist of the paper is that hypertension can be caused by certain populations of gut microbiota via metabolites which cause the kidneys to import more sodium into its cells than it exports via inhibiting an enzyme which also happens to be inhibited by licorice root. It would be very interesting if licorice root causes rapid and negative effects in those with autism which might suggest peripheral blood pressure issues leading to worsening autism symptoms (just to be clear obviously not the primary contributing factor to autism).

    This research of course deals with the kidneys, but one might ask if similar mechanisms could happen in the brain via indirect influx of metabolites from gut bacteria. That gut bacteria may produce metabolites that cause deleterious effects in the autistic brain of course is a very old hypothesis and the reasoning behind the GFCF diet, but what is new here is the idea that ion channels can be impacted directly via inhibition of what you might call "praetorian guard" enzymes that act as a last measure of defense for ion channels being opened too long.

    Could there be a similar mechanism via gut bacteria producing metabolites that effects chloride homeostasis in inhibitory neurons in some people? Perhaps, improvements from a regimen of antibiotics in some people with autism is due to the temporary removal of gut bacteria which are problematic in terms of their metabolites affecting ion channels in the brain in this manner.

    These are some interesting questions that popped into my head from this paper, even though it is not directly related to autism issues at all.

  9. Hi Peter,

    What is your knowledge of Zonegran? We are currently trialling it on our daughter at the moment and while we have had some moderate success in the areas like sleep, however when I compare our experiences with the good and bad experiences of other users on epilepsy forums we seem closer to the latter group, increased irritability, more stereotypes etc. However we are sticking it out for now as subsequent EEG testing has shown the sub clinical seizures are still present, so we and our daughter’s are keen to she what happens if we can stop them altogether.

    1. Kei, I have no knowledge of that drug.

    2. Hi Again Peter,

      It’s a pity you haven’t heard of it, I’ll just have to trust our Neurologist for now.

      In the interest of sharing, Zonegran’s generic name is Zonisamide. From Wikipedia,”Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[5] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant, acetazolamide). It is also known to modulate GABAergic and glutamatergic neurotransmission.”


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