Careful now: oral colostrum MAF and Chronic Fatigue Syndrome?

I should perhaps begin this slightly longer than usual post by reiterating my well-trodden caveat on this blog about not giving anything that looks, sounds or smells like medical or clinical advice during my musings. This is a blog [mainly] about peer-reviewed science, nothing more. Added to that, I'm not your Dr Ross and you are not my patient.

So... I've been seeing quite a bit about Gc-MAF (Gc Macrophage Activating Factor) in the news recently. The various headlines about autism and Gc-MAF (see here and see here) have made up the bulk of media coverage but other reports of scientific retractions (see here) have similarly filled some column inches in recent times.

Whilst treading carefully in this area, Gc-MAF has cropped up on this blog a few times based on some of the peer-reviewed literature with autism in mind (see here and see here for further information including what Gc-MAF is). Even Drs Hornig & Lipkin have mentioned Gc-MAF and its precursors in other non peer-reviewed literature (see here). Indeed, given the straddling of autism research and studies on Chronic Fatigue Syndrome (CFS) by Drs Hornig and Lipkin, it is timely that I discuss the paper from Toshio Inui and colleagues [1] (open-access available here) detailing a few case studies suggesting that: "oral colostrum MAF can be used for serious infection and chronic fatigue syndrome (CFS) without adverse effects."

OK. First things first. Oral colostrum MAF is, we are told, a "new form of macrophage-activating factor (MAF) made from colostrum in collaboration with the Tokushima University." Macrophages are known as the 'big eaters' of the immune system getting rid of various molecular debris including viruses, bacteria and the odd 'worn out cell'. The Star Wars version (yes, you heard/read me right) of the role of macrophages can be read in this article [2] by Debra Laskin. Gc-MAF as the name implies is an 'activating factor' for macrophages, also seemingly affected by something called nagalase.

"This new form, referred to as colostrum MAF, is manufactured using bovine colostrum instead of human serum. It is administered orally in an acid-resistant enteric capsule to activate macrophages in the gut-associated lymphoid tissue (GALT) and as a powder in the mouth to activate macrophages in the lymphoid tissue of the mouth and throat."

Given the immune system / macrophage slant to colostrum MAF, the authors moved into the area of CFS and the idea that: "infections and immune dysfunction are thought to play a critical role in the development of the disease." I'll chip in here and reiterate that science does seem to be moving closer to the idea that CFS (and myalgic encephalomyelitis, ME) has origins in organic disease albeit still a little undecided as to what factors are involved. On that basis, two of the three case reports detailed in the Inui paper are on adults with CFS and their experiences of colostrum MAF.

Focusing on those two case reports - both females - they were reported to show some pretty interesting effects concurrent to the use of colostrum MAF. Statements like "reduced malaise" and "being able to do her usual work with more energy like most other people do" are included in the text, even accompanied by "improvements in hair growth on her head." The authors attempt to link such changes to increased phagocytosis. They suggest further work is needed to "elucidate the mechanisms by which MAF has beneficial effects."

These are interesting results but I'm afraid that I need a little more convincing on safety and efficacy yet. Case reports, as I've mentioned in the context of autism (a heterogeneous condition), can provide some really informative data about a specific person diagnosed with a particular condition as a starting point for further investigations more generalised to more people in those specific circumstances. That same logic applies to the Inui findings and the need for further controlled studies on the potential effects of colostrum MAF including specific measures of fatigue and other symptom changes as a result of any intervention(s). This also includes the need for a little more information about the biology behind any reported changes and longer-term, what any effects might be bearing in mind where it comes from. Without casting aspersions, one needs to remember how powerful even a placebo can be (see here).

Insofar as the comments about hair regrowth in relation to CFS, whilst I have heard that hair loss is not uncommon (see here) I can't yet find anything in the peer-reviewed domain specifically about this phenomenon. This doesn't mean that co-occurring issues alongside a diagnosis of CFS might not involve such a symptom but as far as I am aware, it is not a primary part of the [current] diagnostic criteria. In order to avoid any mis-interpretations about colostrum MAF being the next hair growth agent of choice, in future studies I would like to see a little more 'controlled' scientific engagement over such processes.

It is as easy to get carried away with the Inui results as it is to pooh-pooh the findings, particularly in light of all that media coverage of Gc-MAF recently. Throughout the whole history of this compound and now colostrum MAF, there has been a tendency to make some pretty big claims often at the expense of really methodologically sound objective science. Given however the ways and means that a condition like CFS can impact on a person - disable a person - I would suggest that this might be an occasion where sound independent research can come take a lead and put some scientific flesh on the bones on any effect or not.

Music: Carly Rae Jepsen - Call Me Maybe.

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[1] Inui T. et al. Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer Res. 2015 Aug;35(8):4545-9.

[2] Laskin DL. Macrophages and inflammatory mediators in chemical toxicity: a battle of forces. Chem Res Toxicol. 2009 Aug;22(8):1376-85.

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Inui T, Kubo K, Kuchiike D, Uto Y, Nishikata T, Sakamoto N, & Mette M (2015). Oral Colostrum Macrophage-activating Factor for Serious Infection and Chronic Fatigue Syndrome: Three Case Reports. Anticancer research, 35 (8), 4545-9 PMID: 26168499

Inflammatory bowel disease and autism: increased prevalence

A quote to begin today's post:

"Across each population with different kinds of ascertainment, there was a consistent and statistically significant increased prevalence of IBD [inflammatory bowel disease] in patients with ASD [autism spectrum disorder] than their respective controls and nationally reported rates for pediatric IBD."

That was the conclusion reached in the paper published by Finale Doshi-Velez and colleagues [1] including one very notable name on the authorship list, Isaac Kohane (he of comorbidity clusters and autism research fame).

Drawing on data from various sources - "rates of IBD among patients with and without ASD were measured in 4 study populations with distinct modes of ascertainment: a health care benefits company, 2 pediatric tertiary care centers, and a national ASD repository" - researchers set about establishing whether there were any differences between those with autism and those without autism in terms of IBD frequency. IBDs by the way, were characterised using ICD-9-CM codes and primarily included diagnoses of Crohn's disease and/or ulcerative colitis.

Researchers reported that "the rates of IBD-related ICD-9-CM codes for patients with ASD were significantly higher than that of their respective controls" despite the actual numbers diagnosed with an IBD being quite low (23 out of a cumulative population of nearly 10,000 participants). For those 23 people on the autism spectrum however, formal diagnosis of an inflammatory bowel disease is probably a very real thing to them and their families.

As mentioned in previous discussions on this blog, to talk about inflammatory bowel disease and autism can stir up some quite intense emotions and debates (see here) despite the fact that a diagnosis of autism is seemingly not protective against presenting with such issues (see here). Alongside the acceptance that more functional bowel issues such as constipation and diarrhoea are quite a frequent feature for quite a few cases of autism (see here), research attention needs to turn towards the underlying reasons why such functional bowel problems present and whether they may be reflective of something more pathological than just as a consequence of poor eating habits (see here) or any psychological / behavioural comorbidity (see here).

I'd wager that there is a lot more to see in this area of research particularly in light of ideas about the gut-brain axis being something potentially important to [some] autism (see here) alongside the idea that there may be specific neurological consequences of IBDs (see here). The idea that parental experiences of IBDs may also not be associated with offspring autism risk (see here) invites some interesting research discussing the ways and means that IBD risk comes to be heightened in relation to autism...

Music and have you heard that bird is the word?

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[1] Doshi-Velez F. et al. Prevalence of Inflammatory Bowel Disease Among Patients with Autism Spectrum Disorders. Inflamm Bowel Dis. 2015 Jul 25.

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Doshi-Velez F, Avillach P, Palmer N, Bousvaros A, Ge Y, Fox K, Steinberg G, Spettell C, Juster I, & Kohane I (2015). Prevalence of Inflammatory Bowel Disease Among Patients with Autism Spectrum Disorders. Inflammatory bowel diseases PMID: 26218138

Gluten psychosis

"The present case-report confirms that psychosis may be a manifestation of NCGS [non-coeliac gluten sensitivity], and may also involve children; the diagnosis is difficult with many cases remaining undiagnosed."

Elena Lionetti and colleagues [1] (open-access) provide an interesting read in today's post on how diet and psychiatry might once again be linked. Presenting a case report of a 14-year old girl coming to the attention of clinical services "for psychotic symptoms that were apparently associated with gluten consumption", the authors describe the experiences of an otherwise well child quite quickly developing various psychiatric symptoms. Although initially thought to be autoimmune encephalitis (see here) it became apparent that dietary gluten might be a culprit behind the psychiatric presentation and not necessarily because of the classical gluten-related autoimmune condition called coeliac (celiac) disease (CD) either.

"To our knowledge, this is the first description of a pre-pubertal child presenting with a severe psychotic manifestation that was clearly related to the ingestion of gluten-containing food and showing complete resolution of symptoms after starting treatment with the gluten-free diet." Well actually, it's not; as previous ramblings on this blog come to mind (see here) albeit not with the same serological profile as discussed in the Lionetti paper. Interestingly however is the 'autoimmune' link noted in the paper by Eaton and colleagues [2] potentially overlapping with the Lionetti case report: "The only abnormal parameters were anti-thyroglobulin and thyroperoxidase antibodies (103 IU/mL, and 110 IU/mL; v.n. 0–40 IU/mL)." In light of other 'psychiatric' manifestations correlating with autoimmune issues with thyroid function in mind (see here) I'm beginning to wonder whether there might be a few research studies to do in this area...

Hopefully without plagiarising the Lionetti report, another long quote is coming up: "In our case report, the correlation of psychotic symptoms with gluten ingestion and the following diagnosis of NGCS were well demonstrated; the girl was, indeed, not affected by CD, because she showed neither the typical CD-related autoantibodies (anti-tTG and EMA) nor the signs of intestinal damage at the small intestinal biopsy. Features of an allergic reaction to gluten were lacking as well, as shown by the absence of IgE or T-cell-mediated abnormalities of immune response to wheat proteins. The double-blind gluten challenge, currently considered the gold standard for the diagnosis of NCGS, clearly showed that the elimination and reintroduction of gluten was followed by the disappearance and reappearance of symptoms." I might add that mention of 'leaky gut' in the Lionetti paper might offer a further expansion for the role of intestinal hyperpermeability in psychiatry (see here).

Need I say any more aside from: (i) this being further evidence that Dohan might have been on to something and (ii) more scientifically controlled research is most definitely warranted. Oh, and that the spectrum of possible behavioural and/or psychiatric effects from gluten in some people may be expanding...

Music: Shake Some Action.

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[1] Lionetti E. et al. Gluten Psychosis: Confirmation of a New Clinical Entity. Nutrients. 2015;7(7): 5532-5539.

[2] Eaton WW. et al. Improvement in Psychotic Symptoms After a Gluten-Free Diet in a Boy With Complex Autoimmune Illness. Am J Psychiatry. 2015; 172: 219-221.

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Lionetti, E., Leonardi, S., Franzonello, C., Mancardi, M., Ruggieri, M., & Catassi, C. (2015). Gluten Psychosis: Confirmation of a New Clinical Entity Nutrients, 7 (7), 5532-5539 DOI: 10.3390/nu7075235

Adult outcomes following childhood psychiatric problems

A long quote to begin:

"If the goal of public health efforts is to increase opportunity and optimal outcomes, and to reduce distress, then there may be no better target than the reduction of childhood psychiatric distress—at the clinical and subthreshold levels."

That was the bottom line reported by William Copeland and colleagues [1] (open-access) who set out to test whether psychiatric problems presenting in childhood can "adversely affect adult functioning even if the problems themselves do not persist." The Copeland study also has an accompanying editorial in the publishing journal [2].

Based on data derived from a prospective study of nearly 1500 participants "from 11 predominantly rural counties of North Carolina" researchers looked for the presence of "common psychiatric diagnoses and subthreshold psychiatric problems" by means of structured assessments during childhood (9-16 years of age). "The common childhood psychiatric disorders assessed included anxiety disorders (separation anxiety, generalized anxiety, social phobia, specific phobia, agoraphobia, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), mood disorders (major depression, dysthymia, mania, and hypomania), conduct disorder, oppositional defiant disorder, attention-deficit/hyperactivity disorder, and substance disorders."

Just over 1200 of these research participants were then followed into adulthood - young adulthood - and assessed "for adverse outcomes related to health, the legal system, personal finances, and social functioning." This included responses on the the Young Adult Psychiatric Assessment (YAPA) and accessing official criminal records.

Results: of the original childhood cohort, just over a quarter of children/young adults "met criteria for a common behavioral or emotional disorder at some point in childhood/adolescence (9-16 years of age)." Whilst this might sound a lot, other studies have reached similar conclusions (see here). Added to that, about a third of participants at this stage of development "displayed subthreshold psychiatric problems only."

For those followed into adulthood: "Participants with a childhood disorder had 6 times higher odds... of at least 1 adverse adult outcome (ie, indicator) compared with those with no history of psychiatric problems." In more detail: "41.5% of participants who were subthreshold cases only and 59.5% of participants who were psychiatric cases reported an adult outcome" where an 'adult outcome' was classified as one of those 'adverse outcomes' in the areas inspected. "Psychiatric and subthreshold cases made up close to 80% of participants with an adult indicator (42.3% of psychiatric cases, 35.7% of subthreshold cases, and 22.0% of noncases) and close to 90% of participants with 2 or more such indicators (48.2% of psychiatric cases, 39.4% of subthreshold cases, and 12.3% of noncases)."

Drilling down into the details of what diagnosis or subthreshold diagnosis specifically translated into adverse adult outcomes, the authors reported that "childhood depression and conduct disorder were associated with a higher likelihood of having an adverse outcome, and only conduct disorder predicted having 2 or more adverse outcomes." These results held true even when various covariates were taken into account such as low socio-economic status, unstable family structure and maltreatment.

The accompanying editorial does make a case for not jumping to too many conclusions on the basis of the Copeland findings in terms of their meaning. "It is possible that some or all of the causes of psychopathology across the lifespan operate early in life" is one sentiment expressed. Being careful not to make any sweeping generalisations, I would tend to suggest that the evidence does seem to be pointing to early life psychopathology as expressing quite a effect when it comes to later life outcome. Taking for example the idea that a neurodevelopmental disorder might for example, influence the risk of psychosis in later life (see here) is one area where supporting peer-reviewed evidence has been produced. A possible link between the diagnosis of autism (Asperger syndrome) and an elevated risk of bipolar disorder (see here) in adult life is another.

Irrespective of the hows and whys, the data from Copeland adds to the idea that significantly more efforts are perhaps required to 'tackle' childhood psychopathology with the hope of reducing adverse adult outcomes and improving quality of life across the lifespan. Accepting that societal factors might also need some inspection alongside the idea that economics might enter into the equation at some point [3], questions remain about the best way to achieve this aim and how one goes about providing an evidence-based approach to analysing the success or not of any approach to this matter.

Music: LCD Soundsystem - Someone Great.

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[1] Copeland WE. et al. Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study. JAMA Psychiatry. 2015. July 15.

[2] Lahey BB. Why Are Children Who Exhibit Psychopathology at High Risk for Psychopathology and Dysfunction in Adulthood? JAMA Psychiatry. 2015. July 15.

[3] Chorozoglou M. et al. Preschool hyperactivity is associated with long-term economic burden: evidence from a longitudinal health economic analysis of costs incurred across childhood, adolescence and young adulthood. Journal of Child Psychology and Psychiatry. 2015. June 13.

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Copeland WE, Wolke D, Shanahan L, & Costello EJ (2015). Adult Functional Outcomes of Common Childhood Psychiatric Problems: A Prospective, Longitudinal Study. JAMA psychiatry PMID: 26176785

Incontinence and paediatric autism

Urinary incontinence - "the unintentional passing of urine" - is a fairly common issue affecting millions of people of all ages worldwide. Achieving full bladder and bowel control is seen as a typical part of growing up but for some children, particularly those diagnosed with a behavioural or developmental condition, issues with incontinence can persist much later into life [1].

The findings reported by Alexander von Gontard and colleagues [2] bring the issue of incontinence into the autism research spotlight with their observations that: "children with ASD [autism spectrum disorder] are at a greater risk of being affected by different forms of incontinence and LUTS [lower urinary tract symptoms]."

Based on responses to a questionnaire "referring to incontinence and the International Consultation on Incontinence Questionnaire-Pediatric LUTS (ICIQ-CLUTS)" researchers were able to compare results for 40 children diagnosed with ASD (mean age 11 years) with 43 aged-matched asymptomatic controls. Assessing various different types of incontinence, results suggested that nearly a third of participants with ASD showed nocturnal enuresis (night-time urinary incontinence) and nearly a quarter with daytime urinary incontinence. Control responses were 0% and ~5% respectively. Presentation of lower urinary tract symptoms (LUTS) in general were more frequently noted in the ASD group including "urgency and postponement".

Given that psychological symptoms can to some extent also overlap with incontinence issues, researchers also reported that "children with ASD showed higher rates of clinically relevant psychological symptoms (externalizing and internalizing symptoms), and according to the psychiatric interview, they had higher rates of comorbid psychological disorders." The conclusion: "children with ASD are at a greater risk of being affected by different forms of incontinence and LUTS. Therefore, screening for incontinence and, if indicated, treatment of these disorders is recommended."

This is not the first time that incontinence issues have been reported as occurring alongside a diagnosis of autism. Geier and colleagues [3] observed a fairly high number of their cohort with autism (mean age ~ 6 years) as also presenting with incontinence issues. Other studies have suggested a connection between certain medication use and the onset of incontinence in cases of autism [4]. Incontinence has tended to be something of unspoken issue in autism research and practice down the years as reports of children 'still in nappies' have circulated. I can't say for sure why such issues seemed to have been just left as part of the expected outcome for children with 'special needs' as the earlier article from von Gontard [1] described them, but it strikes me that we should perhaps be doing more to tackle such issues when present. The idea that continence problems might also have specific presentation profile(s) when noted in cases of autism is also interesting in light of other work [5] suggesting that screening for autism in case of "functional defecation disorders" might be indicated. Added to research on slow bowel transit time and autism (see here) and the closer inspection of general incontinence issues allied to autism is very much indicated.

Music: The Beatles - Hello Goodbye. Well, make up your mind...

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[1] von Gontard A. Urinary incontinence in children with special needs. Nat Rev Urol. 2013 Nov;10(11):667-74.

[2] von Gontard A. et al. Incontinence in children with autism spectrum disorder. Journal of Pediatric Urology. 2015. May 22.

[3] Geier DA. et al. A prospective Cross-sectional Cohort Assessment of Health, Physical, and Behavioral Problems in Autism Spectrum Disorders. Maedica (Buchar). 2012 Sep;7(3):193-200.

[4] Kumazaki H. et al. Risperidone-associated urinary incontinence in patients with autistic disorder with mental retardation. J Clin Psychopharmacol. 2014 Oct;34(5):624-6.

[5] Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. 2013 Sep;163(3):873-8.

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von Gontard A, Pirrung M, Niemczyk J, & Equit M (2015). Incontinence in children with autism spectrum disorder. Journal of pediatric urology PMID: 26052001

Medical comorbidity and adult autism (again)

Regular readers are probably tired of reading blog titles like the one for today on this site. It's not as if the idea that a diagnosis of autism might predispose someone to quite a few more comorbid conditions (see here and see here) hasn't been discussed on quite a few occasions.

But just in case the message hasn't got through, I draw your attention to the paper by Kyle Jones and colleagues [1] concluding that: "Adults in this cohort of autism spectrum disorder first ascertained in the 1980s experience a high number of chronic medical conditions, regardless of intellectual ability."

The cohort in question was part of the 1980s Utah/UCLA autism epidemiologic study and some further follow-up of some of the people who participated in this quite early research foray into the epidemiology of autism. I say 'some' of the cohort because, as has been discussed previously on this blog (see here), sadly not everyone has survived over the years. Part and parcel of that 'excess mortality' in this cohort discussed by Bilder and colleagues [2] was thought due to "the presence of comorbid medical conditions" among other things.

The recent Jones paper "queried medical symptoms, disorders, hospitalizations, surgeries, and medication use" for 92 participants from the original cohort, mostly aged in their mid-30s. The found that: "The most common medical conditions were seizures, obesity, insomnia, and constipation." Further: "The median number of medical conditions per person was 11." Interestingly, researchers suggested that various factors might further increase the risk of such medical comorbidity including gender (females over males) and the presence of obesity. I say that bearing in mind the relatively small participant numbers included for study (69 of the 92 participants were male).

What's more to say on the basis of these and other findings? Well, the need for greater appreciation that autism seems to go much further than the presentation of core symptoms might be one thing (see here). As per my various ramblings on physical health and activity with the autism spectrum in mind (see here) tackling issues such as obesity might be another thing (see here) bearing in mind how various eating/feeding issues for example, might complicate matters when it comes to autism and obesity (see here). The same also goes for sleep (see here).

In the words of Jones et al: "Understanding of these conditions commonly experienced should direct community-based and medical primary care for this population." Once again, I cannot disagree with such sentiments.

Music: Glen Campbell - Wichita Lineman.

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[1] Jones KB. et al. A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study. Autism. 2015. July 10.

[2] Bilder D. et al. Excess mortality and causes of death in autism spectrum disorders: a follow up of the 1980s Utah/UCLA autism epidemiologic study. J Autism Dev Disord. 2013 May;43(5):1196-204.

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Jones, K., Cottle, K., Bakian, A., Farley, M., Bilder, D., Coon, H., & McMahon, W. (2015). A description of medical conditions in adults with autism spectrum disorder: A follow-up of the 1980s Utah/UCLA Autism Epidemiologic Study Autism DOI: 10.1177/1362361315594798

Autism, asthma and IL-17

"IL-17 was increased in ASD [autism spectrum disorder] children with co-morbid asthma compared to controls with the same condition."

That was the conclusion reached by Marjannie Eloi Akintunde and colleagues [1] including some notable names on the authorship list from the University of California, Davis. IL-17 (Interleukin 17) by the way, refers to a group of cytokines - chemical messengers of the immune system - linked to various processes centred on inflammation. Jin & Dong [2] provide quite a good overview of the complexities of IL-17 with respect to immune function and inflammation.

Asthma crops up yet again on this blog. Based on the idea that overlapping diagnoses of autism and asthma might be more frequent than one would perhaps anticipate (see here and see here), researchers looked at the production of various cytokines including IL-17 in biological samples provided by a group of young children with ASD compared to asymptomatic controls "following ex vivo mitogen stimulation." They reported that levels of IL-17 were elevated in samples from the group with ASD compared to controls and for those with ASD and comorbid asthma, levels of IL-17 were elevated compared with those diagnosed with ASD minus asthma.

This is not the first time that IL-17 has cropped up on the autism research radar as per the findings reported by Al-Ayadhi & Mostafa [3] also covered on this blog (see here). Other, more case report data has also hinted that IL-17 as part of a "proinflammatory, autoimmune-polarized cytokine profile" [4] might also show some connection with [some] autism. Even some of the co-authors on the Akintunde paper have previously reported on IL-17 in relation to autism [5] albeit not necessarily central to the cytokine 'profile' of autism.

It is important to note that whilst there were group differences noted between autism and controls, the idea that IL-17 might distinguish autism + asthma from autism alone is not an entirely unexpected finding. Elevated levels of IL-17 have been reported in cases of asthma [6] and in some quarters, has been touted as a possible 'therapeutic target' specifically in those cases of steroid-insensitive asthma [7]. Questions do however remain about the hows and whys of the association between autism and asthma and importantly, whether there may be overlapping aetiological factors leading to both conditions developing alongside the idea that other comorbidity might be also implicated (see here).

Music: MGMT - Time To Pretend.

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[1] Akintunde ME. et al. Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma. Journal of Neuroimmunology. 2015. July 11.

[2] Jin W. & Dong C. IL-17 cytokines in immunity and inflammation. Emerging Microbes & Infections. 2013; 2: e60.

[3] Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. J Neuroinflammation. 2012 Jul 2;9:158.

[4] Magid-Bernstein J. et al. Case report: cytokine and CD4+ T-cell profiles of monozygotic twins with autism and divergent comorbidities and drug treatment. J Child Neurol. 2015 Mar;30(3):386-90.

[5] Onore C. et al. Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders. J Neuroimmunol. 2009 Nov 30;216(1-2):126-9.

[6] Chesné J. et al. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med. 2014 Nov 15;190(10):1094-101.

[7] Morishima Y. et al. Th17-associated cytokines as a therapeutic target for steroid-insensitive asthma. Clin Dev Immunol. 2013;2013:609395.

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Akintunde, M., Rose, M., Krakowiak, P., Heuer, L., Ashwood, P., Hansen, R., Hertz-Picciotto, I., & Van de Water, J. (2015). Increased production of IL-17 in children with autism spectrum disorders and co-morbid asthma Journal of Neuroimmunology DOI: 10.1016/j.jneuroim.2015.07.003

Sickle cell disease, asthma and behaviour

"Children with sickle cell disease may have increased risk for certain neurodevelopmental diagnoses based on their disease characteristics and associated comorbidities."

That was the conclusion reached by Eboni Lance and colleagues [1] following their retrospective chart review including "59 children with sickle cell disease with a documented neurodevelopmental diagnosis, specifically attention deficit hyperactivity disorder [ADHD], attention issues, behavioral issues, executive dysfunction, specific learning disabilities in math, reading, and reading comprehension, intellectual disabilities, developmental delay, fine motor disorders, language disorders, or autism spectrum disorders."

Sickle cell disease covers quite a bit of diagnostic ground, describing how haemoglobin - the stuff that transports oxygen from the lungs to the rest of the body - shows specific morphological changes that impact on the shape of red blood cells and onwards their ability to transport oxygen to various tissues. Described as life-long conditions, some of the main symptoms include pain crises and anaemia. They can also increase vulnerability to certain infections too as a result of the effect on the spleen. Risk of cerebral infarction (a type of stroke) is also a known potential issue [2] associated with sickle cell disease.

Of particular interest to me was the observation that a reported history of asthma comorbid to sickle cell disease seemed to increase the risk of "behavioral issues" compared with those where no history of asthma was present. This association held true even when the type of sickle cell disease was taken into account and adjustment for other factors such as gender. Quite a few times on this blog I've talked about peer-reviewed data that seems to suggest that a childhood diagnosis of asthma might be linked to an elevated risk of certain behaviours and developmental diagnoses including ADHD (see here and see here) and perhaps to a lesser extent [some] autism (see here and see here). The precise hows and whys of any connection are still up for debate (I'd hazard a guess and say that there are likely to be multiple factors at work) but the evidence is getting stronger for a connection all the time.

I'm not necessarily implying that behavioural issues / diagnoses when present alongside sickle cell disease are all due to comorbidity such as asthma. Other science in this area has for example, detailed associations between the presence of sickle cell disease and poorer cognitive functioning [3] as well as attentional issues being present and partially moderated by that heightened risk of stroke [4]. I might even throw in some very preliminary science suggesting that certain types of stroke have also been linked to the presentation of certain types of autism (see here) too.

But I do think it is interesting that once again asthma turns up with a potential behaviour link...

Music: Lana Del Rey - Video Games.

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[1] Lance EI. et al. Risk Factors for Attention and Behavioral Issues in Pediatric Sickle Cell Disease. Clin Pediatr (Phila). 2015 Jul 6. pii: 0009922815594356.

[2] Schatz J. et al. Cognitive functioning in children with sickle cell disease: a meta-analysis. J Pediatr Psychol. 2002 Dec;27(8):739-48.

[3] Nabors NA. & Freymuth AK. Attention deficits in children with sickle cell disease. Percept Mot Skills. 2002 Aug;95(1):57-67.

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Lance EI, Comi AM, Johnston MV, Casella JF, & Shapiro BK (2015). Risk Factors for Attention and Behavioral Issues in Pediatric Sickle Cell Disease. Clinical pediatrics PMID: 26149844

Health-related quality of life in CFS/ME

Hvidberg et al (2015) PLoS One. e0132421

Two papers are served up for your reading today. Both provide stark peer-reviewed evidence that when it comes to chronic fatigue syndrome (CFS) / myalgic encephalomyelitis (ME), measures of quality of life (QoL) rank this/these condition(s) as potentially causing great suffering compared with population norms and various other states.

The first paper is by Michael Falk Hvidberg and colleagues [1] (open-access available here) and details response of Danish participants diagnosed with ME/CFS on the EQ-5D-3L "a generic, self-reported questionnaire with five dimensions: 1) mobility; 2) self-care; 3) usual activities; 4) pain/discomfort; and 5) anxiety/depression."

Taking into account various other variables such as gender/sex and education, researchers reported that the "ME/CFS study population is more disabled and socially marginalized than the average population with regards to the subjects of long-term illness, number of illnesses, proportion of disability pensioners and relationships." Further based on the examination of various other data utilising the EQ-5D-3L schedule "the ME/CFS patients of the current study have the lowest, unadjusted EQ-5D-3L measured HRQoL [health-related quality of life] of 20 conditions, thus even worse than multiple sclerosis and stroke." The figure reproduced from the Hvidberg study shows how ME/CFS measures up against those other conditions.

Continuing the theme of of health-related QoL are the results published by Anette Winger and colleagues [2] (open-access available here). Detailing the experiences of some 120 Norwegian adolescents, researchers delivered "The Pediatric Quality of Life Inventory™, 4.0 (PedsQL)" among other things to participants and "39 healthy controls (HC)." They concluded that: "adolescents with CFS have a significantly lower quality of life compared with healthy controls, demonstrated by lower overall HRQOL score and sub-score levels for specific HRQOL domains." Further: "Depressive symptoms were found in both adolescents with CFS and HCs, but the score levels were higher among the adolescents with CFS. The low HRQOL level in the CFS group was not explained by depressive symptoms but by having CFS."

Bearing in mind potential methodological issues such as the relatively small participant numbers included and the reliance on self-report as a measure of QoL (though not necessarily a bad thing when it comes to an individual's perceived quality of life), there are some pretty stark messages to come from this and other peer-reviewed data on this topic.

First and foremost is the idea that a diagnosis of ME/CFS really, really impacts on a person's life. For those suffering (yes, people diagnosed with ME/CFS do suffer) from this disorder, this is not likely to be new news. If you want just one story about how far-reaching the effects of this disorder can be, you can read it here. That a reduction in health-related QoL which follows ME/CFS is likely to be compounded by the 'stigma' built up around the condition(s) should also not be under-estimated. Indeed, only this year (2015) has science really started to put some flesh on the bones that ME/CFS is a 'biological illness' as per the Hornig/Lipkin results (see here) and those from others (see here).

Second, and as per some comment in the Winger results, is the idea that 'school functioning' is an important area that is impacted when it comes to adolescent ME/CFS. To quote: "school functioning was the most affected HRQOL domain, with a score level... substantially lower compared with previous studies on CFS patients." I've covered the idea that ME/CFS might show something of a connection to school attendance before on this blog (see here) and how onset of symptoms during such a critical period of development might be something in need of much greater inspection in terms of improving access to education for those diagnosed.

Finally is the question of what can be done to improve QoL for those diagnosed with ME/CFS. From a biological perspective, I might draw your attention to various discussions on this blog about the ways and means research has tried to intervene to ameliorate symptoms as a possible means to improve QoL (see here and see here for example). With no medical or clinical advice given or intended, science continues to approach the idea that within the spectrum of conditions probably included under the heading(s) of ME/CFS, there may be viable treatment options available [3] assuming further investigations. I might add that one area that particularly interests me is a possible role for enterovirus in at least some ME/CFS [4] and where this could eventually lead in terms of potential intervention(s). Added to this are the various other ways and means that society can help insofar as improving healthcare access, recognising that the risk of various comorbidity might be heightened following a diagnosis (see here) and ensuring that appropriate adjustments are made for a person in terms of finance, education and/or employment and other areas when a diagnosis is eventually made.

In short, more needs to be done to ensure that those diagnosed with ME/CFS are not subject to further health inequality...

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[1] Falk Hvidberg M. et al. The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Jul 6;10(7):e0132421.

[2] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13(1):96.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE; 2015: 10(7): e0129898.

[4] Chia JK. The role of enterovirus in chronic fatigue syndrome. J Clin Pathol. 2005 Nov;58(11):1126-32

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Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, & Ehlers L (2015). The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PloS one, 10 (7) PMID: 26147503





Winger A, Kvarstein G, Wyller VB, Ekstedt M, Sulheim D, Fagermoen E, Småstuen MC, & Helseth S (2015). Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health and quality of life outcomes, 13 (1) PMID: 26138694

Early pregnancy maternal hypothyroxinemia and offspring ADHD symptoms

"Children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD [attention-deficit/hyperactivity disorder] symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring."

That was the bottom line reported by Thiago Modesto and colleagues [1] looking at how "mild thyroid hormone insufficiency" in early pregnancy might link into offspring behavioural outcomes a few years down the line. Based on data collected as part of the Generation R initiative - itself the source of previous research looking at the potential involvement of thyroid hormones and offspring outcome - researchers looked at maternal hypothyroxinemia "characterized by low levels of free thyroxine coexisting with reference thyrotropin levels" during pregnancy and how it correlated (or not) with parental report of offspring ADHD type behaviours based on scores on the Conners' Parent Rating Scale-Revised Short Form. They reported something of a possible association where: "Maternal hypothyroxinemia... in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (ie, sex, ethnicity, maternal age, maternal educational level, and income)." Interestingly too, when those presenting with thyroid peroxidase antibodies (a marker of autoimmune-related issues) were excluded from the analyses, the results did not differ to any great extent suggesting that the processes of being exposed to too lower a dose of thyroid hormone during early pregnancy seems to be the important factor outside of the possible reasons for such lower levels such as autoimmunity.

I've been pretty interested in the various [peer-reviewed] research looking at pregnancy thyroid hormones and offspring developmental outcomes down the years. In amongst that collected research, the idea that ADHD (or ADHD type symptoms) and even the presentation of autism might tie into the pregnancy levels of thyroid hormones has been quite a frequent feature (see here for example). Indeed, other research such as that from Libbe Kooistra and colleagues [2] over 10 years ago, had indicated that "maternal hypothyroxinemia constitutes a serious risk factor for neurodevelopmental difficulties" potentially detectable even as young as 3 weeks of age. Insofar as a role for autoimmunity in relation to pregnancy thyroid functions and offspring outcome, I'm also not quite ready to move on from a possible association as per other findings with autism in mind (see here).

Questions remains about the hows and whys of such an association and whether more could be done to extend screening for thyroid hormones particularly during early pregnancy in order to intervene and potentially 'offset' any additional developmental risks to offspring. Without making any clinical recommendations or giving anything like medical advice, I would also be interested to see how such thyroid findings might intersect with the body of work looking at issues with iodine availability (see here) and whether a wider research aim of looking at what happens in cases of pregnancy iodine deficiency in relation to thyroid hormone production and subsequent offspring development and behaviour is merited. It's not as if there isn't already some basis for further research inspection [3] in this area, also potentially extending into [some] autism (see here) too...

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[1] Modesto T. et al. Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children. JAMA Pediatr. 2015 Jul 6.

[2] Kooistra L. et al. Neonatal Effects of Maternal Hypothyroxinemia During Early Pregnancy. Pediatrics. 2006; 117: 161-167.

[3] Vermiglio F. et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab. 2004 Dec;89(12):6054-60.

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Modesto T, Tiemeier H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, & Ghassabian A (2015). Maternal Mild Thyroid Hormone Insufficiency in Early Pregnancy and Attention-Deficit/Hyperactivity Disorder Symptoms in Children. JAMA pediatrics PMID: 26146876

Homocysteine and autism: yet more...

It's been a while since I've discussed the issue of homocysteine - that's homocysteine not homocystine - with autism in mind, so consider this short blog entry a bit of an update to previous discussions (see here and see here).

In case you need to know it, homocysteine is an important component of the trans-sulfuration pathway intersecting with both the methione cycle and the folate cycle. Collectively, these biological processes have important functions for various aspects of biology including the process of methylation and the issue of oxidative stress leading into the important role of glutathione (see here) for example.

I was brought to this post following the publication of two recent paper from Carmen Puig-Alcaraz and colleagues [1] and from Yu Han and colleagues [2] that both reported on elevated levels of homocysteine to be present in their cohorts of children diagnosed with an autism spectrum disorder (ASD) compared with asymptomatic controls. These findings are pretty much in line with what most other research has reported in this area.

Puig-Alcaraz et al reported that alongside an overall increased level of urinary homocysteine in their cohort, there seemed to be something of a relationship between elevated urinary homocysteine with "the severity of the deficit in communication skills" in their participant group. Something that was not seen when looking at the other core areas of autism (social interaction and repetitive/restricted behaviour). I'm intrigued at the prospect that specific traits may be linked to something like elevated levels of homocysteine although recognise the need for far greater scrutiny of this finding with larger cohorts. That this group only measured homocysteine in urine is another issue that needs to be further explored.

Han et al report results based on Chinese children. This in itself is an important cohort suggesting that issues with homocysteine might cross geography and ethnicity when it comes to autism on the basis of other studies looking at different populations. Alongside reporting on elevations in homocysteine, researchers also noted that total levels of glutathione and cysteine were lower in the autism group; findings that accord with meta-analyses of glutathione and related compounds with autism in mind (see here). Further: "Hcy [homocysteine] levels correlated significantly with increasing CARS [Childhood Autism Rating Scale] scores and GSSG [oxidized glutathione] levels in children with ASD" with the proviso that further investigations are needed in this area.

The peer-reviewed evidence is indeed stacking up for something potentially fundamental at work when it comes to autism and homocysteine. At this stage it would be difficult to tease apart homocysteine alone as being 'linked' to [some] autism given the myriad of other compounds/pathways also potentially implicated as per the literature on the B vitamins and their important links to homocysteine. I'm also wondering whether another relation of one of the B vitamins, methylmalonic acid, that has languished in the autism science desert for far too long might also need resurrecting in future studies on the 'big H' and autism?

And yes, screening is important [3]...

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[1] Puig-Alcaraz C. et al. Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry Res. 2015 May 29. pii: S0165-1781(15)00290-5.

[2] Han Y. et al. Abnormal transsulfuration metabolism and reduced antioxidant capacity in Chinese children with autism spectrum disorders. International Journal of Developmental Neuroscience. 2015. July 3.

[3] Ranjan S. & Nasser JA. Nutritional Status of Individuals with Autism Spectrum Disorders: Do We Know Enough? Adv Nutr. 2015 Jul 15;6(4):397-407.

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Puig-Alcaraz C, Fuentes-Albero M, Calderón J, Garrote D, & Cauli O (2015). Increased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry research PMID: 26070768





Han, Y., Xi, Q., Dai, W., Yang, S., Gao, L., Su, Y., & Zhang, X. (2015). Abnormal transsulfuration metabolism and reduced antioxidant capacity in Chinese children with autism spectrum disorders International Journal of Developmental Neuroscience DOI: 10.1016/j.ijdevneu.2015.06.006

Person with autism or autistic person?

Although it might seem like a bit of a distraction, I read with interest the paper by Lorcan Kenny and colleagues [1] (open-access) discussing the ways and means that we talk about autism here in Blighty. Some related media on the paper can be found here and here.

I mentioned the word 'distraction' because I'm sure that some people (many people?) might be wondering why we are discussing the various ways and means that autism is described when there is so much more for research to do in trying to improve the lives of those diagnosed as being on the autism spectrum. Indeed, saving lives may be more accurate in some cases. I would agree that the autism research agenda is pretty full when it comes to issues such as early identification, experimentally testing the myriad of interventions out there and how the various 'comorbidities' that seem to be over-represented alongside a diagnosis can impact on quality of life and what we can do about them. I'm also, however, of the opinion that the way we talk about autism can also impact on a person's life in important areas such as dignity, self-esteem and self-identity and such viewpoints may have important knock-on effects for people and society at large.

The Kenny paper is open-access so it requires little additional rambling from me. Continuing a theme of some of the authors looking to ask various stakeholders (people with autism / autistic people, parents, professionals) about facets of the autism research and practice landscape (see here and see here), they sought views "about the terms they use to describe autism." This was all done via an online survey so one has to be a little bit guarded about the quality of the results obtained, although some 3500 people did complete the survey and had their results included.

"The results clearly show that people use many terms to describe autism." No real surprises there considering the various groups that responded and the myriad of ways that autism has been described past and present. "The most highly endorsed terms were ‘autism’ and ‘on the autism spectrum’, and to a lesser extent, ‘autism spectrum disorder’, for which there was consensus across community groups." Again, I'd be hard-pressed to say there was anything too novel there.

But: "The groups disagreed, however, on the use of several terms. The term ‘autistic’ was endorsed by a large percentage of autistic adults, family members/friends and parents but by considerably fewer professionals; ‘person with autism’ was endorsed by almost half of professionals but by fewer autistic adults and parents." Quite a bit of this seemed to touch on the idea of 'ownership' of the label and "one’s relative distance from autism." Further: "the closer one was to directly experiencing autism hour-to-hour, day-to-day, the more likely the community member endorsed the use of disability-first (rather than person-first) terms."

Various themes also emerge in the Kenny paper covering the ideas of 'natural diversity' and the use of "value-laden terms such as ‘disability’, ‘deficit’ or ‘disorder’, which imply that any difficulties experienced by autistic people are a result of them being ‘broken’ in some way." I agree to some extent that autism and the wider concept of the broader autism phenotype (BAP) do indeed root the behavioural presentation of autism as part of the tapestry known as humanity. As someone once said to me 'everything seen in autism is also seen at some stage of typical maturation -- it is the intensity and nature of the behaviour(s) and its effect on a person's life that merits diagnosis'. I'd perhaps also suggest that as other commentators have mentioned, one has to be a little careful not to overdo the whole natural diversity bit as a means to water down what autism can mean for a lot of people in terms of 'disability' and it's sometimes stark effects on quality of life.

Finally, and hopefully without upsetting anyone, I do have to take issue with a particular point raised in the Kenny paper: "Many adults were keen to emphasise other qualities of autism, counteracting commonly held beliefs that perpetuate in the media. They stressed that autism is a lifelong condition – that they do not ‘grow out of it’ when they become adults." 'Growing out' of autism is not necessarily the best way of describing the idea that some of the signs and symptoms of autism might change over time but it is a topic that has cropped up on this blog before (see here) under the guise of 'optimal outcome'. As per the findings reported by Helles and colleagues [2] there is an increasing realisation that for some on the autism spectrum, the behavioural presentation is not static and indeed might 'move' someone outside of the diagnostic confines of the label (see here for more explanation). The ways and means that this happens is still up for debate (learned strategies, intervention, maturation?) and even when this happens does not mean a symptom-free, problem-free life (see here); although even here I'm slightly guarded [3] in making too many sweeping generalisations.

Perpetuation of the ideas that (a) all autism is the same and (b) all autism is fixed and 'lifelong' however does little to forward the agenda of (neuro)diversity and the full meaning of the important sentence: 'if you've met one person with autism, you've met one person with autism'.

More than that though, they don't seem to be supported by the available peer-reviewed science...

Music: Nirvana - About A Girl.

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[1] Kenny L. et al. Which terms should be used to describe autism? Perspectives from the UK autism community. Autism. 2015. July 1.

[2] Helles A. et al. Asperger syndrome in males over two decades: stability and predictors of diagnosis. Journal of Child Psychology and Psychiatry. 2014. 3 October.

[3] Orinstein A. et al. Psychiatric Symptoms in Youth with a History of Autism and Optimal Outcome. J Autism Dev Disorder. 2015. July 9.

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Kenny L, Hattersley C, Molins B, Buckley C, Povey C, & Pellicano E (2015). Which terms should be used to describe autism? Perspectives from the UK autism community. Autism : the international journal of research and practice PMID: 26134030