Autism is a behavioral disorder characterized by impairment of social contact and communication and by restricted and repetitive interests and behaviors (1). Of these cardinal features, deficits in social contact and interaction are usually the most prominent; typically, at least one of these features is apparent by the age of 3 yr. Children often seem normal at birth, only to develop regression to autistic behavior between the first or second years of life: a most distressing scenario for the parents and caregivers (2).

The manifestations of this disorder may vary in severity and may be associated with a wide range of levels of intelligence from normal to impaired. Related disorders include Asperger's syndrome, pervasive development disorder, not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Rett syndrome.

The etiology of autism remains unknown. Recent studies have suggested a possible genetic contribution (3), and there is also evidence for a developmental abnormality in the brainstem (4). Others have emphasized the possible impact of a number of postnatal factors ranging from environmental toxins to dietary factors, and a variety of infectious agents. Of these, the possible relationship to casein and gluten intolerance (5), on one hand, and measles and MMR vaccination (6), on the other, have generated particular interest.

As a consequence of the former, many of these children, who often already have a very limited diet because of highly selective eating patterns, are placed on casein and gluten-free diets, rendering an already precarious dietary intake even more so. The association between autism and measles virus and measles vaccination has generated considerable controversy (7) reaching the lay press and even a Congressional hearing (8).

Autistic children frequently develop gastrointestinal symptoms including constipation, diarrhea, abdominal discomfort, gaseousness, and distension. Horvath et al. reported a 69% prevalence of histological esophagitis and a 58% prevalence of intestinal disaccheridase deficiency in a group of 36 autistic children studied by upper gastrointestinal endoscopy and biopsy (9). Pancreatic insufficiency has also been suggested (10).

However, it is the possible association of autism with ileocolonic disease that has attracted the most attention. Wakefield et al. first reported prominent ileal lymphoid nodular hyperplasia (LNH) and ileocolitis in an uncontrolled study of 12 autistic children and went on to speculate a link to MMR vaccination (6). The same group had previously postulated a similar link between measles, MMR, and inflammatory bowel disease in adults (11, 12). In this issue of the Journal, Wakefield et al. report on a total 60 children with developmental disorders (primarily autism) and compare their ileocolonoscopic findings (both macroscopic and histological) with those of 22 "control" children and 20 with ulcerative colitis.

In all, 93% of affected children had LNH in comparison to 29% of "controls" and chronic colitis was identified in 88% of affected children in comparison to 5% of "controls" (13). The authors conclude that children with developmental disorders frequently exhibit a new variant of inflammatory bowel disease: "autistic enterocolitis."

The gut-brain connection is now recognized as a basic tenet of physiology and medicine, and examples of gastrointestinal involvement in a variety of neurological diseases are extensive (14). The pathophysiology of these gastrointestinal expressions of a central nervous system is often unclear, but may variably reflect the parallel involvement of the gut and brain by the same disease process or the consequences of a primary disease of the brain or gut on the gut or brain, respectively.

The description of gastrointestinal dysfunction in autism should come as no surprise, therefore. Indeed, some of the symptoms manifested by these children are quite similar to those reported by adults with degenerative central nervous system disorders, such as Parkinson's disease, for example (15). What is of particular interest is the suggestion that a developmental disorder may be associated with inflammatory bowel disease. How firm is this association? Certain features of the study limit our ability to adequately address this question.

With regard to the association with LNH, it remains unclear whether this finding reflects a true abnormality, given the differences in median age between patients and "controls". This group was also confronted with a ubiquitous issue in pediatric research: that of obtaining a true control population. Their "controls" were, in fact a group of symptomatic children in whom the diagnosis of inflammatory bowel disease had been excluded: hardly a perfect comparator. LNH could also be a secondary phenomenon, related to infections or infestations, immunodeficiency, or even constipation (16).

The histological appearances of the ileal biopsies, reviewed blindly by three pathologists, commonly included reactive follicular hyperplasia, marked expansion of lymphoid tissue, and acute cryptitis; ileitis, eosinophil infiltration, and an increase in intraepithelial lymphocytes (IELs) were unusual. In the colon, biopsies showed appearances that were similar to, but less severe than, those seen in the children with established ulcerative colitis, being perhaps more reminiscent of the features of lymphocytic colitis, as seen in adults (17). It is of interest, given the proposed association of autism with gluten intolerance, that colonic inflammation has also been described in adult celiac disease (18).

These findings also need to be interpreted with caution. In particular, one must bear in mind that this was a highly selected series -- children referred to a highly specialized center being selected for investigation on the basis of the presence of gastrointestinal symptoms. Pending the performance of appropriate studies, which should include both asymptomatic autistic children as well as children with other developmental disorders, these findings cannot and should not be extrapolated to children with autism in general.

Indeed, a strategy development subgroup of the Medical Research Council in the UK recently concluded that the case for "autistic enterocolitis" had not been proven (16). Nor is there sufficient evidence to enable us, in any way, to define the nature of the relationship between these gastrointestinal findings and the neurodevelopmental disorder. In particular there is, at present, insufficient evidence to establish either a direct or indirect link, (e.g., through an associated alteration in intestinal permeability) (19) between an inflamed gut and the brain, in autism.

We must, in particular, resist the temptation to predict causation without the necessary evidence; to do so could engender false hope and further burden families who already have more than their fair share of crosses to bear. Furthermore, there is at present no evidence to suggest that the presence or absence of these features influences the expression or progression of this distressing disorder, nor is there any suggestion that therapy based on these findings might ameliorate either the developmental disorder itself or the associated gastrointestinal symptoms. Ileocolonoscopy should continue to be regarded, therefore, in the absence of other indications, as an investigational tool in these patients.

Wakefield et al. (13) are to be congratulated on opening yet another window onto the ever-broadening spectrum of gut-brain interactions. Their findings raise many challenging questions that should provoke further much-needed research in this area, research that may provide true grounds for optimism for affected patients and their families.

References

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994.

2. Frith U, ed. Autism and Asperger syndrome. Cambridge: Cambridge University Press, 1991.

3. Rodier PM. The early origins of autism. Sci Am 2000;282:38-45.

4. Rodier PM, Ingram JL, Tisdale B, et al. Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei. J Compar Neurol 1996;370:247-61.

5. Reichelt KL, Scott H, Ekrem J. Gluten, milk proteins and autism: The results of dietary intervention on behaviour and peptide secretion. J Appl Nutr 1990;42:1-11.

6. Wakefield AJ, Murch SH, Anthony A, et al. Ileal nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children. Lancet 1998;351:637-41.

7. Taylor B, Miller E, Farrington CP, et al. Autism and measles mumps and rubella vaccine: No epidemiological evidence for a causal association. Lancet 1999;353:2026-9.

8. Anonymous. Measles, MMR, and autism: The confusion continues. Lancet 2000;355:1379.

9. Horvath K, Papadimitriou JC, Rabsztyn A, et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999;135:559-63.

10. Lightdale JR, Hayer CA, Duer A, et al. Evaluation of gastrointestinal symptoms in autistic children before and following secretin infusion. Gastroenterology 2000;118:A66.

11. Wakefield AJ, Montgomery SM, Pounder RE. Crohn's disease: The case for measles virus. Ital J Gastroenterol 1999;31:247-54.

12. Wakefield AJ, Montgomery SM. Measles virus as a risk factor for inflammatory bowel disease: An unusually tolerant approach. Am J Gastroenterol 2000;95:1389-92.

13. Wakefield AJ, Anthony A, Murch SH, et al. Enterocolitis in children with developmental disorders. Am J Gastroenterol 2000;95:2285-95.

14. Pfeiffer RF, Quigley EMM. Neurogastroenterology. Semin Neurol 1996;16.

15. Edwards LL, Pfeiffer RF, Quigley EMM, et al. Gastrointestinal symptoms in Parkinson's disease. Mov Disord 1991;6:151-6.

16. Medical Research Council. Report of the strategy development group subgroup on research into inflammatory bowel disorders and autism. London: MRC, 1999.

17. Fernandez-Banares F, Salas A, Forne M, et al. Incidence of collagenous and lymphocytic colitis: A 5-year population-based study. Am J Gastroenterol 1999;94:418-23.

18. McCashland TJ, Donovan JP, Strobach SJ, et al. Collagenous enterocolitis: A manifestation of gluten-sensitive enteropathy. J Clin Gastroenterol 1992;15:52-4.

19. D'Eufemia P, Celli M, Finocchiaro R, et al. Abnormal intestinal permeability in children with autism. Acta Paediatr 1996;85:1076-9.

American Journal of Gastroenterology September 2000; 95: 2154-2156.

Dr. Mercola's Comments:

I have enormous respect for Dr. Wakefield. He is one of the leading investigators in the world in establishing the link between vaccine induced causes of autism and is able to publish his work in the leading peer reviewed journals as this article indicates. Unfortunately, he is still rooted to many traditional paradigms in his treatment protocols and is still in favor of many drug based approaches which I disagree with. The articles below will provide some more natural based options. Copyright ©2000 the American College of Gastroenterology Published by Elsevier Science Inc. Related Articles: Autism and Mercury Detoxification Autism: a Novel Form of Mercury Poisoning Studies on the Effects of Secretin in Children With Autism Single Injection Of Secretin Does Not Treat Autism Objections to the Study That Showed Secretin Does Not Work for Autism Short-Term Benefit In Treating Autism With Antibiotics The Neurobiology of Lipids In Autistic Spectrum Disorder Link Between Autism and Vaccination Autism May Be Caused By an Immune System Response To a Virus Vaccine - Autism Link Feared Vaccine Induced Autism Milk Link To Autism