Back to School (again)

Another September passes and another school year is underway. For Monty, aged 14 with ASD, he moved up to the secondary/high school building with his 12 year old classmates.  He has attended the same small international school for ten years.

The experience autism parents have with schools varies widely, both from country to country and within the same country.

This blog is mainly read by people in North America, where autism is generally much better treated than in the rest of the world.  Publicly funded early intervention in the US is available from birth to three; it actually finishes before most people in the rest of the world even get a diagnosis.

While many people complain about the services they receive, it is ultimately up to the parents to make the best of it, using whatever means they have at their disposal.  The results appear to be extremely varied.

Our method was to go part time to school to the age of twelve, leaving plenty of time to have a home-based learning program.  Up to the age of eight almost all learning actually took place at home; school was more for “socialization”.  Then there was a big behavioral regression for almost a year; school continued but skills were lost. Then I started my Polypill interventions and in that September agreed Monty move back two years at school.

For the last five years Monty has stayed with the same NT peer group who are two years his junior.  Much to everyone’s surprise, he participates in the same assessments as his classmates, something inconceivable up to the age of eight. Moreover he does not get the lowest grades in class, which would have been the case up to the age of 8 had the teacher used the same tests as the rest of the class.

At some point, I assume he will not be able to move forward, but that point has not yet come.  This year we have already had tests in all subjects and the average grade has been “B”, which has surprised everyone. If you treat classic autism you will still have autism, but normal learning becomes possible. 

Progress to date

There is much in previous posts about how people with classic autism start to acquire skills long after their peers, and that even then their rate of acquisition of new skills is much slower. The end result is that the learning gap between people with autism and their NT peers starts out wide and then grows. Many people with classic autism leave high school with a skill level ten years lower.

NT kids start acquiring skills from an earlier age and at a faster rate than those with Classic autism. Adjust for this and “catch up”.

The idea of this blog is to use science to close the gap as much as possible, so rather than being left totally behind, aim to leave school with much more than just a very minimal education.

People with Asperger’s clearly do not have these problems and most people diagnosed today with autism have this kind of mild autism.   

One good thing about not being in a selective school is that you have a wide range of intelligence and indeed motivation among the class. If you have a selective school with hard working intelligent kids, you clearly could not include someone with classic autism, but you should be able to have people with Asperger’s.  They were there long before Asperger’s was a diagnosis. 

As I have pointed out in previous back-to-school posts, there may well come a September when moving forward a year may not happen, but for the last five years it has been possible.

The idea of explaining concepts such as elements, compounds, atoms and molecules really would have seemed absurd, just a few years ago. I may even be putting up a poster of the periodic table in Monty’s room.  It is of course just a very basic understanding; so H₂O is water where H is hydrogen, O is oxygen.  It was not so long ago that it was proving impossible to teach the concept of bigger and smaller with single digit numbers or the meaning of basic prepositions.

The biggest issue currently involves history, where rather than just learning what happened and when, it is already more about your opinions about why something happened. So the problem is more one of language and I would myself struggle to understand and explain the causes of World War 1 in my second language. People with classic autism really do not have a mother tongue, their first language is silence and so language will remain limited and be matter of fact and literal.

So we will focus on numeracy/math, literacy (English), a second language, science, geography (which is surprisingly teachable) and make something of history. The non-academic subjects, music and physical education/PE work very well and autism is not a limiting factor.  

Because the class is of mixed abilities and perhaps more importantly varying motivations, in spite of his obvious disadvantages, Monty does not come bottom. I think if you come bottom in every subject, then inclusion may not be appropriate.

There is a view that you should give different tasks and simpler assessments to special needs kids included in mainstream classrooms. This is like the old village school where one teacher is teaching different age groups at the same time. This does put a burden on the class teacher and you can see why it does not happen, unless the teacher is very motivated and well supported. I do not see how classes in public schools with 30 kids and two of those have special needs and assistants can function well. The risk is you end up failing the 28 NT kids.

The key to successful inclusion of someone with classic autism seems to be pharmacologically raising their cognitive function (IQ) as much possible, having good one to one classroom assistants and having a smaller class size.

These days most people diagnosed with autism are more likely to have Asperger’s, so they did not have a speech delay and all the biological consequences of that. People with Asperger’s face very different issues at school. In theory these issues are much easier to deal with, but because they appear minor they may get ignored. Issues include sensory gating, sensory overload and bullying; none of which affect my son at school.  Selective schools would seem a good choice for those with Asperger’s, since they will have more in common with at least some of those clever hard working types.  I continue to be surprised that special schools for Asperger’s exist in some countries.  They may be a refuge from bullying, but cannot be a good preparation for future life and employment.

Special schools for more severe autism vary widely.  In some countries there are some very good ones, but this kind of provision is extremely expensive and so is often not available.

I think if you are behaviourally and academically “includable”, mainstreaming is the ideal option. If inclusion is just a class within a class, with the assistant teaching the child in a corner of the mainstream classroom, then it is not going to be a success.  

You have to be behaviourally and academically includable.  If you are just behaviourally includable but understand nothing from the teacher, there is not much point being there.  If you are not behaviourally includable it is not fair on all the NT kids.

In kindergarten and the next couple of years the fact someone has autism does not stand out so much, because many kids behave badly. So you have till the age of 7 to get things in as good a shape as you can.

Treating autism pharmacologically makes learners much more includable and hopefully one day will be available on demand. It can reduce negative behaviors like aggression and anxiety, while raising cognitive functioning.   

Conclusion

The US system is based on the idea of making a huge effort before the age of four in the hope that things will get very much better and fast.  There is indeed evidence that in about 10-15% of people with autism, by the age of five things have pretty much fixed themselves, regardless of intervention.

Few people will be able to keep up the pace of this early intervention for the next ten or more years. It is too expensive and just too labour intensive. In the US there are some publicly funded special schools that do have this level of provision, but not in most countries.

Having been very focused on behavioral intervention until my son was eight, it is clear that the optimal solution is to start pharmacological intervention in parallel, meaning from diagnosis.  Some people in the UK wait for years just for a diagnosis, which is absurd. I think an astute observer can diagnose more severe autism at 18 months of age, with 90% accuracy.  In some countries they wait till five years old before diagnosing autism, preferring to use words like apraxia instead. Outside the US there is no rush to diagnose autism, because there are no services.  If there are no services, nor interventions, there is little point having a diagnosis, it is just a label.

Pharmacological intervention is going to be rather hit and miss, but this is also true in many other medical conditions (dementia, multiple sclerosis, epilepsy, depression …).  For the 85% that are not going to magically recover, pharmacological intervention combined with 1:1 teaching/support is the way to go.  It is the 1:1 part that is expensive, but for many people that is already available in many countries, meaning a teaching assistant in a mainstream classroom.  All the 1:1 therapy is much more effective, when you improve some of biological dysfunctions.

Why more people cannot have a one or two year “catch-up” adjustment in mainstream school is not clear to me. It is a very simple strategy that does not cost anything, since in many countries people with special needs get free education beyond 18 years of age. There is a rigid belief that you must educate a 9 year old with other 9 year olds, rather than matching people by their stage of cognitive development. In my world no NT kid would leave primary/junior school until he had mastered basic numeracy and literacy, which often is not the case, even in developed countries.

Sodium Benzoate and GABRA5 - Raising Cognitive Function in Autism

I am still looking for additional cognitive enhancing autism therapies. It seems the best way to find them may actually be to reread my own blog.

A long time ago I suggested that Cinnamon could well be therapeutic in autism, most likely (but not entirely) due to the sodium benzoate (NaB) it produces in your body.

https://epiphanyasd.blogspot.com/search/label/Cinnamon 

Sodium benzoate (NaB) is both a drug used to reduce ammonia in your blood and a common food additive that acts as a preservative.

NaB has many biological effects.  One effect relates to a protein called DJ-1, which is produced by a Parkinson’s gene (PARK7). I had noticed that when the body tries to turn on its anti-oxidant genes after the switch Nrf2 is activated, the process cannot proceed without enough DJ-1.  This is why Peter Barnes, from my Dean’s list, suggested that patients with COPD might benefit from more DJ-1.  COPD is a kind of severe asthma which occurs with severe oxidative stress, the oxidative stress stops the standard asthma drugs from working, which is why so many people die from COPD. Oxidative stress is a key feature of most autism.

To make more DJ-1 you can use sodium benzoate (NaB) which is produced gradually in the body if you eat cinnamon. So in theory cinnamon is like sustained release NaB, it is also extremely cheap.

Independently of all this NaB has been trialled in schizophrenia and a further larger trial is in progress.  Autism is not schizophrenia, but the hundreds of genes miss-expressed in autism do overlap with the hundreds of genes miss-expressed in schizophrenia, so I call schizophrenia autism’s big brother. 

GABA_A α5 subunit

The scientist readers of this blog may recall that there are two sub-units of the GABA_A receptor that I am seeking to modify, to improve cognition.  One is the α3 subunit and the other is the α5 subunit. Low dose clonazepam works for α3.

The α5 subunit is the target of a new drug to improve cognition in people with Down Syndrome (DS).

Very recent research links the same sub-unit to autism, so it is not just me looking at this.

Reduced expression of α5GABAA receptors elicits autism-like alterations in EEG patterns and sleep-wake behavior                                                                                                              

As is often the case, it looks like some people might need to “turn up the volume” from α5GABA_A receptors and others might need to turn it down.

I had yet to find a practical way to affect α5GABA_A. Now I have realized that I have already stumbled upon such a way to do it.

Pahan, a researcher in Chicago, has shown that he can improve cognition in mice using cinnamon. He noted that in poor learners GABRA5 was elevated, but that after one month of cinnamon GABRA5 was normalized. 

Cognitive loss in autism, schizophrenia and Down Syndrome

Most people might associate MR/ID with autism and indeed Down Syndrome; you likely do not really consider people with schizophrenia to have MR/ID. In reality, cognitive loss is a common feature/problem in schizophrenia and indeed bipolar, just not enough to be called MR/ID.

Those researching schizophrenia seem to focus on NMDA receptors, whereas my blog only goes into the great depths of science when it comes to GABA_A . To the schizophrenia researchers NaB is interesting because it is a d-amino acid oxidase inhibitor, which means that it will enhance NMDA function.  So if you are one of those people with too little NDMA activity (NMDAR hypofunction) then sodium benzoate should make you feel better.

The schizophrenia researchers think NaB is helpful because of its effect on NMDA, for me it is GABRA5 that is of great interest. The same should be true for parents of kids with Down Syndrome (DS). We have seen that bumetanide should, and indeed does, help DS.  It looks to me that NaB/Cinnamon should further help them and no need to wait for Roche to commercialize their GABRA5 drug. 

NaB and Cinnamon

I am yet to determine how much NaB is produced by say 3g of cinnamon.

The clinical trials of NaB use 1g per day in adults. People using cinnamon, like Dr Pahan, for cognition or just lowing blood pressure and blood sugar use around 3g.

It is quite difficult to give a teaspoonful of cinnamon to a child, whereas NaB dissolves in water and does not taste so bad. 

NaB and Cinnamon Trials

I did trial cinnamon by putting it in in large gelatin capsules and at the time I did think it had an effect, but I doubt I got close to Dr Pahan’s dosage.

A prudent dose of NaB would seem to be 6mg/Kg twice a day. This is similar to what is now being trialed in schizophrenia.

A small number of people do not tolerate NaB and logically also cinnamon.  They are DAAO inhibitors, just like Risperidone. People who are histamine intolerant need to avoid DAAO inhibitors. If you have allergies it does not mean you are histamine intolerant.

I did try NaB on myself and I did not notice any effect.

Conclusion

I had already obtained some NaB to follow up on my earlier trial of cinnamon.  Having read about the effect of NaB on GABRA5 expression, I am even more curious to see if it helps.

Any positive effect might be due to DJ-1 boosting the effect of Nrf-2, it might be boosting NMDA or it might be reducing GABRA5 expression. In some people all three would be useful.

Press release:- 

Cinnamon may be fragrant medicine for the brain 

Pahan a researcher at Rush University and the Jesse Brown VA Medical Center in Chicago, has found that cinnamon turns poor learners into good ones—among mice, that is. He hopes the same will hold true for people.

His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.

"The increase in learning in poor-learning mice after cinnamon treatment was significant," says Pahan. "For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds."

Pahan's research shows that the effect appears to be due mainly to sodium benzoate—a chemical produced as cinnamon is broken down in the body.

In their study, Pahan's group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food. 

In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given. 

"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment." 

The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the cells—namely in the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells. 

As for himself, Pahan isn't waiting for clinical trials. He takes about a teaspoonful—about 3.5 grams—of cinnamon powder mixed with honey as a supplement every night.  

Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide. 

The paper itself:- 

Cinnamon Converts Poor Learning Mice to Good Learners: Implications for Memory Improvement. 

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in converting poor learning mice to good learning ones. NaB, but not sodium formate, was found to upregulate plasticity-related molecules, stimulate NMDA- and AMPA-sensitive calcium influx and increase of spine density in cultured hippocampal neurons. NaB induced the activation of CREB in hippocampal neurons via protein kinase A (PKA), which was responsible for the upregulation of plasticity-related molecules. Finally, spatial memory consolidation-induced activation of CREB and expression of different plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones. However, oral treatment of cinnamon and NaB increased spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules in the hippocampus of poor-learning mice and converted poor learners into good learners. These results describe a novel property of cinnamon in switching poor learners to good learners via stimulating hippocampal plasticity. 

We have seen that cinnamon and NaB modify T cells and protect mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Cinnamon and NaB also upregulate neuroprotective molecules (Parkin and DJ-1) and protect dopaminergic neurons in MPTP mouse model of Parkinson’s disease.  Recently, we have seen that cinnamon and NaB attenuate the activation of p21ras, reduce the formation of reactive oxygen species and protect memory and learning in 5XFAD model of AD. Here we delineate that NaB is also capable of improving plasticity in cultured hippocampal neurons. Our conclusion is based on the following: First, NaB upregulated the expression of a number of plasticity-associated molecules (NR2A, GluR1, Arc, and PSD95) in hippocampal neurons. Second, Gabra5 is known to support long-term depression. It is interesting to see that NaB did not stimulate the expression of Gabra5 in hippocampal neurons. Third, NaB increased the number, size and maturation of dendritic spines in cultured hippocampal neurons, suggesting a beneficial role of NaB in regulating the synaptic efficacy of neurons. Fourth, we observed that NaB did not alter the calcium dependent excitability of hippocampal neurons, but rather stimulated inbound calcium currents in these neurons through ionotropic glutamate receptor. Together, these results clearly demonstrate that NaB is capable of increasing neuronal plasticity.

These results suggest that NaB and cinnamon should not cause health problems and that these compounds may have prospects in boosting plasticity in poor learners and in dementia patients. In summary, we have demonstrated that cinnamon metabolite NaB upregulates plasticity-associated molecules and calcium influx in cultured hippocampal neurons via activation of CREB. While spatial memory consolidation-induced activation of CREB and expression of plasticity-related molecules were less in the hippocampus of poor learning mice as compared to good learning ones, oral administration of cinnamon and NaB increased memory consolidation-induced activation of CREB and expression of plasticity-related molecules in vivo in the hippocampus of poor learning mice and improved their memory and learning almost to the level that observed in untreated good learning ones. These results highlight a novel plasticity-boosting property of cinnamon and its metabolite NaB and suggest that this widely-used spice and/or NaB may be explored for stimulating synaptic plasticity and performance in poor learners.

The schizophrenia trials:-

The efficacy ofsodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: study protocol for a randomized controlled trial

Add-on Treatmentof Benzoate for Schizophrenia A Randomized, Double-blind,Placebo-Controlled Trial of d-Amino Acid Oxidase Inhibitor

Plenty of people with schizophrenia now self-treat with NaB; just look on google.

P.S.

There is now is a small trial in autism:-

A Pilot Trial of Sodium Benzoate, a D-Amino Acid Oxidase Inhibitor, Added on Augmentative and Alternative Communication Intervention for Non-Communicative Children with Autism Spectrum Disorders

https://www.omicsonline.org/open-access/a-pilot-trial-of-sodium-benzoate-a-damino-acid-oxidase-inhibitor-added-on-augmentative-and-alternative-communication-intervention-2161-1025-1000192.php?aid=83472&view=mobile


Results: We noted improvement of communication in half of the children on benzoate. An activation effect was reported by caregivers in three of the six children, and was corroborated by clinician’s observation. Conclusion: Though the data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, and worthy of a double-blind placebo-controlled study with more children participated for clarification of its efficacy.

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.

Hypoperfusion in Autism Revisited

One old post from this blog has been going viral recently (3,000 views in one day, via Facebook) and it is quite relevant to a debate that has been going on in the comments about the potential merits and mechanisms of Hyperbaric Oxygen Therapy (HBOT). Two commenters are big fans of HBOT.

Hypoperfusion is reduced blood flow, which is found in some people with autism and also in people with some types of dementia  

Having reread my old post I would recommend it to those who are looking into the treatment of brain damage caused by ischemia. 

Brain Hypoperfusion in Autism & Cocoa

While much in neuroscience is extremely complicated, there are some pretty basic things to consider that are not. Adequate blood supply is one of the basic issues and is something that can be improved.

You can increase blood flow by reducing vascular resistance, which means reducing the work the heart has to do to circulate blood around the body. As you reduce this resistance, blood pressure will fall, but that does not mean the flow rate of blood has reduced, it just means it is circulating more freely.

You can measure cerebral blood flow and this is how researchers know that it can be abnormal in autism.

As I noted in the old post above, HBOT is one therapy proposed by some. Using an MRI you could establish with certainty if HBOT was effective in any particular individual, in regard to increasing cerebral blood flow.

I think there will be many ways to improve perfusion in an affected individual. Without a particular type of MRI you cannot really know for sure if your case of autism is one of these.

The dementia research pointed me towards cocoa flavanols, which seem to affect nitric oxide (NO), but do not directly produce it.

Nitric oxide (NO) is very important in the body and one of its roles is vasodilation (widening of blood vessels).

Some people believe that nootropic drugs work by vasodilation, i.e. more blood flow increases cognitive function.  I think that this is one of many possible ways to improve cognition, which will work in some people, but not others. 

To understand Nitric oxide (NO) you have to go a little deeper and look at eNOS (endothelial nitric oxide synthase), iNOS (inducible NO synthase) and nNOS (neuronal NO synthase). Nitric oxide can be very good for you, but it can also be very bad for you.  The short version is that Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia.,

For a thorough explanation here is a highly cited paper:-

Nitric oxide synthases: regulation and function

Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins. 

Statins are already in my Polypill. Telmisartan seemed to be the most likely ACE inhibitor or ARB (angiotensin receptor blocker) to help some autism, when I reviewed them in a previous post. Telmisartan produced more singing, as does Agmatine (see below).

Now look at how NO is produced by eNOS:-

           https://en.wikipedia.org/wiki/Endothelial_NOS 

“In the vascular endothelium, NO is synthesized by eNOS from L-arginine and molecular oxygen, which binds to the heme group of eNOS, is reduced and finally incorporated into L- arginine to form NO and L-citrulline. The binding of the cofactor BH4 is essential for eNOS to efficiently generate NO. In the absence of this cofactor, eNOS shifts from a dimeric to a monomeric form, thus becoming uncoupled. In this conformation, instead of synthesizing NO, eNOS produces superoxide anion, a highly reactive free radical with deleterious consequences to the cardiovascular system.^”

BH4 (Tetrahydrobiopterin/Kuvan) is one of substances that comes up in autism research from time to time.  You would not want to be deficient in BH4 and if you have autism and BH4 deficiency you have a very obvious therapy.   

Biomarin’s Kuvan autism treatment faces reservations on the part of experts 

A good article, surprisingly from the UK Financial Times, which they ask not to be cut and paste, so I have not. Take a look.

If Kuvan lights up the brain, as Dr Frye suggested in the above FT article, I wonder what else can, in those people.  L-arginine might help, or perhaps its metabolite Agmatine, as used by our reader Tyler.

If you read the quite complicated paper below you will see that, in rats at least, Agmatine increases eNOS, while reducing  iNOS. 

You compare EC6 (experimental control after 6 hours) with Agm6 (Agmatine after 6 hours) and then EC24 with Agm24. 

Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain

Effects of eNOS and iNOS expression by agmatine treatment following transient global ischemia in rat hippocampus. Representative expressional levels of eNOS (A) and iNOS (C) at 6 h after agmatine treatment (100 mg/kg, i.p), and densitometric data (B, D). Data represent means±SD for n=5/NC, n=3/EC and Agm group per each time point. ^*

Cost

BH4/Kuvan/Sapropterin is rather expensive, but people do use it off-label in autism.  It is the only FDA-approved medication for Phenylketonuria (PKU) to reduce blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU.

http://www.biomarin.com/products/kuvan

PKU is one of those rare inborn errors of metabolism that lead to intellectual disability/MR and, not surprisingly, also autism. It is included in my Treatable ID tab at the top of every page.  The link will take you here  http://www.treatable-id.org/page36/Phenylketonuria.html

Agmatine is cheap and does have an almost immediate positive effect in some people with autism.

Do people who respond to BH4 respond to Agmatine and vice versa?

Agmatine does have many other modes of action, other than increasing eNOS and reducing iNOS.

I have been experimenting with Agmatine, and while Dr Frye suggests Kuvan can “light up the brain”, my impression of Agmatine brings the Energizer(US)/Duracell (Europe) Bunny to mind.

A daily dose of Agmatine is like having better battery in your toy bunny, at least in my house.  It is also associated with more singing.

Judging from Tyler’s comments perhaps he is seeing the same magnitude of effects that Dr Frye attributes to Kuvan.