Wednesday, 28 September 2016

Postural tachycardia syndrome and gluten?

Please use your full stops wisely.
I believe that this is the first time that I've talked about postural tachycardia syndrome (PoTS) on this blog as I bring to your attention some rather intriguing findings reported by Hugo Penny and colleagues [1] on how PoTS and gluten-related disorders might not be unstrange diagnostic bedfellows.

PoTS by the way, describes symptoms where standing upright / sitting down induces dizziness, fainting and other symptoms. As well as being quite prevalent in a certain condition called Ehlers-Danlos syndrome (see here), PoTS is also described fairly frequently in cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) too.

Describing how "patients with postural tachycardia syndrome (PoTS) were placing themselves on a gluten-free diet without medical consultation" the authorship team (mentioned previously on this blog) residing in the great city of Sheffield decided to look-see whether there may be underlying medical reasons why such gluten-free moves seemed to be used in cases of PoTS. They screened their 100 participants with PoTS "for gluten sensitivity, related symptoms and dietary habits" as well as assessing for coeliac disease, the archetypal gluten-related autoimmune condition.

Results: compared with a couple of control groups numbering in total above 1500 local participants, coeliac disease (CD) seemed to be more common in the PoTS groups - "serology and biopsy-proven coeliac disease." Alongside: "PoTS patients also had a higher prevalence of self-reported gluten sensitivity... compared with age-matched and sex-matched controls." The authors conclude that there may be more to see when it comes to the presence of classical and non-classical gluten-related disorders in relation to PoTS.

This is potentially important stuff. Accepting that outside of the immediate dizziness and fainting symptoms associated with PoTS there may be other 'gastrointestinal' involvement [2] the intriguing idea that [certain] symptoms might be to some degree alleviated by use of a dietary change is worthy of greater inspection. Indeed, set within the context of an associated diagnostic label, orthostatic intolerance, where an upright posture provokes related symptoms, also being potentially linked to gastrointestinal issues [3] one has an interesting template as to how gut and brain might show some important links. That a gluten-free diet will most likely target both gut and brain (yes, it might) provides plenty of food for thought as to possible mechanisms.

I'm also pretty interested in the growing research base looking at a possible autoimmune component to at least some cases of PoTS [4]. I know this takes us into some 'brow-furrowing' areas of peer-reviewed science [5] (indeed, complicated science) but the potential importance of cases of autoimmune PoTS intersecting with cases of autoimmune coeliac disease provides yet another example of how birds of an autoimmune feather tend to flock together (see here). The implication being that cases of PoTS should perhaps be screened for CD and other autoimmune disease/features and perhaps treated accordingly, offers some new directions for research and clinical practice.

And just in case you are still convinced that use of a gluten-free diet outside of CD is all bunk, the worm still continues to turn...

To close, 'Shatner's Bassoon'. That is all.

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[1] Penny HA. et al. Is there a relationship between gluten sensitivity and postural tachycardia syndrome? Eur J Gastroenterol Hepatol. 2016 Sep 7.

[2] Wang LB. et al. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci. 2015 Dec 15;359(1-2):193-6.

[3] Sullivan SD. et al. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr. 2005 Apr;40(4):425-8.

[4] Thieben MJ. et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007 Mar;82(3):308-13.

[5] Blitshteyn S. & Brook J. Postural tachycardia syndrome (POTS) with anti-NMDA receptor antibodies after human papillomavirus vaccination. Immunol Res. 2016 Aug 25.

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ResearchBlogging.org Penny, H., Aziz, I., Ferrar, M., Atkinson, J., Hoggard, N., Hadjivassiliou, M., West, J., & Sanders, D. (2016). Is there a relationship between gluten sensitivity and postural tachycardia syndrome? European Journal of Gastroenterology & Hepatology DOI: 10.1097/MEG.0000000000000740

Tuesday, 27 September 2016

Neurotensin, intestinal inflammation and autism?

"Elevated peripheral pro-NT [neurotensin] levels reflect more severe forms of active celiac disease, indicating a potential role of NT in intestinal inflammation."

The suggestion, from Caroline Montén and colleagues [1], that the neuropeptide called neurotensin might play a role in paediatric coeliac disease is an interesting one that caught my eye recently. Interesting not only because of the potential implications for the archetypal 'gluten-causing' autoimmune condition called coeliac disease, but also because neurotensin might have some rather important links to [some] autism too [2].

OK, a quick recap is perhaps useful. Neurotensin when it comes to autism typically means one name, Theoharis Theoharides, he of mast cells fame (see here). The idea is that neurotensin (NT) is, among other things, quite a 'potent trigger' of mast cells and when activated these mast cells can release their inner contents that include quite a few substances linked to allergic inflammation. At least some of the talk linking 'inflammation' and autism might include a role for mast cells [3]  and so hey presto, a potentially important chain of biological events might therefore be linked.

Going back to the original Montén paper on NT and coeliac (celiac) disease, researchers set about investigating "if plasma pro-NT levels correlated with the degree of intestinal mucosal damage and tissue transglutaminase autoantibody (tTGA) levels in children with celiac disease." They did find elevated levels of one of the NT precursor fragments in a coeliac disease group (n=96) compared with controls (n=89) and there did seem to be something of a possible connection between pro-NT levels and tTGA. On these basis, they concluded that NT might indeed be linked to the intestinal inflammation noted in cases of coeliac disease. Mast cells might also be important to coeliac disease too according to recent findings.

Accepting that coeliac disease is not autism (even though in some individual cases they may be linked [4]), there are a few further studies that might be required on this topic with autism in mind. As I've already mentioned, inflammation - particularly inflammation of the gastrointestinal (GI) tract - is not something unheard of in autism research/practice circles (see here). I know furrowed brows can be associated with this area of discussion but I'm talking about peer-reviewed science not anecdote and speculation. One might for example, see an investigation whereby those with autism and GI-related issues (including an inflammatory component) might be more closely inspected for something like NT to see if it is something important. You could even include those potentially falling into the grey area of non-coeliac gluten sensitivity (NCGS) if you so wished (see here). Given also related findings for some on the autism spectrum in relation to tTGA too (see here) and the possibility of another link there with NT, some brave research team might also wish to inspect this parameter. I might also suggest that looking at gut motility patterns in relation to NT levels could be another area ripe for further investigation with autism in mind (see here) given some previous discussions on the effects of NT.

Just a few suggestions for how a little more work in this area might prove illuminating.

Insofar as what to do about a possible link between NT and autism, well someone it seems has already started that conversation [5] and discussions are seemingly continuing in the peer-reviewed domain [6]...

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[1] Montén C. et al. Role of pro-neurotensin as marker of paediatric celiac disease. Clin Exp Immunol. 2016 Sep 10.

[2] Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010 Aug 23;7:48.

[3] Theoharides TC. et al. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016 Jun 28;6(6):e844.

[4] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

[5] Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7:58.

[6] Patel AB. et al. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A. 2016 Sep 23. pii: 201604992.

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ResearchBlogging.org Montén C, Torinsson Naluai Å, & Agardh D (2016). Role of pro-neurotensin as marker of paediatric celiac disease. Clinical and experimental immunology PMID: 27612962

Monday, 26 September 2016

On HERV-H, autism, ADHD and methylphenidate?

Today's post is a bit of a mash-up including two paper: the first from Emanuela  Balestrieri and colleagues [1] (open-access available here) talking about "increased HERV-H [Human Endogenous Retroviruses - H] transcriptional activity in all autistic patients" included in their cohort (author's words not mine) and the second from D'Agati and colleagues [2] (open-access available here) describing "the reduction of HERV-H expression and the significant improvement of ADHD [attention-deficit hyperactivity disorder] symptoms after 6 months of methylphenidate treatment."

Taken together, both papers provide some potentially important information on how those fossil viruses that litter the human genome might not be as redundant as we might have first thought. Also how some of the commonly used medications to treat/manage certain psychiatric labels might have quite a few more effects than those listed on the package insert. A shocker indeed.

I've covered HERVs a few times on this blog in relation to quite a few labels (see here and see here and see here). If you've clicked on that first link, you'll know that this is not the first time that Balestrieri et al have talked about HERVs with autism in mind [2]. On that first occasion, they even went as far as proposing that "HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder." This time around "the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs)" was examined in 30 children diagnosed with autism spectrum disorder (ASD) and 30 asypmtomatic controls. Quantitative real-time PCR was the analytical weapon of choice, as "transcriptional levels of env of HERV families were quantitatively evaluated." As I've already mentioned, HERV-H expression showed some interesting trends compared to the not-autism controls. The authors note that this data from Albanian children is pretty much the same as what they found in Italian children diagnosed with autism.

The D'Agati findings - also including Balestrieri on the authorship list - although discussing a case report on what happened to HERV-H expression following use of methlyphenidate (MPH) in relation to ADHD, might also have some implications for [some] autism. Reiterating that this was a case report where both before and after HERV-H expression levels were measured, it potentially offers a road map for how HERV-H expression might be 'affected' by the use of certain medicines. Yes, I know that researchers only measured one variable (HERV-H) and one variable/measurement does not a link make. But given the quite significant overlap between ADHD and autism (see here) and the insinuation that over-expression of HERV-H might not necessarily be a 'good thing', one could see how further [independent] studies might be informative in this area.

Although slightly complicated by the fact that we are only beginning to realise how important HERVs might be to things like stem cells for example or even potentially being involved in the process of genetic deletion (see here), what is becoming clear is that these fossil viruses might be something to watch when it comes to health and wellbeing at different times of development. I've tried not to be too enthusiastic about HERVs and autism / ADHD / other (delete as appropriate) on this blog given our lack of understanding on any connection, specifically the hows and whys of any effect on either aetiology or symptoms. But it is getting harder not to wonder what role these and other mobile elements might play in development and behaviour, particularly in the context of HERVs being implicated in autoimmunity [3] (yes, that might also show a connection to some autism) and a possible role for the still emerging science of epigenetics in both HERV expression [4] and also [some] autism. There is lots more research to be done on this topic.

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[1] Balestrieri E. et al. Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders. New Microbiol. 2016 Sep;39(3):228-31.

[2] D'Agati E. et al. First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD. New Microbiol. 2016 Sep;39(3):237-9.

[3] Tugnet N. et al. Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link? The Open Rheumatology Journal. 2013;7:13-21.

[4] Lavie L. et al. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J Virol. 2005 Jan;79(2):876-83.

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ResearchBlogging.org Balestrieri E, Cipriani C, Matteucci C, Capodicasa N, Pilika A, Korca I, Sorrentino R, Argaw-Denboba A, Bucci I, Miele MT, Coniglio A, Alessandrelli R, & Sinibaldi Vallebona P (2016). Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders. The new microbiologica, 39 (3), 228-31 PMID: 27602423


ResearchBlogging.org D'Agati E, Pitzianti M, Balestrieri E, Matteucci C, Sinibaldi Vallebona P, & Pasini A (2016). First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD. The new microbiologica, 39 (3), 237-9 PMID: 27602426

Saturday, 24 September 2016

Correcting ophthalmic problems in autism

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

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

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

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

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

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

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

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

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

Friday, 23 September 2016

Epilepsy and systemic autoimmune diseases: birds of a feather?

A couple of years back on this blog I talked about some rather intriguing research suggesting that epilepsy and autoimmune disease might not be unstrange diagnostic bedfellows (see here) and that a "potential role of autoimmunity must be given due consideration in epilepsy." [1]

Today, I'm continuing that research theme as the findings from Zhang Lin and colleagues [2] caught my eye concluding that: "There is an association between epilepsy and SAD [systemic autoimmune diseases], which was shown to be stronger at a young age."

Relying on that rather important methodological tool called a meta-analysis, where various study findings are lumped together and conclusions (hopefully) derived from the whole, Lin et al included data from some 25 studies where epilepsy and SAD had been examined together "which included 10,972 patients with epilepsy (PWE) and 2,618,637 patients with SAD."

Aside from those with epilepsy showing "more than a 2.5-fold increased risk of SAD" the authors also observed the opposite too: "patients with SAD were also shown to have a more than 2.5-fold increased risk of epilepsy." When it came to specifics, those diagnosed with epilepsy were observed to show "a 2.6-fold increased risk of celiac disease" and those "patients with systemic lupus erythematosus had a 4.5-fold increased risk of epilepsy."

I remain intrigued about this topic. Appreciating that within the peer-reviewed literature there is such a thing as autoimmune epilepsy [3] and that even in cases of epilepsy seemingly without the autoimmune encephalitis element to it, there may be antibodies to neuronal tissue involved [4], there are perhaps some further important clinical studies to be done in this area. It is for example, not uncommon to see more than one autoimmune condition appearing at the same time (see here) as various autoimmune overlaps have been noted in the quite voluminous science literature on this topic. The implications perhaps being that if one could find some of the 'causes' behind such autoimmune issues (be that related to molecular mimicry or the presence of a superantigen for examples) one may potentially be able to treat/manage quite a few conditions.

Wearing my autism research blogging hat and extending the possibility of an 'autism link' discussed on my previous post on this topic, I'd like to think there may be some scope for further inquiry with autism in mind too. Not only because epilepsy is one of the prime comorbidites attached to a diagnosis of autism (see here) but also that for some people on the autism spectrum, autoimmunity is also potentially something to contend with (see here). Should we therefore be so surprised at the possibility that autism, epilepsy and autoimmunity could form an important clinical triad for some?

And with full caveats in action about not giving medical or clinical advice on this blog, there is a body of evidence out there supporting immunotherapy for certain types of epilepsy [5] where other interventions have failed. Mmm, I also wonder...

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[1] Ong MS. et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol. 2014 May;71(5):569-74.

[2] Lin Z. et al. Association between epilepsy and systemic autoimmune diseases: A meta-analysis. Seizure. 2016 Aug 23;41:160-166.

[3] Britton J. Autoimmune epilepsy. Handb Clin Neurol. 2016;133:219-45.

[4] Wright S. et al. Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. Epilepsia. 2016 May;57(5):823-31.

[5] Bello-Espinosa LE. et al. Efficacy of intravenous immunoglobulin in a cohort of children with drug-resistant epilepsy. Pediatr Neurol. 2015 May;52(5):509-16.

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ResearchBlogging.org Lin Z, Si Q, & Xiaoyi Z (2016). Association between epilepsy and systemic autoimmune diseases: A meta-analysis. Seizure, 41, 160-166 PMID: 27592469

Thursday, 22 September 2016

"Paediatricians are seeing more children with developmental-behavioural conditions"

The findings reported by Harriet Hiscock and colleagues [1] are brought to the blogging table today, specifically that suggestion that paediatricians, at least in Australia, might be encountering an increased number of "developmental/behavioural conditions" as part of their workload.

Looking at the clinical experiences of some 180 paediatricians who took part in the study in late 2013 and comparing them with data from 2008, researchers probed a number of practices relating to "(i) conditions seen; (ii) consultation duration; (iii) imaging and pathology ordered; and (iv) prescribing." The details associated with seeing an increasing number of children "with developmental-behavioural conditions" included: "More paediatricians reported diagnoses of autism spectrum disorder... attention-deficit/hyperactivity disorder... and intellectual disability... in first consultations."

Whilst being slightly careful that 'seeing more children with developmental-behavioural conditions' is not necessarily equated with there 'being' more children with such issues, I'm inclined to suggest that such data is important. Quite a few times in the British media at least, stories have emerged about long waiting times for developmental assessments (see here for one example) and how an already stretched National Health Service (NHS) is seemingly struggling in some parts, to cope with the number of referrals coming through (see here).

As part of a wider peer-reviewed and 'other' evidence base suggesting that (a) the estimated prevalence rates for autism have increased (see here) and (b) there may be a 'real' increase in 'rates of behaviour' associated with an autism spectrum disorder (ASD) (see here) I am becoming more and more convinced that old arguments about 'better awareness' or 'diagnostic switching' are becoming less relevant to the debate about the increasing numbers of cases of autism (see here for example).

I don't doubt that as a society we are far more aware of autism than we ever were (we've even started 'screening for it' during early infancy here in Blighty) and where decades ago someone for example, might have been diagnosed with a learning disability even though they presented with autistic features so things are a little different nowadays. But the sorts of stresses and strains being placed on developmental screening and diagnostic services (particularly paediatric services) in comparison to times gone by are seemingly not comparable anymore. Even taking into account population increases and changes to the organisation of screening and diagnostic services, talk of a growing tide of children being diagnosed, or waiting to be assessed, as being on the autism spectrum is something that really should be prompting a lot more urgency and action. I might also add that arguments about better clinical awareness - did they really miss all those children? - really do a disservice to those who have been skillfully diagnosing autism for many years. Value our experts!

And alongside the talk about children being diagnosed, adult services too are also under a lot more pressure these days...

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[1] Hiscock H. et al. Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. J Paediatr Child Health. 2016 Sep 4.

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ResearchBlogging.org Hiscock H, Danchin MH, Efron D, Gulenc A, Hearps S, Freed GL, Perera P, & Wake M (2016). Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. Journal of paediatrics and child health PMID: 27594610

Wednesday, 21 September 2016

Respite care and parent stress with autism in mind

"While most studies found that respite care was associated with lower stress, several found that respite care was associated with higher stress."

That sentence is perhaps the most important finding recorded in the 'integrative review' published by Kim Whitmore [1] looking at "the relationship between respite care and stress among caregivers of children with ASD [autism spectrum disorder]."

Covering a "final sample of 11 primary research reports" the author provides yet another example of how sweeping generalisations in relation to autism really do no-one no good and how "tailoring respite care services to the unique family needs" is most definitely the way forward.

This is important stuff [2]. I've previously talked about how - again, minus any sweeping generalisations - parental stress in relation to raising a child with autism is one of the more pressing issues when it comes to the health and wellbeing of carers (see here). A steady flow of firsthand accounts also substantiate this finding even in some instances talking about "trauma-related symptomatology" [3]. Respite as one tool in the arsenal to care for the carers is something important; not least because of how such stress can sometimes severely impact on parental quality of life (see here) and potentially onward parent-child (and other) relationships. In amongst all the discussions about autism - how we view it and the implications for the person diagnosed - the effect of a diagnosis on parents/carers can sometimes get a little lost in all the noise.

What's more to say on this topic? Well, I think it is perhaps important to bring in the paper by Southby [4] who brought up an interesting point about how: "Residential respite appears to be the default conceptualization of 'respite' for carers, service users and stakeholders." It's not, and as per the organisation that I'm linked to, something like domiciliary support (otherwise known as home care) can sometimes provide a viable alternative to residential respite/placement. The knowledge that a person does not have to leave the family home, for example, can in some instances have a more positive impact on carer stress, and indeed, most probably will be less cost- and resource-intensive too. I don't also doubt that when it comes to stress for the person diagnosed with autism (an important consideration), for some the familiarity of the home environment is something not to be tinkered with by thoughts of residential respite. But again as per the idea of 'tailoring' resources to individual needs, for some families [5], residential respite every now-and-again should not be discounted.

Finally, it's all well and good talking about the benefits of respite and tailoring respite to meet individual needs, but the cold, hard reality of providing respite in these austere times should not also be forgotten. Indeed, as social purse strings are tightened alongside criteria for eligibility for such services, the factors associated with use and non-use of such services present some difficult choices [6] and are only likely to become even more narrow in future...

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[1] Whitmore KE. Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. J Pediatr Nurs. 2016 Aug 31. pii: S0882-5963(16)30150-6.

[2] Dyches TT. et al. Respite Care for Single Mothers of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2016 Mar;46(3):812-24.

[3] Stewart M. et al. Through a trauma-based lens: A qualitative analysis of the experience of parenting a child with an autism spectrum disorder. Journal of Intellectual and Developmental Disability. 2016. Sep 16.

[4] Southby K. Barriers to non-residential respite care for adults with moderate to complex needs: A UK perspective. J Intellect Disabil. 2016 Jul 20. pii: 1744629516658577.

[5] Harper A. et al. Respite care, marital quality, and stress in parents of children with autism spectrum disorders. J Autism Dev Disord. 2013 Nov;43(11):2604-16.

[6] Preece D. & Jordan R. Short breaks services for children with autistic spectrum disorders: factors associated with service use and non-use. J Autism Dev Disord. 2007 Feb;37(2):374-85.

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ResearchBlogging.org Whitmore KE (2016). Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. Journal of pediatric nursing PMID: 27592275