Diet and Autism 2

One of the questions that came up in the comments on my first post of the series was why are researchers (and celebrities) stuck on gluten-free, casein-free diets to treat autism?  The whole idea is based on the idea that the exorphins (dietary opiate proteins) found in gluten and casein somehow cause or exacerbate the neurological issues in autism spectrum disorders (ASDs).  Also, it is well documented that kids with ASDs seem to have more gut and dietary issues than other kids, so a dietary culprit was an obvious place to look.

A weakness to these theories is that we have been eating gluten and casein for a long time (the beta casein A1 is found in about 50% of cows of European descent, which are also the cows who make American, Australian, and New Zealand milk at least), and the autism rates have been (possibly) escalating only recently.  Or have they?


Back in 2003, JAMA released a study and editorial on the rates of autism.  At the time, most studies were showing that rates were somewhere around 1 per 1,000 children.  Since previous studies (from the 60s and 70s) usually estimated around 4-5 per 10,000 children, that means a doubling of prevalence from the 1970s to the 1990s and early 2000s.  (There are many issues with trying to put a reliable number together- I recommend you read the editorial I linked as it seems to be a very fair presentation of the data - the main issue being that the definition for autism spectrum disorders widened considerably between 1960 and 1990, which could certainly explain an increase in prevalence in studies without an actual increase in prevalence in the population).   Then a number of very large survey studies were done in 2006-2009, including 78,000 parents in the National Children's Health Study (1), and another multi-site study in the Autism and Developmental Disabilities Monitoring (ADDM) Network (2).  These were all big news last year, as several of these studies came out at the same time, and the rate had jumped to approximately 110 per 10,000 children.  I'll let the second study speak for itself at this point:

"Approximate range: 1:80--1:240 children [males: 1:70; females: 1:315]. The average prevalence of ASDs identified among children aged 8 years increased 57% in 10 sites from the 2002 to the 2006 ADDM surveillance year. Although improved ascertainment accounts for some of the prevalence increases documented in the ADDM sites, a true increase in the risk for children to develop ASD symptoms cannot be ruled out. On average, although delays in identification persisted, ASDs were being diagnosed by community professionals at earlier ages in 2006 than in 2002."

A 57% increase in four years.  That sounds really, really bad.  However, much of this increase was felt to be due to increased awareness, and recognition that early intervention and treatment could help kids with ASDs, so kids were being diagnosed earlier, and the diagnosis would be made more readily so kids could be eligible for early intervention services.  In fact, the latest studies may be the ones that actually have a more realistic estimate of the number of kids affected, and previous studies grossly underestimated the number of cases.  In my opinion, the best evidence that autism may not be increasing at all is a report from the Adult Psychiatric Morbidity Study from the UK in 2007 (3).  They found that approximately 1% of adults living in households have symptoms consistent with ASDs.  Since that is pretty close to the 1 in 110 number we have for today's children, it suggests that the enormous increase in diagnosis in kids may be due to increased outreach and widening of diagnostic categories.  However, a more recent increase can't entirely be ruled out.

In any event - that means that we don't necessarily have to look for something brand spanking new or rapidly changing in our society to explain the increase.  We can take a broader view.  So back to gluten and casein and those pesky exorphins. 

Couple of interesting tidbits.  Really, the theorized mechanism of wheat and casein exorphins causing neurotoxic events that are expressed as our brains develop is quite similar to the same theory in schizophrenia.  It's probably coincidence, but schizophrenia and autism both affect about 1% of the population.  Some of the same genetic chromosomal deletion syndromes are implicated in both autism and schizophrenia.

And, frankly, the exorphin question is an easy one to test, at least indirectly.  We have naltrexone, after all, a readily available, relatively inexpensive opiate blocker in pill form.  Once taken, it will sit on our opiate receptors like a lock on a door, blocking exorphins from casein and gluten just as readily as heroin or morphine, and keep the opiates from activating our opiate receptors.  So if dietary exorphins worsen autism in those of us with vulnerable phenotypes, naltrexone should help.

Fortunately, there are several studies of naltrexone and autism (4)(5)(6).   And, overall, the studies lean towards naltrexone being a useful treatment for some kids.  It seems most effective in decreasing self-injurious behavior (interesting in light of the findings I wrote about in this post, linking alterations in the opiate symptoms and self-injurious behavior), like self-picking, finger-biting, and head-banging.  It also seems to help some kids with improved attention and eye contact, hyperactivity, agitation, stereotyped behaviors, social withdrawal, and temper tantrums. (Naltrexone is not FDA approved for use in autistic disorder in kids, but due to the limitations of therapeutic alternatives, it is mentioned often in review papers as a useful medicine that might be worth giving a try).

Does that mean that dietary exorphins are definitely the cause of the problem, or at least piece of the cause?  Not so fast.  The whole reason scientists studied naltrexone in autism in the first place had nothing to do with wheat or casein.   Turns out a paper in 1979 hypothesized a link between derangements in the opiate systems of autistic children and the symptoms of autism, and later naltrexone studies showed that some kids with autism seem to produce an excess of beta-endorphin (our own, natural opiates).  Theory goes like this - flooding the immature brains of kids with beta-endorphins may delay or hamper maturation in some way, causing the brains of autistic kids to stay in an infantile stage of development, particularly with regards to social interaction and sensory response.  Kids who responded best to naltrexone had the biggest decreases in the amount of their own beta-endorphins.

All right, let's bring it all together.  A large subset of autistic kids seem to have leaky guts (remember - no robust link between the amount of leakiness in the gut and either positive celiac markers OR gastrointestinal symptoms such as diarrhea, bloating, or abdominal pain - you can't tell if a kid has a leaky gut using these kinds of criteria or tests!).  Another subset of autistic kids have elevated levels of their own natural beta-endorphins and seem responsive to an opiate blocker, naltrexone.  Gluten and casein have exorphins (opiates) which can hypothetically wriggle through that leaky gut and may have an effect on the central nervous system.

There, finally, a plausible link between gluten, casein, and autism.  Not as necessarily a cause, and certainly not a cure, but perhaps as an exacerbating factor.  But, before April 2010, the dietary studies were crap.  And too small.  Enter the ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders.  Published in Nutritional Neuroscience in April 2010, this study combined a lot of nice features.  It had a decent sample size - 72 Danish kids with ASDs (established by standard diagnostic criteria), and it was long - two years.  It had a sort of modified cross-over design.  It was honest about being single blind - meaning the researchers (except the nutritionists) didn't know which kids were getting the special diets, but the parents (of course) knew. The kids' urine was tested for any abnormal metabolic byproducts.

Here's what the researchers did - for the first year, they put about half the kids on a gluten-free, casein-free diet and monitored their progress for 8 months.  If the improvements in the kids on the diet were significantly better than the kids off the diet, they would extend the trial and put everyone on the GF-CF diet at 12 months, and monitor them for a total of 24 months (this is what happened in the actual trial - there was significant improvement in the study diet kids, and a worsening in the kids on the standard diet, so everyone was put on the study diet for the last 12 months).  The researches used a battery of different tests, measuring a bunch of different subsets of autistic behaviors and ADHD symptoms at points along the trial.  The results?

"Introducing a gluten-free, casein-free diet had a significant beneficial group effect at 8, 12, and 24 months of intervention on core autistic and related behaviors..."  The improvement was less dramatic after the first 8 months, and could represent a plateau effect.  Attentional and communication symptoms seemed to improve the most.  About half the kids dropped out in the second year, perhaps the kids that didn't benefit.  The researchers note that there aren't long-term safety studies of gluten-free casein-free diets in kids, and that a knowledgeable nutritionist should be consulted.

Whew.

One last little thing.  The leaky gut study I wrote about extensively in my first post on diet and autism had a very interesting component I didn't mention then.  Some of the kids in that study, turns out, were already on a gluten-free, casein-free diet.  The leakiness of the gut was measured via the IPT test - two sugars, lactulose and mannitol, are given orally to fasting kids, and their urine is collected for the next five hours.  Mannitol is small and absorbed via the cells of the gut, and the amount absorbed reflects the "absorptive capacity of the gut."  Lactulose is too large to be absorbed directly by the cells, so it has to squeeze in between the cells, and if a lot can squeeze through, the gut is "leaky" and the ratio of lactulose to mannitol in the excreted urine goes way up.  A "normal" ratio is less than 0.03, and the higher the number is, the more leaky the gut is.  Control kids in that study had ratio average of 0.023.  In the autistic kids overall, the ratio was an average of 0.041.  But in the autistic kids who were on the gluten-free, casein free diet, the ratio was less than 0.02, and when only data from the autistic kids not on the special diet was used, the average ratio jumped up to approximately 0.055.   And, once again, the leakiness measured in these kids had no relation to GI symptoms or positive celiac marker testing.

The take-away point?  Once again, I think there is enough scientific evidence to suggest that some kids with ASDs will, in fact, benefit from a gluten-free, casein-free diet, and while it is no cure and may not be a part of the original cause (some known teratogens that cause autism seem to work at around 8 weeks gestation (7)), it may be worth a try.  It shouldn't be attempted without some professional nutritional advice, especially in a picky kid.  And it's clearly no holy grail.

Another point - gluten is (once again) creepy.  Gliadin and zonulin do not a good combination make.  No one wants a leaky gut.  Just something to think about.

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Diet and Autism 1

Let's begin with the Harvard Mental Health Letter (April 2010 page 4). HMHL just loves to rain on my "diet and mental health" parade:

"Researchers have long disagreed about whether gastrointestinal problems may underlie some symptoms of autism spectrum disorders. This has not stopped some researchers and celebrities from promoting theories and special "autism diets" with no scientific support. Yet these unfounded recommendations might appeal to grieving and vulnerable parents who are heartbroken about a child's sudden developmental regression."

Wow. That's harsh. I hope to use the next several posts to explore some of the theories behind what might be causing austim and to see just how wacky and dangerous these diets really are.

Autism spectrum disorders (autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified, together known as "ASDs") seem to impair a child's ability to communicate and interact with other people. ASDs are also characterized by ritualistic or repetitive behaviors, such as tapping fingers or head banging, or picking. Autistic children in general are more picky than children without ASDs, and temper tantrums around unsatisfactory meal times can be extreme. (A decent point is that restricting a picky child's menu by going gluten and casein free could be a nutritional issue.) Constipation is also more common among kids with autism, and it seems that kids with ASDs frequently experience abdominal pain, stool leakage, bloating, and reflux (1).

The Harvard Mental Health Letter is blunt, at this point: "There is not enough evidence to support special "autism diets" that eliminate casein... or gluten." Previous studies were not properly done, or too small, or didn't even use standard measures to diagnose autism in the first place. There is only one double-blind, crossover trial of casein and gluten free vs. regular diets (not sure how you really double-blind that but okay), of 15 children with ASDs, and after 12 weeks the diet seemed to have no effect (2). Some of the parents felt the intervention trial was more successful than the independent reviewers.

All right, all right, we get the picture, Harvard Mental Health Letter. But let's step back a bit. What is autism, and what causes it? Well, there is no universal theory, no consistent genetic findings (though autism does seem to run in families sometimes), and no agreed upon biological mechanism for what causes autism (3). Some researchers feel it is a brain development problem. Others wonder if autism is a set of disorders similar to phenylketonuria (where an inability to metabolize a certain amino acid can lead to progressive mental retardation, brain damage, and seizures, but can be averted by not eating that amino acid, phenylalanine).

The whole idea that gluten-free casein-free diets might be useful for autism is based on theories that exorphins (protein fragments that act as opiates) from gluten and casein might make it through the intestinal barrier and go on to act on the brain, causing harm. A similar theory is at work in gluten-free diets and schizophrenia. One very interesting tidbit of information: kids with autism and their family members seem to have leakier guts than families without autism (4). (Here's a finding which makes the Harvard Mental Health Letter's statement that researchers are promoting "autism diets" with no scientific support, seem, well, cranky. To be fair, the largest and best gluten-free casein-free diet trial was published in April of 2010 too, and the leaky gut study I'm looking at is epublished ahead of print, meaning it doesn't seem to even be officially published yet.)

Wait a minute. Back up. How does one measure a leaky gut? Well, to test the gut integrity, one can drink a solution of metabolically inert sugars, like lactulose and mannitol, and in a person with a leaky gut, those sugars will end up in the urine (this is called an IPT test). In addition, a leaky gut tends to be an inflamed gut, and one can skip intestinal biopsies and check fecal calprotectin (FC), a protein produced by intestinal granulocytes. Lots of FC in your poop apparently means you probably have an inflamed bowel. Of course celiac disease is associated with inflamed, leaky guts, so the researchers in the study took 90 kids with autism spectrum disorders and 146 of their first-degree relatives, and also 64 children and 146 adult controls. Everyone was given an IPT test, some were checked for FC, and all the kids with autism were screened for celiac (using anti-tTG antibodies, IgG anti-gliadin antibodies, and IgA anti-gliadin antibodies, anti-endomysium antibodies, and the genetic testing for HLA DQ2 and 8). Relatives and controls with abnormal IPT and FC tests were similarly screened for celiac.

Sounds interesting! What are the results?


Abnormal leaky gut - the IPT test (a higher percentage of lactulose and mannitol in the urine)
Adult controls = 4.8%
Child controls = 0%
ASD patients = 36.7%
Relatives = 21.2%
(p<0.0001)

Pathological fecal calprotectin (FC - measure of gut inflammation)
ASD patients = 24.6%
Relatives = 11.7%
(Due to budget constraints, FC was only measured in controls who had an abnormal IPT test - none of them had FC values above the normal range)

ASD patients and celiac testing
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 32% of kids with "leaky" IPT test
Genetic predisposition for celiac (+HLA DQ2 and/or DQ8): 35.9% of kids with normal IPT test
Gastrointestinal symptoms: 45.5% of kids with "leaky" IPT test
Gastrointestinal symptoms: 47.4% of kids with normal IPT test.
Positive AGA IgA: 1.6% +/- 2.5%
Positive AGA IgG: 13.8% +/- 24.2%
Positive tTG: 1.04% +/- 0.91%
EMA: all negative


Relatives and celiac testing
Positive AGA IgA: 0.8% +/- 0.4%
Positive AGA IgG:8.4% +/- 5.9%
Positive tTG: 3.0% +/- 3.7%
EMA: all negative

Well! That's a mixed bag. The overall findings - there seems to be a subgroup of kids with autism and their close relatives who have leaky guts. The celiac findings are a little more all over the place. GI symptoms seemed to have no correlation with gut leakiness, meaning the standard recommendation to investigate for celiac or intestinal barrier problems only in autistic kids with GI symptoms seems to fly in the face of scientific findings.

Perhaps more importantly, "gluten itself augments IPT" (in other words, makes gut leakiness worse in cellular models (5)(6)(7)). "We can hypothesize that subjects with ASD are gluten-sensitive.... and hence their intestinal barrier function [abnormalities] will ameliorate with with a gluten-free diet. The well-recognized intestinal mucosal effects of gliadin - the major component of gluten - would justify a treatment with gluten-free diet in ASD."

There is a lot more to discuss. But for now, I'll leave the above information to simmer for a little while.

The bottom line from this post:  The clinical trials evidence for gluten-free, casein free diets is poor, so far (though I'll go over what I consider to be the best study later this week).  BUT, there is newer evidence of a rather large subset of kids with ASDs who have an especially leaky gut, and the susceptibility to the leakiness seems to be genetic.  You are not going to find these kids by looking at patients with celiac markers or by looking at patients with GI symptoms.

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The Case for Evolution - Octopuses, Grandmothers, Iceland, and Poor Dr. T. Colin Campbell

It has been a while since I reviewed my basic premise, that homo sapiens walk around in bodies and brains exceptionally well suited for hunting and gathering in small family groups in the wilderness, and that we are not evolved for agriculture as a whole, and industrial agriculture in particular. I subscribe to the concept of Evolutionary Medicine, that diseases of civilization (I'm focused on mental health in my blog) are caused by differences between our current lives and our evolutionary suitability, and that replicating a hunter-gatherer life in many ways (as makes scientific and practical sense) can lead to better health, both physical and mental.

Here's what T. Colin Campbell, PhD and full professor (of nutritional biochemistry) at Cornell has to say about that (1): "Those who follow evolutionary history and who support the inclusion of substantial amounts of animal protein as a recommended dietary practice, make this error. Our dietary evolutionary history, while interesting, absolutely does not yield critical clues for optimal nutritional practices. Human evolution required that our ancestors make dietary choices that maximized gene proliferation."

To which I say - maximized gene proliferation means living past 30 and well into old age. Humans have grandmothers. Women are designed to live 20-30 years past menopause in order to favor a higher overall birthrate as grandmothers helped gather for their offspring's offspring and taught valuable cultural information (Textbook of Evolutionary Psychiatry: The origins of psychopathology). How could tens of thousands of generations not have selected for relative longevity and freedom from disease (both mental and physical) based on our evolutionary diets? For me it honestly makes no sense to view health data from another perspective. Bizarrely, Campbell goes on to write of how chimpanzees eat a plant-based diet (we split off from chimpanzees 5 million years ago) so the preponderance of evolution data must lean towards a plant-based (low protein) diet. So evolution (of an entirely different species) is important when it explains his theories, but not so when it doesn't.

If you watched the television series "Life," you might have seen the segment about the octopus that reproduces once then dies, leaving a zillion offspring who feast on mom's dead body, and hopefully a few make it to go on. I am not an octopus! Humans are rather on the extreme "k" side of the r versus k selection species. We have few, quality offspring and spend a lot of energy nursing them to reproductive age and beyond. Our genes want us to live for a very long time, to teach our toddling young and their toddling young how to make it in this big, bad world. What plants to eat, how to chase down a large land mammal, how to set fishing traps, where the best water holes are, how to select the "Children and Family ages 2-4 movies" on netflix and how to get the kangaroo through the alphabet maze on starfall.com (seriously, I never get to use my own computer anymore) - all of this is knowledge we are not born with, and is most efficiently learned from our elders. Though my youngest figured out how to post on facebook all on her own at 12 months. Darned intuitive apple iPhone technology!

(An aside - I definitely recommend Evolution's Captain: The Story of the Kidnapping That Led to Charles Darwin's Voyage Aboard the Beagle if you are a student of evolution. Darwin was selected to go on the voyage as a gentleman companion to the young Captain Fitzroy, who had a family and personal history of depressive mental illness, in order to offer him company and hopefully to forestall any depression on the long voyage returning some kidnapped Tierra del Fuegans back to the southernmost part of South America (no, I am not making this up). Sadly, Fitzroy, who ended up being the second governor of New Zealand and was also a devout Christian, eventually killed himself a few years after watching a debate on evolution between the Archbishop of Canterbury, Thomas Huxley, and Samuel Wilberforce.)

But what about those genetic diseases that occur after reproducing? Diseases such as Huntington's Chorea? Clearly those genes survived and are genetic, not dietary, so that evolutionary (dietary) paradigm doesn't support links to those aspects of ultimate human health. Cardiovascular disease and those other diseases of civilization (let's leave out acne and many autoimmune diseases which strike young) get us when we are old and no longer contributing to the gene pool (tell that to my 9th grade band director who died in his late 40s of an MI). Okay, decent argument, but that brings me to Iceland.

Way back in the infancy of my blog, a commenter from Iceland left me two links to some very interesting information. Turns out there is an autosomal dominant genetic disease in Iceland called Hereditary Cystatin C Amyloid Angiopathy. It is caused by a mutant protein that is deposited in the walls of small arteries, leading to brain hemorrhage and death in young adults (average age of 30). Since this is Iceland, and everyone knows everybody, the family trees of everyone with the disease were deciphered and studied. Turns out the deadly hereditary cystatin C mutation occurred in Iceland sometime around 1550, and carriers of the gene lived normal lifespans until 1830, when over the next 70 years the lifespan of those afflicted decreased from 65 to 30. "This change in life-span is an indication of a strong environmental effect on the penetrance of the mutation. The effect must have been very common as it happened in [almost] all families simultaneously in all parts of the country." In the time from 1830 to 1900, Iceland changed from a traditional cow and milk based diets to a more "Western" diet similar to Europeans. In one remote region of Iceland, the lifespan shortening occurred 20 years later than in the other related family groups - that was one of the later regions to adopt the Western diet. So here we have an example of how an autosomal dominant genetic disease seems to be affected by diet.

Which brings me back to Huntington's Chorea. In my last post, I mentioned a study that showed that carriers of the mutant huntingtin gene (an autosomal dominant gene with complete penetrance, meaning everyone with the gene gets a progressive, deadly neurological illness with no cure but steady and inevitable degeneration leading to death over 20 years that begins between the ages of 20 and 44, thereabouts) had a much higher rate of positive test for anti-gliadin (wheat protein) antibodies than the general population. The huntingtin gene probably codes for a type of microtubule or vesicle protein, basically structural proteins that anchor the mitochondria in nerve cells. The mutant, deadly gene has extra trinucleotide repeats of CAG, coding for an unstable version of the huntingtin protein. A normal gene will have less than 20 CAGs in a row. A mutant gene 36 or more. The more trinucleotide repeats, the earlier the disease seems to strike. What does this have to do with wheat?

Here's the really weird part. That CAG DNA code repeat I was talking about? CAG is the genetic code for the amino acid glutamine. The mutant extra repeats is called a "polyglutamine repeat", and there are a number of genetic diseases that are also caused by this polyglutamine repeat. Turns out that polyglutamine tracts are also present in gliadin - the wheat protein. A possible explanation is that the body recognized the abnormal polyglutamine tracts made in the cells with the abnormal gene, and the wheat proteins looked a lot like the abnormal protein so that the people with Huntington's mounted an immune response to the wheat proteins. But wheat protein exposure has also been associated with non-Huntington's ataxias. Could wheat gliadin polyglutamine exposure itself and an abnormal autoimmune response lead to the protein aggregation in Huntington's disease? In other words, does our ubiquitous exposure to dietary wheat protein modify the natural history of Huntington's disease? Somewhat like Western dietary exposure seems to modify the natural history of Hereditary Cystatin C Amyloid Angiopathy?

No one knows.

But an evolutionary perspective would lead one to pursue those questions.

For decades, the U.S. government has been freewheeling with sugar and heart disease, repeating the fact that there was no data to suggest sugar had anything to do with it. Well, here's an abstract from a study in JAMA in April of 2010, showing a strong correlation between dietary sweetener consumption and a bad cholesterol profile (low HDL and high triglycerides). The money quote from the abstract? "No known studies have examined the association between the consumption of added sugars and lipid measures."

That's right. No one bothered to publish a study on sugar and blood lipid profiles until 2010.

The jury on wheat is still out. In the mean time, I'll fall back to the safe evolutionary medicine position, and avoid it.

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Woe is Wheat

(Shirt available at Cafe Press)

I don't eat wheat as a general rule, and the reasons I don't are circumstantial, to be sure.  The most compelling reasons to me are all those healthy non-wheat eating cultures.  Read enough of Food and Western Disease: Health and nutrition from an evolutionary perspective, or The Primal Blueprint: Reprogram your genes for effortless weight loss, vibrant health, and boundless energy, or Dangerous Grains: Why Gluten Cereal Grains May Be Hazardous To Your Health, and wheat just doesn't seem tasty anymore.  If it ever did.  Well, maybe in a pizza.

However, the beautiful Ms. Minger has used the (admittedly fairly useless) China Study data to make the smokey fire around wheat flare up again.  The handsome Dr. Guyenet has a reasonable overview at his site.  (Hmmm... there seems to be a strong correlation between non-wheat eating blogging and good health and good looks.)

And, very recently, Dr. Rodney Ford published a paper where he makes an argument that there should be a medical condition labeled "The Gluten Syndrome,"  and that everyone with many common neurological and psychiatric conditions (such as ataxia, hypotonia, developmental delay, migraine, depression, anxiety, etc.) be tested for gluten sensitivity via the IgG anti-gliadin antibody.  His reasoning being that IgG antigliadin positive people can have negative intestinal biopsies (if they have latent disease or patchy involvement of the intestine), and they can also have negative IgA tTG testing (another pretty specific celiac antibody test) and still have improvement in symptoms on a gluten free diet.

While looking into the matter, I stumbled upon a very good paper called Neurological complications of coeliac disease: what is the evidence?  If you have institutional access, I highly recommend checking this one out.  It has some nice suggestions for teasing out biases and inaccuracies in research papers, and it has a good review of the pathophysiology of celiac disease.   Neurologists are one of my favorite species of doctor, as they tend to be brilliant and cranky*, and these authors point out very fairly that the evidence linking gluten exposure to ataxias, certain types of epilepsy, and peripheral neuropathy is often poor and contradictory.  Bless their clinical hearts, though, they end up recommending a trial of gluten-free diet for anyone who's game, educated about the type of data there is, and who has a positive celiac biopsy or positive celiac or gliadin antibody testing for those with certain neurologic conditions, recognizing that the harm of a gluten-free diet is minimal, and there are some case reports where going gluten-free improved ataxias, peripheral neuropathy, and seizures.


I have the same take with schizophrenia - the indirect evidence is damning, the direct not as much, but enough case studies and small studies to suggest that at least some (especially new onset) schizophrenics could really benefit from a gluten-free diet.  And seeing as how we are dealing with a progressive, devastating brain illness with no cure, it seems fair to give patients and families the option and explaining the data.  For most it won't make a difference, but for a few... I wouldn't hold off medication for a new onset psychosis to try a gluten-free diet, though. 

I'm not sure about testing everyone with depression and anxiety (or schizophrenia) for IgG or IgA ani-gliadin, or even IgA tTG.  I'd probably just recommend the gluten-free diet trial idea to anyone interested.  Mostly it's the schizophrenia data that puts me in this mindset.  All sorts of anti-wheat antibodies were found in the serum and urine of schizophrenics, after all, but most of them were entirely different than the celiac antibodies.  Until we know more about what to test for, I think you risk giving someone with a negative test a false sense of security about gluten.

No classical music link this week.  Nope.  It's a holiday weekend and there's a hurricane coming, and that calls for something a little more modern.

I'll still be blogging over the weekend, though.  Did you know that in a study of 52 patients with Huntington's disease (invariably fatal genetic autosomal dominant ataxia condition), 44% had a positive IgA or IgG (or both) anti-gliadin antibodies?  The general population is about 4.8% positive.  Wild, huh?  (No, don't jump on that and say OMG WHEAT causes HUNTINGTON's because that might not be what it means at all.  But still, pretty wild). This means a post on evolution, Iceland, genetics, anthropology, and even a mention of poor Dr. T. Colin Campbell. In the mean time, keep eating meat, fish, veggies, and a bit of fruit and nuts.

*Neurologists are almost always right handed.  The field of psychiatry has more left handers (I have no source for this and it may be an urban medical myth).  There was a Nova episode last year about Oliver Sachs (famous neurologist) and music.  In it he admitted to preferring Bach to Beethoven.  I think that is the very definition of a neurologist.

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Migraines and Neurotoxicity

Jamie Scott sent me a link a couple days ago to this science daily article:

First Genetic Link to Common Migraine Exposed

So I chased down the study, as the article mentions some of my favorite words, glutamate and synapse. And it is a cool study! You've got to love the large, population based genetic studies they can do now, because they get p values (which is (sort of*) the chance that the finding occurred by chance) of 5.38X10-9. After scouring the nutrition literature for a while, it has been nice to read up on neurologists and geneticists who are gleefully obsessive rather than the nutrition epidemiologists who try to play Jedi mind tricks. "Bran is good for you. Also whole wheat. You will eat bran! You will!" I mean, I expect a pharmaceutical company to try to con me a little. They're in it to win it, after all. Where's the fun in reading another drug trial except to find the underdosed competitor medicine or the fouled up control? But it's no fun when the nutritionists do it. Especially with my tax dollars. I'd rather have a iRobot 330 Scooba Floor-Washing Robot, really, with the money.

But back to the study! I'll just gush a little, because you can certainly go read the Science Daily article yourselves. These geneticists took DNA from 3,279 headache-afflicted people from very nice countries with socialized medicine and possibly no need to buy disability insurance where they feel cool about giving up DNA to the government. They also took DNA from 10,747 matched controls. Then they used magical DNA replication and reading machines to roll out the genes for all these people, to find which ones the migraine sufferers had in common, and the controls didn't. Turns out it there was only one (of significance). The minor allele A of marker rs1835740 (p=5.38X10-9).

Genes have been found for migraines before, but always in rare family clusters with somewhat bizarre ion channel issues, and none of those genes were ever found in a large number of average migraine sufferers (8% of men and 17% of women). So to find a gene by splashing everyone's DNA out on a big canvas and finding the pattern is pretty big news! The researchers did all sorts of cute tests involving geneticists' favorite words, like HapMap and ssSNPs ("snips"), and no matter how they spliced the data, the same gene (rs1835740) came out as the common migraine one (not in every headache sufferer, to be sure, but in many!)

This is where geneticists get the full thumbs up Awesome. They went out and recruited another 3,202 cases (including some from some different socialized medicine countries), and 40,062 more matched controls, and they did the analysis again. And found that the same gene was over-represented in the migraine group, this time with p=1.69X10-11. Heh.

The punchline. rs1835740 is an area of a chromosome that has two genes for glutamate regulation. Yes, glutamate, that excitatory neurotransmitter that can be exceedingly annoying and cause all sorts of trouble (like seizures, bipolar disorder, depression, and migraines) when the regulation is out of whack. The actual gene they think is implicated is MTDH. MTDH is responsible for downregulating the major glutamate transporter in the brain.

The hypothesis of migraines is that too much glutamate is left out in the synapse, causing too much excitement in the wrong place at the wrong time, leading to spreading neurotoxic communication, head pain, sometimes aura - a migraine. Why would too much glutamate be left out in the synapse? Because some people appear to have inefficient pumping mechanisms to get it back into the cell. The glutamate transporter is one you need to be working tip top!

This is all indirect evidence, but it is sensible and very cool. Maybe your common migraines are due to this very gene and mechanism. Perhaps topamax or valproate or other GABA-influencing medicines could work to improve the headaches. Or you could actively work to reduce your stress so the glutamate isn't so prevalent. Or maybe even try a ketogenic diet. (not an FDA approved treatment for migraine - and I couldn't even find any case trials on pubmed, but I have heard of cases mentioned on the internet. I'll look harder) Intriguing!

* I've been called out - here's the precise definition of the p value -"In statistical hypothesis testing, the p-value is the probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true."

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Your Brain on Ketones

Ketogenic diets have been prescribed for seizures for a long time.  The actual research diets used in the past were pretty dismal and seemed to involve drinking a lot of cream and eating a lot of mayonnaise.  At Johns Hopkins, pediatric patients were admitted to the hospital for a 48 hour fast and then given eggnog (minus the rum and sugar, I'm guessing) until ketosis was achieved (usually took about 4 days).  In addition, ketogenic diets were calorie restricted to just 75-90% of what would be considered a child's usual calorie intake, and often they were fluid-restricted too (1)!  If we're talking soybean oil mayonnaise, you could see how someone could get into trouble with mineral deficiencies and liver problems pretty quickly.

To understand "dismal,"  some of the latest research showed that a "modified Atkins protocol" was just as good as the classic ketogenic diet, and so much more liberating, as the patients were allowed up to 10 grams of carbohydrates daily, and they didn't begin with the fast, and they weren't calorie restricted (2)(3).  While the classic ketogenic diet was 4:1:1 fat to carbs to protein.  If you use MCT oil for 50% of your calories (have to add it in slowly though to prevent vomiting, diarrhea, and cramping!), you could increase the carbohydrates and proteins to a 1.2:1:1 fat:carb:protein and still get the same numbers of magical ketones circulating.  And while "MCT oil" sounds nice and yummy when it is gorgeous coconut milk, this MCT Oil 100% Pure 32 fl.oz doesn't look quite as appetizing, especially when that is going the be half of what you eat for the foreseeable future (4).   You can see why researchers consider ketogenic diets (especially the original versions) to be extremely difficult and unappetizing (they were), whereas seasoned low-carbers (who have a bit of a different idea what a ketogenic diet is) will find that attitude ridiculous, especially when you compare a ketogenic diet to the side effects of some anti-epileptic medications.

So it looks like modified Atkins (very very low carb, but not zero carb) and a preponderance of MCT is the same, ketone-wise, for the brain as the classic cream-heavy ketogenic diet.  And what does it mean to have a ketogenic brain?  Before, we talked about protons, but now I'm going to examine neurotransmitters and brain energy more closely.  Specifically, glutamate and GABA (5).

If you recall, GABA is the major inhibitory neurotransmitter in the mammalian nervous system.  Turns out, GABA is made from glutamate, which just happens to be the major excitatory neurotransmitter.  You need them both, but we seem to get into trouble when have too much glutamate.  Too much excitement in the brain means neurotoxicity, the extreme manifestation of which is seizures.  But neurological diseases as varied as depression, bipolar disorder, migraines, ALS, and dementia have all been linked in some way to neurotoxicity.

Glutamate has several fates, rather like our old buddy tryptophan.  It can become GABA (inhibitory), or aspartate (excitatory and, in excess, neurotoxic).  Ketogenic diets seem to favor glutamate becoming GABA rather than aspartate.  No one knows exactly why, but part of the reason has to do with how ketones are metabolized, and how ketosis favors using acetate (acetoacetate is one of the ketone bodies, after all) for fuel.  Acetate becomes glutamine, an essential precursor for GABA. 

Here's the confusing part.  A classic ketogenic diet had three major components which were thought to contribute to the anti-seizure effect.  One, it was calorie restricted.  Just calorie restricting epileptic monkeys (no matter what the macronutrient ratios) reduces seizure frequency (and increases longevity).  Secondly, it was acidic, and the extra protons themselves could block proton-sensitive ion channels, or the ketone bodies or fats themselves could affect the neuron membranes, making them harder to excite.  (For the biochem geeks out there, ketones or fats seem to affect ATP sensitive K+ ion channels, making hyperpolarization easier to maintain).   Thirdly, it lowered glucose levels.  And lower glucose is associated with a higher seizure threshold (that's good - once doesn't want to easily have a seizure!) and less neuronal excitability.  Gads.  Doesn't sound to me like glucose really is the preferred fuel for the brain after all.

And now let's really get down to the mitochondrial level.  Mitochondria are the power plants of our cells, where all the energy is produced (as ATP).  Now, when I was taught about biochemical fuel-burning, I was taught that glucose was "clean" and ketones were "smokey."  That glucose was clearly the preferred fuel for our muscles for exercise and definitely the key fuel for the brain.  Except here's the dirty little secret about glucose - when you look at the amount of garbage leftover in the mitochondria, it is actually less efficient to make ATP from glucose than it is to make ATP from ketone bodies!  A more efficient energy supply makes it easier to restore membranes in the brain to their normal states after a depolarizing electrical energy spike occurs, and means that energy is produced with fewer destructive free radicals leftover.

Umph.  What does it all mean?  Well, in the brain, energy is everything.  The brain needs a crapload of energy to keep all those membrane potentials maintained - to keep pushing sodium out of the cells and pulling potassium into the cells.  In fact, the brain, which is only 2% of our body weight, uses 20% of our oxygen and 10% of our glucose stores just to keep running.  (Some cells in our brain are actually too small (or have tendrils that are too small) to accommodate mitochondria (the power plants).  In those places, we must use glucose itself (via glycolysis) to create ATP.)  When we change the main fuel of the brain from glucose to ketones, we change amino acid handling.  And that means we change the ratios of glutamate and GABA.  The best responders to a ketogenic diet for epilepsy end up with the highest amount of GABA in the central nervous system.

One of the things the brain has to keep a tight rein on is the amount of glutamate hanging out in the synapse.  Lots of glutamate in the synapse means brain injury, or seizures, or low level ongoing damaging excitotoxicity as you might see in depression.  The brain is humming along, using energy like a madman.  Even a little bit more efficient use of the energy makes it easier for the brain to pull the glutamate back into the cells. And that, my friends, is a good thing.

Let me put it this way.  Breastmilk is high in fat.  Newborns (should) spend a lot of time in ketosis, and are therefore ketoadapted.  Being ketoadapted means that babies can more easily turn ketone bodies into acetyl-coA and into myelin.  Ketosis helps babies construct and grow their brains. (Update - looked more into this specifically and it seems that babies are in mild ketosis, but very young babies seem to utilize lactate as a fuel in lieu of glucose also - some of these were rat studies, though - and the utilization of lactate also promotes the same use of acetyl-CoA and gives the neonates some of the advantages of ketoadaptation without being in heavy ketosis.)


We know (more or less) what all this means for epilepsy (and babies!).  We don't precisely know what it means for everyone else, at least brain-wise.  Ketosis occurs with carbohydrate restriction, MCT oil use, or fasting.  Some people believe that being ketoadapted is the ideal - others will suggest that we can be more relaxed, and eat a mostly low sugar diet with a bit of intermittent fasting thrown in to give us periods of ketosis (though in general I don't recommend intermittent fasting for anyone with an eating disorder).  Ketosis for the body means fat-burning (hip hip hooray!).  For the brain, it means a lower seizure risk and a better environment for neuronal recovery and repair.

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Proof that Our Ancestors May Have Practiced an Early Form of Yoga

She called the pose, "I'm being a bunny frog."

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