Monday, 27 April 2015

When optimal outcome in autism meets ESSENCE

I recently came across the paper by Martina Barnevik Olsson and colleagues [1] (open-access) and their rather interesting take on the issue of optimal outcome and autism (see here for some background on this concept).

Based on the idea that a diagnosis of autism or autism spectrum disorder (ASD) might not be as immutable as perhaps once thought (as in 'no longer meeting the diagnostic criteria for the condition'), Barnevik Olsson et al reported that loss of the autism/ASD label does not necessarily translate into typical developmental service being resumed. Indeed, that the concept of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) or autism+ [2] if you prefer, might still influence clinical presentation and the subsequent continued "need of support, educationally, from a neurodevelopmental and a medical point of view."

Following 17 children originally diagnosed with ASD who "recovered from autism" after behavioural intervention, researchers took various 'readings' at follow-up points covering "the child’s daily functioning, school situation, and need of support." Alongside a parental interview, authors also used the Vineland Adaptive Behavior Scales (VABS) and the "Autism – Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC) telephone interview" to see whether loss of the ASD label meant 'symptom-free'.

Results, and a long quote coming up:

"At the new follow-up around age 10 years, all the children had major behavioral and/or academic problems. Of the 13 children with social interaction problems in the semistructured parental interview, 12 also had repeated tantrums, nine had difficulties with hyperactivity or impulsivity, and two with passivity. Eleven of the children had difficulties concentrating, and ten had speech problems. Hence, it was evident that a majority of the children had problems in several different domains." The authors note that many of these presented symptoms fall under the umbrella term of ESSENCE. Further, that of the 14 children who's parents were available for the A-TAC interview, three of them were again considered to meet the criteria for ASD and "another six had pronounced subthreshold ASD symptoms."

Hopefully without the 'I told you so' attitude coming out to much, I have covered the issue of optimal outcome not necessarily translating into 'symptom-free' before on this blog (see here). Once again, I'm not trying to reverse my excitement about the original results from Deborah Fein and colleagues [2] but rather pushing the idea that autism is very often much more than the sum of the triad/dyad of characteristics which we use (see here). Further research from Fein and colleagues [3] has also hinted that functioning outside of the label of autism does not necessarily translate into a complete loss of certain issues too as has data from other groups.

Fluidity in the presentation of autistic traits is still something of real interest to autism research including that reaching into adulthood (see here). The Barnevik Olsson results add to that interest, incorporating the idea that quite a bit of the heightened comorbidity potentially present alongside a diagnosis of ASD may very well have some pretty significant effects on a person in terms of daily functioning and onwards issues affecting quality of life [4]. In policy terms, what this means is that just because a child (or adult) drops off the autism spectrum symptom threshold wise, may not necessarily translate into no additional help and support being required. Indeed, as per the increasing interest in the DSM-5 criteria change for autism (see here) and the rise and rise of labels such as social communication disorder (SCD) one wonders how many optimal outcomers will merely fall out of the autism/ASD label and into the SCD category?

Music: Seasick Steve - Summertime Boy.

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[1] Barnevik Olsson M. et al. “Recovery” from the diagnosis of autism – and then?  Neuropsychiatric Disease and Treatment. 2015. 11: 999-1005.

[2] Fein D. et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013 Feb;54(2):195-205.

[3] Orinstein AJ. et al. Social Function and Communication in Optimal Outcome Children and Adolescents with an Autism History on Structured Test Measures. J Autism Dev Disord. 2015 Mar 11.

[4] Gotham K. et al. Depressive and anxiety symptom trajectories from school age through young adulthood in samples with autism spectrum disorder and developmental delay. J Am Acad Child Adolesc Psychiatry. 2015 May;54(5):369-376.e3.

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ResearchBlogging.org Barnevik Olsson, M., Westerlund, J., Lundström, S., Giacobini, M., Fernell, E., & Gillberg, C. (2015). “Recovery” from the diagnosis of autism – and then? Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S78707

Saturday, 25 April 2015

Kids with autism: a highly [psychotropic] medicated group?

"In keeping with international studies this sample of children with ASD [autism spectrum disorder] was a highly medicated group."

So said the results of the study reported by Kerry-Ann Louw and colleagues [1] back in 2013 who noted that approximately one quarter of their cohort were currently in receipt of "psychotropic medications". I don't want to linger too much on this topic given that such findings tally with other peer-reviewed reports including those with much larger participant numbers [2].

I am slightly concerned that "Antipsychotics were the most common reportedly used psychotropics" according to Louw et al given that this is a paediatric group we are talking about and the special caution that is perhaps required (see here). I'm not pharma-bashing by saying that, just being mindful of issues like side-effects and the whole developing infant/child brain bit.

I've covered the area of 'challenging behaviour' - one of the main reasons for medication - in the context of autism before on this blog (see here for example). In that post as in this, I can see that as a last resort and in very specific cases (accompanied by the correct medicines management and monitoring) certain psychotropic pharmaceutics can potentially bring some very positive benefits to quality of life. One only needs to look at how destructive challenging behaviours can be in the context of self-injury for example (see here) to see how medication for the right group can be a life-transformer. That being said, a careful and managed approach to medication is always the way forward, alongside treating such pharmaceutic use as a time-limited experiment...

Music: Manish Boy by Muddy Waters.

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[1] Louw KA. et al. Prevalence and patterns of medication use in children and adolescents with autism spectrum disorders in the Western Cape, South Africa. J Child Adolesc Ment Health. 2013 Jul;25(1):69-79.

[2] Coury DL. et al. Use of psychotropic medication in children and adolescents with autism spectrum disorders. Pediatrics. 2012 Nov;130 Suppl 2:S69-76.

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ResearchBlogging.org Louw KA, Bentley J, Sorsdahl K, & Adnams CM (2013). Prevalence and patterns of medication use in children and adolescents with autism spectrum disorders in the Western Cape, South Africa. Journal of child and adolescent mental health, 25 (1), 69-79 PMID: 25860309

Friday, 24 April 2015

DSM-5 impacting on autism numbers

"Consistent with previous reviews, the majority of included studies indicated between 50 and 75 % of individuals will maintain diagnoses."

That was one of the conclusions reached by Isaac Smith and colleagues [1] following their systematic review of studies comparing DSM-IV and DSM-5 criteria for autism spectrum disorder (ASD) and what the changes mean for eligibility for the label.

Authors further reported that: "the greatest decreases [were] among high-functioning populations with IQs over 70 and/or previous diagnoses of PDD-NOS or Asperger's disorder" when it came to those not fitting the latest autism description in DSM.

I've got little more to say on this topic over what has been discussed previously on this blog with DSM-5 in mind (see here). The newly appointed catch-all category of social communication disorder (SCD) remains a label to watch, not just with respect to how many people will be diagnosed and what level of services/support will be offered, but also with the idea that the broader autism phenotype (BAP) might also gain some clinical recognition.

Music: Nirvana - Drain You.

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[1] Smith IC. et al. The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. J Autism Dev Disord. 2015 Mar 22.

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ResearchBlogging.org Smith IC, Reichow B, & Volkmar FR (2015). The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. Journal of autism and developmental disorders PMID: 25796195

Thursday, 23 April 2015

Does maternal asthma 'prime' for offspring neurodevelopmental disorder?

The paper from Jared Schwartzer and colleagues [1] (open-access) including a couple of familiar names on the authorship list (Charity Onore and Paul Ashwood) caught my attention recently. Based on mouse studies and the artificial induction of maternal allergy/asthma in pregnant mice, researchers reported that: "Activation of the maternal immune system with an allergy/asthma insult significantly perturbed developmental growth and species-typical behaviors in offspring." Further that their results: "support the notion that the maternal immune system has a crucial role in shaping fetal development and is an important factor contributing to the etiology of neurodevelopmental disorders" (in mice at least).

This is not the first time that maternal immune activation (MIA) has been looked at by this authorship group as per some of their other results on the development of "autism-like behaviors" in offspring mice of mother mice exposed to an agent leading to immune activation during pregnancy [2] (see here for my take on this). This following a whole area of research on MIA in relation to [some] autism and [some] schizophrenia (see here).

On this latest occasion, the authors report on their testing of the hypothesis that: "maternal allergy/asthma (MAA) imparts neurobehavioral alterations in brain and behavior of offspring reminiscent of the common endophenotypes observed in neurodevelopmental disorders." This involved the induction of "allergic airway inflammation" in pregnant mice - C57Bl/6J mice - via the use of an injection of ovalbumin (OVA) for initial sensitisation and then a further "aerosolized solution of 1% (wt/vl) OVA in PBS" or just PBS as a control when mother mice were pregnant corresponding to "early, middle and late gestation." OVA, by the way, is quite a typical way of experimentally inducing allergic reactions.

Offspring of MAA and control mice (39 PBS, 43 MAA) were then put through their behavioural paces to determine whether their were any consequences following said maternal immune stimulation during pregnancy. This involved looking at aspects such as marble-burying behaviour ("analogous to the restricted, repetitive patterns of behavior observed in neurodevelopmental disorders") and social approach behaviour among other things. A small number of mice were also sacrificed for the "analysis of serotonin transporter protein levels in the cortex."

Results: well, we already know that there were some differences between the MAA and PBS (control) group. "Offspring of MAA dams... exhibited increased marble-burying behavior, a perseverative behavior analogous to repetitive behaviors observed in neuropsychiatric disorders including obsessive compulsive disorder and ASD." Social approaches were also different in MAA offspring - "Mice born to mothers repeatedly exposed to allergy/asthma displayed significantly reduced sociability scores compared with control mice from PBS-treated dams." MAA offspring who were sacrificed (a small number) also "had a 33% increase in the expression of SERT compared with control offspring of PBS-exposed dams."  Ergo, a mouse model of immune activation during pregnancy may very well show effects on offspring mice.

Obviously we have to be a little cautious in interpreting these results and applying them to the very wide and very complex conditions that are autism and/or schizophrenia for example. As I've said before mice can make for good animal models of a condition/label but they will always be just models (see here). Likewise, when it comes to that SERT finding in the MAA vs control mice, we have to be slightly cautious about generalisation based on examination of one parameter in a very small number of mice.

That being said, one might be open to the idea that the Schwartzer results might translate into something like real life [3] as and when further investigations are undertaken. The authors use the example of air pollution as potentially mapping onto their results: "For example, exposure to air pollutants, such as diesel fuel and other particulate matter, can result in the development of asthma, and exposure to pollutants is associated with an increased risk of having a child with a neurodevelopmental disorder." There are a few generalisations made in that story but I was kinda interested in how they talked about asthma linking into neurodevelopmental disorders following my discussions on this topic in previous musings (see here). I might add that other agents have also been linked to asthma as per some discussions on paracetamol (acetaminophen) and offspring outcomes. Maybe these represent the next mouse studies in this area?

Music: The Horrors - Sea Within A Sea.

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[1] Schwartzer JJ. et al. Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice. Translational Psychiatry. 2015; 5: e543.

[2] Schwartzer JJ. et al. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational Psychiatry. 2013; 3: e240.

[3] Croen LA. et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Arch Pediatr Adolesc Med. 2005 Feb;159(2):151-7.

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ResearchBlogging.org Schwartzer, J., Careaga, M., Chang, C., Onore, C., & Ashwood, P. (2015). Allergic fetal priming leads to developmental, behavioral and neurobiological changes in mice Translational Psychiatry, 5 (4) DOI: 10.1038/tp.2015.40

Wednesday, 22 April 2015

MMR vaccine was not associated with increased risk of autism

"In this large sample of privately insured children with older siblings, receipt of the MMR [measles-mumps-rubella] vaccine was not associated with increased risk of ASD [autism spectrum disorder], regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD."

That was the conclusion reached in the study by Anjali Jain and colleagues [1] (open-access) based on an analysis of data for over 95,000 children with an older sibling held on "an administrative claims database associated with a large US health plan (the Optum Research Database)." With the aim of reporting "ASD occurrence by MMR vaccine status in a large sample of US children who have older siblings with and without ASD" researchers trawled through the collected data looking "for autistic disorder or other specified pervasive developmental disorder (PDD) including Asperger syndrome, or unspecified PDD (International Classification of Diseases, Ninth Revision, Clinical Modification 299.0x, 299.8x, 299.9x)" as a function of MMR vaccine receipt between birth and the 5 years of age.

They found that nearly 2000 of the 95,000+ children included for study had a sibling diagnosed with autism (2%). As per the results of quite a bit of research in this area, having an older sibling with autism was associated with an increased risk of autism among study participants compared with having an older sibling without autism (6.9% vs. 0.9%).

Then to the MMR...

Vaccination rates were lower for those with an older sibling with autism compared with those with an older sibling without autism (73% at 2 years & 86% at 5 years vs. 84% at 2 years & 92% at 5 years respectively). This difference was present despite similar rates of 'vaccination-associated allergies' being reported. The presence of seizures and the variable of preterm birth were somewhat different between the sibling with ASD and sibling without ASD groupings but the authors don't appear to be reporting such differences to be statistically significant. The issue of vaccine uptake as a function of having an older sibling with autism has been covered before on this blog (see here).

And then to the headlines: 'No association found between MMR vaccine and autism, even among children at higher risk'. This was based on the calculation of unadjusted relative risks (RRs) - "cumulative incidence rate ratios by taking the ratio of the proportion of children who had an ASD diagnosis in an exposed group (either 1 MMR dose or 2 MMR doses) to the proportion of children who had an ASD diagnosis in the unvaccinated group at a given age" and adjusted RRs - "hazard rate ratios estimated from a single Cox proportional hazard regression model that used age since birth as the time scale and included MMR receipt as a time-varying covariate ascribing follow-up time to either the unvaccinated group, the 1-dose group, or the 2-dose group, depending on immunization status at any given age." Further: "An interaction term between MMR receipt and older sibling ASD status was included to allow adjusted RRs to vary by older sibling ASD status." What this boiled down to based on either one dose of MMR received at age 2 or two doses of MMR by age 5 was pretty much nothing in terms of any elevated statistical risk of autism among cases as a function of either having an older sibling with autism or not.

The editorial from Bryan King [2] accompanying the Jain results is also quite illuminating specifically on the possibility that some of the results might be "arguing that MMR vaccine actually reduces the risk of ASD in those who were immunized by age 2 years." I tread very carefully in discussing this sentiment given the confidence intervals (CIs) reported and the idea that delayed MMR vaccination past some pervceived 'critical period' might artificially decrease the risk of autism being diagnosed. I'll come back to this shortly.

The Jain results add further weight to the idea that childhood vaccination is probably not going to be a significant risk factor for the subsequent development of autism. The impressive participant numbers included for study cannot be readily ignored. The data is however not perfect as per the authors critique and issues such as "children in our study who are considered unvaccinated may have received vaccines in settings such as schools or public health clinics in which claims were not submitted." MMR might also not mean MMR in terms of a single combined vaccine as per the comment: "The date of administration of the trivalent MMR (or the last-administered component of monovalent vaccines) was used to determine age at administration for each dose (first or second)."

Vaccination and autism has appeared before on this blog as per my mega-post back in 2014 (see here) and previous musings on the 'too many too soon' suggestion (see here). In both those posts, the data pointed towards no population wide link between vaccination and autism as well as reiterating the important public health message on the value of vaccination. Other subsequent studies have found similar things [3]. This does not rule out isolated events potentially temporally linked to vaccine administration (as per the sentiments of 'Four Kingdoms' post from Dr Tom Insel and past other high-profile cases [4]) but certainly does not mirror the narcolepsy - H1N1 influenza vaccine story for example (see here for some background).

Just before I go, I do want to go back to the issue of whether childhood MMR vaccination (or other vaccines) might actually reduce the risk of autism. Taking into account the research literature looking at something like congenital rubella with autism in mind (see here) one might make a case for suggesting that the rubella vaccine part of MMR vaccine has potentially impacted on the numbers of cases of autism down the years [5]. Whether vaccination with MMR or other immunisations might more directly confer some protection against the development of autism is something that perhaps needs further exploration alongside the possible mechanisms of effect. I'd also put forward the idea that variables such as post-vaccination paracetamol (acetaminophen) use might also require a little more study too [6].

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[1] Jain A. et al. Autism Occurrence by MMR Vaccine Status Among US Children With Older Siblings With and Without Autism. JAMA. 2015; 313: 1534-1540.

[2] King BH. Promising Forecast for Autism Spectrum Disorders. JAMA. 2015; 313: 1518-1519.

[3] Uno Y. et al. Early exposure to the combined measles-mumps-rubella vaccine and thimerosal-containing vaccines and risk of autism spectrum disorder. Vaccine. 2015 Jan 3. pii: S0264-410X(14)01689-2.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Berger BE. et al. Congenital rubella syndrome and autism spectrum disorder prevented by rubella vaccination--United States, 2001-2010. BMC Public Health. 2011 May 19;11:340.

[6] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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ResearchBlogging.org Jain, A., Marshall, J., Buikema, A., Bancroft, T., Kelly, J., & Newschaffer, C. (2015). Autism Occurrence by MMR Vaccine Status Among US Children With Older Siblings With and Without Autism JAMA, 313 (15) DOI: 10.1001/jama.2015.3077

Tuesday, 21 April 2015

Jessica Biesiekierski on non-coeliac gluten sensitivity (NCGS)

It's not often that I dedicate a blog post to a specific individual and their views and opinions on a particular topic. Today however, I'm doing just that to provide you with a link to the paper from Jessica Biesiekierski on the topic of non-coeliac gluten sensitivity (NCGS) [1] (open-access).

The reason? Well, aside from being one of the primary protagonists in the research topic of gluten-related ills outside of the autoimmune condition known as coeliac (celiac) disease (itself the topic of some considerable bafflement to me), the work from Dr Biesiekierski and others has also invited quite a bit more inspection of other dietary components ("FODMAPs: Fermentable Oligo-, Di-, and Mono-saccharides And Polyols") as potentially taking the strain off just gluten/wheat when it comes to ideas about health and wellbeing.

The review paper is open-access so no need for any grand discussions from me on the topic. I will however extract a choice quote or two from the paper with some comment. So: "There is some evidence that NCGS may exist, but probably only in a small number of people." I would second that statement particularly in light of recent discussions (see here). I might also direct you to some of the discussions from Brusca [2] too, and the idea that: "About half of NCGS patients are DQ2 positive and have IgG AGA [Anti-gliadin antibodies]."

Also: "Currently, there is no evidence for efficacy of gluten exclusion in mental disorders... therefore care must be given when discussing these early results and awareness given to understanding that a major effect of gluten in NCGS patients may be in the perception of their general well-being." Accepting that the term 'mental disorders' is not one that I would necessarily use and certainly not when using it in the context of referencing the paper from Millward and colleagues [3] and the Cochrane Review of gluten- and casein-free diets for [some] autism, I'd be minded to disagree with such a final statement. As has been mentioned previously on this blog, there is evidence for issues with gluten in some cases of conditions like schizophrenia (see here) and autism (see here). Insofar as 'no evidence of efficacy of gluten exclusion', well, again I'd be minded to suggest there have been hints that there may be more to see in this area (see here for example) albeit with the requirement for further, more experimentally strong research to be conducted. This also includes the notion that there may be best and non-responders to this type of intervention (see here) and that core autism symptoms might not be the primary 'target' of such dietary interventions.

And if you really want yet more reviews of NCGS, then look no further [4] or further [5] or further [6]...

Music: OutKast - Ms. Jackson. Oh, and how would art look without the gluten?

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[1] Biesiekierski JR. Non-coeliac gluten sensitivity: piecing the puzzle together. United European Gastroenterology Journal. 2015; 3: 160-165.

[2] Brusca I. Overview of biomarkers for diagnosis and monitoring of celiac disease. Adv Clin Chem. 2015;68:1-55.

[3] Millward C. et al. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498.

[4] Czaja-Bulsa G. Non coeliac gluten sensitivity – A new disease with gluten intolerance. Clinical Nutrition. 2015; 34: 189-194.

[5] Molina-Infante J. et al. Systematic review: noncoeliac gluten sensitivity. Aliment Pharmacol Ther. 2015 May;41(9):807-20.

[6] Fasano A. et al. Nonceliac Gluten Sensitivity. Gastroenterology. 2015 Jan 9. pii: S0016-5085(15)00029-3.

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ResearchBlogging.org Biesiekierski, J., & Iven, J. (2015). Non-coeliac gluten sensitivity: piecing the puzzle together United European Gastroenterology Journal, 3 (2), 160-165 DOI: 10.1177/2050640615578388

Monday, 20 April 2015

Tics are common in adults with autism

The title of this post comes from a quote included in the paper by Ursula Kahl and colleagues [1] based on their study of the "phenomenology and characteristics" of tics in adults diagnosed with an autism spectrum disorder (ASD) compared with a small control group of adults with Gilles de la Tourette syndrome (GTS). A tic by the way, is a "sudden, fast, repeated movement or sound."

This is not the first time that tics have been examined with the autism spectrum in mind. The paper from Canitano & Vivanti [2] for example, looking at tics and GTS in cases of autism (N=105) concluded that nearly a quarter of children/young adults with autism presented with a tic disorder and about 1 in 10 with GTS. This followed previous research that came to similar conclusions [3].

The hows and whys of an association between tics and [some] autism is still a little up in the air. The presentation of tics has quite a strong genetic influence insofar as the data on familial linkage [4] and their frequency alongside other symptoms such as attention-deficit hyperactivity disorder (ADHD) and/or obsessive compulsive disorder (OCD). With the figures on ADHD comorbidity with autism in mind (see here), one shouldn't perhaps be surprised that tics might be present in some cases of autism. Indeed, my musings on the paper from Chen and colleagues [5] (see here) pretty much said as much.

"Tic awareness is limited in ASD" was the conclusion from Kahl et al.  I'd agree that tics aren't the first thing to come to mind when one talks about autism. That being said, with the increasing moves towards autism or autistic traits co-existing with a variety of other symptoms/diagnoses we shouldn't really be so surprised that tics might be part and parcel of presentation for some on the autism spectrum. As to the issue of management, well, I'd be minded to suggest that a case-by-case approach be taken [6] with something of an open mind to possible correlates bearing in mind no medical advice is given or intended...

Music: Spiritualized - Electricity.

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[1] Kahl U. et al. Tic Phenomenology and Tic Awareness in Adults With Autism. Movement Disorders Clinical Practice. 2015. March 30.

[2] Canitano R. & Vivanti G. Tics and Tourette syndrome in autism spectrum disorders. Autism. 2007 Jan;11(1):19-28.

[3] Ringman JM. & Jankovic J. Occurrence of tics in Asperger's syndrome and autistic disorder. J Child Neurol. 2000 Jun;15(6):394-400.

[4] O'Rourke JA. et al. The Genetics of Tourette Syndrome: A review. J Psychosom Res. 2009 Dec; 67(6): 533–545.

[5] Chen M-H. et al. Autistic spectrum disorder, attention deficit hyperactivity disorder, and psychiatric comorbidities: A nationwide study. Research in Autism Spectrum Disorders. 2015; 10: 1-6.

[6] Shprecher D. & Kurlan R. The management of tics. Mov Disord. 2009 Jan 15;24(1):15-24.

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ResearchBlogging.org Kahl, U., Schunke, O., Schöttle, D., David, N., Brandt, V., Bäumer, T., Roessner, V., Münchau, A., & Ganos, C. (2015). Tic Phenomenology and Tic Awareness in Adults With Autism Movement Disorders Clinical Practice DOI: 10.1002/mdc3.12154