MBJ Letter

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Hello

In case this has not been shared on the list- the point of this letter was to

show that there are data that support gut issues being statistically associated

with regression and a range of behavioural symptoms, and that autism can seen as

sub-groups sharing common features (developmentatl, clinial and behavioural).

http://www.bmj.com/cgi/eletters/340/apr15_2/c1127

Autism Syndromes: Clinical issues behind the label.

Lorene E A Amet, Pippa Line (12 May 2010)

Deer's article questions the existence of " autistic enterocolitis " in the

`Lancet' children. The letter from Drs McClure and O'Hare questions the validity

of the autism diagnosis of the same children. How long before someone pops up

and questions the children's very existence? It would appear these children are

an inconvenience in this heavily charged debate.

Notwithstanding, questioning the accuracy of an autism diagnosis is always very

pertinent and needs to be properly addressed. Autism spectrums disorders (ASD)

comprise a heterogeneous spectrum of developmental conditions that include

autism, Asperger Syndrome and pervasive developmental disorder not otherwise

specified (PDD-NOS). The diagnosis is based on the detailed assessment of the

individual's communication, social, behavioural and developmental presentation.

In the last three decades, however, numerous peer-reviewed studies have shown

that ASD can be associated with a great variety of unrelated aetiologies of a

genetic and/or environmental nature (1). The psychiatric presentation of

individuals is therefore important (2) but insufficient to understand and define

this heterogeneous group of developmental disorders.

The questions in autism are a lot broader than those raised by Deer (3). The

issues are to provide adequate evaluation of the condition in order to address

each individual's needs as fully as possible (4). The clinical concerns raised

by parents are many and should be investigated systematically and in great

detail. At the Autism Treatment Trust (ATT) clinic in Edinburgh in a sample of

360 autistic children, 59% presented with chronic clinical gastro- intestinal

complaints, characterised by abnormal bowel movements (74%), chronic

constipation (31%) and/or diarrhoea (30%), abdominal bloating (30%) and

abdominal pain (31%). Commonly, children with affected digestive systems

presented with abnormal body posturing (32%), leaning over furniture etc, in

order to provide relief to their lower abdomen.

Importantly, children with chronic gut problems are more likely to present with

hyperactivity (÷2 (1) = 9.665, p = .002, this is reflected by the odds ratio

whereby those with current gut problems were 2.33 times more likely to have

hyperactivity than those without), sleep issues (÷2 (1) = 6.649, p = .010, this

is reflected by the odds ratio whereby those with gut problems were 1.96 times

more likely to have sleep problems than those without) and abnormal fits of

crying spells, occurring suddenly and even at night time (÷2 (1) = 5.075, p =

..024, this is reflected by the odds ratio whereby those with current gut

problems were 1.80 times more likely to have crying problems than those

without). Developmentally, these children are also more likely to have

experienced regressive autism, characterised by a loss of acquired developmental

skills in the areas of communication and socialisation and to present with novel

deviant restricted and repetitive behaviours (÷2 (1) = 5.619, p = .018, this is

reflected by the odds ratio whereby those with current gut problems were 1.93

times more likely to have regression than those without). In terms of markers,

20% of children presenting with chronic gut issues have abnormal levels of

faecal calprotectin, a surrogate marker of Inflammatory Bowel Disease

characterised by pathological inflammation of the bowel wall (5). These findings

indicate that the gastro-intestinal problems encountered in autism are related

to a range of behavioural and developmental abnormalities, and are associated

with markers of inflammation, consistent with other reports (6-8). These are

therefore likely to be central to the dysfunction experienced by this sub-set of

autistic individuals.

Children with autism also commonly present with severe chronic immune problems

(observed in 65% of a group of 258 children with autism at the ATT clinic).

These include eczema (24%), repetitive chronic and long- lasting infection

issues (36%), food and/or inhalant allergies (37%), asthma (7%). A significant

association between children presenting with immune problems and those with

parental immune problems was found indicating a common genetic susceptibility

(÷2 (1) = 5.543, p = .013, this is reflected by the odds ratio whereby those

with immune problems were 1.86 times more likely to have parents with immune

problems than those without). Additionally, there was also a significant

association between immune problems and self- injurious behaviour (÷2 (1) =

4.152, p = .028, this is reflected by the odds ratio whereby those with immune

problems were 1.85 times more likely to have self-injurious behaviour than those

without). In terms of markers, a surrogate marker for cell immunity called

neopterine (9) was found to statistically correlate with isoprostane (10), a

marker of oxidative stress (r =0.547, p (one- tailed) <.001. The R2 value of

..299 indicates that the markers account for 30% of the variation in the levels

of each other). Both immune and oxidative stress-issues have been reported to be

centrally associated with a sub-set autism (11-12).

In conclusion, autism spectrum disorders include a range of syndromes

characterised by varying degrees of clinical, developmental and behavioural

symptoms. It is essential to provide a systematic evaluation of affected

individuals in order to address the range of abnormalities identified. Autistic

individuals have suffered greatly due to internal medical politics. It is time

to move on.

References:

1. Gillberg, C. and , M. 2000. The biology of the autistic syndromes.

Cambridge University Press.

2. Iain McClure, Anne O'Hare (28 April 2010). How can we be confident that the

children with " autistic enterolcolitis " have autism? Rapid response BMJ

2010:340.

3. Deer B. Wakefield's `autistic colitis' under the microscope. BMJ 2010; 340:

838-41.

4. Buie T, Fuchs GJ 3rd, Furuta GT, et al. 2010. Recommendations for evaluation

and treatment of common gastrointestinal problems in children with ASDs.

Pediatrics. Jan;125 Suppl 1:S19-29.

5. Costa F, Mumolo MG, Ceccarelli L, Bellini M, Romano MR, Sterpi C, Ricchiuti

A, Marchi S, Bottai M..Calprotectin is a stronger predictive marker of relapse

in ulcerative colitis than in Crohn's disease. Gut. 2005 Mar;54(3):364- 8.

6. Ashwood, P., , A., Pellicer, A.A., et al. 2003. Intestinal lymphocyte

populations in children with regressive autism: evidence for extensive mucosal

immunopathology. Journal of Clinical Immunology, 23:504- 517.

7. Krigsman, A., Boris, M., Goldblatt, A., and Stott. C. Clinical Presentation

and Histologic Findings at Ileocolonoscopy in Children with Autistic Spectrum

Disorder and Chronic Gastrointestinal Symptoms. Autism Insights 2009:1 1– 11.

8. Balzola, F., Barbon V., Repici, A., Rizzetto, M., Clauser, D., Gandione, M.,

and Sapino, A. Panenteric IBD-like disease in a patient with regressive autism

shown for the first time by wireless capsule enteroscopy: Another piece in the

jig-saw of the gut-brain syndrome American Journal of Gastroenterology, 2005.

100(4): p. 979- 981.

9. Sweeten, T.L., Posey, D.J. and McDougle, C.J. High blood monocyte counts and

neopterin levels in children with autistic disorder. Am. J. Psychiatry 2003:160,

1691-1693.

10. Wu X, Cai H, Xiang YB, Cai Q, Yang G, Liu D, S, Zheng W, Milne G,

Shu XO. Intra-person variation of urinary biomarkers of oxidative stress and

inflammation. Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):947-52. Epub 2010

Mar 23.

11. Vargas, D.L., Nascimbene, C., Krishnan, C., et al. 2005. Neuroglial

activation and neuroinflammation in the brain of patients with autism. Ann.

Neurol. 57(1):67-81.

12. Sweeten, T.L., Bowyer, S.L., Posey, D.J., Halberstadt, G.M., and

McDougle,C.J. Increased prevalence of familial autoimmunity in probands with

pervasive developmental disorders. Pediatrics 2003:112(5):e420.

Competing interests: None declared