Tuesday, 31 May 2011


Most people of my generation who went to school in the UK during the 1970s-1980s will perhaps remember what I am about to describe. Picture this. You are 7 or 8 years old. You sit at one of a number of large tables in a school dining hall filled with all your school-mates. Everyone is chattering and talking about yesterdays TV episode of Rentaghost or the revelation that Darth Vader is Luke's father - 'your destiny lies with me Skywalker'. Then from out of nowhere a large tray arrives filled with third-of-a-pint bottles of milk with a straw in them. You all look apprehensively at each other and the bottles of milk, noting that the cream at the top of the milk seems to travel about a third of a way down the bottle. You touch the bottle - it is warm; 'warm' you say to your friends. The word gets passed down the table, 'it's warm'. You pick up the bottle and straw... 'be brave' you say to yourself and then down the hatch. At the time I never understood why we were made to drink these warm bottles of milk everyday at school. I say 'warm' but the only reason they were warm is because they had been stood out all morning awaiting their fate. It was only when I was old enough to read up about milk and calcium (and 'Thatcher, Thatcher milk snatcher') that I understood the true reasons. One of the reasons was calcium.

Calcium is pretty important for human health. I would be here all night if I was to list all of its known functions in relation to health and disease. Suffice to say calcium has a role to play in things like bone health and the correct functioning of various enzymes and other biological processes. There is still some debate on how much is required but generally speaking, the figures look like this (see page 265) and vary between 525 mg/day for infants up to 1000mg /day for adolescents. Adults are suggested to take in about 700 mg/day (assuming they are not lactating women where greater intake might be required).

Whilst milk and dairy products are quite a good source of calcium, it is by no means the only source of calcium. Foods such as sardines, sesame seeds, figs and spinach (all the things that children love - not!) also rank up there with milk. Added to the fact that many products such as bread and breakfast cereals are now fortified with calcium and other nutrients means that everyone should be able to get their recommended daily intake with pretty minimal effort from diet. Where there is some indication that dietary needs may not meet required calcium intake, there are a variety of supplements on the market to use.

I think that covers the basics of calcium; now on to some of the important details and debates. There is already recognition that calcium on its own is an important mineral. In recent years, that recognition has however given way to the concept of synergy, where other components are also required to give something that 'va-va voom'. For calcium it is vitamin D.

Most people will probably have heard of vitamin D - if only they have heard of what happens when you don't get enough - rickets. It is slightly disturbing to see that rickets might be making an unwelcome return here in the UK and across the developed world perhaps as a function of our diets, our increasingly sedentary lifestyles and our guidelines for sun protection. The so-called 'sunshine vitamin' is pretty important when it comes to calcium and ensuring that it is properly absorbed from the gut via calcitriol. I talked briefly about calcium supplementation. There are various conditions where calcium supplementation (and vitamin D) might be a requirement, particularly in bone conditions such as osteoporosis. Research also seems to suggest that other conditions might benefit from calcium supplementation including hypertension and a possible reduction of the risk of some cancers (although the effect is not magnificent).

There is however a potential downside to calcium supplementation which came from this study. Bolland and colleagues (2010) conducted a meta-analysis of 11 trials of calcium supplementation (alone) in women aged 40 years and above, and concluded that the data implied an elevated risk for adverse events such as myocardial infarction (alongside a non-significant risk for stroke and early mortality). Quite a lot of discussion and media coverage has followed this review paper, not least because of the findings relating to calcium supplementation alone without accompanying vitamin D. A more recent analysis (2011) here from by the same authors suggested that even where calcium and vitamin D were administered, there remained an increased risk of myocardial infarction or stroke in this population. Whether the results can be extrapolated outside of women over 40 years old remains unknown.

Getting back to my particular interest in calcium in relation to autism and various gastrointestinal disorders, there are some final notes to make. In a recent post I talked about osteopontin in relation to autism. In that post I touched upon a study conducted by Hediger and colleagues which reported reduced bone thickness as being present in autism and specifically in those cases where a casein-free diet was being followed. The authors recommended that monitoring be put in place for this at-risk group. Based on these results and general dietetic advice where casein (dairy products) is being removed from the diet, there is perhaps some assumption that calcium and vitamin D supplement may be indicated.

Another point to arise from the Hediger paper was that their results might also indicate some GI disorder or lack of sunlight exposure (p.854) as also accounting for their results. Sunlight exposure has already been mentioned. The GI disorder suggestion stems from work in coeliac disease where absorption problems associated with gut pathology place affected individuals at greater risk of low calcium (and vitamin D) levels which tend to normalise when a gluten-free diet in implemented. Bone health can surprising also be aided by such a diet in certain cases. The logic: your gut is more permeable than it should be in coeliac disease hence you do not absorb your vitamins and minerals properly. Cutting out gluten helps to decrease permeability (and other things) which means you absorb more from your diet. I do wonder if this might also be the case with the gut hyperpermeability (leaky gut) problems detailed in autism?

One final word on calcium and autism relates to the issue of chelation. From the outset I will say that I am not an expert on chelation for the removal of heavy metals and offer no opinion on effect or not. From my limited understanding, various chelating agents have been suggested to remove an excessive metal burden thought to be associated with some cases of autism, although at the current time very limited evidence of effect or safety has been published. Having heard about a very sad story about fatality linked to chelation therapy for autism I chanced upon this article reporting the facts of the case. Calcium is a metal and hence potentially susceptible to some forms of chelating agent (EDTA) resulting in hypocalcaemia.

So there you have it. I hark back to my opening memories of warm milk and school-days; all with the best intentions as 'be brave' is whispered under my breath.

Monday, 30 May 2011

Fatigue syndromes: any link with autism?

We all feel a little bit run down now and again. Lack of sleep, too much work, keeping the children entertained, getting over illness, etc. But what happens when that run down feeling turns into something altogether more chronic and long-lasting? What happens when an active person who perhaps runs/jogs/walks miles every week suddenly can't even climb a flight of stairs without stopping half-way or maybe even not being able to get to the top at all? Welcome to Chronic Fatigue Syndrome (CFS) and/or Myalgic Encephalomyelitis (ME).

I would also like to acknowledge related conditions such as  fibromyalgia (FM) and Multiple Chemical Sensitivity (MCS) but in order not to confuse either myself or the issue won't go any further into the terminology on this occasions. A caveat also before I continue: I am in no way suggesting that I am an expert on CFS/ME. Indeed I don't claim to be an expert on anything in particular (aside from a bit of Star Wars trivia) so please bear this, and my previous posting caveat about not giving medical advice in mind before reading on. Onwards. There are quite a few accounts of Chronic Fatigue Syndrome (CFS) and/or Myalgic Encephalomyelitis (ME) on the web and I would encourage readers to have a look. Some of them are pretty harrowing in terms of how sudden symptoms can appear and the far-reaching consequences they have on a person's health and their life in general. I would perhaps also draw readers attention to this site also which carries some fairly comprehensive information on the various research into CFS/ME.

The stats: prevalence of CFS at some point in life has been estimated at anything between 0.1% and around 2% of the population depending on where you look, what age-group you look at and what diagnostic criteria you use. Gender-wise, females are about 6 times more likely to be diagnosed. And there are also some interesting co-morbidities potentially attached to a diagnosis.

Why am I talking about CFS/ME on this blog?

Well, for many years there have been some suggestions that CFS/ME might share some interesting connections with autism, even if not in presented symptoms. The more generalised links first. In many ways like some cases of autism, CFS/ME is also a hidden condition. Outside of those people who are bed-bound, a person with CFS/ME exhibits no outward 'differences' which immediately label that person as having CFS/ME. One might even argue that CFS/ME is also a spectral condition - or at least a condition based on observable phenotypes, based on active and remissive periods of symptoms and determinations of what 'abilities' or 'functions' a person has as a consequence of their symptoms severity. Phenotypes have also been tentatively suggested via gene expression (thanks to Maff at the Environmental Illness Resource for this information). Likewise, when it comes to the big question "what causes CFS/ME" we are in the same territory as "what causes autism". A big, fat, juicy question mark or more precisely lots of different question marks over lots of different factors. Some general similarities at least.

There are also some grassroots suggestions that autism and CFS/ME might also share some commonality as co-morbidities also or at least as part of a familial element. Although not the focus on this post, some of the various studies conducted on CFS/ME and Xenotropic Murine Leukemia Virus-Related Virus (XMRV) demonstrate a familial connection between CFS/ME and autism as witnessed by the way that children were recruited for this study. At the moment I have not seen any formal data on the co-morbidity of autism and CFS/ME together so I cannot provide such information. What I will reiterate from previous posts is that, at the moment, a diagnosis of autism does not seem to confer any protection against the risk of developing other conditions potentially to include CFS/ME.

A few weeks back I posted this entry on an article describing some possible connections between some cases of CFS/ME and gluten sensitivity. Regular readers might know of my interest in all things gluten, particularly related to autism. Delving into the research on CFS/ME, there are a few other overlapping areas which also caught my eye. Leaky gut and gut bacterial issues? Yes, those has been mentioned in connection to CFS/ME. Gastrointestinal inflammation? Yep that too. Immune function markers such as cytokines? Yes, and possibly as biomarkers for specific phenotypes. Even those humble neuropeptides and blood-brain barrier permeability might have a role in at least some cases of CFS/ME. There are other areas too numerous to mention in detail.

Intervention-wise, outside of dietary intervention, there are also a few familiar names being used, whether to affect core or peripheral symptoms. Melatonin is one of the main ones, but there are also some initial suggestions that things like probiotics might also help with ancillary symptoms and naltrexone has been mentioned in the lay-literature. I would at this point also say that I am by no means offering any opinion on the safety or effectiveness of these strategies for CFS/ME or anything else nor on the more 'physical and psychological' therapies put forward for treating CFS/ME.

OK I am not going to get carried away here. It is easy for me to 'cherry-pick' studies to prove my argument (there is generally no peer review on blog entries) and I might add that there are studies which go contrary to those I have highlighted (such as this one). Also, as with autism, many of these findings require quite a lot more replication and information on whether they are 'correlation', 'causation' or 'epiphenonemal'; whether also we talking about core or peripheral symptoms presentation.

The possibility of some shared genetics, biochemistry, etc between CFS/ME and autism exists in probably the same way that it exists in lots of different conditions. I perhaps would however be interested to see if anyone takes up the research gauntlet and takes the first step to see for example, just how prevalent CFS/ME is in autism (allowing for the possible communication and intellectual disability issues) and take things from there. If there is a possible connection, maybe we could start talking about a more generalised model of aetiology and pathology. If not, nothing lost.

Saturday, 28 May 2011

Overweight and obesity: just a simple in and out computation?

I want to pose a simple question: why do people become overweight and obese?

If, like me, you thought the simple answer was something like: 'because people eat too much and don't exercise enough' you might think you were right and that's it; the issue is solved by that simple equation: food in = energy in, exercise out = energy out. But what if it just wasn't that simple. What if there were maybe other factors which influence our relationship with food?

Two studies have caught my eye in recent days related to just this question. The first is this one from the University of Otago in New Zealand published in the BMJ. The basic premise of the study was to ascertain any relationship between sleep and weight (as measured by body mass index, BMI and body fat). The authors followed 244 children from age 3 to age 7 taking regular anthropometric measures (height, weight) and body fat measures. At the same time, sleep duration and physical activity were measured again at regular intervals.

Before I get to the results, I will ask another question: what would you expect to happen? Would you perhaps expect those who slept longer, and hence were physically less active for greater periods of time, to show a higher or lower BMI than those who slept less? Well, if you thought that longer sleeping time was associated with higher BMI... you would be wrong. The authors actually found that less sleep was associated with higher BMI alongside other studies examining this issue.

Why? Well the obvious answer would be that with more time awake, there was more time to do things like eat. The only problem with this argument is that dietary intake was controlled for during this study, alongside other variables such as birth weight, maternal smoking during pregnancy and quite a few other variables that could have potentially impacted on results. The results suggested that each additional hour of sleep between the ages of 3 and 5 were associated with a BMI reduction of 0.49 at age 7. The explanation for the results seemed to lie in what happened to fat in the body and its accumulation.

The second study is this one which relates to a doctoral thesis delivered at Lund University in Sweden. The student, Caroline Karlsson, reports that comparisons between rats fed so-called 'good' bacteria (in this case the aerobic species, Lactobacillus plantarum HEAL 19) against those fed inflammation-causing Escherichia coli (E.coli) seemed to account for differences in weight gain when eating the same type and quantity of food. More 'bad' bacteria = more weight gain - at least in rats (although interestingly the differences between bacteria type just missed significance, p=0.086). Similar observations have been made in other studies adding to the increasingly wider role that our gut bacteria seems to play in maintaining health (and disease).

Going back to the original question then: why do people become overweight and obese? These studies imply that to maintain that healthy weight it might not just be a case of monitoring what goes in and what comes out. Getting plenty of sleep when you are a nipper and perhaps keeping an eye on your gut bacteria before tucking into that full English might be important factors also. How such findings relate to autism and other conditions where early sleep patterns might be impaired and gut bacteria aberrant in some cases, is perhaps the next question to be asked.

Functional bowel problems and autism

It is perhaps one of the more widely discussed body parts related to autism spectrum conditions - the gastrointestinal (GI) tract. I say discussed, but this is at times perhaps too 'polite' a word to use given the various debates there have been on gut problems and autism, linked to all sorts of issues including: how prevalent they are, what causes them, whether they are linked to autism symptom onset and presentation and what can be done about them.

I should perhaps make a distinction at this initial point between the two types of GI involvement postulated in autism. On the one hand we have a potential association between some cases of autism and GI disease - things like variants of inflammatory bowel disease, coeliac disease, etc. On the other hand we have the association with functional bowel problems - things like constipation, diarrhea, bloating. Both types of GI disorder are linked to each other and both have been linked to autism to varying degrees, generating a considerable body of research literature in the process. I have touched upon GI disease co-morbidity in a few posts (most notably here and here). For this post I am focusing on the functional bowel patterns and symptoms in light of this recently published study following other independent research.

Before proceeding I will provide you with some information on constipation (prevalence: 5-30%) and diarrhea (prevalence: ???) with particular reference to the pediatric population. The prevalence figures for constipation should be the standard that should be borne in mind when looking at the data subsequently presented in this post. OK. The study in question is from the MIND Institute by Wang and colleagues, and looked at the prevalence of functional bowel problems in autism. The details: the parents/primary caregivers of 589 people with autism were interviewed and medical history data extracted. Data for 163 siblings (unaffected by autism) were also captured. Compared with siblings, parent reports detailed significantly more functional GI problems in the autism group (42% vs. 12%) (p<0.001). Constipation and diarrhea were the most commonly cited problems and having more severe autism was associated with a higher risk of presenting with GI problems.

Bearing in mind that this study was based on retrospective recall and relied on non-specialist testimony, there was a degree of overlap from the findings and other work in this area (a sample of which is here and here) although balanced with some disparity also (here and here). There are a few points we can draw from this collected information.
  • Allowing for differences in the way that such functional bowel problems are described and reported (by who, using what criteria, compared against who, etc), a diagnosis of autism does not seem to confer any protection against co-morbid functional bowel problems, at least to the same extent that they occur in age-matched populations. Whether there is any effect from gender remains to be seen.  
  • There is some evidence for functional bowel problems to be present more frequently in some cases of autism over others also being moderated by autism severity. At the present time however there are additional co-morbidities attached to autism (such as learning disability) that could at least partially account for results. 
  • In amongst the various investigations on functional bowel problems, there are only a small number of studies looking at the various reasons why such functional bowel problems could be present. I tend to cite this study by Afzal and colleagues quite a bit, simply because they suggested that milk consumption was the strongest predictor of constipation in their group. Are there other factors such as quality of diet, water intake, medication or other environmental effects which could also affect presentation? 

Before I end this post, I would briefly like to touch upon the thorny issue of treatment for functional bowel problems co-occurring in autism. I say this is a thorny issue because quite a few people I have talked to down the years have not had a great experience when trying to get theirs or their child's functional bowel symptoms examined and treated properly despite some formal guidance being in place.

I am not assigning any blame and do not wish to offend anyone involved in such treatments, who do sterling work. The problem of treatment seems to exist for many reasons: low numbers of suitably qualified professionals (particularly pediatric gastroenterologists), a continued state of 'not-knowing' when it comes to autism and functional bowel issues (despite available guidance) and also perhaps other factors.

I would like to think that here in the UK, with the commencement of the NICE guidelines on autism, we will see some credit given to functional bowel problems as a potential co-morbidity to autism. Also hopefully not too far behind, some authoritative research on strategies for alleviating such problems specifically with autism in mind, and recognition of the pain and suffering that they can potentially cause.  

Thursday, 26 May 2011

Pesticides and autism: chapter I

As we are constantly being told, autism is one of many conditions whose aetiology is thought to be governed by a variable, yet symbiotic relationship between genes and environment. I personally find this explanation to be quite a satisfying one because lots of conditions, Phenylketonuria (PKU) and coeliac disease for example, offer similar templates to work from despite being (supposedly) separate and independent of autism. My last post on pre- and peri-natal vitamin use combined with the presentation of SNPs in particular genes as indicators of 'risk' of autism is also a good example of such a gene-environment relationship.

A few questions do however remain: what is the relative percentage contribution of genes and environment? If it is variable, both inter- and intra-conditions, why? and what are the precise genes and environmental stressors in relation to something like autism for example outside of co-morbidity? I would perhaps like to tackle some of the evidence covering these questions (anyone have an eternity?) over the course of my blog-a-thon, but for today, I want to discuss the potential role of one particular environmental stressor: pesticides.

'Travelling through hyperspace ain't like dusting crops boy'. Wise words from Mr Han Solo in Star Wars IV: A New Hope. Actually dusting crops is a classic example of pesticides in use (I suppose they have pests even on Tatooine). Despite all the good intentions for using them, pesticides have however developed a bit of a bad name in some quarters, perhaps with some good reason. This, despite the fact that they actually do quite a good job at doing their job, i.e. getting rid of pests.

Perhaps the core problem is that some of the same biological processes that certain pesticides are designed to target in order to kill insects/rodents/plants are processes that we humans tend to use quite a lot as well. Humans are after all, not that dissimilar in basic biology from our flatmates who we share this lovely rock with. Who knows if the tables were reversed, we would probably be extinguished by our insect masters using the same cocktail of pesticides.

Seriously though, when it comes to a possible connection between pesticides and autism, the research is equivocal, at least at the moment. There is quite a lot of opinion linking the rise in autism prevalence at least partially with things like pesticide use. There is, for example, some suggestion of susceptibility genes being geographically distributed in autism, with particular reference to the paraoxonase (PON) gene and its variants. Levels of paraoxonase (PON1), an enzyme involved in clearing certain pesticides, has for example, been examined in conjunction with certain pesticides and infant neurodevelopment. All this and data from environmental tracking programmes suggesting a possible association between autism and pesticide use makes for a feasible relationship at least in some cases.

The issues, however, with the research so far are these:
  • Pesticides cover a range of different products - the chances are that you will have had some in your medicine cabinet at home at one point or another.
  • Because of their extensive use over the years, pesticide residues are endemic to our environment (some taking years to break down) hence we are all pretty much involved in this chemical soup in our day-to-day lives.
  • The fact that so many pesticides have been, and continue to be, used means that we don't have a lot of data on their potential combined, synergistic effects.
  • Establishing a 'cause and effect' relationship outside of other factors potentially involved is problematic. Unless you have a direct exposure event, like during sheep dipping for example, it is easy to pose the question: what about the contribution of other (environmental) factors?

That is not to say there may not be a relationship between onset of developmental conditions, pesticide exposure and genes - indeed, the evidence does appear to be swaying towards such a notion. But as always, things are rarely so simple and straight-forward. Take for example one quite important, but perhaps peripheral area of inquiry, on the possible usefulness of compounds such as galantmine in autism.

Galantamine is an interesting compound normally used in the treatment of Alzheimer's disease. One of the proposed modes of action of galantamine is its inhibitory action on acetylcholinesterase activity; whereby it increases the amount of acetylcholine available. This is pretty much the same action that certain types of pesticides (particularly the organophosphate variety) are known to do with the exception that galantamine tends to be reversible in its inhibition and some of the OPs not so. Query: pesticides and galantamine might work on the same type of enzyme - why then is galantamine suggested to be a possible intervention option for autism (and not only just in one trial)?

This is where it starts to get confusing as I am fast reaching the limits of my knowledge on this topic. Granted that there are many, many different classes of pesticides with various different modes of action and I am sure that the pharmacologists and toxicologists out there would be able to provide an explanation based on dosage and that reversible/irreversible mode of action. It could also well be that galantamine has other effects on autism outside of acetylcholinesterase which produce the positive effects reported and likewise pesticides might be acting on other biological systems potentially pertinent to conditions like autism. Let us also not forget that autism is more likely autisms and hence not readily carrying universal connections from case to case even despite the recent neurological findings. I think I need to do a little more reading on this topic, so perhaps be prepared for a chapter II and a few more chapters to this post.

Cue the Star Wars opening crawl.

Wednesday, 25 May 2011

Pre- and peri-natal vitamins, genes and autism

I remember speaking a few years ago to a specialist doctor in obstetrics. We were discussing pregnancy (as two men might do!) and he made a very interesting point during our conversation. On the topic of the developing foetus and nutrition, he said "oh, they take everything they need from mum, it's mum that suffers". He implied from this statement that the developing foetus is king/queen; and that it derives all its nutrients from mum, irrespective of whether she has enough herself and irrespective of what her needs are. He is of course right; hence the umbilical cord and its very important role in nourishment and the fact that conditions such as iron deficiency / anaemia are so prevalent during pregnancy (associated also with the increased plasma volume accompanying pregnancy I might add). I do also wonder if the association between post-natal depression and low levels of certain fatty acids might also be part of this one-way 'take all I can' relationship.

For this reason, and some quite important evidence on the risk of certain conditions being reduced, nutritional supplementation is generally recommended to pregnant women, particularly during the first trimester. A new study published in the journal of Epidemiology has suggested that a lack of maternal consumption of vitamins pre- and peri-natal might be linked to autism. The author group (again from MIND!) also took a look at our old friend MTHFR and found maternal mutations in this, and in another gene (in children) involved in the metabolism of another friend, homocysteine (COMT) also raised the risk of autism. Cumulatively if vitamin/mineral supplements were not taken and the various mutations were present, the greatest increased risk of autism was observed.

Aside from incorporating both genes and environment, there are some important messages to be taken from this study. First, it needs replication. From what I gather, the question of whether or not supplements were taken pre- and peri-natally were derived from memory for the study rather than medical records. Certainly here in the UK, there are a number of questions asked by Midwives during pregnancy about whether or not supplements (mainly folic acid) are/have been taken. I don't think that this extends to the pre-conception stage; hence a more prospective study is required. Second, I would be intrigued as to whether or not the authors have actually looked at things like current plasma homocysteine levels in mums and their children involved in the study. There is some, quite recent evidence, to suggest that homocysteine levels may be elevated in some cases of autism and can potentially be lowered by simple vitamin supplementation. Finally (finally!), MTHFR (methylenetetrahydrofolate reductase) has some interesting tie-ins to the methionine cycle and some other old friends (including sulphate). There are lots of different compounds to look at in these pathways; all crying out for further study and in particular, the various ratios among the compounds in these pathways. All in all though a nice study, decent numbers, well-defined group and a valuable addition to the MIND repertoire of autism research.

Tuesday, 24 May 2011

Cuddle me oxytocin

Without wishing to sound like I have had one beer to many, if this blog was an ice-cream I would generally liken it to a neapolitan. The reason being that I'd like to think that rather than just being 'plain' and providing only one flavour of interest, I try and make it more of a 'selection' ice-cream (bearing in mind that the chocolate portion always seems to go first). In my quest to provide the 'near-perfect neapolitan', I offer up this post on the hormone oxytocin.

Oxytocin (OT) has, whether fortunately or unfortunately, picked up the label of being the 'cuddle hormone' in certain circles given its connection to pair-bonding between mother and baby during that most sensitive of times, early infancy (very early infancy) and its empathetic undertones. It is quite a small peptide synthesised in the hypothalamus. Outside of uterine contraction and involvement with lactation, OT has found some interest in relation to quite a few different things. The more 'saucy' areas of OT are still the subject of some debate and given that this is 'not that type of blog' I will perhaps put such research to one side.

The attachment side of OT has meant that it has been looked at in relation to autism spectrum and related conditions given the focus (rightly or wrongly) on social interactive behaviours. Outside of the interest in possible genetic issues with oxytocin chemistry in autism, quite a lot of discussion has centred on the potential therapeutic properties of oxytocin administration for autism in light of lower plasma levels of OT being reported in some cases. The research is quite interesting: this study (randomised, double-blind, placebo-controlled) suggested the OT administration reduced repetitive behaviours. This study suggested that emotion recognition was improved following intranasal administration of OT. I like this study in particular, given its quite ingenious method of drug delivery - a nasal spray - a method which could no doubt be applied to lots of other pharmacotherapies used as part of symptom management, particularly those with a need to bypass the gastrointestinal route. OT is also showing some promising results for conditions such as schizophrenia.

There is perhaps another side to OT which also deserves some attention. A quite speculative article published in Medical Hypotheses theorised at a possible relationship between pitocin (OT) induction and autism. So far however the evidence for such an assertion is weak although there is some suggestion of similar correlations related to ADHD (an important co-morbidity to autism). It does look like oxytocin might have some role to play in some components of autism (in some cases). A quick search of ClinicalTrials.gov suggests that there is quite a lot of research on-going on autism and OT. The question is whether OT is the chocolate part of our neapolitan ice-cream or just the strawberry or vanilla sections? We wait to see.

Monday, 23 May 2011

1 in 6 children with a developmental disability

A short post this one with a headline which really does grab your attention. There I was watching Barack Obama rediscovering his Irish roots, and his missing apostrophe, whilst actually drinking his pint of Guinness (unlike a certain other person) on the news and my PC comes to life with the startling headline: 1 in 6 US children with a developmental disability. The headline is attached to an article that has appeared in Pediatrics titled: Trends in the prevalence of developmental disabilities in US children, 1997-2008. From the abstract and a few early media reports there are a few noteworthy points from this CDC sponsored investigation:

  • An increased prevalence of various conditions including autism, ADHD and developmental delays for children aged 3-17 years between 1997 and 2008.
  • Prevalence of these conditions increased from 12.8% (~8 million children) in 1997-1999 to 15% (~10 million children) in 2006-2008.
  • Prevalence of reported ADHD increased from 5.7% (1997-1999) to 7.6% (2006-2008).
  • Prevalence of reported autism increased from 0.19% (1997-1999) to 0.74% (2006-2008).
  • Lower income was associated with a higher prevalence of a developmental disability.
  • Hispanic children had the lowest prevalence of developmental disability (compared with non-Hispanic white or black children).

Bearing all this in mind, it is worthwhile pointing out that the data was derived from the US National Health Interview Survey. Similar methods of data collection have been reported previously for autism, where results from 2003-2004 for children aged 4-17 years suggested a prevalence rate of 0.57%. This would tend to fit with the data provided by the new study based on the dates studied. Previous results for prevalence of ADHD and ADHD-type symptoms can be viewed here. The finding that lower income was associated with a higher prevalence is an interesting one and kinda coincides with some of the discussions in this previous post looking at SES and autism following the recent King and Bearman paper. A reversal of the negative socio-economic status health gradient? The authors apparently have suggested lots of reasons for the increase in cases: better awareness, better screening and assessment facilities, etc. They also suggest that increasing parental age might be a factor alongside an increase in preterm births. Preterm births are something that have been examined using the same methodology - particularly birth weights - and found to present with a relationship (albeit not straightforward) with 'disability' prevalence.

So in May 2011 alone we have had 1 in 100 adults with an autism spectrum condition in the UK, 1 in 77 children with autism in Utah, 1 in 38 children with autism in South Korea and now this. Quite a month I'm sure you will admit. The question is what do we do next?

The nose knows

I always consider it a bit of bonus when PubMed lists a paper which is a bit out of left-field. Not that I am complaining when more "mainstream" science is also published. But every now and again something crops up leading to one of those 'mmm?' moments. The paper in question this time relates to the curious title of this post (which incidentally was a book I remember reading as a child, one of the few, I might add, myself not being a great reader of books in general): odor detection threshold, but not odor identification, is impaired in children with autism.

Why was I so drawn to this paper? Well, I can't say for sure. Maybe it was the connection to perception and the human senses, some of which I have blogged about previously in relation to autism (vision and hearing). Maybe it was the use of the unusual 'Sniffin Sticks' test. Maybe it was the focus on one of the more under-represented senses. I can't say.

The study and findings: a small-ish sized group with Asperger syndrome/high-functioning autism compared with age and gender matched non-AS controls.  The odor/odour detection threshold (the point at which a smell is smelled) using the Sniffin' Sticks method was different (higher) in the AS compared to control groups. The AS group were also better at smelling orange but worse at smelling cloves (no other significant differences in other smells were found). The same group have published in this area before and the other research in this area is equivocal.

Assuming that there is a biological explanation for the results, I do wonder if this might be a small part of the proposed social side of things relevant to autism. More and more the research seems to imply that the traditionally held beliefs on problems with social cues in autism for example are not being borne out by the research. Even eye movements in relation to attention in autism appear fairly typical.

Smell on the other hand is our hidden social moderator. Aside from providing us with quite a bit of information about the person or place or other thing we are presented with, smell is also tied into things like pheromones. I know that there is still some debate on 'the human sex scent' and whether we are so swayed by it. One however only needs to look at menstrual synchrony to see that there may still be something in it, even at a subconscious level.

One could also assume that issues with smell might also tie into problems with feeding behaviours given that the olfactory and gustational (taste) senses are inter-linked (as we all find out when we eat whilst having a cold). I do perhaps think it might be a step too far to say that the feeding problems described in autism are exclusively tied into a problem with smell, but you never know, it might be at least contributory.

I would be interested to see what other research comes out in this area in future.

Saturday, 21 May 2011

Hey sugar: diabetes and autism

I have a few mantras that I try and stick to on this blog. Probabilities, not absolutes, drive science is perhaps the primary one. Not too far behind is the fact that based on the current evidence, autism, in all its forms, does not seem to confer any protection against the development of other diseases/infections/conditions co-morbid to autistic symptoms. It is sometimes easy to forget that autism as a concept is really just a descriptive label covering a number of clinically-relevant characteristics. Underneath that label is a person with genes and an environment which confer the same variable protection/risk against all the different things out there which can potentially affect health, quality of life and also mortality the same as everyone else. The characteristics and severity of autism (and its co-morbidities) might be a barrier to either communicating needs or accessing appropriate healthcare; and if so, this is what we need to work on if we are ever going to truly have a society of equality. In this post I want to talk about quite an important condition - diabetes - and its links (or not) to autism spectrum conditions.

There are a number of good definitions of diabetes on the web. Diabetes UK has probably the most understandable description that I have found, discussing the primary forms of the condition, type-1 and type-2 diabetes. Importantly they also discuss some of the risks and myths around diabetes. The stats first: diabetes affects an estimated 4-5% of the general population, and the incidence of diabetes (type-2) seems to be increasing. Treatment depends on the type of diabetes. Type-1 diabetes is where the body does not produce insulin and so must be regularly supplemented. Type-2 diabetes is characterised by some endogenous insulin production but either not enough or the development of insulin resistance.

Insulin injections are the most common management option for type-1 diabetes, but there are other modes of delivery; the oral dosage form does have a few issues not least what happens to proteins and peptides in the gut. There is a link between diabetes and things like being overweight/obese and according to Diabetes UK, the risk of diabetes is increased where a 'severe mental health problem' exists. The risk of several other 'conditions' is elevated when diabetes is present; one of the more interesting for me was this paper suggesting quite a high rate of IgA antitissue transglutaminase (tTG) following on from my recent post on such findings in autism.

Whilst not wishing to imply that shared risk factors cover the entire autism spectrum, there is perhaps some scope for looking more closely at people with autism and their risk of developing diabetes. I have previously blogged about being overweight / obese in relation to autism and concluded that a similar risk of such issues seemed to be reported in autism and the more general not-autism population. Likewise co-morbidity of mental health problems in autism has also come under discussion and evidence suggests that there is perhaps a greater risk present in some cases of autism. Added to the fact that autism is generally not a life-limiting diagnosis in terms of early mortality (outside of mortality caused by accidents, etc), alongside other issues such as the use of various pharmacotherapies which carry some increased risk of potential risk factors for diabetes (i.e. weight gain), one could assume that autism carries at least some risk of developing diabetes. So what does the research literature tell us about autism and diabetes?

Well, quite a bit. There is some suggestion that there is an increased history of autoimmune conditions to include diabetes, in other family members of people with autism compared with control populations and evidence is not just from one study either. Interestingly, it appears that parental type-1 diabetes is the more common association over type-2. This study suggested that maternal diabetes during pregnancy might be one of several risk factors for autism. A paper delivered at the recent IMFAR 2011 meeting has put the association back on the agenda (association at least).

Getting an actual prevalence figure of diabetes in autism is slightly more elusive. There is some data from a few years back, reporting that rates of type-1 diabetes may be elevated in autism compared to population estimates (0.9% vs. 0.3-0.7%). This study also suggested that within a sample of nearly 6000 adults with 'developmental disability' over 11% presented with diabetes, although the terminology used does not necessarily translate as just autism. I would perhaps be inclined on the basis of the available data to suggest that diabetes, or at least type-1 diabetes, seems to show some association with autism perhaps a slightly greater levels than those present in the general population.

One of the main problems is how to ensure that appropriate monitoring for conditions like diabetes is put in place for people with autism. One would perhaps expect that those who are on the more severe end of the autism spectrum, who are perhaps not living independently and potentially in receipt of pharmacotherapy, would be subject to some kind of monitoring for diabetes, just as part of good practice and good medicines management. As for those higher-functioning people, who live independently and may not access healthcare quite so routinely, the question must be asked: who is monitoring their health?

Thursday, 19 May 2011

Dem bones dem bones dem dry bones

There is some very interesting research into autism coming out of King Saud University in Saudi Arabia this year. The various papers published in 2011 include this one on fatty acids, this one again on fatty acids and this one on anti-ganglioside auto-antibodies. There is even a trial on-going at the same centre on the use of camel milk in autism, I assume as an alternative to the bovine (cow) version. One study in particular caught my attention looking at serum osteopontin levels in autism.

Osteopontin is a glycoprotein primarily charged with the maintenance of tissue integrity during inflammatory processes. It has some structural duties in relation to bone health but also acts as a cytokine (inducer). The main study findings from Saudi Arabia: children with autism (n=42) had higher levels of serum osteopontin than matched controls; indeed over 80% of the kids with autism presented with increased levels (I assume this means over and above the top reference range). Importantly also that levels seemed to correlate quite well according to severity of symptoms as measured by the CARS: the more affected the person, the higher the levels detected.

This is a relatively small study and as such requires further replication. When however authors start talking about significant differences alongside elevated levels of something present in approaching 80% of a particular group, it grabs my attention the same way that the recent Buie paper did when they suggested lactase deficiency in over 50% of their group with autism. The two functions detailed in relation to osteopontin, bone and immune system, have cropped up a few times in relation to autism spectrum conditions.

'Dem bones, dem bones, dem dry bones' have been studied in autism quite a bit, but of particular interest to me was this paper from Hediger and colleagues. They suggested problems with bone cortical thickness in autism potentially exacerbated by use of a casein-free diet linked to calcium intake (although acknowledging to be also potentially due to accompanying GI disorders, lack of sunlight exposure and /or limited physical activity). I have a post scheduled for posting in the next few weeks specifically on calcium so will discuss this more then. Suffice to say that recent research has not indicated any increased risk of fracture in autism compared with controls.

OK I hear you cry - he is going to use the osteopontin findings to try and explain away the Hediger results and protect his beautiful casein-free diet. Well, no I am not; even aside from the suggestion, outside of autism, that high levels of osteopontin might correlate with things like onset of osteoporosis, at least in post-menopausal women. Of more interest to me in this post are the potential immune effects of osteopontin.

I will warn you that it gets a little complicated from here on in (for you and me both), but please stay with me. Osteopontin has been linked to the production of various cytokines including IL-6 and IL-17 in various states. As an amplifier of the Th-1 immune response (pro-inflammatory), osteopontin has also been suggested to show involvement in inflammatory bowel conditions such as Crohns disease, at least in mice. This paper for example suggested  that osteopontin was a good cop / bad cop depending on whether inflammation was acute or chronic. During an acute event (short-term) it reduced tissue damage and actually helped in mucosal repair. During chronic inflammation, it turns bad guy and promotes further inflammation. The question in relation to the levels detected in the autism group is whether or not the findings represent a reaction to an acute event or a more chronic one and if so against what? (Note: IL-17 has been reported in relation to autism here and IL-6 more widely so, including this paper here).

The autism study authors end their abstract with a question as to whether anti-osteopontin antibodies might be a useful intervention for cases of autism associated with (consistently) high levels of the compound. The literature on the use of such antibodies is interesting. This study for example, suggested that one type of monoclonal antibody might be useful to treat a particular type of arthritis. This study suggested a more general effect on organ atrophy.

I would very much like to see a little more data on osteopontin as a marker and data on the suggested intervention options in the test-tube first before adding my tuppence worth on possible efficacy on either autism symptoms or associated co-morbidities. I do wonder also whether the results obtained are 'transferable' across the different peoples and ethnicites where autism is present given that no other group has yet published on this compound as far as I can see.

I finish with a song.

Wednesday, 18 May 2011

More prevalence and incidence data on autism

Only a quick post this one, I promise. I, like many people, have been following the various studies looking at the prevalence of autism spectrum conditions quite closely over the years. There are literally hundreds of research papers on prevalence out there to choose from; nearly all pretty much saying the same thing - the prevalence of autism spectrum conditions is increasing. We can add a few more papers to the roll call following on from my mammoth post(s) covering the South Korean study, the UK adult study, the Utah data and the others that I have discussed during my short time on (in?) the blogosphere.

First, there was this paper describing the prevalence of autism in Israel between 1986 and 2005 from registry information. I say 2005, but these dates covered the children born. The actual data presented suggested an increase in the prevalence rate from those born in 1986 (1.2 per 1,000 children) to 3.6 per 1,000 for those born in 2003.

Second, there was this paper describing the incidence (note the word incidence) of autism spectrum conditions in Massachusetts, USA. The authors reported that incidence increased from 56 per 10,000 for those born in 2001, to 93 per 10,000 for those born in 2005 - again based on administrative records.

Both these studies are interesting. The Massachusetts (I always seem to think about the Bee Gees song when I say this place) study is particularly interesting because they have used the word 'incidence' over 'prevalence' which implies that the risk of being diagnosed with an autism spectrum condition increased between 2001 and 2005, at least in Massachusetts, USA. 

I am not convinced that from the abstract the Israeli study may also have been determining incidence (being based on birth cohort data); but without yet seeing the full-text of the paper, I can offer no more information at this time.

Tuesday, 17 May 2011

Immunophenotypes and autism

I knew it. Once I started blogging about the immune findings potentially connected to autism I would have difficulty stopping and indeed it has happened as predicted. It was the same when I got my very first Sinclair ZX Spectrum computer all those years ago: '10 PRINT "HELLO", 20 GOTO 10' - once bitten by the computer bug, forever smitten.

I do however promise that this blog with still continue to look at as wide a variety of research as possible so please read on confident that if this is not your cup of tea, soon there will (hopefully) be something.
The paper in question for this post is this one from that research behemoth, the UC Davis MIND Institute.

The title: In search of cellular immunophenotypes in the blood of children with autism published in PLoS One. I was drawn to this post because: (i) it is an interesting paper and (ii) some of the authors also lead on this paper including a technique very close to my heart (TOF LC-MS).

The title is perhaps more complicated than the study implies: look in blood samples taken from children with autism and controls for various immune cell populations and see if you can spot a 'signature' profile which might define one or other group and differentiate them. Pretty much the same concept as that wonderful 'metabolomics' field which I discussed previously.

OK the study did get pretty complicated but together we will go through the main findings.

The basics first: initially 2 groups: autism (n=70) and age-matched controls (4-6 years old) not presenting with autistic features (n=70). The autism group were subsequently divided into 'low' and 'high' functioning on the basis of IQ measures. There was a lot of diagnostic work-up on the participants to ensure that things like co-morbidities linked to immune dysfunction were minimised as much as possible.

5ml of blood were collected from each participant and subject to laser scanning cytometry, basically a very sophisticated counting machine (the molecular biologists might not like my simplification) coupled with some analysis of the intensity of antigens.

Alot of counting of various immune cell populations was done and then the results: depending on the significance level, anywhere between 21-151 markers were different between autism and controls. A smaller number of markers showed differences between the 'low' and 'high' functioning groups (between 1-33). Absolute numbers of B cells and NK (natural killer) cells were reported significantly higher in autism vs. controls. A few other types of cell populations were almost significantly different, including our old friends the eosinophils (p=0.066). There were a few other interesting results, not least the intensity of cell surface markers expressed on immune cells such as CD26/dipeptidyl peptidase-IV on CD8 T cells in the autism group over controls. Some might have heard about CD26/dipeptidyl peptidase-IV from some suggestion a while back on a possible relation to autism and peptide chemistry.

There is quite a bit of overlap from these results and the research literature so far although not all of it is in the same direction. NK cell activity in this paper for example, was lower in autism. Even the late Reed Warren and his early results suggested a similar pattern. The current paper explains such differences in terms of the younger age group included and methodological/analytical differences. The fact that the current participant group were so tightly controlled in terms of co-morbidity might also be a factor.

Given that the aim of this blog is to question answers, I have to say that I am struggling with this one. I could perhaps argue that an additional control group made up of children diagnosed with non-specific learning difficulties (without autism) might have given an additional dimension to the study. One could also suggest that a similar analysis based on either the same participant group 3-5 years down the line when diagnoses potentially become a little less unstable might also be a good idea or failing that an independent adult participant group. Finally I can't seem to find anything in the paper about participant use of medication, diets, etc (whether this would have an effect, I don't know). These are but observations, and I don't want to unduly criticise just for the sake of it.

I probably have not done this new paper justice in terms of my summarising such an extensive piece of work into a short blog description. I do however tip my hat and say to rack up another one for the MIND Institute (who I have heard have just received quite a large pot of money to start looking at gastrointestinal co-morbiditiy in autism).

Monday, 16 May 2011

Don't let me in: the blood-brain barrier

Several of the posts on this blog include the concept of biological barriers and what potentially might be the effects of problems with hyperporosity (leakiness) of such barriers. This is particularly true of the gastrointestinal barrier in relation to things like coeliac disease and inflammatory bowel disease. Autism also seems to figure to varying degrees in such discussions.

The gastrointestinal barrier may well be important for lots of different reasons; predominantly stopping things getting out - fragments of food proteins, peptides, eosinophils, etc. which could conceivably have various somatic effects (and possibly a few psychological ones too).

In this post I want to talk about a barrier which is primarily charged with stopping things getting in - the blood-brain barrier (BBB). I am not going to just recite the various descriptions of the BBB. Suffice to say that it is a partly chemical and partly physical barrier which protects perhaps our most complex organ. The scientific literature extensively discusses the BBB with reference to just about everything - structure, development, disease, etc. With regards to autism, there is also a fair amount of material to analyse.

One might assume some potential relationship between the BBB and some cases of autism given the effect of conditions such as encephalitis and meningitis on barrier function potentially connected to autism onset tied into such infections. The fact that seizures and epileptic syndromes can also affect/be affected by the barrier might also be of some interest given the presence of this fairly common co-morbidity.

Quite a bit of the early autism-BBB material is taken up on peptide-hormone chemistry and in particular the opioid-excess theory of autism. There is still a degree of speculation on this theory with reference to the BBB (not so much the gut membrane), and not everyone is as much a fan as I am of the potential for the theory, but that is perhaps fodder for another post. There are also subtle hints of immune effects to things like cows milk protein potentially tied into 'alterations in the blood-brain barrier' in autism. Although the precise mechanism has yet to be elucidated, inflammation seems to be key, and cytokines might have quite a significant role to play.

Other research has suggested a connection between aberrant amino acid transport across the BBB and autism. Levels of serum tryptophan, for example, have been suggested to be perturbed in some cases of autism with possible implications for levels available for subsequent brain 5-HT synthesis given also the enzyme kinetics linked to the presence of other amino acids.

Our old friend tetrahydrobiopterin (BH4) has also been mentioned with the BBB and autism in mind.
This is an interesting study on the possibility that genetic differences in one or more of the proteins which potentially aid transport of drugs across the BBB might (partially) account for differences in the effectiveness of some medications used for autistic symptoms. I do wonder if similar studies might also shed some light on the different experiences of medication used in autism.

What seems to be missing from the research on the BBB and autism is data on the integrity of the BBB. There are quite a few ways to measure such permeability based on the various drug transport studies around including use of Evans Blue and other contrast agents coupled with MRI.

I assume that research will eventually get round to looking further at the BBB in relation to autism given the current focus on brain structure and autism. I will perhaps come back to the BBB at a later date given its potential importance for lots of things related to autism and beyond.

Saturday, 14 May 2011

The South Korean study

It is not that often that a study marks a turning point in autism research. It is something that most researchers in every field of endeavour, whether they admit or not, aspire to produce. Whether out of professional pride or insatiable scientific curiosity or for more personal reasons, the desire for their paper - their hard work - to be hallowed forever after is at the back of the mind.

We have had a few such studies down the years that have perhaps fulfilled this criteria including: Kanner's original 1943 descriptions, the 1979 epidemiological study by Lorna Wing and Judy Gould, the 1995 strongly genetic disorder study, the now-retracted 1998 Lancet bowel problems case series, the 2006 1% prevalence paper, the 2010 AAP position papers on GI dysfunction and autism (here and here) and the recent 2011 1% adult prevalence study. I would perhaps add Asperger's 1944 contribution to this list, if only I could put my GCSE German to good use.

I apologise if I have not included more of your particular choices, but these are the movers and shakers that I remember (not necessarily first-hand I might add - I'm not that old). I would by the way, also say that I am not offering any opinion on whether these studies were right or wrong in their findings, and am also mindful that some people might disagree with the presented choice given the various debates that continue to occur. The point I am however trying to make is that these papers have, in one way or another, secured a place in autism research history. I would also perhaps add a few other studies - not mine - related to my small area of interest in autism research (maybe this one and this one) as a side-line; make of these what you will.

I think we can safely say that the 'South Korean' study will also be added to this list given the quite phenomenal prevalence rate of 1 in 38 children with an autism spectrum disorder reported therein. I say all this mindful of the fact that the figure of 1 in 38 children with autism represents real people and real lives rather than just being some academic exercise. I will attempt to highlight some research points from the South Korean paper in due course but first wish to reflect a little on the human implications of the study now that the media dust is beginning to settle.

There are already some views emerging following the publication of this paper. Views as to what it means to have autism (or rather an autism spectrum condition) and views on what the potential implications are from this study. For some, this study and the astounding prevalence rate, is support for the 'neurodiversity' movement suggesting that autism is a part of the complex tapestry called the human condition. For others this study is support for the growing health issue that is autism, with a vast increase in numbers of cases (people) who will require often significant help and support in the years ahead. The perspectives tend to differ as a result of lots of factors not least a persons' own personal experiences of autism, whether they are a person with autism, a parent or caregiver, professional or policy-maker and what 'autism' they are talking about. Looking at the South Korean study, I would forward the argument that both viewpoints are actually correct; you will see why (hopefully) shortly.

As I posted previously, the study (which will henceforth be referred to as the SK study to save my poor typing fingers), whilst looking at one specific district in South Korea, actually looked at 2 different populations: those in 'regular' school (n=36,592) and those in 'special education' school or on a disability register - a so-called 'high probability group' (n=294). The paper cites a total population of 55,266 7-12 year old children in the abstract (used as the final denominator of prevalence) but about 1 in 4 schools initially approached said they did not want to participate in the study leaving a combined total of 36,886 participants.

A 2-stage design was used during the study; the first stage involved screening children for autistic traits using the Autism Spectrum Screening Questionnaire (ASSQ). For those positive screeners, a subsequent battery of gold-standard, autism-specific assessments (ADOS and ADI) combined with cognitive-intellectual testing was carried out. A similar design was used in the recent 1 in 100 adult study albeit with a different screening instrument.

The results.

  • The initial response rates from the ASSQ screen were quite different (35% high probability vs. 63% general population). Interesting also, that ASSQ data for 314 children were completed by teachers not parents.
  • The crude, unadjusted prevalence rates (unadjusted for non-participants in the study) per group for all autism spectrum disorders were: high probability group = 0.18% and general population = 0.19%. Remember, these were prevalence rates which took no account of those who did not participate in the study and were based on the total population figure denominator of 55,256. (If you calculate prevalence based on those actually sampled, (n=36,866) you get 0.4% and 0.1% per group with a cumulative 0.5% prevalence rate).
  • The adjusted prevalence rates were: high probability group = 0.75% and general population = 1.89%. The cumulative prevalence rate was 2.64%. I have tried to look at how the 'adjustments' were made but fear that my limits have been reached on such statistical challenges.

A few other interesting points are noteworthy.

I made a comment on my first post about this study that because the majority of the prevalence was in the general population group who were in regular school and unrecognised to disability registers, this might imply a large group of children with an autism spectrum disorder with average (or above average) intellectual functioning were driving the prevalence figures. The study text does seem to bear this suggestion out. The percentages of children, for example, in the general population group with autism (core autism) falling into categories of superior and average IQ groups were 11.1% and 55.6% respectively. This is compared with figures of 6.8% and 28.4% in the high probability group.

The flip-side of the coin is the fact that autism, particularly in the high probability group, was accompanied by a considerable degree of intellectual disability; again looking just at core autism, borderline and profound intellectual disability were present in 33.8% and 27.0% respectively (compared with 25.9% and 7.4% in the general population group). The research literature would agree with these figures.

Also, the authors reported finding no cases of Rett syndrome and no cases of Childhood Disintegrative Disorder/Heller's syndrome in the cohort. I am a little bit surprised at this given the large sample size included and the estimated prevalences of such conditions (Rett syndrome figures here); indeed the figures for CDD prevalence come from one of the authors of the SK paper. Does this imply that South Koreans are somehow 'protected' from Rett syndrome and CDD?

So there you have it, 1 in 38 children in this study of autism in a district of South Korea. What this means for other prevalence studies and for the estimates for other parts of the world remains to be seen.
I hope I have made a case for how this study straddles both the neurodiversity and need for more services suggestions and how one way or another, society really does need to sit up and take notice.

Friday, 13 May 2011

Risk, season of birth and autism

Risk is a strange thing. We are told by many different sources about the risk of this happening, or that happening, normally accompanied by some smart figure. This page offers quite a good example of risk in action based on the UK mortality figures. What the statistics tell me is that, as a man, I am at greater risk than a woman of death at every stage of my life, from my first breath to my last, and without giving my age to you, I am currently on the borderline of a low-to-moderate risk of dying anytime soon. Great (he says reaching for the Smiths CD).

I was in two minds whether or not to make this post relating to possible seasonal influences and risk of receiving a diagnosis of an autism spectrum condition. Two minds because you could give me almost any reasonably well-known condition and I could probably provide some evidence that season or month of birth is potentially connected in some way. For example, the risk of brain tumor is greater for those born in the Winter according to this study. Interesting yes? But consider how many factors might be involved in developing a brain tumor - not least your subsequent exposure events to lots of things - and then such statistics begin to mean less and less.

I am not disputing that there may be a connection between some conditions and season of birth. There are perhaps some important connections to be made in respect to things like maternal risk of exposure to viral or other infectious agents, whether pollen counts are high, sunlight exposure, and even depending on where you live, whether or not there is increased exposure to environmental pollutants such as car fumes or pesticides.
I merely suggest that when we start to say that heterogeneous conditions like autism are 'related' to this month or that month of birth or conception, we start to enter some pretty shaky territory.

The paper which attracted my interest was this one published in Epidemiology from the MIND Institute. It has been followed by quite a few headlines like this one. Their findings: based on an analysis of quite a large participant base of people with autism (n=19,238), there was an increased 'risk' of autism where conception occurred in December through to March.

I say an increased risk but the odds ratios (OR) ranged between 1.08 - 1.16). Assuming that 1 implies the likelihood of something occurring in equal measure across 2 groups, you can see that the stats are not exactly jumping out at us (even with the confidence interval data presented). Consider as a comparator the OR of developing autism and living close to a motorway (freeway) by some of the same author group (OR = 1.86, CI: 1.04-3.45). See what I mean?

The MIND paper is not the first (and no doubt won't be the last) to suggest such a correlation to onset of autism. Last year we had this paper which suggested that in a UK cohort, conception during the summer months was associated with an increased risk of autism. Yes, I know that the participant group was far, far less (n=86) but importantly this was a prospective study based on the ALSPAC initiative.

I could go on with other studies, all seemingly suggesting different things. There are of course various factors to consider: where the study was conducted, how many people were included, etc. All of which can (and do) impact on the results obtained. There may very well be some sub-groups of autism with a seasonality factor attached, but at the moment we can't say for sure.

Importantly also some studies have reported no seasonality effect. This paper from Fred Volkmar and colleagues says it all in their title - even showing no association when sub-categorising participants based on language ability.

I will close with our contribution to this issue published in 2009. We did a slightly different kind of analysis, looking at the various sub-diagnoses of pervasive developmental disorder according to season of birth compared with population data (from the ONS) and found... absolutely nothing - no differences across the different cohorts and no differences overall. I would not presume to say that this issue is closed but I am inclined to say whilst an interesting area of research there is probably no overall relationship with autism.

Tuesday, 10 May 2011

Anti-malarials and schizophrenia (and autism?)

Schizophrenia has been of some interest to me over the course of my research career. I have never (knowingly) been involved in any research to do with schizophrenia but a few things have pointed me in the direction of its symptoms and potential aetiology-pathology as a consequence of my interest in autism spectrum conditions.

A little bit of background first. Schizophrenia is a psychiatric condition primarily diagnosed on the basis of presented psychological symptoms to include hallucinations and delusions; whereby distinguishing thoughts and ideas from reality is problematic. There are quite a few misconceptions about schizophrenia related to things like the concept of a 'split personality' (based on the literal Greek translation of schizophrenia).

Many, many years ago autism was 'associated' with childhood schizophrenia (the journal, JADD used to be called the Journal of Autism and Childhood Schizophrenia). Suffice to say, autism is not childhood schizophrenia.

Schizophrenia and autism coincided in my work primarily because of the research of the late Curt Dohan and his suggestion that where gluten was rarely eaten, the prevalence of schizophrenia was also low. Indeed, my recent communication with Dr Dohan's son, Dr F. Curtis Dohan Jr (who is also interested in the connections between gluten, schizophrenia and autism!) confirmed a story that I heard many years ago, that on the day he died, Dohan Sr was reading/being read a manuscript from Dr Kalle (Tiny) Reichelt on the possible association between autism and gluten. I hope I don't reveal too much when I say that Dr Dohan apparently got to page 5 of the manuscript in question before he passed away - enough time for him to hopefully see how influential his ideas were.

The possibility of an association between schizophrenia and gluten has been rumbling on for many years. Emily Deans over at Evolutionary Psychiatry posted an excellent entry on this last year. Coeliac disease and schizophrenia? Got that. Gut hyperpermeability and schizophrenia? That too.

In more recent years, the work of Faith Dickerson and colleagues has suggested quite a few 'issues' with gluten in conditions like schizophrenia. All in all, I am inclined to say that assuming that schizophrenia is a heterogeneous condition too, there may be a sub-group of people who, like in autism, show some sensitivity to gluten through whatever process.

I digress. The title of this post concerns this paper from Dickerson and colleagues on the possible effect of an anti-malarial agent on the presentation of antibodies to gluten (gliadin) in schizophrenia. The anti-malarial agent in question was artemisinin, which by a strange twist of fate I had heard about recently from discussions with a group who have been developing assays examining yields of artemisinin for treating malaria.

The Dickerson paper is interesting for several reasons. They were examining the possible effectiveness of artemisinin as part of their studies on a possible connection between schizophrenia and Toxoplasma gondii. I did briefly touch upon these studies in a past post on PANDAS. They did not however, find any specific effect from artemisinin administration on either antibodies to T.gondii or psychiatric symptoms associated with schizophrenia. The only effect was on gliadin antibodies which were reduced in the active treatment group (significance level: p<0.005) when compared to the placebo arm of their trial.

I am quite interested in these findings. Interested that an anti-malarial compound could have such pronounced effects on the presentation of gluten antibodies (at least in this study group). Interested also in the possible mode of action, for which I have been able to find only limited data on, for example, its immuno-suppressive effects and a potential role for heme. The immuno-supressive bit could be interesting and tie into helminthic therapy (could!). It makes me wonder if such a reduction could also be achieved for other groups with other gluten-related immune-mediated conditions, such as coeliac disease for example.

Also, without wishing to offer any advice or opinion (please do not run down to your nearest anti-malarial shop and purchase), I also wonder whether such an effect would benefit that proportion of people with autism who also show raised gluten antibody levels (whether as a result of co-morbid gluten sensitivity or other by some other means) and whether or not it would affect other areas of functioning - an alternative to a gluten-free diet perhaps?

I must reiterate that all of this is speculation on my part only and should remain just that. Dickerson and colleagues noted no significant side-effects from artemisinin administration over 12-weeks but that does not necessarily mean the compound is safe. The WHO have politely asked that artemisinin monotherapy be phased out in order to combat drug resistance.

As we have seen in recent days, there is folly in extolling a non-tested intervention for autism without the appropriate safety and efficacy studies being done. I, for one, do not wish to fall into that trap.