HBOT and autism systematically reviewed again (and the same results?)

"To date, there is no evidence that hyperbaric oxygen therapy improves core symptoms and associated symptoms of ASD [autism spectrum disorder]."

So said the results of the review by Xiong and colleagues [1] (open-access available here) completed under the auspices of the Cochrane Collaboration, leaders in the science and publication of systematic reviews (see here for another example).

Looking at the collected peer-reviewed science on the topic of hyperbaric oxygen therapy (HBOT) for autism - where "the patient breathes near 100% oxygen intermittently while inside a hyperbaric chamber pressurized to greater than sea level pressure", authors looked to determine several factors. Whether "treatment with hyperbaric oxygen: 1. improves core symptoms of ASD, including social communication problems and stereotypical and repetitive behaviors; 2. improves noncore symptoms of ASD, such as challenging behaviors; 3. improves comorbid states, such as depression and anxiety; and 4. causes adverse effects."

The results kinda mirrored what has already been previously described in the existing research review literature (see here), that based on one trial only [2] reaching their inclusion criteria, there is little evidence at the moment to say that HBOT is blanket indicated for autism.

Obviously one has to be a little careful that 'absence of science' is not construed as 'absence of evidence'. Indeed, I'm a little annoyed that the authors start suggesting that HBOT "may not be appropriate" for further study with autism in mind in light of the lack of studies in this area based on "the absence of a persuasive theory of change from experimental and clinical studies, the unknown long-term safety of the treatment, and the financial and opportunity costs of not participating in other proven therapies." No, I'm not defending HBOT as an intervention for autism but I am defending the idea that research reviews based on one study should really be trying to clarify the science rather than block future research efforts. Indeed, I'm inclined to direct you to the paper by Rossignol and colleagues [3] potentially answering questions such as mode of action and how one might want to look at potential best-responders to this type of intervention (autisms people, autisms). That and what the Sampanthavivat study included in the Xiong review actually said about 'safety' during their trial: "interventions were safe and well tolerated with minimal side effect from middle ear barotraumas."

To close, and in keeping with the date, a spooky song (and a rather spooky singer it has to be said...)

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[1] Xiong T. et al. Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2016 Oct 13;10:CD010922.

[2] Sampanthavivat M. et al. Hyperbaric oxygen in the treatment of childhood autism: a randomised controlled trial. Diving Hyperb Med. 2012 Sep;42(3):128-33.

[3] Rossignol DA et al. Hyperbaric oxygen treatment in autism spectrum disorders. Medical Gas Research. 2012; 2: 16.

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Xiong T, Chen H, Luo R, & Mu D (2016). Hyperbaric oxygen therapy for people with autism spectrum disorder (ASD). The Cochrane database of systematic reviews, 10 PMID: 27737490

HBOT and autism systematically reviewed

"Current evidence indicates that HBOT [Hyperbaric Oxygen Therapy] is not an effective treatment for children and youth with autism."

That was the conclusion reached by Cynthia Goldfarb and colleagues [1] following their "systematic review of the literature evaluating the clinical impact of HBOT on behavior and development in ASD [autism spectrum disorder]." Drawing on guidance from the American Academy of Neurology and their "Classification of Recommendations", authors looked at the collected peer-reviewed literature "focusing on clinical outcomes of HBOT in ASD." They determined that the research literature as it currently stands (a review based on 5 articles) does not support HBOT as an intervention option for children and young people diagnosed with an ASD.

I appreciate that for some people this will be slightly disappointing news. As per the multitude of other interventions put forward to improve quality of life or ameliorate the more disabling aspects of autism, there are nearly always reports of 'positive changes' [2] and such over-arching reviews say little about how individuals might be impacted by such intervention. Indeed, in a post a few years back on the topic of HBOT and autism (see here) I was cautiously optimistic about this approach; not least because alongside descriptions of positive changes, side-effects seemed to be few and far between when it came to HBOT ('first, do no harm' and all that).

Without trying to second-guess the findings from Goldfarb et al and without coming across as being a supporter of HBOT, I do think it's worthwhile reiterating a few points. The recent review was only based on data from 5 studies. Most of those studies were quite small scale (in terms of participant numbers) and carried out under slightly different conditions in terms of pressures used. The authors rightly make use of the term 'current evidence' as balancing their findings in these respects. Indeed, quite a few of the research 'issues' potentially involved in the study of HBOT have been covered in the review by Dan Rossignol and colleagues [3]. Among other things they suggested that the frequency of HBOT sessions might be an important factor and also: "certain subgroups of children with ASD [respond] differently to HBOT." Autisms people, autisms; and bearing in mind that inflammation seems to be a key target when it comes to the use of HBOT in this context (well, C-reactive protein (CRP) anyway).

The message however, based on the currently available evidence, is that HBOT is probably not blanket indicated for all autism...

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[1] Goldfarb C. et al. Hyperbaric oxygen therapy for the treatment of children and youth with Autism Spectrum Disorders: An evidence-based systematic review. Research in Autism Spectrum Disorders. 2016; 29-30: 1-7.

[2] Rossignol DA. et al. The effects of hyperbaric oxygen therapy on oxidative stress, inflammation, and symptoms in children with autism: an open-label pilot study. BMC Pediatr. 2007 Nov 16;7:36.

[3] Rossignol DA. et al. Hyperbaric oxygen treatment in autism spectrum disorders. Medical Gas Research. 2012;2:16. doi:10.1186/2045-9912-2-16.

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Goldfarb, C., Genore, L., Hunt, C., Flanagan, J., Handley-Derry, M., Jethwa, A., Jones-Stokreef, N., Kirkpatrick, S., Richards, A., Rojnica, L., Schwartz, C., Shawn, D., Superina-Bell, D., Young, E., & Anagnostou, E. (2016). Hyperbaric oxygen therapy for the treatment of children and youth with Autism Spectrum Disorders: An evidence-based systematic review Research in Autism Spectrum Disorders, 29-30, 1-7 DOI: 10.1016/j.rasd.2016.05.004

Cerebral palsy and autism

I seem to keep saying this but one of the many important things about autism is that the diagnosis of autism has not yet been found to be protective against other conditions occurring alongside. This is probably not new news to many as per the comorbities which have been, and continue to be found in cases of autism; recognised even by official guidance on autism (see here).

Importantly however in recent times, more attention is being directed to the overlap of autism with other conditions and how those other conditions might potentially further inform sub-groups (endophenotypes) within the autism spectrum in terms of aetiology and pathology. I'm specifically thinking of the 'significantly over-represented' paper published earlier this year (2012) as a prime example.

Enter then another paper by Pål Surén and colleagues* looking at the overlap between autism spectrum conditions, ADHD, epilepsy and cerebral palsy and reportedly finding a "significant burden of disease associated with neurologic and neurodevelopmental disorders in children".

I'm not specifically going to discuss Surén's paper in excruciating detail because the results really don't need me complicating them. What however I am interested in is the body of work in the peer-reviewed arena suggesting a link between the presence of autism and one comorbidity detailed in their paper, cerebral palsy, and what, if anything, we can draw from such an association.

Perhaps best to first describe what cerebral palsy (CP) is (and isn't). The UK charity Scope have quite a good description of CP (here) alongside more detailed information being available. Basically, CP is a catch-all term for a group of conditions primarily affecting movement and resulting in physical disability. The brain is a central organ to CP (hence the name cerebral palsy) and in particular how certain adverse factors whether inborn or during pregnancy and/or the neonatal period may affect brain development. That being said, the mechanisms of brain disturbances linked to CP is still a work in progress and new-ish ideas are still emerging about things like inflammation for example, being potentially linked to CP (see this study by Marlow and colleagues**) and indeed some familiar themes on food and gut hyperpermeability*** when extended to other parts of the body.

Whilst issues with movement is a core symptom of CP, there are a variety of other presentations that also seem to be evident in children with CP. So learning disability, epilepsy and sensory issues have all been noted, as well as more physical issues such as functional bowel problems like constipation. Without wishing to make bridges where none might be required, I was struck by how much overlap in peripheral features there is between CP and cases of autism.

So then to some of the links (or not) between CP and autism:

• Estimated prevalence rates of CP are slightly difficult to interpret bearing in mind that factors such as twin/multiple births are seen as risk factors. Figures from the US report an estimated prevalence of CP of about 0.3%. This paper by Glinianaia and colleagues**** suggested an estimated prevalence rate of 0.2% for singletons and 1.1% in multiple UK births, with birth weight also being a potential modifying risk factor. That multiple birth link with CP also seems to hold where an autism link perhaps doesn't (see here).
• In terms of the overlap between autism and CP, Mouridsen and colleagues***** confirmed that there seems to be an over-representation of CP in cases of autism compared to non-autism controls as per the findings of other datasets (here, here, here, here and here - phew!). Of the limited studies done on the presentation of autism and CP, preliminary results suggest that the severity of core autistic symptoms may also be adversely influenced by the two conditions appearing alongside each other (here).
• Although the brain is undoubtedly implicated in CP, there is still some debate about the precise areas of the brain involved in the different presentations of the condition. Current thought is that different areas of the brain may be involved in individual cases of CP according to how symptoms present. The link between brain and autism is an equally complex relationship made even more complicated by the wide range of abilities/disabilities noted across different cases. I could tentatively suggest a link to brain areas involved with motor control given the overlap (yes, motor issues have been mentioned in cases of autism) between the conditions. Indeed, ataxic CP has been linked to issues with the cerebellum; the cerebellum being a favourite target for some autism research also as per the recent consensus paper by Fatemi and colleagues******. I hasten to add that I am by no means reducing both conditions down to just one area of the brain however. 
• Interestingly, infections such as cytomegalovirus (CMV), previously linked to the onset of autism (here) have also been overlapped with CP (here). Maternal infection and fever during pregnancy has also been associated with an increased risk of offspring CP as per the results of this study****** and some familiar names to autism research. Again without making too many unwarranted connections, the recent CHARGE results spring to mind as a possible comparator.
• The immune system and CP... how long have you got? To take one example, those dastardly IL-6 cytokines rear their head in cases of CP both from a genetics point of view (here) and possibly tied into increasing amounts of circulating IL-6 (here). Other patterns of cytokine presentation have also been reported alongside coagulation anomalies (here). Need I say anymore about IL-6 (and other cytokines) and autism?

There are other instances of 'overlap' between autism and CP but I am wary of listing all of them because of the risk of falling into the trap of just reciting research and actively looking for connections. Taking the model of autoimmunity and the presence of one autoimmune condition potentially raising the risk of other autoimmune conditions appearing/being diagnosed, I think we might be looking at a similar process here with regards to the various connections being made between autism and CP - be they structural brain issues, infections, immune function or others.

What this and other investigations reiterate is that the links noted between autism and a wide variety of other conditions form an important part of the research landscape and potential clues as to the underlying nature of the condition. Accepting the current stance that both CP and autism are categorised as 'lifelong conditions' the very preliminary shared links between intervention strategies such as HBOT for CP and HBOT for autism (no endorsement given or intended) makes me wonder about the need for some more detailed investigation.

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* Surén P. et al. Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics. June 2012.
DOI: 10.1542/peds.2011-3217

** Marlow N. et al. Characteristics of children with cerebral palsy in the ORACLE children study. Developmental Medicine & Child Neurology. 2012; 54: 640-646.

*** Stenberg R. et al. Increased prevalence of antibodies against dietary proteins in children and young adults With cerebral palsy. Journal of Pediatric Gastroenterology & Nutrition. September 2012.

**** Glinianaia SC. et al. Cerebral palsy rates by birth weight, gestation and severity in North of England, 1991-2000 singleton births. Archives of Disease in Childhood. 2011; 96: 180-185.

***** Mouridsen SE. et al. A longitudinal study of epilepsy and other central nervous system diseases in individuals with and without a history of infantile autism. Brain & Development. 2011; 33: 361-366.

****** Fatemi SH. et al. Consensus paper: pathological role of the cerebellum in autism. Cerebellum. 2012; 11: 777-807.

******* Grether JK. & Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997; 278: 207-211.

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Surén P, Bakken IJ, Aase H, Chin R, Gunnes N, Lie KK, Magnus P, Reichborn-Kjennerud T, Schjølberg S, Øyen AS, & Stoltenberg C (2012). Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. Pediatrics, 130 (1) PMID: 22711729

I am a HBOT

Happy New Year. A slightly belated welcome to Questioning Answers in 2012. My second calendar year of blogging (good grief, when is he going to stop..!).

Demetrious Haracopos

I start this new year post with a short note to remember the recent passing away of Dr Demetrious Haracopos previously of the Center for Autisme in Denmark. To those that knew him Demetrious was one of the warmest, friendliest and inquisitive men you could know; a perfect combination for his work on autism, ranging from sexuality and autism to dietary intervention for autism. Rest in peace Demetri from all those whose lives you touched.

To task. I must confess that I was slightly reluctant to write this first post of the new year. Reluctant because I am not an expert on hyperbaric oxygen therapy (HBOT) as a proposed intervention for autism and related conditions. Nevertheless there is a research base to HBOT and autism (albeit currently quite limited), and given that this is a blog supposedly about autism research, the time has come to put pen to paper so to speak.

I got to this post via an interesting report on whether or not a US hospital should be offering HBOT as an intervention option for children with autism. Opinions abound on this topic it seems.

The first thing that comes to my mind (emphasis on the 'my') when talking about anything related to hyperbaric is a scene in the James Bond film, License to Kill. Mr Bond, played by Timothy Dalton, convinces the main villain to pop another villain into a hyperbaric chamber leading to quite a nasty depressurised end. I appreciate that this may not be the best advert for the hyperbaric chamber, but unfortunately that is my recollection, no doubt influenced by my 1980s movie mindset.

The more realistic view of HBOT for treating things like decompression sickness is thankfully a little safer and controlled where the proper expertise is on hand. The technique involves administering oxygen at pressures greater than one atmosphere (atm). Outside of the more traditional uses for HBOT, the theory is that whole body saturation with oxygen administered at pressure might have some onward positive effects for things like brain function particularly where blood flow is impaired and oxygenated levels might be poor. Looking at the evidence base with regards to things like traumatic brain injury and acute migraine, one can perhaps see some promise of effect from HBOT.

Given all the interest in the brain in relation to autism spectrum conditions, it is little wonder that HBOT has been touted as a possible intervention option. More than that however is the potential link between autism and inflammation in all its forms, which might provide another therapeutic target for HBOT.

The research base is, as I said, currently quite small for HBOT use in autism. It started with a few speculative papers published in the journal Medical Hypotheses (here and here). These have been subsequently followed by a few open and more controlled trials on HBOT with some encouraging but mixed results. This paper for example by Dan Rossignol, who seems very much to have lead the advancement of HBOT for autism (more on in him in future posts), suggested some effect on behavioural measures and inflammatory markers (C-reactive protein). The study was an open one and had no control group (either asymptomatic or receiving a sham intervention). Same with this study and same results (behavioural) and this more recent trial which found behavioural improvements but no significant changes to cytokine levels. Other studies have not found any significant effect.

Where a randomised-controlled design has been used, the results did indicate some potential for HBOT for at least some cases of autism. This study came to the conclusion that hyperbaric treatment at 1.3 atmospheres (24% oxygen) over a number of sessions produced a significant effect compared with normal atmosphere, normal oxygen levels. To reiterate my non-professional status with HBOT, I don't know enough about it to say what an increase of 3% over and above normal air oxygen levels administered at 1.3 atmospheres might do. It is difficult to match hyperbaric results with studies for other conditions because parameters can be different (how much oxygen is used and at what pressure). Studies of HBOT for cerebral palsy in children for example, have noted no overall difference between groups when greater oxygen levels were delivered at 1.75 atmospheres compared with only slightly pressurised air being delivered (results were beneficial in both cases). Other studies looking at using HBOT to tackle radiation-induced necrosis in children for example, reported on conditions of 100% oxygen delivered at 2-2.4 atm pressure and noted some potential effect.

On balance, the results obtained for HBOT for autism so far (stress: so far), whilst limited, do tend to suggest that it might be a beneficial intervention option for some. I hasten to add that I am in no way endorsing such an intervention given factors like the accepted uses for HBOT, the price of HBOT and the requirement for multiple sessions. The potential longer-term safety aspects also require a little more study.

To end, a song to reinvigorate you after the post-party/hangover season (although not for any tongue phobics)... "we'll drive you wild.."