Cerebral palsy and autism continued

"Our findings support the need for a multidisciplinary approach to management of children with CP [cerebral palsy] to adequately identify and address all facets of presentation, including ASD [autism spectrum disorder]."

So said the results of the study published by Malika Delobel-Ayoub and colleagues [1] who looked at the "prevalence of co-occurring autism spectrum disorders (ASDs) among children with cerebral palsy (CP)" among other things. Continuing a research theme (see here), researchers reported that around 9% of their 1200+ cohort of children diagnosed with CP had an "associated diagnosis of ASD". Said participant data coming from various European registries including one here in the bracing North-East of England.

What's more to say other than yet again, preferential screening for autism might be indicated? One might also advance the idea that clues about the origins of at least some autism may be forthcoming when the label is comorbid to CP. The particular finding that 'co-occurring epilepsy' might be something important for example, is as good a research starting point as any given what other independent datasets have similarly observed [2] combined with the ever-growing [bidirectional] links being discussed between epilepsy and autism / autistic traits (see here).

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[1] Delobel-Ayoub M. et al. Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy. Dev Med Child Neurol. 2017 Apr 25.

[2] Christensen D. et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65.

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Delobel-Ayoub M, Klapouszczak D, van Bakel MME, Horridge K, Sigurdardottir S, Himmelmann K, & Arnaud C (2017). Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy. Developmental medicine and child neurology PMID: 28439889

Physical activity and fitness levels and autism

Although at present having to be slightly more cautious following some recent surgery (general anaesthetic is awesome by the way!), I normally consider myself to be quite an active person. Through previous discussions on this blog covering topics on the positive effects of walking (see here) and the physical+ benefits of the martial arts (see here) I'd like to think that there are quite a few ways and means that the population at large can easily increase their daily physical activity levels. That physical activity might have quite a few knock-on effects for mental health and wellbeing is another angle to which I subscribe.

"'A storm is coming,' Frank says"

With my autism research blogging hat on, I've talked about how quite a bit of the peer-reviewed literature looking at autism and physical activity levels seems to imply 'more to do' when it comes to decreasing sedentary behaviours and getting people up and active (see here). A recent paper from Kiley Tyler and colleagues [1] (open-access) confirms this assertion.

The Tyler paper in open-access but a few pointers might be useful...

• Small groups of children and young adults with autism (n=17) and asymptomatic controls (n=12) were included for study and following an assessment looking at diagnostic and developmental factors were investigated using "a series of physical fitness assessments in aerobic fitness, muscular strength, flexibility, and anthropometric measures (height and weight)". We are also told that: "Physical activity was measured through accelerometry".
• If, like me, measures like aerobic fitness mean very little to you, this particular assessment involved something called the 20-metre multistage shuttle run [2] used to "determine the estimated maximal aerobic power (VO2max) for that individual". Basically, run back and forth across 20m to an ever frequent pinging sound until you can do no more and measure your maximum rate of oxygen consumption. 
• Muscular strength was measured "using a handgrip strength assessment". Reading about this assessment brought to mind some other autism research in this area which I read about recently from Janet Kern and colleagues [3].
• Physical activity levels were assessed using an accelerometer worn over 7 days. 
• Results: well, most of the physical fitness parameters did not significantly differ between the autism and not-autism groups. Strength did come out as reduced in the autism group as per the findings from Kern et al but that's about it. 
• But... physical activity levels were different between the groups across the various gradings describing sedentary, light and moderate activity levels. "Children with ASD spent less time in light, moderate, and moderate-to-vigorous physical activity and spent more time in sedentary behavior when compared to typically developing peers".
• The authors conclude that: "more research is needed on the physical activity determinants specific to children with ASD [autism spectrum disorder]". But also that their results were "encouraging as they indicate that children and youth with an ASD show capacity to meet daily guidelines for physical fitness and activity".

So basically, this particular cohort of children and young adults with autism do not lack the capacity to engage in physical activity but for whatever reason, physical activity levels are down compared to those not in receipt of a diagnosis of autism. I should also say that I summarise this without pointing any fingers of blame.

A quick trawl of some of the related research literature in this area provides one or two clues as to what might be influencing those activity levels. Schenkelberg and colleagues [4] talked about features of the social environment potentially influencing physical activity levels of children with autism. It is perhaps an under-appreciated aspect of the social side of autism that solitary play for example, is probably not going to include any great degree of physical activity as compared to what you might see in shared play with peers for example. Schenkelberg et al kinda hint at this with their observation of no significant differences in physical activity levels between their small group with autism vs. asymptomatic controls when engaged in "organized activity".

I mentioned previously that capacity to engage in physical activity did not seem to be affected in the participants of the Tyler study but one should also not assume this is pertinent to all on the autism spectrum. Motor issues have been talked about previously on this blog (see here) and, as per the findings from Christensen and colleagues [5] there is a growing appreciation that an autism diagnosis might increase the risk for conditions potentially affecting motor function: "The higher frequency of ASD in non-spastic than in spastic subtypes of CP [cerebral palsy] calls for closer examination". Again, something discussed on this blog before (see here). Rather more speculatively, I'm also minded to point you to a gap in the research base looking at something like comorbidity of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) with autism (see here) as another area to potentially investigate.

Physical inactivity is pretty endemic these days across all walks of life. Autism is not unique in its general relationship to relative inactivity although does seem to rank up there when it comes to the available data [6]. Allied to the data on levels of obesity in cases (see here) and the corresponding issues circling things like eating habits for example (see here), there are some important factors to tackle here to ensure that such physical inactivity does not further 'disable' or disadvantage many people who are perhaps already subject to significant health inequality...

Oh, and just in case you were wondering, it's as easy as 10,000 steps [7].

Music then. Fill My Little World by The Feeling.

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[1] Tyler K. et al. Physical Activity and Physical Fitness of School-Aged Children and Youth with Autism Spectrum Disorders. Autism Research and Treatment. 2014; Article ID 312163.

[2] Léger LA. et al. The multistage 20 metre shuttle run test for aerobic fitness. J Sports Sci. 1988 Summer;6(2):93-101.

[3] Kern JK. et al. Handgrip strength in autism spectrum disorder compared with controls. J Strength Cond Res. 2013 Aug;27(8):2277-81.

[4] Schenkelberg MA. et al. Social Environmental Influences on Physical Activity of Children With Autism Spectrum Disorders. J Phys Act Health. 2014 Aug 7. [Epub ahead of print]

[5] Christensen D. et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65.

[6] Mangerud WL. et al. Physical activity in adolescents with psychiatric disorders and in the general population. Child Adolesc Psychiatry Ment Health. 2014 Jan 22;8(1):2.

[7] LaLonde KB. et al. Increasing physical activity in young adults with autism spectrum disorders. Research in Autism Spectrum Disorders. 2014; 8: 1679-1684.

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Tyler, K., MacDonald, M., & Menear, K. (2014). Physical Activity and Physical Fitness of School-Aged Children and Youth with Autism Spectrum Disorders Autism Research and Treatment, 2014, 1-6 DOI: 10.1155/2014/312163

Neonatal intensive care unit (NICU) survivors and greater risk of autism?

"In term NICU [neonatal intensive care unit] survivors, ASD [autism spectrum disorder] occurs with a greater frequency than in the general population and often develops alongside comorbid conditions". That was the conclusion from the study by Alexander Winkler-Schwartz and colleagues [1] looking at term at-risk infants who survived NICU.

"You were only meant to blow the bloody doors off"

'Surviving' their earliest days spent in NICU brings a bit of lump to my throat. As a parent, I can only imagine how worrying and daunting a prospect it must be to watch your child, your baby, spending what is meant to be the very happiest of occasions housed in an incubator with every aspect of their being monitored and controlled. I appreciate that with the technology and medical advances available these days, the prospects for many infants 'surviving' NICU are pretty good compared to even a few decades ago. But still, I imagine it can be an overwhelming prospect.

The Winkler-Schwartz paper reported that out of 180 infants analysed as part of their study, 12 of them (6%) were later diagnosed with an ASD. This compared with ~40% diagnosed with global developmental delay and between 25-30% diagnosed with cerebral palsy (CP) and epilepsy. The authors also noted that: "Nine patients with ASD (75%) were diagnosed with at least one other adverse outcome", a point which ties in with their comorbidity finding.

At least one of the authors on the Winkler-Schwartz paper has some interest in looking at the cognitive-behavioural profile of neonates under adverse conditions. A quick trawl of the peer-reviewed literature base confirms that Michael Shevell has some research form specifically focused in areas such as neurodevelopment associated with congenital heart defects for example [2]. The word 'autism' has also been discussed in some of his previous research investigations too [3].

Aside from the primary conclusion included in the Winkler-Schwartz paper on NICU survivors and autism risk, the other important message is on how comorbidities might fit in with the presentation of autism. Autism and epilepsy has been an oft-discussed topic on this blog so I don't really need to say much more there. CP and autism is something of increasing interest (see here) particularly so when taking into account the findings from Christensen and colleagues [4] seemingly suggesting different autism risk profiles according to different types of CP.

I close with another quote from the Winkler-Schwartz paper on: "the importance of screening term NICU survivors for ASD, particularly when comorbidities are present". Yes another group where screening for autism might be preferentially indicated...

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[1] Winkler-Schwartz A. et al. Autism spectrum disorder in a term birth neonatal intensive care unit population. Pediatric Neurology. 2014. July 16.

[2] Limperopoulos C. et al. Neurologic status of newborns with congenital heart defects before open heart surgery. Pediatrics. 1999 Feb;103(2):402-8.

[3] Webster RI. et al. The clinical spectrum of developmental language impairment in school-aged children: language, cognitive, and motor findings. Pediatrics. 2006 Nov;118(5):e1541-9.

[4] Christensen D. et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65.

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Winkler-Schwartz, A., Garfinkle, J., & Shevell, M. (2014). Autism spectrum disorder in a term birth neonatal intensive care unit population Pediatric Neurology DOI: 10.1016/j.pediatrneurol.2014.07.009

Autism, the autisms or "developmental brain dysfunction"?

"If you've met one person with autism, you've met one person with autism" so the oft-cited phrase goes.

The implication is that whilst unified under the label of presenting with the triad/dyad characteristics of an autism spectrum condition, the heterogeneity present across the spectrum coupled with other comorbidity, allied to factors such as genes, personality, temperament, maturation, environment et al, mean that everyone is different and importantly everyone is dynamic.

Umbrella under an umbrella? @ Wikipedia  

Another term used by some people (including researchers) is that of 'neurotypical'  to somehow denote not-autism. For me however, that's always been a little too simplistic. It implied (a) that there is a definite line between autism and not-autism which kinda over-simplifies things including the broader autism phenotype (BAP), and (b) that there is such as thing as 'neurotypical' and indeed is counter to the phrase: 'if you've met one person, you've met one person' which should surely be as pertinent to not-autism as it is to autism; if you get me?

These concepts are relevant as today I'm talking about two papers: a paper by Whitehouse & Stanley* (open-access) questioning whether autism is one condition or multiple conditions, and a paper by Moreno-De-Luca and colleagues** which implies that we should even be doing away with behaviourally-defined labels such as autism and schizophrenia in favour of an altogether broader definition of 'developmental brain dysfunction' or DBD.

Regular readers might recognise the name Andrew Whitehouse as being one and the same researcher who has talked about various autism-related results from the Raine study (see here and here and here). His latest opinion piece builds on the fact that despite the 70 year anniversary since the first description of autism was published by Kanner (with appropriate consideration for Hans Asperger too), alongside huge amounts of time, money and research efforts, we are really still only scratching the research surface of the condition(s) known as autism. Certainly science hasn't yet come up with many defining 'universal' reasons to account for the appearance of the the clustering of symptoms and as for intervention options, well take a look at the recent draft guidance from NICE to see what I mean. One of the main stumbling blocks he and his colleague opine on is the "phenotypic variability" and how moves should be made towards defining smaller subgroups on the autism spectrum. In effect talking about the autisms over autism as per another very interesting paper by Poot*** (open-access).

To many people this is not new news. That the search for an 'autism gene' or 'autism genetic mutation' (sorry about the cold science term) or indeed 'autism environmental variable' has so far been underwhelming in terms of results coupled to the cost/benefit ratio of such research for example, is testament to the variability present in both autism and not-autism. This demonstrates also how complex a continuum the autism spectrum is. Indeed how complex a thing the human spectrum is****.

Likewise when it comes to intervention, I've talked before on this blog about how we should perhaps be re-assessing the way we look at proposed interventions and in particular focusing on subgroup responses rather than some almighty universal spectrum response to denote intervention success of not. Without equating autism with cancer or vice-versa, the recent opinion paper by Stewart & Kurzrock***** (open-access) might inform this methodological discussion somewhat further.

Whitehouse and Stanley also talk about the lessons learned from cerebral palsy (CP) and how where once CP was thought of as "a unitary disorder", the more contemporary view is somewhat more "umbrella" like. I've covered CP on this blog before so won't say much more about that; I think many people might agree that autism is similarly an umbrella term; even more so when the DSM-V comes into force in literally weeks time (Monday 20th May 2013 apparently).

The Moreno-De-Luca paper goes one stage further. As per the paper and some associated media attention (see here) the suggestion is that not only is there the autisms, but that because of the various overlapping genetic features between the autisms and conditions such as schizophrenia (the schizophrenias), we should be looking at using an even more over-arching concept to group these collected diagnoses together: developmental brain dysfunction (DBD). A sort of umbrella for the umbrella if you like. It's not a new suggestion by the way****** (open-access).

I can imagine that your view of autism - be that a personal perspective of autism, a parental perspective or just an observer looking in - is probably going to influence how you receive this suggestion to some degree. For a researcher looking at the possibility of shared genetics or even epigenetics between conditions which might overlap, there is some sense in looking at the bigger picture. My recent post on common ground (see here) based on the 'five psychiatric disorders linked' paper******* kinda reiterates this position alongside other papers including this one from Caamaño and colleagues******** on subclinical comorbid psychopathology. That and the fact that there might be some convergence when it comes to the autism and schizophrenia spectrums for example (see here) also makes a case. The authors sum it up well: "genes don't respect our diagnostic classification boundaries, but that really isn't surprising given the overlapping symptoms and frequent co-existence of neurodevelopmental disorders".

Other perspectives - and I am only speculating on such viewpoints - might not necessarily share the same sentiments. Aside from leaving out any important relationship that genes might have with little things like the environment, as in maternal immune activation during pregnancy, or all those correlations with other facets of modern living (see here and here), the implication of 'brain dysfunction' takes us back to the whole neurotypical 'us and them' scenario and the questions: what exactly is 'normal' brain function? and what factors can and do affect it? I might add that I can also see how some people might not necessarily be taken with the concept of autism being akin to 'brain dysfunction' in the same way that lumping autism and schizophrenia together might have other, more societal connotations.

I'm going to stop there with this post, save any charges of over-analysing the papers and potential implications. Accepting that a diagnosis is currently the best way for people to [theoretically] receive the help and support they may need, I'm not sure we are in a position to re-write the diagnostic manuals just yet with autism and schizophrenia in mind. That umbrella-ing (is that a word?) autism with other conditions might also impact on the autism awareness message that we've all just had with World Autism Awareness Day is another consideration to bear in mind.

That being said, I do think we have already started to see hints of this brave new world of links and threads coming together. The DSM-V diagnosis of autism seems to be quite explicitly spectral and whilst not yet knowing the consequences of removing diagnoses such as Asperger syndrome and how that Social Communication Disorder category will work, the idea behind the change is sub-type removal similar to that envisaged for schizophrenia (see here and here). I'm not altogether sure but I am also wondering how and whether there will be any exclusion criteria on for example a dual diagnosis of autism and schizophrenia in the new guidance and what effect this might have? We wait and see.

"OK stop already". And I will.

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* Whitehouse AJO. & Stanley FJ. Is autism one or multiple disorders? Med J Aust 2013; 198: 302-303.

** Moreno-De-Luca A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. The Lancet Neurology. 2013; 12: 406-414.

*** Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Molecular Syndromology. February 2013.

**** Mitchell KJ. What is complex about complex disorders? Genome Biology. 2012; 13: 237.

***** Stewart DJ. & Kurzrock R. Fool's gold, lost treasures, and the randomized clinical trial. BMC Cancer 2013; 13: 193.

****** Hrdlicka M. & Dudova I. Controversies in autism: is a broader model of social disorders needed? Child & Adolescent Psychiatry and Mental Health 2013; 7: 9.

******* Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis The Lancet. February 2013.

******** Caamaño M. et al. Psychopathology in children and adolescents with ASD without mental retardation. JADD March 2013.

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Whitehouse AJ, & Stanley FJ (2013). Is autism one or multiple disorders? The Medical journal of Australia, 198 (6), 302-3 PMID: 23545020

Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, & Ledbetter DH (2013). Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet neurology, 12 (4), 406-14 PMID: 23518333

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