"Ashleigh's vision problems were misdiagnosed as autism"

The quote titling this post - "Ashleigh's vision problems were misdiagnosed as autism" - comes from a TV programme that was picked up by the BBC news website recently.

It continues a theme in recent times showing examples where autism has been seemingly 'misdiagnosed' (see here and see here) at the cost of other recognised medical conditions being present. Such misdiagnoses have many potential implications; not least for the various trends in some quarters to 'self-diagnose' autism or self-identify as autistic without any formal assessment seemingly being undertaken (see here and see here).

So what was the misdiagnosed condition this time around? Well, it's potentially an important one because is covers a topic rather salient to autism: vision and the processing of visual (sensory) information (see here for example). To quote: "After being misdiagnosed with Asperger syndrome, Ashleigh later found out that her behavioural problems actually came from Cerebral Visual Impairment (CVI)." When describing CVI, the key point I get from the descriptive literature is that vision is not just about the eyes but also what the brain does to/with the visual information collected through the eyes.

Aside from the label 'Asperger syndrome' disappearing from diagnostic texts and discussions for various reasons (see here and see here), a quick glance at some of the information on CVI reveals that the potential misdiagnosis of autism when CVI was present is not something entirely new (see here). To quote from the RNIB (Royal National Institute for the Blind) website here in Blighty: "Many of the standard special needs assessments generally fail to identify children with CVI. If anything there is a danger that they may be misdiagnosed as possibly having autistic spectrum condition, due to some of the characteristics being shared. Not being able to maintain eye contact or respond to facial expressions, may be due to poor contrast sensitivity or to the part of the brain that recognises facial expressions being impaired." They don't however discount the idea that CVI and autism can co-occur - "Of course CVI and autism can co-exist" - something that an expert I mentioned this study to confirmed and something noted in the peer-reviewed science literature [1] too. But misdiagnosis is also a potential risk.

I'm not going to say too much more on this topic aside from reiterating an oft-mentioned phrase on this blog: the diagnosis of autism should be a starting point for further investigations and not the finishing line. I appreciate that to many people - individuals and their parents/caregivers - the time and effort spent actually getting and going through assessment and diagnosis of autism feels like it should be the finishing line (see here). But please, don't stop there. Keep questioning and importantly, keep screening, and screening for lots of different things. As per the example of Ashleigh, there may be lots more to see (pardon the pun) and in some cases, potentially novel and important 'intervention' avenues to consider to improve quality of life [2]...

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[1] Bosch DG. et al. Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12. Clin Dysmorphol. 2015 Jan;24(1):34-7.

[2] Bartel T. Mystery solved: Our son's autism and extreme self-injury is genetic and treatable. Am J Med Genet A. 2017 May;173(5):1190-1193.

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"Hyperopia, astigmatism, and strabismus seem to be independently associated with ADHD"

The findings reported by Charlotte Reimelt and colleagues [1] provide the brief blogging fodder today and the observation that following their analysis: "all examined forms of refractive error and strabismus showed an association with ADHD [attention-deficit hyperactivity disorder]."

Refractive error (e.g. near and far sightedness) and strabismus (squint) are not uncommon eye/vision issues among the general population. I've previously talked on this blog about such issues being potentially over-represented among certain diagnostic labels (see here) but up until now I don't think I've talked about such issues with ADHD in mind. I have discussed visual impairment and ADHD (see here) but not these specific eye issues.

Drawing on data derived from "the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study (N = 13,488)", researchers observed "an increased risk for ADHD in children with hyperopia, astigmatism, and strabismus compared with the control group." They also make a case for further research in this area.

Obviously the oft-used tenet 'correlation is not the same as causation' comes into play here. It means that we have to be quite careful not to say that such eye/visions are a *cause* of ADHD or vice-verse because that has not been proven by such data. The Reimelt findings do however imply that preferential screening for such eye conditions when a diagnosis of ADHD is received might be a good idea. They also imply that preferential screening for ADHD and/or related behavioural issues, might also be a good idea as and when such eye/vision conditions are also detected.

So, Merry Christmas and as is typical, Kirsty MacColl and The Pogues. And just in case you thought 'drunk tanks' were a thing of the past, think again...

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[1] Reimelt C. et al. The Underestimated Role of Refractive Error (Hyperopia, Myopia, and Astigmatism) and Strabismus in Children With ADHD. J Atten Disord. 2018 Oct 29:1087054718808599.

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Physical conditions accompanying intellectual disabilities

By linking to some media discussing the inquest findings for Richard Handley (see here) I don't want to trivialise his death or use it as some kind of 'I told you so' example. Here was a man who died as a result of "gross failures" in his care as someone with Down's syndrome who also had a history of bowel issues. His death, linked to chronic constipation and "as a result of choking on his own vomit having inhaled gastric contents following complications with surgery", represents failures on many different levels. Not least is a seeming lack of appreciation of how bowel issues can very much be part of the clinical profile of many conditions / labels / diagnoses considered within the spectrum of intellectual or learning disabilities. Said issues require both regular monitoring and appropriate and timely intervention.

It is perhaps notable then that the paper by Deborah Kinnear and colleagues [1] is published these days, highlighting how various physical conditions are over-represented alongside diagnoses characterised by intellectual (learning) disability. The authors reported that: "The five most prevalent were visual impairment, obesity, epilepsy, constipation and ataxic/gait disorders."

Based on the examination of data for "people with intellectual disabilities living within the geographical area of Greater Glasgow Health Board, Scotland" between 2002 and 2004, researchers reviewed case records and "completed a comprehensive semi-structured health interview and targeted physical examination and followed a phlebotomy protocol, with the person with intellectual disabilities and their carer." This was time consuming affair - the "complete assessment process took about 4 hours per participant" - covering over 1000 people.

Alongside the reporting of those 'top five most prevalent conditions', researchers also observed several other important details. Namely that nearly all of their cohort had a least one co-existing health condition. The average number of comorbid conditions was 11. Yes, that's 11. And some people had over 25 comorbid physical conditions. When also taking into account the presence or not of Down's syndrome, not much changed in relation to the detected physical comorbidity. Similarly, when age and sex/gender were examined, the authors concluded that there only minor differences noted in terms of comorbidity profiles for example.

Relevant to the case of Richard Handley are some discussions in the Kinnear paper about constipation and learning disability. So: "Constipation was the fourth most prevalent physical health condition." Further, they note in another study [2]: "Eight people with chronic constipation had serious side effects (rectal prolapse, diverticula of colon, intestinal obstruction, megacolon and haemorrhoids) and four eventually died of intestinal obstruction... Thus, as well as being painful, constipation may remain undetected for a long time and can cause death due to missed clinical symptoms." Constipation can cause death. It shouldn't in this day and age, but it still does...

In relation to the implications of their findings, the authors make some additional comments. So: "Medical education is also focused on assessment and management of single conditions, yet management of multimorbidity is far more complex." This is important. It implies that outside of the view of one [primary] diagnosis being present per patient, clinicians and others need to have a more plural view, particularly when it comes to something like learning disability. The focus also on 'physical' comorbidities is also important insofar as how various developmental / behavioural / psychiatric conditions can very much manifest other non-developmental / behavioural / psychiatric conditions. This kinda mirrors what has been discussed with autism in mind (see here and see here for examples) and, alongside, the barriers that need to be overcome when it comes to appropriate diagnoses being made in such contexts (see here).

Set within other data indicating that premature mortality is very much over-represented when it comes to learning disability (see here), and that much of that early mortality is due to the presence of physical health conditions, the Kinnear findings should serve as a wake-up call to many sectors of the professional and other communities. Screening, diagnosing and implementing timely and appropriate intervention(s) are key recommendations; with a specific focus on the person as a whole rather than just being the sum of individual somethings like the diagnosis of learning disability. Bear in mind also that guidance on the management of something like constipation in the context of learning disability does exist in the peer-reviewed domain [3].

And finally, just in case you think that today's discussions aren't directly relevant to autism, constipation has also been mentioned in the death of another young person (see here)...

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[1] Kinnear D. et al. Prevalence of physical conditions and multimorbidity in a cohort of adults with intellectual disabilities with and without Down syndrome: cross-sectional study. BMJ Open. 2018; 8: e018292.

[2] Evenhuis HM. Medical aspects of ageing in a population with intellectual disability: III. Mobility, internal conditions and cancer. J Intellect Disabil Res. 1997 Feb;41 ( Pt 1):8-18.

[3] Robertson J. et al. Constipation management in people with intellectual disability: A systematic review. J Appl Res Intellect Disabil. 2017 Nov 23.

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Including the "full intellectual range" in autism vision research

The paper by Alyse Brown and colleagues [1] (open-access available here) is probably not going to gain any significant media headlines (unlike other recent studies - see here and see here) but does cover a rather important question regarding the autism research landscape: how representative is autism research?

Specifically looking at the collected research on visual processing (distinct from physical issues with the eyes that still require greater awareness) with autism in mind, the authors surveyed the research literature to determine "what extent the ASD with-ID [intellectual disability] population has been excluded from visual research." Intellectual or learning disability is one of the more frequently over-represented comorbidities that can accompany a diagnosis of autism or autism spectrum disorder (ASD). Their answer: "our searches indicate that 80% of the vision research associated with ASD is representative of less than 60% of the appropriate population, i.e., those with ASD without ID while the ASD with ID group who we argue currently represent 42% of the ASD population, have not been adequately considered."

You may well quibble with the "recalculation of ASD prevalence figures, using the criteria of DSM-5" as a means of calculating that '~40% of those with autism have ID too' figure. For me however, the message is quite stark: autism research - specifically related to visual processing issues - is not yet representative of  'all autism'.

"Reluctance to test individuals who are below 80 in IQ is presumably a practical stance as the data collected from these individuals are often hard to obtain, and often close to floor level performance." The authors note however that the presence of ID alongside autism in the area of visual processing is not something that cannot be 'overcome' by researchers with some creative thinking and a few modification(s) to their experimental designs. Indeed, visual processing research lends itself well to quite a few alterations to methods [2]...

How applicable might these results be to other areas of autism research? Well, we just don't know. I daresay that quite a lot of the 'psychology' based autism research in particular might show a bias towards autism without intellectual disability for just those reasons listed above. The problem then of grand, over-arching generalisations to 'all autism' on the basis of results from the more 'cognitively-able' becomes apparent. Of course, in these days of the plural 'autisms' (see here) and the realisation that 'heterogeneity means heterogeneity' when it comes to autism (see here) one could argue that even characterisations based on the presence of ID or not when it comes to autism are equally 'simplistic' and equally 'useless'. How many autisms might well have an ID element to them? Is ID a comorbidity or something rather more central to some of the autisms? These questions and related others are ones that autism research as a whole will eventually have to start looking at and taking into account.

And going back to the issue of eye disorders being potentially over-represented and under-diagnosed in relation to autism, the paper by Mouridsen and colleagues [3] reiterates that intellectual ability when accompanying autism needs more health equality: "The rate of eye disorder was particularly high (24.5%) in those with a co-occurring profound or severe learning disability (IQ < 50)."

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[1] Brown AC. et al. Vision Research Literature May Not Represent the Full Intellectual Range of Autism Spectrum Disorder. Front Hum Neurosci. 2017 Feb 14;11:57.

[2] Boot FH. et al. Delayed visual orienting responses in children with developmental and/or intellectual disabilities. J Intellect Disabil Res. 2013 Dec;57(12):1093-103.

[3] Mouridsen SE. et al. Eye Disorders among Adult People Diagnosed with Infantile Autism in Childhood: A Longitudinal Case Control Study. Ophthalmic Epidemiol. 2017 Mar 15:1-4.

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Brown AC, Chouinard PA, & Crewther SG (2017). Vision Research Literature May Not Represent the Full Intellectual Range of Autism Spectrum Disorder. Frontiers in human neuroscience, 11 PMID: 28261072

Autism and visual impairment reviewed

Of the various autism science journals out there in peer-reviewed (La-La!) land, one journal in particular is really starting to grow on me: [The] Review Journal of Autism and Developmental Disorders.

I like this journal because it is basically systematic review and meta-analysis heaven when it comes to the quite voluminous autism research literature and seems to publish some real gems (see here for example).

Another paper from this journal caught my eye recently by Maggie Butchart and colleagues [1] (open-access) synthesising the collected research on "the prevalence of visual impairments in children and adults with Autism Spectrum Disorder (ASD), and the similar behavioural traits associated with both visual impairment and autism." Affiliated with the RNIB - Royal National Institute of Blind People - Scotland among other groups, the authors trawled the research literature looking at reported visual impairments in relation to the autism spectrum and provide quite a nice overview of 'where we're at' with regards to "papers published from 2000-2015."

The paper is open-access but a few comments are required bearing in mind my relative lack of knowledge on the complexities of visual impairments.

First: "Collating the evidence from six of the seven prevalence studies suggests a refractive error rate in the childhood ASD population studied at 22.9–32.7%, which is comparable with general childhood refractive error rates in 6–7 year olds at 29%, and 32.3% in 12–13 year olds." What this means is that a diagnosis of autism does not protect against the presence of refractive errors ('when the shape of the eye prevents light from focusing directly on the retina').

Second: "Estimates of childhood strabismus in the UK is 1.5 to 5.3%... but in the evidence collated in this review, the incidence of strabismus amongst autistic participants is higher at 8.3%." Strabismus, where the eyes don't align properly, seems to be a little bit more prevalent when it comes to autism compared with general population statistics. This is a topic that I've talked about before on this blog in relation to correcting such an issue with autism in mind (see here).

Finally: "There were no studies examining ophthalmic conditions and adult autistic populations who are more at risk of age-related visual impairments." Bearing in mind the search parameters included in the Butchart paper, I'm kinda dismayed that this is the current state of affairs. You'd have thought with all the money and resources being thrown into autism research that someone, somewhere might have thought more about eye health in adults with autism? Eye-tracking, reading the mind in the eyes test... the word 'eye' or 'eyes' is prominent in autism research but just not in relation to eye health it seems. And bear in mind that issues with eye health probably will affect the results of some of those autism 'eye' studies.

Eye or vision issues related to autism have often been a topic of discussion on this blog (see here and see here for examples) and so I'm glad that someone has finally brought a review of this area into the peer-reviewed arena. Screening is important; even if some of those on the autism spectrum may not always be by first sight (pardon the pun) particularly amenable to taking part in an eye exam - adjustments can and should be made.

And finally consider this: "Undiagnosed visual impairment is likely to severely impact quality of life. There is a need therefore for education and training that equip autism support practitioners with the awareness and skills to identify potential visual impairment, to refer individuals to optometry professionals if necessary, and to make necessary adjustments to service environments and support practices for individuals identified as having a visual impairment." Not much more to say really is there aside from 'make it so'.

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[1] Butchart M. et al. Autism and Visual Impairment: a Review of the Literature. Review Journal of Autism and Developmental Disorders. 2017. Jan 5.

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Butchart, M., Long, J., Brown, M., McMillan, A., Bain, J., & Karatzias, T. (2017). Autism and Visual Impairment: a Review of the Literature Review Journal of Autism and Developmental Disorders DOI: 10.1007/s40489-016-0101-1

Correcting ophthalmic problems in autism

'Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder?' went the title of the paper by Pinar Ozer and colleagues [1]. Yes, it may very well do was the answer (but with certain caveats and the requirement for a lot more research in this area).

Strabismus, a condition where the eyes don't line up in the same direction, can sometime have some quite noticeable effects on a person's vision and indeed, has been linked to various other non-vision related symptoms and outcomes.

Ozer et al looked to identify "the impact of optical or surgical correction of the strabismus on the child using a questionnaire for parents." The published research of this team has been previously discussed on this blog (see here) with ophthalmic findings in mind, and the requirement for quite a few more resources to be put into eye examinations when autism is diagnosed (see here). This time around they were discussing what happens when such eye issues are resolved.

I'm not completely convinced that the Ozer findings this time around reporting 'significant improvements' in areas of "psychosocial interactions" is as it stands, a methodologically firm finding just pertinent to autism. Although no expert on strabismus, from what I gather, the 'cosmetic' side of the condition can have some far-reaching effects on 'psychosocial' functions. I daresay that such effects would be just as prevalent in autism as they are in the general population and hence, correction would likely have similar outcomes.

I am more open to the idea that if strabismus is affecting vision, as in causing something like blurred or double vision, correction of the issue may in some cases have some important 'effects' in relation to autism. Accepting that structural issues with the eye are not necessarily the same as or causative of visual perceptual issues that seem to crop up quite often in the autism research arena, it is not outside the realms of possibility that something like strabismus could be part and parcel of visual effects for some people.

I suppose to reiterate, screening for structural eye/vision issues when it comes to autism remains a pretty important area.

To close, karate gradings for one of my brood today and this is what they will be attempting...

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[1] Ozer PA. et al. Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder: Results of a Parent Survey by Ophthalmologists. Semin Ophthalmol. 2016 Sep 6:1-6.

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Ozer PA, Kabatas EU, Bicer BK, Bodur S, & Kurtul BE (2016). Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder: Results of a Parent Survey by Ophthalmologists. Seminars in ophthalmology, 1-6 PMID: 27599387

The force is strong with autism?

"Tablet and phone games could help diagnose autism, study suggests" went the BBC headline covering the paper by Anna Anzulewicz and colleagues [1] (open-access). The idea being that the way that touch screens are used on tablet and smart phones could potentially 'separate out' those with autism from those with not-autism.

Based on a small participant number of "37 children 3–6 years old with autism and 45 age- and gender-matched children developing typically" researchers set about examining "autism-specific motor patterns in the gameplay of children as they engaged with a smart tablet computer (iPad mini) under natural conditions and with minimal instructions." Motor issues accompanying autism are something gaining some renewed (and welcomed) research attention in recent times (see here). Specifically, researchers were utilising the astounding technology that goes into all those swipes and taps that we're also used to these days, and whether under 'serious' game conditions, aspects like force impact and gesture pressure could differentiate the two groups.

As per the headline and the rather cheesy title to this post, there were some differences picked up between the autism and control groups based on touch and swiping responses being put through their machine-learning paces (something else that has a growing following in autism research circles). So: "The inertial data indicate children with autism engaged in gameplay with greater force of impact than those developing typically." This and other potential differences led researchers to conclude that: "children with autism applied a significantly different distribution of forces into the device during gameplay than the typically developing children did."

Whilst interesting research there is quite a bit more to do before anyone starts using taps and swipes as a means to diagnose autism (or anything else). I don't really need to say that this was a study including a relatively small participant group nor that whilst "All participants had normal or corrected-to-normal vision and no other sensory or motor deficits" this does not preclude the possibility that subtle issues might also be at work (see here). That also recent discussions have suggested moving away from the singular diagnosis of autism as a research starting point is also worth reiterating (see here).

Still, I can see some opportunities arising from this area of research and how perhaps combined with other innovative areas of screening and diagnosis there may be much more to see including how subtle differences in movement might also influence variables such as interaction [2]. Yes indeed, "smart tablet technology offers an attractive, new paradigm for clinical autism assessment and bio-behavioural research of pre-school children, enabling engaging, ecological testing of children’s motor behaviour in a fun, accessible format fit for precise computational analysis of neuropsychological function."

To close: Danny Boy (from the Proms 2013 although this years version was pretty good too).

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[1] Anzulewicz A. et al. Toward the Autism Motor Signature: Gesture patterns during smart tablet gameplay identify children with autism. Scientific Reports. 2016; 6: 31107.

[2] Edey R. et al. Interaction Takes Two: Typical Adults Exhibit Mind-Blindness Towards Those With Autism Spectrum Disorder. J Abnorm Psychol. 2016 Sep 1.

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Anzulewicz A, Sobota K, & Delafield-Butt JT (2016). Toward the Autism Motor Signature: Gesture patterns during smart tablet gameplay identify children with autism. Scientific reports, 6 PMID: 27553971

Chronic fatigue syndrome, headaches and intracranial hypertension

Of the many important lessons that I've learned down the years of research, perhaps the most important one is that grand over-arching diagnostic labels rarely give a true reflection of the massive heterogeneity that they include in terms of clinical presentation and onwards, discussions about the possibility of differing aetiologies and pathologies. Symptoms, conditions, and diseases are compartmentalised for convenience but that does not mean that everyone shares the same experiences of that label nor arrives at it in exactly the same way.

This lesson is no better illustrated than in the paper by Nicholas Higgins and colleagues [1] (open-access here) who report on how "a 49-year-old woman with a long and debilitating history of chronic fatigue syndrome" was further inspected for "intracranial pressure because of headache, then diagnosed with borderline idiopathic intracranial hypertension after lumbar puncture and cerebrospinal fluid drainage." Further: "Stenting of both transverse sinuses brought about a life-changing remission of symptoms with no regression in 2 years of follow-up."

The authors report on how this patient had a 20-year history of fatigue that developed "after a viral illness" (there was evidence of "previous exposure to Epstein-Barr virus") and how after 3 months of "being unable to keep awake" fatigue symptoms fluctuated over several years. When presented to the authors, the woman "complained of being tired all the time, near constant headache, fogginess in the head, an inability to concentrate, muscle and joint aches, shortness of breath, and a sore throat." I had to cast a wry smile at the sentence: "She refused cognitive behavioral therapy" in light of some current goings-on with this and other 'interventions' being discussed in chronic fatigue syndrome (CFS) circles.

Kudos to the authors however and their protocol being developed whereby patients who present with chronic fatigue and headaches are "offered investigations to exclude raised intracranial pressure" as a source of their symptoms based on other studies reported by the research team [2]. Indeed, after some further investigations she showed symptoms "consistent with raised intracranial pressure." Treatment followed (although I wouldn't even begin to pretend that I understood it all) and that 'life-changing remission of symptoms' began and continued up to 2 years post diagnosis and intervention.

Not surprisingly the authors conclude that: "The unequivocally favorable outcome suggests that this is an area ripe for further study" based on this case report. Yes, one has to be careful not to generalise too much on the basis of the experiences of one patient, but given the current lack of effective interventions for something like CFS (or myalgic encephalomyelitis, ME), I'd suggest that there should be a degree of urgency to undertake additional studies in this area.

In addition to providing further evidence to suggest that we need to do more about looking at subgroups when it comes to CFS/ME (see here), I'd also be minded to suggest that this research area might also show more than a passing connection to a few other aspects covered on this blog. So for example, the idea that visual perception might be 'altered' as a symptom in at least some CFS/ME (see here) becomes potentially relevant in light of the link between idiopathic intracranial hypertension (IIH) and vision. The reports that "fogginess in the head" might also be part of the suite of cognitive effects that follow ME/CFS and are to some degree resolved by treatment of IIH in this patient group is also something that I pay quite a bit of attention to (see here). I'll finally direct you to a couple of posts I wrote about some research on Epstein-Barr virus (EBV) and some rather unusual findings (see here and see here) potentially relevant to some cases of CFS/ME with the requirement for quite a bit more research to do as part of a more multi-pronged intervention approach.

So, who is going to take up the research gauntlet and put further scientific flesh on the bones pertinent to a possible connection between IIH and [some] cases of CFS?

Music: Elle King - Ex's & Oh's.

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[1] Higgins N. et al. Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. J Neurol Surg Rep. 2015 Nov;76(2):e244-e247.

[2] Higgins N. et al. Looking for idiopathic intracranial hypertension in patients with chronic fatigue syndrome. Journal of Observational Pain Medicine. 2013; 1: 28-35.

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Higgins N, Pickard J, & Lever A (2015). Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting. Journal of neurological surgery reports, 76 (2) PMID: 26623235

Pattern-related visual stress in ME/CFS

At the time of writing this post, important discussions about ME (myalgic encephalomyelitis) and/or CFS (chronic fatigue syndrome) are coming thick and fast.

Years of talk about 'yuppie flu' and other even more derogatory terms to describe the often very disabling experience of ME/CFS (SEID if you wish) have seemingly been replaced by sensible discussion on things like a research agenda for CFS/ME (at least in some parts of the world). As per other blogging occasions where CFS/ME has figured, 2015 is proving to be a bit of a turning point...

Who do we have to thank for this shift in thinking? Well, my bet would be on the thousands of people who suffer with ME/CFS (yes, people do suffer with the condition) and their families and loved ones who have tirelessly campaigned down the years for appropriate recognition of the condition despite living an often torrid existence as a consequence of their symptoms. Patient power in action you might say. I'd also drop in a name or two for some research pioneers such as Jose Montoya (see here) and colleagues and the research tag-team that is Mady Hornig and Ian Lipkin (see here) (they have fingers in many research pies!) for their important contributions. A colleague of mine, Prof. Malcolm Hooper, also deserves a mention (see here) in that list of the great and the good, alongside countless other investigators and clinician folk.

Part of the shift in our thinking and understanding of ME/CFS, aside from some recognition that several states/conditions/diagnoses might reside under the umbrella terms ME/CFS, is the idea that the physiology and biology of the disease course are deserving of quite a bit more study over and above the focus on just the psychological 'effects' of the condition. Heated discussions about the PACE trial (see here) and its follow-up (see here) have served a useful purpose insofar as stressing that 'psychology' may be part and parcel of CFS/ME as an 'effect' (see here) but this does not mean that more fundamental biology and biochemistry should be ignored as potential aetiological and intervention options (see here).

The idea that there may be psychological 'effects' to cases of ME/CFS is something explored in a recent paper by Rachel Wilson and colleagues [1] who concluded that their findings "provide evidence of altered visual perception in ME/CFS." Based on data from a small group of people diagnosed with ME/CFS compared with age and sex-matched asymptomatic controls, researchers set out to "determine vulnerability to pattern-related visual stress." Pattern-related visual stress (PRVS) by the way, refers to problems stemming from looking at certain types of visual stimuli. For the purposes of their study, Wilson et al used the Pattern Glare Test to determine PRVS (further information can be read here although I am told that those with photosensitive epilepsy should resist any further temptations to look for the patterns used).

"Pattern-related visual stress may represent an identifiable clinical feature of ME/CFS that will prove useful in its diagnosis." That was the conclusion reached on the basis of the results obtained, and specifically that: "ME/CFS patients exhibited significantly higher pattern glare scores than controls for the mid-SF [spatial frequency] pattern" among other things. I might reiterate that this was quite a small study in terms of participant numbers and also in the context of assessing visual stress so I'm cautious about any claims of such a variable being somehow diagnostic at this time. Some media write-up of the study can be seen here.

Nonetheless, these are interesting results and perhaps map on to other related data from some of the authors on the Wilson paper [2]. Quite a few moons ago, my colleagues and I also talked about the possibility of visual manifestations included in the context of [some] ME/CFS [3]. On that occasion, we discussed the idea that light sensitivity or photophobia might be something to look at, allied to issues such as auditory hyperacuity (noise sensitivity) and other, more cognitive-related issues appearing alongside the more traditional fatigue-related aspects to presentation. I cannot say for sure that visual stress and auditory acuity issues are linked, but one might reason that within the wider context of perceptual issues being part and parcel of at least some cases of ME/CFS, there may be more research to do in this area with multi-sensory perception in mind. I might add that ME/CFS research might be able to learn a few things from other areas of research too (see here and see here) given some research history with ocular manifestations in mind [4].

The question is then: what are the biological underpinnings of such issues? Well, I have some ideas about that too including entertaining the potentially controversial notion that there may be an 'infectious' component to something like ME/CFS [5] at least in some cases...

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[1] Wilson RL. et al. Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis. Perception. 2015 Nov 3. pii: 0301006615614467.

[2] Hutchinson CV. et al. Vision-related symptoms as a clinical feature of chronic fatigue syndrome/myalgic encephalomyelitis? Evidence from the DePaul Symptom Questionnaire. Br J Ophthalmol. 2014 Jan;98(1):144-5.

[3] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional & Environmental Medicine. 2004; 14: 247-259.

[4] Potaznick W. & Kozol N. Ocular manifestations of chronic fatigue and immune dysfunction syndrome. Optom Vis Sci. 1992 Oct;69(10):811-4.

[5] Underhill RA. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease. Med Hypotheses. 2015 Oct 19. pii: S0306-9877(15)00382-5.

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Wilson RL, Paterson KB, & Hutchinson CV (2015). Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis. Perception PMID: 26562880

More ophthalmic findings in autism

"Ophthalmic pathology was noted in 26.9 % of patients with ASD [autism spectrum disorder], of which 22 % had significant refractive errors and 8.6 % had strabismus."

That was the conclusion reached in the paper by Emrah Utku Kabatas and colleagues [1] based on the premise that: "Children with autism spectrum disorders (ASD) frequently have ophthalmologic disorders"; that is, issues with the anatomy and function of the eyes.

We've been here before. I'll take you back to the post that I wrote around the paper by Ikeda and colleagues [2] and their quite remarkable suggestion that ophthalmic pathology was present in 40% of people with autism or a related disorder. Such cumulative evidence should be enough to convince even the most sceptical healthcare providers that they should be setting up regular eye care appointments for every person diagnosed with autism. More so when perhaps autism is joined with faddy eating habits and the important effects that nutritional deficiency might also bring to eye health (see here).

Music: Kate Bush - Hounds of Love.

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[1] Kabatas EU. et al. Initial Ophthalmic Findings in Turkish Children with Autism Spectrum Disorder. J Autism Dev Disord. 2015 Mar 24. 

[2] Ikeda J. et al. Brief report: incidence of ophthalmologic disorders in children with autism. J Autism Dev Disord. 2013 Jun;43(6):1447-51.

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Kabatas EU, Ozer PA, Ertugrul GT, Kurtul BE, Bodur S, & Alan BE (2015). Initial Ophthalmic Findings in Turkish Children with Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 25800865

Vision impairment and ADHD?

Science often has the ability to surprise.

So it was when I first read the paper by Dawn Decarlo and colleagues* (open-access here) which suggested that: "children with vision impairment may be more likely to be diagnosed with ADHD [attention deficit hyperactivity disorder] than children in the general population". I should point out that this observation should not be totally unexpected given some media for other studies by the authors (see here).

Lady in a green jacket @ Wikipedia  

The Decarlo study was based on a question of "whether the prevalence of parent-reported ADHD diagnosis in a cohort of pediatric low vision subjects was similar to that reported for the general population". It seems researchers were a little bit worried that there may be some mixing up of the signs and symptoms of possible ADHD as a consequence of a child's visual impairment and sought to further look into the issue.

So, bearing in mind the paper is open-access, a few study details:

• Alabama, USA was the study setting, and the medical records of participants (N=245) with low vision were drawn from two sites. Researchers garnered various details about participants covering basic demographic information and that relevant to vision including "primary ocular diagnosis, presence or absence of nystagmus, and best-corrected visual acuity in each eye". They also asked participants' parents whether or not their child had ever received a diagnosis of ADHD and had state and national ADHD prevalence estimates to hand.
• Results: the Alabama state ADHD prevalence estimate (based on 2007 data) was 14.3% and the US national prevalence 9.5%. The parent-reported prevalence rate of study children ever having a diagnosis of ADHD was 22.9% (56.245). Examination of an additional cohort of 19 children with almost total vision loss for a diagnosis of ADHD was 10%.
• Albinism - a condition concerned with the production of melanin - was the most frequently reported eye problem among participants (16%) and similar to the issue of optic nerve hypoplasia (ONH), saw a prevalence of ADHD diagnosis at 20% of these cases. Indeed, ONH has previously been linked with 'behavioural problems' in other research** and indeed, some of the features of autism***.
• Researchers concluded: "the prevalence of parent-reported ADHD among children with vision impairment in the present study is considerably higher than that reported by the Centers for Disease Control and Prevention".

There is obviously more to do in this area insofar as ascertaining whether these results are more widely applicable to cases of paediatric vision impairment or just a statistical blip. Noting for example, that the State of Alabama has an ADHD prevalence estimate some way above the US national estimate, might imply that ADHD is more generally apparent as a diagnosis there, so children were more likely to receive a diagnosis as a result of better screening facilities for example. Indeed, in my review of some of the [worldwide] prevalence rates of pediatric ADHD rates (see here), the figures coming back were nearer the US national average than the Alabama state estimate although potentially rising.

The lack of an external control group looking both at asymptomatic controls or even those children with something like hearing impairment in the Decarlo study, means that some caution must be exercised before leaning too far into the suggestion of any relationship.

The question of what mechanism might be behind any association is also important. I could suggest that the quite recent report of a link between solar intensity and ADHD (see here) might potentially offer some clues if one is to assume that vision is a common denominator across these areas of research. That being said, it is quite a tentative link and as yet, I can offer no further support for this suggestion.

Perhaps more relevant are the discussions about shared genetic/environmental influences which affect vision and potentially, risk of ADHD, as being linked to any association. Taking you back to the paper by Antoine and colleagues**** which was discussed in another post (see here) on inner ear conditions being linked to hyperactivity, one might assume similar mechanisms to be plausible. That also the paper by Kim and colleagues***** reported issues with vision function and colour vision to be linked with cases of adult ADHD is something else to throw into the mix.

Whatever the reason(s) for such a correlation, I am intrigued by the Decarlo findings and wait attentively for any further movement in this area of investigation.

Music to close, and having recently heard the song Purple Rain on the radio, I have a rekindled respect for Prince...

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* Decarlo DK. et al. Prevalence of attention-deficit/hyperactivity disorder among children with vision impairment. J AAPOS. 2014 Feb;18(1):10-4.

** Teär Fahnehjelm K. et al. Optic nerve hypoplasia in children and adolescents; prevalence, ocular characteristics and behavioural problems. Acta Ophthalmol. 2013 Oct 7.

*** Parr JR. et al. Social communication difficulties and autism spectrum disorder in young children with optic nerve hypoplasia and/or septo-optic dysplasia. Dev Med Child Neurol. 2010 Oct;52(10):917-21.

**** Antione MW. et al. A Causative Link Between Inner Ear Defects and Long-Term Striatal Dysfunction. Science. 2013; 341: 1120-1123.

***** Kim S. et al. Visual function and color vision in adults with Attention-Deficit/Hyperactivity Disorder. J Optom. 2014 Jan-Mar;7(1):22-36.

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Decarlo DK, Bowman E, Monroe C, Kline R, McGwin G Jr, & Owsley C (2014). Prevalence of attention-deficit/hyperactivity disorder among children with vision impairment. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus, 18 (1), 10-4 PMID: 24568975

Pain predicting sleep problems in autism

Not so long ago I talked about the paper from Smith and colleagues [1] on autism and obstacles to medical [comorbidity] diagnosis and treatment (see here). Aside from the need for professionals to overcome the issue of "a lack of expressive speech" as an impediment to undertaking a thorough medical work-up when presented with a person with autism, an important theme of that paper was the requirement to see beyond autism as being the 'reason' for every single behaviour or issue that affects a person. It's not.

Indeed, the paper by Megan Tudor and colleagues [2] which makes up the material for today's post, adds to that message with their report on pain as being a predictor of sleep problems for some children/young adults with autism. Once again, my thanks go to Natasa for providing the full-text version of the paper for my blogging consumption (yum!).

The long-and-short of the Tudor paper was as follows:

• Take two issues which have cropped up in the autism research literature more than once - sleeping issues and pain - and aim to examine "pain-related behaviors as a predictor of sleep problems in youth with parent-reported ASD using standardized parent-report measurement of both variables".
• Mothers of a sample of 62 children/young adults drawn from a larger study [3] [note to authors, your date is wrong for this reference] were questioned using several measures including the NCCPC-R (see here) and the CSHQ [4] (open-access) looking at pain and sleep respectively. I should also note that questionnaires were completed on-line and participants received a financial incentive to complete [a large chunk of] questionnaires.
• Results: parent-reported participant pain levels according to NCCPC-R scores "was high compared to normative information for this measure". Sleep issues were similarly elevated in the sample, particularly parasomnias. The discussion notes that pain scores were gathered across a slightly different timespan to the normative data (1 week retrospective report for the study vs. 2-hour observation period for the normative data) so one perhaps need to be a little cautious about this.
• Some regression analysis for scores on the two instruments revealed some potentially important results. So higher pain scores "predicted higher scores on CSHQ Total Sleep Disturbance" although with an R-squared value of 0.22 this is not necessarily a straight-forward connection. 
• Specific sleep problems including sleep duration, parasomnias and sleep-disorder breathing were also reported as being accompanied by a previous weeks pain-related behaviours and may well have had some very individual behaviours linked to them e.g. "problems with sleep duration were predicted by social communication of pain, such as comfort-seeking and being difficult to pacify" and "Parasomnias were predicted by facial communication of pain, such as grimacing or brow furrowing".
• The authors conclude that whilst there is more to do in this area of investigation (including the important use of control groups) their results should serve as a marker for healthcare professionals when dealing with children with autism who also present with sleeping issues. To quote: "how pain and sleep problems relate to one another and may affect children's daytime functioning...". This may have some far-reaching effects in terms of how sleep issues are traditionally managed when it comes to autism and other developmental disorders.

Going back to the my starting paragraph about autism not being to blame for every single behavioural manifestation noted among cases, I can't help but ask the question: why were parent-reported indicators of pain-related behaviours seemingly elevated in this sample? As far as I know - and I am just an outsider looking in - autism is not necessarily defined as a painful condition. Indeed, even the authors point to the possibility of a "high threshold for pain" [5] described in the DSM-IV TR diagnostic schedule for autism. Certainly if it was shown that autism 'is a painful condition', it would perhaps change some of the dialogue noted in Dr Insel's Four Kingdoms of Autism.

I do have a few theories about this notion of pain and autism however so bear with me. Tudor and colleagues allude to one of them insofar as discussions about "ongoing mild digestive discomfort" and "severe inflammatory bowel disease" with both issues having cropped up before on this blog previously. Thinking back to the paper by Kushak and colleagues [6] discussed in this post on lactase enzymes and autism, there is the suggestion that lactose intolerance (related to the sugar found in milk and dairy produce) "may contribute to abdominal discomfort, pain and observed aberrant behavior". With autism and inflammatory bowel disease in mind, the Walker paper [7] published a while back (discussed in this post) springs to mind.

Of course, I don't claim that every expression of pain noted in autism is necessarily one of being related to gastrointestinal (GI) function or dysfunction but one could certainly look to rule these issues out if one were being assiduous. As per some other potentially important issues, I might also refer you to a post I wrote a while back on self-injurious behaviour (see here) and other areas that one might look at when it comes to pain being potentially present in cases of autism.

The final angle that is perhaps worthy of exploration has already been touched upon in the additional reference by Allely [5] (see here again) in relation to how one of the core aspects of autism might itself have the ability to induce pain: sensory sensitivity. I say core aspect but am referring to the recent inclusion of sensory issues into DSM-V noting that not everywhere in the world has made the shift over the DSM-5. So, things like over sensitivity to sound for example, I assume may register on someone's behaviour and manner, just as issues with the visual modality might also have the ability to induce something like pain (see here). Indeed, migraine might be something else to look at with pain and autism in mind [8] and not just with the head in mind either [9]. As per previous statements, it all depends on how far one is willing to look into the issue of pain and the potential reasons for its presence...

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[1] Smith MD. et al. Autism and Obstacles to Medical Diagnosis and Treatment. Focus Autism Other Dev Disabl 2012; 27: 189-195.

[2] Tudor ME. et al. Pain as a predictor of sleep problems in youth with autism spectrum disorders. Autism. 2014 Feb 4. [Epub ahead of print]

[3] Walsh CE. et al. Predictors of parent stress in a sample of children with ASD: Pain, problem behavior, and parental coping. Res Autism Spec Disorder. 2013; 7: 256-264.

[4] Owens JA. et al. The Children's Sleep Habits Questionnaire (CSHQ): psychometric properties of a survey instrument for school-aged children. Sleep. 2000 Dec 15;23(8):1043-51.

[5] Allely CS. Pain Sensitivity and Observer Perception of Pain in Individuals with Autistic Spectrum Disorder. ScientificWorldJournal. 2013; 2013: 916178.

[6] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

[7] Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

[8] Fors S. & Fors MF. Is autism linked to migraine aura? Epidemiology. 2013 May;24(3):472-3.

[9] Casanova MF. The minicolumnopathy of autism: A link between migraine and gastrointestinal symptoms. Med Hypotheses. 2008;70(1):73-80.

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Tudor ME, Walsh CE, Mulder EC, & Lerner MD (2014). Pain as a predictor of sleep problems in youth with autism spectrum disorders. Autism : the international journal of research and practice PMID: 24497628

Synaesthesia prevalent in autism?

The BBC headline 'Study links synaesthesia to autism' recently caught my eye (and nose!) discussing the paper by Baron-Cohen and colleagues* (open-access) who suggested that: "The rate of synaesthesia in adults with autism was 18.9% (31 out of 164), almost three times greater than in controls".

Colour and sensation @ Wikipedia 

Synaesthesia according to the UK Synaesthesia Association is best described as a "union of the senses" whereby "two or more of the five senses that are normally experienced separately are involuntarily and automatically joined together".

In other words, some people might experience certain words as tastes or see colours when they hear music. The BBC follow-up their coverage of the Baron-Cohen paper with a story about a man who can taste the London Underground map and his efforts to re-design the Tube map according to 'sausage and eggs' and 'putrid meat'.

In their paper, the authors tested the suggestion of overlap between autism - adults with "high-functioning autism or Asperger's syndrome" - and synaesthesia by asking participants with autism and asymptomatic controls to complete a questionnaire on any experiences of synaesthesia alongside something called the Test of Genuineness-Revised (ToG-R) "to validate any self-reported auditory-visual forms of grapheme-colour (GC) and sound-colour (SC) synaesthesia and was sent to all participants in order to detect true and false positives and negatives". That being said, response rates to the ToG-R were not brilliant; as per another quote: "Telephone follow-up to find out why ToG-Rs were not being completed revealed that participants with autism reported fatigue from the 241 possible choices".

Based on their data however, they report that "The rate of synaesthesia in autism (18.9%) was almost three times greater than in the typical sample (7.22%)". They also suggest that this figure might be an under-estimate given that some participants with autism "claimed they did not have synaesthesia, but were judged by the experimenters to have synaesthesia on the basis of their questionnaire responses".

I have to say that I'm very interested in these results. Sensory issues with regards to the autism spectrum are something of growing importance given the effect that they can have on both how a person perceives the world around them and also how such perceptions can impact on day-to-day functioning and quality of life. Even the latest version of DSM saw fit to include sensory issues in their latest redefinition of the autism spectrum (see here).

That being said I still want to see more on this topic done before I totally commit to the likelihood that synaesthesia is frequently prevalent in cases of autism. Questions about how representative these results are for example, to those who present with a greater severity of autistic symptoms or with comorbid learning disability remain as does the question of mechanism and whether there are genetic or biological commonalities to be seen.

I'd also hazard a guess that synaesthesia is just the tip of the iceberg when it comes to sensory and visual issues and autism; indeed whether as per the exclusion criteria for acquired synaesthesia in the Baron-Cohen study "the person had any medical conditions affecting vision". Well, if the Ikeda results are anything to go on, yes would probably be the answer for anything up to 40% of those with autism. How such vision issues would impact on the presentation of synaesthesia remains to be seen. And finally there is the question of whether any other -sia conditions also reported in cases of autism might also show some involvement, as per the chatter about prosopagnosia (face-blindness)?

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* Baron-Cohen S. et al. Is synaesthesia more common in autism? Molecular Autism 2013, 4:40

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Simon Baron-Cohen, Donielle Johnson, Julian Asher, Sally Wheelwright, Simon E Fisher, Peter K Gregersen, & Carrie Allison (2013). Is synaesthesia more common in autism? Molecular Autism, 4 DOI: 10.1186/2040-2392-4-40

Vitamin B12 and autism: more to do

The short report by Malhotra and colleagues* linking a case of the regressive condition childhood disintegrative disorder, CDD (otherwise known as Heller's syndrome) with vitamin B12 deficiency and hyperhomocysteinemia has grabbed my attention.

Malhotra et al report that following the identification of said nutritional issues, supplementation with vitamin B12 and a few other nutrients, seemed to correlate with some improvements in the 14 year old at the centre of this paper, according to parental reports. The authors suggest: "A case is made for vitamin B12 deficiency syndrome presenting as CDD".

Methyl Curt Cobain... er, cobalamin @ Wikipedia  

Bearing in mind the overlap between CDD with autism or autistic-like behaviours, and that the Malhotra paper was a case report (good news when it comes to the autism and n=1 philosophy), one has to caution against making any sweeping generalisations to the autisms as a whole. That being said and bearing in mind others have talked about developmental regression** being linked to hypocobalaminemia, it did make me take a look at some of the other scientific literature on any link between vitamin B12 and autism.

I have actually talked about vitamin B12 before on this blog. A few times in fact; ranging from vitamin B12 optic neuropathy presenting in cases of autism (see here and the paper is here), to vitamin B12 deficiency being picked up in cases of autism (see here), to the very much under-investigated issue of methylmalonic acid (MMA) alongside cases of autism (see here). Slightly outside of autism research, vitamin B12 has also been discussed with thin-fat bodies in mind (see here) and its relationship with the epigenome.

Given also the connection between vitamin B12 and that other B-vitamin of the moment with autism in mind, folic acid, this post turns out to be quite timely.

Whilst there is not a great expanse of literature on the topic of vitamin B12 and autism, there are a few other points worth noting:

• Not all vitamin B12 is equal (or some are more equal than others, to coin a phrase). As with the example of folic acid, vitamin B12 can appear in more than one form (the so-called vitamers) seemingly also related to how we ingest/supplement with the stuff and what form our body actually use.
• Methyl B12 (methylcobalamin) has been looked at as a possible intervention for cases of autism as per the study by Bertoglio and colleagues***. The results on that occasion were not exactly universally successful in terms of behavioural outcomes, although there was the suggestion of a sub-group of possible responders to this intervention. Indeed based on an abstract presented at IMFAR 2012, it appears that responders might be linked to another favourite topic of this blog, glutathione (see here).
• The combinatorial use of methylcobalamin and another compound of interest, folinic acid (see this post) has also been the topic of some investigation with autism in mind as reported by Jill James and colleagues**** (open-access). The intervention appeared to affect several important biochemical parameters but some unanswered questions on clinical outcome remained.
• Although seemingly unrelated to vitamin B12, I was alerted to a recent study by Parks and colleagues***** on how specific strains of bacteria have the ability to turn inorganic mercury into methylmercury. Whilst this biochemical process may not initially seem particularly exciting or relevant to this post, when you conisder the role of cobalmin (vitamin B12) in this process (as per the result reported by Choi and Bartha****** for example and the action of being a methyl donor), one becomes slightly more interested in light of reports of elevated heavy metals being present in cases of autism and of course all that gut bacteria work being undertaken. I'm not making too much of this research at the moment despite it being mentioned by others, aside from illustrating how even vitamins are pharmaceutics and their use should be treated as such.

Accepting again that the literature on vitamin B12 and autism is not exactly voluminous, there are some interesting strands of research which potentially connect the two things together requiring much greater study. Outside of the autism connection (or not), vitamin B12 has some interesting links with other things such as propionic acid for example (itself covered in separate posts on this blog, see here and here) which might also be a source of discussion.

One of the main drawbacks of supplementing with vitamin B12 (or specifically methyl B12) where indicated is the requirement for delivery by subcutaneous injection. This might be OK if you are used to repeated injections such as those required for type 1 diabetes for example, but probably a little more invasive if you're not used to having them, given also that children with autism in particular might not be too taken with visiting the doctor or indeed other healthcare professionals such as the dentist.

Without making any recommendations or anything like that, one would assume that some kind of reformulation might be possible to 'rebrand' methly B12 to make it more palatable, either based on a cream, even something like a microneedle preparation or some other transdermal delivery system******* as per other recent news in an unrelated area.

The emphasis however has to be on the requirement for further research in this area and an extension of the notion that a diagnosis of autism or conditions which manifest as autistic symptoms, are seemingly protective of nothing when it comes to other conditions or physiological states including the presence of things like vitamin B12 deficiency.

A song to finish. Sunday Bloody Sunday by U2.

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* Malhotra S. et al. Brief report: Childhood disintegrative disorder as a likely manifestation of vitamin B12 deficiency. J Autism Dev Disord. January 2013.

** Dror DK. & Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008; 66: 250-255.

*** Bertoglio K. et al. Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. J Altern Complement Med. 2010; 16: 555-560.

**** James SJ. et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009; 89: 425-430.

***** Parks JM. et al. The genetic basis for bacterial mercury methylation. Science. January 2013.

****** Choi S-C. & Bartha R. Cobalamin-mediated mercury methylation by
Desulfovibrio desulfuricans LS. Appl Environ Microbiol. 1993; 59: 290-295.

******* Madhaiyan K. et al. Vitamin B(12) loaded polycaprolactone nanofibers: A novel transdermal route for the water soluble energy supplement delivery. Int J Pharm. January 2013.

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Malhotra S, Subodh BN, Parakh P, & Lahariya S (2013). Brief Report: Childhood Disintegrative Disorder as a Likely Manifestation of Vitamin B12 Deficiency. Journal of autism and developmental disorders PMID: 23334842