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Tuesday, 10 December 2013

Autism, a Dynamic Encephalopathy, Indeed

 

With a title like that, not many people will stumble upon this post with Google.
So, for the hard-core of readers, today I am going to develop an idea of Martha Herbert, the pediatric neuroscientist from Harvard, who writes a lot about autism.
Incidentally, most researchers do not like publicity, and particularly those looking at autism.  Martha, herself makes some side remarks as to why this is; as I suggested in earlier posts it dates back 10+ years to a certain Dr Wakefield.

“A further barrier to considering the body’s impact on the brain was the reaction to the work of Wakefield, who argued not only that there was a link  between  autism  and  vaccines  but  also  that  this  link was mediated through the gastrointestinal system. For the better part of a decade any attempt to discuss gastrointestinal or immune issues with autism was construed as a support of Wakefield’s vaccine hypothesis, and it was difficult to discuss, let alone get funding for, clinical or research observations about these problems.  One way around the essentially taboo character of somatic problems in autism was to treat them as coincidental symptoms. For example, one could  talk about gut problems provided one made  it clear that they did not cause the autism in the brain. Improvement after treatment of gut problems, which is often observed, would then be explained as a consequence of reduction of pain and discomfort, but not of any direct impact on core brain mechanisms generating autistic behaviors.”

Another fearless autism researcher, not shy to voice his opinions by blog and tweet, is Paul Whiteley, in Sunderland.   Paul is very much a believer in the role the gut/diet in autism, he and Paul Shattock are the driving force behind the gluten and casein free diet as a therapy for autism.  Given what Martha writes above, and the association between Shattock and Wakefield, is it surprising that the GCF diet remains on the fringes?  I know some parents who wholly endorse it.
Here is a link to one of Martha’s recent works, for Herbert fans:-



Dynamic Encephalopathy
It was Martha who called autism a dynamic Encephalopathy.  Encephalopathy just means a brain disease.

What she means is that over time autism changes, day to day and year to year.  Just as during fever, autism symptoms may wane, other environmental provocations may cause flare ups.  With age come hormonal changes that will inevitably change the central hormonal homeostasis, I hope for the better, as generally is the case.
Other than being a fancy word, Encephalopathy, is probably a much better word than autism.  There are many types of Encephalopathy and there are multiple causes, it refers to a syndrome of global brain dysfunction; this syndrome can have many different organic and inorganic causes.  As with autism the hallmark of encephalopathy is an altered mental state.
 
Forget Autism think Encephalopathy
If you have not already opened up Wikipedia, I suggest you do.

From my desk research and primary research, I know that one factor behind this encephalophy is chronic inflammation, otherwise known as neuroinflammation.
At this point, we should look at what neuroscience can tell us about neuroinflammation

The Dana Foundation is a private philanthropic organization committed to advancing brain research.  Founded in 1950 and with $230+ million in assets I think they should be a good source.  Here  is an excellent paper, that is written for non-scientists. 

Among the many interesting insights are these:- 
 Until recently the CNS and peripheral immune sys­tem were thought to operate independently.”

However, new research has led to important advances in our understanding of how immune-related events in the periphery can influence CNS processes, thereby altering cognition, mood, and behavior, and these advances are suggesting that inflammation may have important long term implica­tions for the brain.”
 Inflammation in the body can lead to inflammation in the brain”
“The same cytokines that participate in produc­ing the inflammatory response in the body also initiate the communication process to the CNS. They accumu­late in the bloodstream and thereby travel to the brain”
“They cross into the brain in regions where the barrier is weak, and they bind to receptors on the insides of the cerebral vascular blood vessels, thereby inducing the production of soluble mediators within the epithelial cells that can cross into the brain.”
“In addition, there are neural as well as blood-borne communication routes. For example, there are cytokine receptors on nerves, such as the vagus, that innervate peripheral immune organs, and these nerves communicate to the brain and are activated during infection.”
“During a normal infection, neuroinflammation and the resulting adaptive sickness behaviors persist only for several days. However, if these responses become exaggerated or prolonged, the outcomes may well become estab­lished, leading to cognitive impairment instead of brief memory disruption,”
 “… physiology can become pathology when a set of processes designed to be rela­tively brief becomes prolonged.”
“However, peripheral inflammation is highly complex and involves many immune cells and their products. Existing anti-inflammatory drugs often target only one of these. For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, inhibit only a hor­mone, prostaglandins, leaving other actors in inflam­mation (cytokines, chemokines, etc.) untouched.”
“A second way that central neuroinflammation could be prolonged is less obvious. The CNS may come to over-respond to the same signal from the peripheral immune system. As noted above, microglia and the cytokines they produce when activated are at the core of the neuroinflammatory response that pro­duces sickness behaviors. If microglia were to become “sensitized,” which means they respond in exagger­ated or prolonged fashion, then sickness behaviors would become intensified and prolonged—pathology instead of physiology.”
“Most encouragingly, studies in numerous animal models show that the development and expression of chronic pain can be blocked with drugs that inhibit either microglial activation within the spinal cord, or the inflammatory cytokines that microglia produce.”
“In addition, microglia also can become sensi­tized without a prolonged peripheral inflammation. For example, aging appears to sensitize microglia so that microglia, particularly in the hippocampus, respond in exaggerated fashion to input. Thus, neuroinflammation produced by surgery, peripheral infection, and the like, is greatly exaggerated in aged subjects. Correspond­ingly, aging also augments the chances of depressive behaviors, cognitive impairments, and pain produced by peripheral inflammatory events. Encouragingly, however, some human studies show that inhibition of microglia and cytokines in the brain blunts such patho­logical outcomes.”
“Blockade of inflammation in the periphery and microglial activation/cytokine action in the CNS, may well become important therapies for a range of disorders not often thought of as mediated by these factors.”

Conclusion
There is nothing new to me in the Dana paper; this in itself is rather a shock.  If you have followed my blog from the start, you should also not be surprised; but I have never seen quite so much scientific good sense written in just four pages.  It tells me a lot and reassures me that I am on the right track with my cytokine blocking therapies, mast cell stabilization and somewhat far fetched, vagus nerve stimmulation ideas.

There are other science-based "inflammation control" therapies and I will be writing about them later.

P.S.  Why no Dean’s List for Martha?
Regular readers of my blog may have noticed that a small number of the several hundred researchers, whose papers are discussed here, are given a pat on the back and moved to the Dean’s List.  Why not Martha?

There is a good reason.  For many years Martha keeps going on about the “Fever Effect” in autism.  This is the strange phenomenon where autistic behaviours abate during fever, i.e. sickness associated with high temperature.  I myself witness this every time Monty, aged 10 with ASD, has a high temperature.  I think that conclusively solving this, might indeed tell us something profound about this wide phenotype of autism.
I think with the resources of Harvard, she should be able to figure this out.  Her TRANSCEND Program gives her a pool of research subjects.

Peter has just one mouse model of autism and, at the age of 10, he is getting a big to be called a mouse.
So Martha, put aside the MRIs and the calcium channelopathies, if you figure it out before me, you get on the Dean’s List.

If I can prove the underlying reason, I will put myself on the Dean’s List.

 

10 comments:

  1. I have just found your blog site and wanted to thank you in general and also particularly endorse the hope that someone can work this one out. My daughter is now two years in remission from Acute Lymphoblastic Leukaemia and was neither up nor down in her autistic behaviours leading up to diagnosis and during most of a punishing treatment. The main factors that influenced her behaviours were the steriod dexamethasone (utter hell every 28 days), raised temperatures due to weak immune system (bittersweet, as hugely worrying for obvious reasons but producing a sociable, conversational individual) and the early onset of puberty. Autistic behaviours started to get very much worse at puberty. Kirsten has just recovered from a bad urinary tract infection with slightly raised temperatures and her behaviour during this time was incredibly improved only for it all to fall apart the minute good health returned. I wish I was clever enough to be able to retain and analyse information in the manner that you are able to concerning the neurology and endocrinology. I try and fail. I am a fervent believer in good science even though I am bad at it myself and am immensely grateful for the application of it that has saved my daughter from dying at an early age from ALL. I am full of new resolve to actually try harder to grapple with some of this and try bumetanide etc as I believe Kirsten is losing out on a great window of opportunity at puberty if don't. I have tried asking advice from researchers with no sucess - apart from Paul Whitely, who is unfailingly helpful and polite. I think they sense my vagueness and are probably at a loss to know how to answer.

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  2. It is rather odd that more researchers do not show interest in people affected by the condition they are researching. Why cannot they be more like Paul ? Ben-Ari also replies, but most do not. The fever effect could be caused by various things such as the thyroid, or even, as I read yesterday, by glutamine. Some people find glutamine helps behavior in autism and apparantly when you have fever you produce more glutamine. Other people say that glutamine makes things worse. The real answer is that nobody really knows 100% what is going on and most likely it varies case by case. Trial and error seems to be one of the most effective strategies in medicine; this may sound rather shocking, but many medical advances were just stumbled upon.

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    1. Thank you so much for taking the time to reply. I will look into the glutamine findings and I will try to contact Ben-Ari again. I tried emailing him via Neurochlore, but I had to resort to english as my french is atrocious.

      Your comments about medicine are very astute. A wonderful Russian consultant at Yorkhill Hospital for children left this field to go back to her initial discipline of mathematics because she found that the uncertainties of it all plagued her and that someone needed to be an artist as much as a scientist/mathematician to try to join the dots together in a helpful way for patients. When my daughters autism started to worsen about 3/4 of the way through her ALL treatment, her haematologists, concerned, as we were, asked me which consultant normally saw her regarding her autism. I nearly fell off my seat laughing. Undaunted, they did try to refer her to neurology and endocrinology initially, but were rebuffed with the answer of 'but what can we do?' I think that a more systematic approach on the ground involving hard science is necessary in order to gather the stats, measurements and observations that will eventually enable a good stumbler to find and join some dots more meaningfully regarding the autisms. I am grateful to many of the psychologists who have seen us over the years and at times saved my (and Kirsten's!) sanity, but it dismays me that too often it is professionals in this field who are left as the sole observers and that the neuroscientists who year after year disprove many of the psychologist's theories (extreme male brain ?) do not get involved on the ground themselves. I do wonder if there is still a slight hangover in the feeling that something is awry with parents in cases of autism as all attempts to access doctors who deal with the physiological side of the child are met with the feeling in them that they are dealing with individuals who cannot come to terms that their child suffers from a developmental disorder for which there is no cure. It doesn't matter how articulately you acknowledge this issue but point to variabilities in your childs behaviour to show that as certain behaviours are not hard wired in them but driven by certain chemical changes within their bodies, why can't these be looked at by a relevent discipline?,- the response is always to send you back to the psychologists.

      I will keep looking at your blog with great interest and fervently hope you are able to patent a drug that at least ameliorates some of the symptoms in some children. Out of interest, as I have said, I do not have the type of brain that easily understands a lot of medical issues, but I did wonder about the problem you mentioned elsewhere regarding a lessening of the effectiveness of bumetanide and statins etc over time and wondered if it was possible to trick the bodies own mechanisms so to speak, in the way that cancer treatments do. Chemos, sometimes an alternating variety of them, have to stalk the cancer and back off time and time again in order to keep it at bay. Is there a possibility, I wonder, that an alternating mix of drugs might be used with short breaks for optimum effect?

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    2. It is an interesting point you make about dosing, particularly when the drug has side effects. The powerful steroid prednisone that is widely used in many conditions, and potentially very effective in some cases of autism, is a case in point. Research showed that a one-off high dose to be as effective in severe asthma cases in hospital as a lower dose for number of days.

      I discovered a similar effect using pulse dosing for drugs like Nexium (a Proton Pump Inhhibitor or PPI) the net result is a big reduction in side effects and the needs for far less drugs.

      One of the issues with autism is that body's feedback loops are actually working against it. For example, high blood levels of T3 or Serotonin, tell the body that levels are fine, even though in the brain they are low. To raise the level in the brain you would have to lower the level in the blood.

      Ben Ari responds best to short emails, and English seems to be no problem.

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    3. Advice taken. Many thanks.

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  3. I am new to this blog, and as you point out, lucky to have found this post with Google (but not with encephalopathy as a search term). : ) Thank you for your blog and for this post! It's also great to see your mention of Paul Whiteley--I'm so impressed with his blog and his graciousness.

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  4. Peter,
    I’ve discussed my son’s severe headaches with you recently. I suspect them to be mast cell degranulation related as he has more such symptoms in such situations, including low blood pressure, flushing etc. There’s one more strange thing about these episodes: during all of them his autism core symptoms diminish dramatically. He has absolutely no stims, speaks better and is able to plan and perform far more complex tasks than usual. This lasts even for 1-2 days after such episode, then disappears. I think it may resemble the fever effect (fever has not happened to my son for last two years).

    So at least my son does not need elevated body temperature to experience this effect. I wonder what these two situations: fever and massive mast cells degranulation with systemic symptoms may have in common? A strong, systemic pro-inflammatory reaction followed by profound, counter-regulatory antiinflammatory response? For infectious fever I am sure about that. My simple thinking is that: if those kids have chronic focal neuroinflammation and may have reduced antiinflammatory capabilities (http://www.ncbi.nlm.nih.gov/pubmed/16360218), then only an intense, systemic “cytokine storm” may increase the antiinflammatory agents like IL-10 (or other) production to the levels that may somehow influence the inflammation in the brain. I’ve tried to recall some basic knowledge, googled IL-10 to see if that makes any sense and found this: “The therapeutic potential of interleukin-10 in neuroimmune diseases“: http://www.ncbi.nlm.nih.gov/pubmed/25446571. It’s not about autism though and therapies are sophisticated. What do you think?

    It is a pity that the fever effect has been studied so little. In many other health problems scientists would be delighted to have so clearly defined condition associated with such improvements...

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    1. There is quite a lot written about defects in IL-10 production and autism. If you look on the "Questioning Answers" blog and search IL-10 you will find plenty.

      Increasing IL-10 is well worth a look.

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  5. Thank you for reading patiently the stories about my son here… Increasing IL-10 to the peak levels seen in infectious fever is probably out of my reach and perhaps not very healthy in the long run, but maybe it could be just another target of many that can be combined together for improvement? http://www.ncbi.nlm.nih.gov/pubmed/25576658

    Questioning Answers refers to your blog and is absolutely right with that.

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    1. I agree that care has to be taken in trying to adjust too many things, like lower IL-6 , raise IL-10 and IL-35. As you say, the result might be just to make something else worse. Understanding the mechanism behind IL-6 and IL-10 does seem worth investigating. There is some interesting research and it does point towards some benefit from SAMe (S-adenosyl methionine) or its precursor L-methionine. Research does show SAMe levels are strange in autism. IL-6 and IL-10 are partially controlled by SAMe. I found it odd a while back when I read that Dr Richard Kelley from Johns Hopkins suggested that L-methionine could be used in regressive autism to enhance cognitive performance.

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