'Self-treatment' with helminths and autism?

At the end of 2013 there was some media interest in the presentation of interim data at the 2013 Annual Meeting of the American College of Neuropsychopharmacology from a couple of studies being run by Prof. Eric Hollander.

It's life Jim but not as we know it... @ CDC

The abstracts for the studies 'Trichuris Suis Ova (TSO) as an Immune-inflammatory Treatment for Repetitive Behaviors in ASD' and 'Hyperthermia and the Improvement of ASD Symptoms' can be found here (look under abstracts T177 and T231).

Whilst the media headlines citing 'worms and hot baths' as potential intervention approaches for autism generated quite a nice soundbite and are probably enough for most people to click on the story to read more, I personally did not think they did justice to how potentially important these areas might be to at least some cases of autism. Indeed hot baths as a way of mimicking fever took me back to the article by Curran and colleagues [1] who "documented behavior change among children with autism spectrum disorders during fever."

Sweeping generalisations about hot baths, fever and autism aside, today I'm discussing the paper by Liu and colleagues [2] who, following a review of "the practices and experiences of individuals 'self-treating' with helminths through the eyes of their physicians" reported that over half of those 'self-treating' had a diagnosis of autism. Helminths by the way, are parasitic worms, and whilst some are rather unpleasant in terms of their detrimental effects to health, others have been used in a more therapeutic capacity. Insofar as the idea of 'self-treatment', well, let's just say that this may not be unusual...

Liu et al describe how: "Five physicians monitoring more than 700 self-treating patients were interviewed" and how: "These observations point toward potential starting points for clinical trials, and provide further support for the importance of such trials and for concerted efforts aimed at probing the potential of helminths, and perhaps other biologicals, for therapeutic use." Although one has to be slightly cautious about this type of 'clinical experiences' methodology ('the plural of anecdote is not data' and all that) adopted in the study, it was interesting to note that: "Physicians reported that the majority of patients with autism and inflammation-associated co-morbidities responded favourably to therapy with either of the two most popular organisms currently used by self-treaters, Hymenolepis diminuta and Trichuris suis." We are also importantly told that about 1% of paediatric patients using H. diminuta "experienced severe gastrointestinal pains" suggesting that any future studies should also be observant for side-effects.

I am still in two minds about this area of study and the 'palatability' of the proposed intervention. I note the full trial by Hollander and colleagues looking at the use of Trichuris Suis Ova in the context of autism has kinda fallen off the radar a little bit judging by the status of the trial entry in ClinicalTrials.gov at the time of writing. Aside from that proposed trial and some other speculations about the use of helminthic therapy potentially applied to autism [3] there is little else in the peer-reviewed research literature on this topic in terms of effects or some further details about any proposed mode of action. With my speculating hat on, one could perhaps see the logic around helminthic therapy with regards to the suggested augmentation of an abnormal immune response thought to involve the Th1/Th2 response (see here [4] for more details about this). With autism in mind, certainly there has been some research chatter about this immunological balancing act being potential important for some [5].

I'm sure also that some readers who've encountered this post are either (a) thinking WTF (apologies for my bad language) or (b) potentially thinking about how unethical this study and intervention sounds. Worms after all, are not generally regarded as a great therapy for anything, particularly when people are talking about eradication of such parasites rather than supplementing with them (see here). I'm certainly not going to stand up and suggest helminthic therapy is the be-all-and-end-all for autism intervention by any means even in the context of inflammatory process being potentially involved in many behaviourally-defined conditions [6]

The thing is though, that our prejudice against all parasites is similar to our prejudice against all bacteria. Not all parasitic worms are the same, just as not all bacteria are the same (he says drinking from his probiotic yoghurt). Indeed, helminthic therapy has found a place in medicine, particularly when it comes to various conditions with an immune system element to them as exemplified by papers such as this one [7]. The review article by Wammes and colleagues [8] kinda summarises the mixed feelings that science has about such intervention and how "a paradox exists between efforts to deworm populations with helminth-associated morbidities, and initiatives to test helminthic therapy on patients with hyperinflammatory diseases". If I remember correctly, I think Dr Michael Mosley also had something to say about swallowing parasites...

Added also to the words of caution about proposed side-effects from helminthic therapy, I will draw your attention to the paper by Bager and colleagues [9] who reported that "gastrointestinal reactions" were quite significantly elevated during the early days of quite a long administration period (every 21 days for 168 days) of pig whipworm in their particular trial and cohort. With all that science now knows about gastrointestinal (GI) issues in relation to autism, one probably doesn't want to compound any existing problems in that particular area of comorbidity.

Palatability aside, there is however more science to do in this area including looking further at potential mechanisms [10] and specifically, how swallowing worm eggs might one day be replaced by swallowing pills with a similar mode of biological action...

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[1] Curran LK. et al. Behaviors associated with fever in children with autism spectrum disorders. Pediatrics. 2007 Dec;120(6):e1386-92.

[2] Liu J. et al. Practices and outcomes of self-treatment with helminths based on physicians' observations. J Helminthol. 2016 May 31:1-11.

[3] Siniscalco D. & Antonucci N. Possible use of Trichuris suis ova in autism spectrum disorders therapy. Med Hypotheses. 2013 Jul;81(1):1-4.

[4] Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev. 2003 Aug;8(3):223-46.

[5] Gupta S. et al. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998 May 1;85(1):106-9.

[6] Friedrich MJ. Research on Psychiatric Disorders Targets Inflammation. JAMA. 2014. July 23.

[7] Elliott DE. & Weinstock JV. Helminthic therapy: using worms to treat immune-mediated disease. Adv Exp Med Biol. 2009;666:157-66.

[8] Wammes LJ. et al. Helminth therapy or elimination: epidemiological, immunological, and clinical considerations. Lancet Infect Dis. 2014 Jun 26. pii: S1473-3099(14)70771-6.

[9] Bager P. et al. Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial. PLoS One. 2011;6(8):e22346.

[10] Chhabra S. et al. Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. FASEB J. 2014 Jun 2. pii: fj.14-251967

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Liu J, Morey RA, Wilson JK, & Parker W (2016). Practices and outcomes of self-treatment with helminths based on physicians' observations. Journal of helminthology, 1-11 PMID: 27240605

Mouse modeling, immune function and autism

Contrary to the title of this post and any images that it may conjure up of mice parading down a runway in this season's 'hottest looks' whilst pouting to the clicks and flashes of multiple cameras, I'm back to mouse models and autism again(!) and an interesting piece of research by Hsiao and colleagues*.

I am kinda standing on the shoulders of giants with this paper given that it comes from the laboratory of Paul Patterson who has already run with a short description about it on his blog (see here). Whilst not pinning my colours to any mast, Prof. Patterson's blog is one I enjoy reading, not least because of the various links being made between the immune system and the brain (at least in mice). I assume most people would recognise by now that the brain does not run independent of the rest of the body despite our implicit need to compartmentalise anything and everything (see this post on labels).

Drawing heavily on Prof. Patterson's latest blog entry and the paper in question - hopefully without plagiarising - a few factoids:

• The Patterson team have previously published results based on a mouse model of stimulated immune activation during pregnancy and the resultant behavioural effects on offspring which seemed to overlap with the core symptoms of autism (see this paper by Malkova and colleagues**).
• In the latest study* the authors report on the profile of immune function in offspring mice of immune-stimulated mothers, suggesting some interesting effects in the area of T regulatory cells and cytokine production. I have recently talked about T-cells in this post on pristine cysteine so will perhaps put that to one side for now. Of just as much interest are elevations in that old favourite IL-6 and similar suggestions for IL-17, again the source of some interest recently on the topic of autoimmunity and autism (here). Roads toward inflammation seemed to be a key part of their findings.
• Coincidental to these findings is the report of "altered myeloid lineage potential and differentiation" in offspring. I'm not even going to profess to begin to know what this actually means, aside from referring you to quite a nice overview of hematopoietic stem cells (here) showing the distinction between myeloid and lymphoid progenitors. 
• Then to the big findings and please don't shoot the messenger: irradiating and transplanting "immunologically normal" bone marrow from both affected and non-affected control mice offspring into the offspring of immune stimulated mother mice seemed to correct some of the autism-type behaviours that were exhibited. So repetitive- and anxiety-like behaviours seemed to be reduced bearing in mind that anxiety is not (yet) a core symptom of autism (see here).
• That and some suggestion that timing might be everything when it comes to programming for immune dysfunction as a result of very few effects being seen when transplanting bone marrow from affected offspring to non-affected offspring over being born into a stimulated maternal immune system environment.

I note that on quite a few sites analysing these latest results, the authors have gone to great lengths to stress that (a) these were mouse findings - I'll say again, these were mouse findings, and (b) at the moment, no-one is suggesting that a bone marrow / stem cell transplant is any kind of 'treatment' for autism given questions for example, about whether the 'irradiation' bit of the procedure might have shown any effect alongside the actual bone marrow transplant. I would most definitely support these statements given both the preliminary nature of this research and also the complications and risks attached to bone marrow transplants (see here).

Having said that this is not the first time that bone marrow transplants and conditions like autism have appeared in the research literature. This paper by Akaho and colleagues*** talks about such transplants in cases of autism (and schizophrenia) occurring alongside leukaemia with a specific focus on maintaining treatment regimes and the anxiety related to the treatment process. Sharma and colleagues**** discussed some rather more direct observations following administration of "autologous bone marrow-derived mononuclear cells" in their quite varied patient group including cases of autism, bearing in mind one tree does not a forest make.

Indeed the concept of stem cell therapy, words which still seem to create quite an emotional response in many people, seems to be occurring more and more often in the research literature on autism as per this review by Siniscalco and colleagues***** (full-text) including a familiar name (Anna Sapone). I know many people might read 'stem cells and autism' and think back to those pop-up ads that seem to appear on various search engines offering some kind of James Bond style 'Die Another Day' rearrangement. Again, no endorsement is intended or given but perhaps what the Patterson lab study is suggesting is that a little more focused research is required in this area just before the door is entirely slammed shut. 

The Hsiao findings do represent another very important preliminary step into the immune-behaviour relationship with conditions like autism in mind. Assuming that the whole is greater than the sum of its parts, these moves towards a more whole body analysis of conditions like autism, where immune function, gut and gut bacterial function and brain function are examined in unison, offer the promise of some truly tantalising insights into autism.

And finally... just in case you are not convinced on the potential for an immune-behaviour link, cast your eye over this recent preliminary report on Alzheimer's disease and the use of IVIg as another area ripe for further inquiry.

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* Hsaio EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS. July 2012.
DOI: 10.1073/pnas.1202556109

** Malkova NV. et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior & Immunity. 2012; 26: 607-616.

*** Akaho R. et al. Bone marrow transplantation in subjects with mental disorders. Psychiatry & Clinical Neurosciences. 2003; 57: 311-315.

**** Sharma A. et al. Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplantation. 2012; 21: Suppl 1: S79-S90.

***** Siniscalco D. et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Journal of Biomedicine & Biotechnology. 2012; 480289.

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Hsiao EY, McBride SW, Chow J, Mazmanian SK, & Patterson PH (2012). Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America PMID: 22802640

IL-17A elevated in cases of autism

"The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia". So say Max Michel and colleagues* in their recent paper reviewing the often intricate findings in this area of investigation. Personally, I have to say that I agree with their sentiments, after having read through quite a lot of the literature on this topic over the years. I hasten to add that both the genetic and environmental effects acting on the immune system, or any other system in cases of autism, is likely to be variable and not uniform across the condition. As far as we know...

Yet more evidence for a potential role for the immune system and certain cytokines in cases of autism has emerged from two very familiar names, Laila Yousef Al-Ayadhi & Gehan Ahmed Mostafa in this paper** (full-text) looking at levels of the proinflammatory cytokine IL-17A. I say that these are familiar names because this research tag-team have been pretty prolific in recent years as per their publication entries on autism (here) and various immune-related findings. I would perhaps also plug a few previous blog posts about their work (here, here and here).

Let's start with a description. I'm sure quite a few people who follow the immune system research in relation to autism will have heard about Th1 and Th2 (type 1 and 2 helper T-cells). As per their name, helper T-cells help; more specifically they are involved in the orchestra that this is the immune response and in particular, cytokines and their expression, different types of cytokines, depending on the type of helper T-cell. Balance seems to be quite an important concept when it comes to Th1 and Th2 as per this article by Berger*** (full-text).

For quite a long time, the concepts of Th1 and Th2 predominated. That is until another kind of helper T-cell came onto the scene: Th17 - T helper 17 cells. Th17 produces the IL-17 family of cytokines which play a role in host defence and inflammation. Th17 has also been tied to quite a few 'autoimmune' conditions such as psoriasis (here) and inflammatory bowel disease (here) among others. There is of course quite a lot of biochemistry behind Th17 cells and the counterbalance, Treg(s) (including an old friend, IL-6) but I have neither the will nor expertise to go too far into all that now.

After that very brief overview, let's go through what Al-Ayadhi & Mostafa did and found:

• A sample of 45 children diagnosed with DSM-IV autism (mean age: 8.4 years) were included for study and compared with 40 age- and sex-matched 'apparently healthy' asymptomatic children. No comorbid autoimmune conditions were recorded in participants as far as the authors could tell.
• Participants with autism were also 'graded' on the severity of their autism presentation by way of the CARS; most fell into the severe category (n=28); the others (n=17) were described as having mild to moderate autism.
• Blood samples were drawn from all participants and serum levels of IL-17A determined by ELISA. Importantly, from an analytical perspective, all samples were run twice in independent experiments to confirm the results and rule out cross-reactivity (see here for a description).
• Results: as a group, the children with autism presented with significant elevations in IL-17A compared to controls. Individually, almost half of the children with autism presented with elevated IL-17A levels based on results on or above the 95th percentile of serum IL-17A noted in the control group.
• Severity of autistic symptoms seemed also to show some relationship with serum IL-17A levels in that the more severe presentation was associated with greater serum levels than those with a more moderate presentation. Age and gender did not seem to show effects.

There are a few things that can be taken from this study. IL-17 and inflammation. IL-17 and autism. Inflammation and autism. Need I say anything else? The association between Th17 and autoimmune disorders is something to bear in mind. I've talked before about autism and both features of autoimmunity seemingly present in some cases (here) or overlap with autoimmune comorbidity (here). The current results seem to suggest that there maybe something which might, at a biochemical level, relate autism and autoimmunity in at least some cases of autism; indeed quite a few cases judging by this latest paper. The question is: are IL-17A levels a core feature of autism or merely describing some hidden autoimmune comorbidity?

This is not the first time that a relationship between Th17 and autism has been suggested. Suzuki and colleagues**** (full-text) reported elevations in IL-17 and various other cytokines in their study of young adolescent boys with autism compared with control. Indeed the current authors also cited a potential role for IL-17 in other findings, specifically related to elevations in osteopontin levels previously discussed with parallel features according to things like symptom severity affecting results.

I suppose the final question should be: what can be done about elevated levels of IL-17? Reiterating my position about not giving medical advice or anything that could be construed as medical advice, the research literature contains a few options for further investigation. The therapeutic application of monoclonal antibodies against human IL-17A has already been mentioned in other areas of investigation. Leonardi and colleagues***** reported some initial success on the use of ixekizumab for a specific type of psoriasis, plaque psoriasis and improvement in clinical symptoms. Similar preliminary findings were also reported by Hueber and colleagues****** based the use of on another IL-17A human monoclonal antibody, AIN457 (secukinumab). Other compounds also seem to have the potential to affect IL-17 levels or production too. Lanzilli and colleagues******* for example, discussed the potential of resveratrol to affect IL-17 levels (at least in vitro).  Again, I reiterate the need for a lot more efficacy and safety research before these and other potential compounds go anywhere near people with autism.

There seems to be a rising tide of research coming through suggestive of links between at least some cases of autism and issues with the immune system and more precisely autoimmunity. Bearing in mind the 'correlation does not equal causation' motif, I think back to the post on Dr Kevin Becker's paper and the other work that has been done in this area and wonder whether we really should be making moves to more generalised screening for autoimmune markers and comorbidity where an autism diagnosis is given, if only to establish how deep the rabbit hole really goes?

To finish, and to coincide with the news about "detecting a particle consistent with the Higgs boson", the Galaxy song by Monty Python. Makes me feel quite insignificant really.

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* Michel M. et al. Immune system gene dysregulation in autism & schizophrenia. Developmental Neurobiology. June 2012.

** Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of interleukin-17A in children with autism. Journal of Neuroinflammation. 2012; 9: 158.
DOI: 10.1186/1742-2094-9-158

*** Berger A. Th1 and Th2 responses: what are they? BMJ. 2000; 321: 424.1.

**** Suzuki K. et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE. 2011; 6: e20470.

***** Leonardi C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. NEJM. 2012; 366: 1190-1199.

****** Heuber W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Science Translational Medicine. 2010; 2: 52ra72.

******* Lanzilli G. et al. Anti-inflammatory effect of resveratrol and polydatin by in vitro IL-17 modulation. Inflammation. 2012; 35: 240-248.