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.


2004


Epileptiform activity in sleep has been described even in the absence of clinical seizures in 43�68% of patients with autistic spectrum disorders (ASDs). Genetic factors may play a significant role in the frequency of epilepsy, yet the frequency in normal age-matched controls is unknown. We studied overnight ambulatory electroencephalograms (EEGs) in 12 nonepileptic, nonautistic children with a sibling with both ASDs and an abnormal EEG. EEG studies were read and described independently by two pediatric epileptologists; 10 were normal studies and 2 were abnormal. The occurrence of abnormal EEGs in our sample (16.6%) was lower than the reported occurrence in children with ASDs. Further, the two abnormal EEGs were of types typically found in childhood and were different from those found in the ASD-affected siblings. The lack of similarity between sibling EEGs suggests that genetic factors alone do not explain the higher frequency of EEG abnormalities reported in ASDs.



2006:

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


Abstract


Autism spectrum disorders (ASDs) affect 1 in 166 births. Although electroencephalogram (EEG) abnormalities and clinical seizures may play a role in ASDs, the exact frequency of EEG abnormalities in an ASD population that has not had clinical seizures or prior abnormal EEGs is unknown. There is no current consensus on whether treatment of EEG abnormalities may influence development. This retrospective review of 24-hour ambulatory digital EEG data collected from 889 ASD patients presenting between 1996 and 2005 (with no known genetic conditions, brain malformations, prior medications, or clinical seizures) shows that 540 of 889 (60.7%) subjects had abnormal EEG epileptiform activity in sleep with no difference based on clinical regression.The most frequent sites of epileptiform abnormalities were localized over the right temporal region. Of 176 patients treated with valproic acid, 80 normalized on EEG and 30 more showed EEG improvement compared with the first EEG (average of 10.1 months to repeat EEG).

  

An easy to read two page review paper: 


Many authors focused their research on the relationship between EEG abnormalities and autistic regression. Our analysis included only studies that involved autistic children with and without regression, i.e. clinically non-selected samples. We excluded studies involving only children with regression, or only children with EEG abnormalities. A summary of our findings is presented in Table 1.

A large majority of the studies (7 of 9 studies) did not find any significant relationship between EEG abnormalities and autistic regression. Only two studies were positive [10,11]. Of all the studies, Tuchman & Rapin [10] had the largest sample (585 children) but only part of the sample (392 children) had EEGs available (i.e. sleep EEGs; only sleep EEGs were performed in this study). Readers of the Tuchman & Rapin [10] study should note that the overall rate of epilepsy in the autistic sample was quite low (11%), as was the rate of epileptiform EEG abnormalities in non-epileptic autistic patients (15%). In comparison, other studies listed in our summary gave higher rates of epileptiform abnormalities in non-epileptic autistic children, 19% [12], 22% [13], and 24% [14]. The overall rate of epileptiform EEG abnormalities in the whole sample (21%) was also very low, where other comparable studies were in the range of 28 - 48% [5,11,14-17].  



What about Keppra (Levetiracetam) ? Here we have a clinical trial


Subclinical epileptiform discharges (SEDs) are common in pediatric patients with autism spectrum disorder (ASD), but the effect of antiepileptic drugs on SEDs in ASD remains inconclusive. This physician-blinded, prospective, randomized controlled trial investigated an association between the anticonvulsant drug levetiracetam and SEDs in children with ASD.

Methods


A total of 70 children with ASD (4�6 years) and SEDs identified by electroencephalogram were randomly divided into two equal groups to receive either levetiracetam and educational training (treatment group) or educational training only (control). At baseline and after 6 months treatment, the following scales were used to assess each individual�s behavioral and cognitive functions: the Chinese version of the Psychoeducational Profile � third edition (PEP-3), Childhood Autism Rating Scale (CARS), and Autism Behavior Checklist (ABC). A 24-hour electroencephalogram was recorded on admission (baseline) and at follow-up. The degree of satisfaction of each patient was also evaluated.

Results


Relative to baseline, at the 6-month follow-up, the PEP-3, CARS, and ABC scores were significantly improved in both the treatment and control groups. At the 6-month follow-up, the PEP-3 scores of the treatment group were significantly higher than those of the control, whereas the CARS and ABC scores were significantly lower, and the rate of electroencephalographic normalization was significantly higher in the treatment group.

Conclusion


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


Levetiracetam


Levetiracetam (LEV) is a broad-spectrum antiepileptic agent that has been used effectively for a variety of seizure types in adults and children, and for different psychiatric disorders.39,40

LEV does not have a direct effect on GABA receptor-mediated responses. In vitro findings reveal that LEV behaves as a modulator of GABA type A and of the glycine receptors, suppressing the inhibitory effect of other negative modulators (beta-carbolines and zinc). LEV inhibits the ability of zinc and beta-carbolines to interrupt chloride influx, an effect that enhances chloride ion influx at the GABA type A receptor complex.



And Lamictal (Lamotrigine)? 

This study is in general autism, not autism with epileptiform activity:- 


In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits
  

Conclusion

What would be nice to know is whether epileptiform activity is a precursor to seizures, in the way that atopic dermatitis is often a precursor to developing asthma. Perhaps by treating epileptiform activity, some people could avoid ever developing epilepsy.
As I have pointed out before, I think that treating the E/I imbalance in autism with Bumetanide may well reduce the likelihood of later developing epilepsy.
In people with epileptiform activity but no seizures, treatment with AEDs can often normalize this activity within a few years.  Does the possible autism benefit correlate with this normalization? Or do you need to maintain the AED treatment even after the epileptiform activity has gone?
Do some people with autism, but no epileptiform activity, also demonstrate behavioral improvement on AEDs? I suspect some might, but it will depend on the AED.
Since medicine does not fully understand how most AEDs work and there are very many types of epilepsy, we cannot really expect concrete answers.
AEDs help many people with seizures, but a substantial number of people have seizures that do not respond to standard AEDs. Matching the AED to the person with seizures is more art than science and I would call it trial and error.
I did write a post a long time ago on the benefit of low dose AEDs in people with autism, but without seizures.  Given the many and varied effects of AEDs, it is not surprising that some people benefit.
The side effects of AEDs vary widely and some look more suitable than others for people that do not actually have seizures.
You might think based on the currently understanding of how Keppra works, it would not be helpful in someone that responds to Bumetanide.  But anecdotally people do respond to both, so most likely Keppra�s mode of action is not quite what we think it is.
So just like a neurologist applies trial and error to find an effective therapy for his patients, the same method can be applied to those with autism.
Clearly some people with autism do benefit from Valproate, others from Keppra and others from Lamotrigine. In my autism Polypill there is a little Potassium Bromide, the original AED from the 19th century.

If your neurologist does not want to treat your child's sub-clinical epileptiform activity, suggest he or she reads the literature and the very recent clinical trial using Keppra.  It is not guaranteed to improve autism, but you have a pretty good chance that one AED will help.







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. 


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:-


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.   


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. 




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.   





Identifying your sub-type of Autism


Today�s post is very much a work in progress, so do not expect all the answers.
It has occurred to me and also some readers of this blog that you could produce a diagnostic decision tree that would narrow down each person�s sub-type of autism. This really does lend itself to a relatively simple computer model, meaning you could have a simple on-line diagnostic program/app. You do wonder why a tiny part of the hundreds of millions of dollars spent on autism research is not allocated in this direction.

A blank screen awaiting more case studies

A company called Verily, formerly Google Life Sciences, would be an appropriate partner for such a project.  Google is currently backing the approach that genetic testing will reveal all about autism, which looks unlikely.
The decision tree computing part of such a project could be done in an afternoon, what would like more time is creating the logical diagnostic steps.
One clever part, where Verily could help, would be the use of software to �read� the research and look for associations; this is after all what I do with the help of Google Scholar and Ctrl F. In this way you could quickly �read� many tens of thousands of research papers, books and case histories, if there were any.
Software can also be used to �read� all the personal data of any volunteer participants, such as genetic tests, MRIs, family history and all lab tests. As our reader Tyler pointed out, just relying on a pair of eyes to read the MRI means tiny variances go unnoticed and perhaps they do mean something.
You cannot automate everything, but technology certainly can help.
Even a primitive decision tree can help, because it pushes you to think logically and stops you wasting time potentially applying therapies that might help some biological dysfunctions, but clearly not yours.

Parent led initiatives have been successful in the past and have resulted in rare diseases or syndromes becoming treatable using so-called orphan drugs. Treating autism is a massive task and parent led initiatives are what exist today - they have not succeeded in making any impact on mainstream medicine. To make an impact in autism you need big money and big companies.


Start with severity
Ideally everyone would have autism diagnosed in early childhood.  In the case of mild autism this usually does not happen.  Ideally all children would be assessed using the same evaluation test, like CARS, but this also does not happen; most people have no evaluation test, just a subjective observational diagnosis.
So you would need unambiguous terminology to define how the person is affected by �autism�.  This would be how verbal they are; level of cognitive dysfunction and how �autistic� they are behaviorally.
Then you can add things like epilepsy, self-injury and adaptive behavior (toileting, feeding etc). 

Family History
While genetic testing is seen by many as the ultimate diagnostic test, in many cases family history tells you a great deal more. Similar family histories will very likely end up with similar sub-types of autism. This would include medical history of relatives, but also educational/job attainment. It would include health before and during pregnancy, type of delivery and health status at birth.
Genetic testing of your DNA can never be the holy grail of autism diagnosis; what matters is gene expression, when and where, and this is something much more complex.
Family history tells you what has happened in the past and most things happen for a reason.
Family history is by its nature very personal, but it is one of the richest areas to identify how people might be usefully grouped together. This may appear highly politically incorrect, but that does not stop it being useful. 

Physical Features
Until very recently even single gene types of disorder were actually diagnosed by their hallmark physical features. These are often facial, or on hands or feet, but can be anywhere.
One of the most useful physical markers is very simple, you just need to know at birth and for the next couple of years was there a tendency towards being big and/or muscular or small and more floppy?  The stronger the tendency to either extreme, the more important is the observation.

A recent study has even used 3D modeling to identify autism by analyzing people's faces. This apparently works particularly well in females with autism, who apparently tend to have more male features. I have no doubt Googlers could improve this.

Hypermasculinised facial morphology in boys and girls with Autism Spectrum Disorder and its association with symptomatology


Comorbidities
Other medical conditions in the child and also in the parents, and in particular in the mother during pregnancy, can help assign people to subgroups. 
In mothers thyroid disorders and diabetes during pregnancy look particularly relevant.
In the child, epilepsy, allergy and GI issues are important. There are many types of GI issue, some of which overlap with allergy and some do not.
Then you have sleep disorders, eating disorders, sensory disorders etc.  Some are only an issue when very young and then fade away, some may remain. 

Biological Markers
There are hundreds of possibly relevant biomarkers and many more that are likely totally irrelevant.  The most reliable tests will use samples taken from spinal fluid, which in effect is part of the central nervous system, and so tell you what is going on inside the blood brain barrier. Blood tests can be useful but often do not tell you what is going on inside the brain. 

The most immediately relevant biomarkers relate to treatable in-born errors of metabolism, each one of these syndromes may indeed be rare, but there are many of them and you would think it worth ruling them all out. 
The risk here is getting lost in hundreds of tests, rather like with genetic testing.
There will be some useful markers like for oxidative stress, inflammatory biomarkers, mitochondrial function etc. 

MRI
It does make sense for everyone with autism to have an MRI, including those with Asperger�s. People who break their arm get an X-ray by default, is an MRI for autism too much to expect?
The brain may appear entirely normal, but there is a significant chance of identifying a relevant variation, albeit small.
There are also some specific tests that can be carried by Functional Magnetic Resonance Imaging (fMRI) at the same time as the basic MRI.  


EEG
Many people with autism, but without epilepsy, do have an abnormal EEG, with so-called epileptiform activity.  Medicine does not have a consensus opinion regarding what to do, but some neurologists, like Dr Chez, believe it should be treated and can reduce the severity of autism.  Detailed knowledge of such epileptiform activity might be useful when defining sub-groups of autism.


Genetic Testing
The tests usually offered are microarray, whole exome and whole genome sequencing.  These tests may reveal something useful or may just reveal a list of variances that do not seem to have any relation to autism.

If funds are unlimited, then whole genome sequencing of the child and both parents is the best choice.  Then you need someone very methodical to review and interpret the results.

What matters is gene expression locally and even whole genome sequencing does not tell you this, it is however a part of the picture.

Nature of Onset
People tend to consider autism as either early onset or regressive. Here it is important to extract the group who were born entirely neurotypical, met all their milestones and then regressed.
Most people�s autism started long before birth but it manifests itself differently over time. This is like the progression of a disease. Indeed one therapeutic idea is that by very early pharmacological intervention you can affect this progression and improve the final outcome.
The point here is that you can have early onset autism that appears to �get worse�, this is not regressive autism.
People with regressive autism need to split into those who profoundly regressed and those who were always different and then became more so.
For people with mild autism the time/nature of onset is likely much less of an issue. 

Variability of Symptoms
Some people with autism exhibit the same severity of symptoms every day, but many do not.  In people with highly variable autism it is very useful to understand what makes it worse.  Many lay people refer to autism as being the result of the brain being "wired-up" differently, as if it was static condition. In those with highly variable autism, the condition is clearly not fixed. Something is making autism worse, you just have to find out what it is. It could very likely be allergy, but could potentially be many things even microorganisms affecting gene expression.

The Goal - Why would you want to collect all this personal data?
As I have noted in this blog, there clearly are groups of people who respond to the same therapies. It is remarkable and it is not a matter of chance.  I do not just mean one therapy, like NAC or bumetanide, but a whole string of them, even the ones that may appear odd to some readers.
If you could predict who fits into which subgroup of autism based on answering a long list of questions on an app on your smartphone and sending some data to Google, widespread treatment of autism would become a reality.
You do need a lot of data and most of it does not yet exist.
I know a lot about one subtype of autism and there is a substantial overlap with the son of one regular commenter. Bumetanide, Potassium, NAC, Atorvastatin, Verapamil, Potassium Bromide etc all appear to have the same (beneficial) effect.
Once you have more data, you look what all these children have in common and then you can try and predict which other people will have a similar drug response. 
You just need a lot of well documented case studies and a lot of experimentation with possible therapies. In other words not just Peter�s Polypill, Tyler�s Polypill, Alli�s Polypill or Dr Kelley�s mito-cocktail,  but very much more.
There does seem to be an effective therapy for regressive autism caused by mitochondrial disease, which is likely to be one of the larger subgroups. Given all the attention given to PANDAS/PANS, I cannot understand why the mitochondrial sub-group has not been similarly �mainstreamed�. The therapy is Dr Kelley�s (from Johns Hopkins) plus add-ons.  One potential add-on being calcium folinate (Leucoverin) to reduce peroxynitrite (ONOO-) from nitrosative stress, but there are undoubtedly other add-ons waiting to be discovered, or perhaps just documented.


Conclusion

Trying to match effective drugs to a long list of markers and other criteria, does have something in common with tracking individuals web browsing to generate personalized relevant advertising. So I do think that the likes of Google/Verily would do a much better job than medical researchers alone. They would of course automate the process, which is not what many doctors are going to like. 

If you happen to know Larry Page or Sergey Brin from Google, you can suggest it. Brin's former wife incidentally is the founder of 23andMe. I am sure both companies employ plenty of people with Asperger's and so likely have some kids with autism. Brin apparently is interested to find a Parkinson's cure, he has a mutation in the gene LRRK2; since this gene is also associated with Crohn's disease, he might want to fund that too. Why does Brin have a LRRK2 mutation? You only need a glance at his family history.




Verapamil still working after 3+ years, for SIB in Autism


There are numerous ideas about how to treat self injurious behavior (SIB) associated with autism. ARI (the former home of Defeat Autism Now) have just had their take on the subject published.
In this blog we have seen that Tyler has developed a BCAA (branch chained amino acid) therapy, based on the idea of Acute Tryptophan Depletion, to control his son�s type of self injury.
The silver bullet for my son�s summer time raging and self-injury continues to be the L-type calcium channel blocker Verapamil.
I think many people will be skeptical of both BCAAs and Verapamil, which is entirely understandable. Unlike other aspects of autism, which are hard to measure, self-injury is really easy to measure and so you know when you have cracked the problem; what other people think tends not to matter.  
Now that Monty, aged 14 with ASD, has moved to secondary/high school the routine has changed a little and his assistant forgets to give him his midday dose of verapamil.
On the days she forgets, between 4.00pm and 4.30pm Monty starts to punch himself. On all other days and during the entire summer there has been no sign of self injury.
So when asked is it really necessary Monty keeps taking his pills, my answer remains yes.  In the case of verapamil I now have further evidence that after more than three years of use, his pollen allergy driven self injury continues to be entirely controllable using this therapy.
I do not know what ARI have put forward in their book. If your child has SIB that does not respond to whatever therapies you have tried, it might well be a helpful read. 

Other readers have noted GI and behavioral improvement from Verapamil and our doctor reader Agnieszka did try and collect case reports, but it seems parents are more interested in reading reports than writing them.
           







Autism Drugs and Supplements A to Z



Today�s post is a draft list of about 130 drugs and supplements that are used by some people with autism. It is not a list of recommendations, just a list of what gets mentioned either in this blog, or is widely known to be used elsewhere.  I did not include bleach, but I did include potent drugs used by some psychiatrists, that may also be ill-advised.

If any item is interesting, you can use Google to find out about its use in autism. With more obscure ideas, Google will direct you back to this blog. 

To add items I have omitted, just send me a comment.



Click on the link below and the list should open in a spreadsheet:-












Autism MRI



Source: Brain MR Imaging Findings and Associated Outcomes in Carriers of the Reciprocal Copy Number Variation at 16p11.2


In the early days of this blog, one medical reader told me that in cases of autism an MRI scan of the brain should appear normal.
This also fits with the idea that once you have a biological diagnosis, you no longer have a case of �autism�. It is only Autism, when it is of unknown origin.  
People who have a single gene type of autism actually can have significant variations in brain structure that appear clearly on an MRI.  This was the subject of a recent study and the source of the MRI in this post.




Many people with autism have abnormalities at a specific site on the 16th chromosome known as 16p11.2. Deletion or duplication of a small piece of chromosome at this site is one of the most common genetic causes of autism spectrum disorder.
People with deletions tend to have brain overgrowth, developmental delays and a higher risk of obesity.
Those with duplications are born with smaller brains and tend to have lower body weight, but also developmental delays. 
For regular readers of this blog there are some interesting points to note.

Agenesis of the Corpus Callosum

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.
Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.
ACC leads to behaviors compatible with a diagnosis of autism or Asperger�s in about half of cases.
Symptoms of ACC vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.  My original post on the subject:-


Agenesis of the Corpus Callosum (ACC)                                                                                 
You may recall that in the film Rain Man, Dustin Hoffman�s character was inspired by a man with ACC called Kim Peak.  It is now thought that Peak had FG Syndrome and this is what caused his ACC. It appears that his brain adapted and made unusual connections leading to his remarkable memory.
The Corpus Callosum is clearly visible on an MRI.
In 16p11.2. deletion you end up with an overgrown (thick) corpus callosum, while in 16p11.2. duplication you end up with a thin corpus callosum, which equates to a partial Agenesis of the Corpus Callosum.                                
At least one reader of this blog has a case of partial Agenesis of the Corpus Callosum and as he told me, it is not autism it is ACC.


Chiari 1 �brain hernia�
Another point of interest on the above MRI has been highlighted as Cerebellar Ectopia. Now if they had called it a Chiari malformation, you might have linked it to an old post on this blog.


In people with brain overgrowth and/or a small skull, what happens when there is no space left for a growing brain? Well it appears that pressure builds up and you get a kind of hernia with the brain expanding downwards into the spine.
This is called a Chiari 1 malformation and it seems to be quite common in the types of autism associated with over active pro-growth signalling pathways.
Since 16p11.2 deletion is associated with too much growth (thick corpus callosum, brain overgrowth and obesity) we should not be surprised that they often present with Chiari 1 �brain hernia�, which is treatable and this should improve symptoms. 

Conclusion

An MRI can sometimes tell you a lot, when you know what to look for and clearly should be carried out on anyone diagnosed with disabling autism.
Undoubtedly there are other areas of the brain where important variances occur.
This would provide useful data to assign individuals with autism into subgroups and hence improve the chance of finding effective therapy.  What works for Peter may help Paul, but what works for Zach probably will not help Amber.






Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD ea...