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Because of the absence, in general, of high-quality clinical research data, evidence-based recommendations are not possible at the present time. However, the panel agreed on a number of statements based on expert opinion that arose from a review of existing evidence. It is acknowledged that, in many areas, evidence is generally confined to case reports, observational or descriptive studies, and poorly controlled or uncontrolled studies.
The expert panel reached consensus on the following statements.
Statement 1 (Key Statement)
Individuals with ASDs who present with gastrointestinal symptoms warrant a thorough evaluation, as would be undertaken for individuals without ASDs who have the same symptoms or signs. Evidence-based algorithms for the assessment of abdominal pain, constipation, chronic diarrhea, and gastroesophageal reflux disease (GERD) should be developed.
Individuals with ASDs deserve the same thorough diagnostic workup for gastrointestinal symptoms as should occur for other patients. There is no evidence for pathogenic mechanisms specific to ASDs that warrant a distinct diagnostic approach. Guidelines for the evaluation of common gastrointestinal symptoms have been developed by medical societies, medical centers, and managed care practices.9–12 Few, if any, published documents have addressed modifications in the diagnostic evaluation on the basis of the needs of persons with disabilities such as impaired language. An evidence base is needed to guide evaluation and therapy, but until appropriate studies are conducted, guidelines must be based on expert opinion.
Statement 2
Gastrointestinal conditions that are reported to be common in individuals without ASDs are also encountered in individuals with ASDs.
In persons with ASDs, gastrointestinal conditions can present typically or atypically as nongastrointestinal manifestations, including behavioral change and/or problem behaviors. Symptom severity can be quite variable in patients with ASDs, as in other patients.
The most common gastrointestinal symptoms and signs reported for persons with ASDs are chronic constipation, abdominal pain with or without diarrhea, and encopresis as a consequence of constipation. Other gastrointestinal abnormalities that have been described for individuals with ASDs include GERD, abdominal bloating, and disaccharidase deficiencies, as well as pathologic findings such as inflammation of the gastrointestinal tract and abnormalities of the enteric nervous system.
Gastrointestinal disorders can present as nongastrointestinal problems. For example, Horvath and Perman13 reported disturbed sleep and nighttime awakening for 52% of children with ASDs who had gastrointestinal symptoms (vs 7% of age-matched healthy siblings; P < .001). Children with ASDs who had reflux esophagitis exhibited unexplained irritability more frequently (43%) than those who did not (13%).13 Behaviors, including problem behavior, may be markers of abdominal pain or discomfort in individuals with ASDs.14,15 Table 2 identifies some vocal and motor behaviors, as well as changes in overall state, that may indicate abdominal pain or discomfort.
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TABLE 2 Behaviors That May Be Markers of Abdominal Pain or Discomfort in Individuals With ASDs
The diagnostic evaluation of potential gastrointestinal disorders can vary depending on the possible problem (Table 3). For example, if one suspects that maldigestion or malabsorption is causing abdominal distension or is associated with self-injurious behavior, an upper endoscopy with measurement of disaccharidases might be considered. Lactose intolerance is common in the general population and therefore common in individuals with ASDs. To clarify the diagnosis, empiric trials of lactase supplementation or dietary restriction might be considered, in the proper clinical context, before referral to a gastrointestinal specialist.
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TABLE 3 Diagnostic Evaluation of Gastrointestinal Symptoms and Disorders in Individuals With ASDs
As for individuals without ASDs, functional abdominal pain (FAP) and irritable bowel syndrome (IBS) can present in individuals with ASDs with behavioral indicators of pain, disordered sleep, diarrhea and/or constipation, and bloating and/or flatulence. The diagnosis of FAP or IBS is a clinical one that is made on the basis of a pattern of predominant symptoms occurring over time in the absence of organic disease. Empiric treatment, initiated by a gastroenterologist or specialist skilled in understanding neurenteric dysregulation, may be warranted for some patients without other indicators of disease, such as weight loss, fever, and bloody stools, before proceeding to invasive evaluations. However, for children with ASDs, behavioral indicators may be the only manifestation of pain, and determining who should be evaluated medically and who should be treated empirically can be problematic. Evaluating all children may result in some with IBS and FAP having potentially unnecessary invasive evaluations; treating children empirically may delay identification of morbidities that could be remedied by medical or surgical intervention. Clearly better biomarkers of disease in children with ASDs are needed to reliably identify those individuals who are most likely to benefit from the more comprehensive diagnostic evaluation.
Statement 3
The prevalence of gastrointestinal abnormalities in individuals with ASDs is incompletely understood.
The reported prevalence of gastrointestinal symptoms in children with ASDs has ranged from 9% to 70% or higher (Table 4). 13,16–25 Prospective descriptive reports from autism clinics have described significant gastrointestinal symptoms in at least 70% of patients,22 data that might reflect a referral bias. In contrast, secondary analysis of a UK database indicated that the prevalence of gastrointestinal symptoms was no different in children with ASDs compared with children without ASDs (9%) at the time of their initial ASD diagnosis.16
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TABLE 4 Prevalence of Gastrointestinal Symptoms in Individuals With ASDs
Most of these studies had 1 or more methodologic limitations, in particular a lack of appropriate (nonrelated) control groups. Despite the limitations in type and quality of available evidence, the preponderance of data were consistent with the likelihood of a high prevalence of gastrointestinal symptoms and disorders associated with ASDs.
The panel agreed that to unequivocally answer the important question of prevalence of gastrointestinal dysfunction in this population, prospective multicenter studies need to be performed by using validated instruments and outcome measures administered to persons with a diagnosis of ASD established by accepted methods and appropriate control groups. Population-based studies are also needed to avoid referral bias and overestimation of the prevalence of gastrointestinal symptoms in patients with ASDs.
Statement 4
The existence of a gastrointestinal disturbance specific to persons with ASDs (eg, "autistic enterocolitis") has not been established.
Some health care providers and researchers have proposed that certain gastrointestinal pathologies are specific to individuals with ASDs. An immune or inflammation-mediated mechanism specific to ASDs, possibly vaccine-triggered in the setting of abnormal immune function or increased gut permeability ("leaky gut"), has been hypothesized to underlie the gastrointestinal disorders seen in individuals with ASDs, mainly on the basis of a finding of ileal nodular lymphoid hyperplasia (NLH) and/or chronic colitis seen on colonoscopy.
In 1998, Wakefield et al26 reported an association between ileocolitis and developmental regression in 12 children and coined the term "autistic enterocolitis." From the same uncontrolled study they reported NLH of the ileum and colon as an abnormal finding in most children with ASDs. However, similar findings are known to be present in children with typical development, as well as children with food allergies and immunodeficiencies.27,28 The significance of these findings, therefore, is unclear. Wakefield et al29 also proposed a causal relation between measles, mumps, and rubella (MMR) vaccination and autism, a suggestion that was later retracted by many of the original authors.
Other study-design limitations in these reports included flawed control groups, lack of validated and standardized definitions, and speculative interpretation of results. In summary, published reports have not established the presence of a unique gastrointestinal pathophysiology specific to ASDs.
Statement 5
The evidence for abnormal gastrointestinal permeability in individuals with ASDs is limited. Prospective studies should be performed to determine the role of abnormal permeability in neuropsychiatric manifestations of ASDs.
Altered intestinal permeability was reported in 9 of 21 (43%) children with ASDs and 0 of 40 healthy age-matched controls.30 The authors of the study speculated that the alteration might be the mechanism for increased passage of food-derived peptides through a damaged gut mucosa. Increased permeability (or a "leaky gut") has been cited as having a key role in various hypotheses regarding the biology of ASDs, including excess opiate activity, diminished peptidase activity, and immune dysfunction.31 Some investigators have reported decreased serum sulfate levels in children with ASDs and hypothesized a link between such deficits and increased gut permeability.13
The available literature has not confirmed the presence of abnormal gastrointestinal permeability in individuals with ASDs, and the presence of increased intestinal permeability has not been correlated with an underlying gastrointestinal disorder or neuropsychiatric manifestations. Studies to date have had methodologic limitations including small subject populations and poor controls; properly powered prospective studies with appropriate controls are needed.
Statement 6
Individuals with ASDs and gastrointestinal symptoms are at risk for problem behaviors. When patients with gastrointestinal disorders present with behavioral manifestations, the diagnostic evaluation can be complex.
An emerging literature suggests that individuals with ASDs and gastrointestinal symptoms may be at higher risk for problem behaviors than those with ASDs who do not have gastrointestinal symptoms.32 Problem behaviors are recurrent behaviors that interfere with an individual's functioning; their occurrence often affects family and community members as well. Problem behaviors are the single most important factor in determining quality of life for individuals with ASDs and their caretakers.33 Vocal and motor behaviors, including problem behaviors such as self-injury and aggression, as well as overall changes in state of being (eg, sleep disturbance or irritability), may be behavioral manifestations of abdominal pain or discomfort in persons with ASDs (Table 2).14,15
The evaluation of individuals with ASDs and gastrointestinal symptoms can be complex. Sleep disturbances and the other problem behaviors mentioned above may indicate abdominal discomfort. In turn, abdominal discomfort, as well as other symptoms (constipation, flatulence, bloating, diarrhea, straining), may be manifestations of neurenteric dysregulation or IBS. A diagnosis of exclusion, IBS is difficult to distinguish from other underlying conditions without invasive testing. For the patient who is not losing weight, has no blood in the stool, and has normal findings on a complete blood count and urinalysis, evaluations are recommended in the order described in Table 3. No evidence-based guidelines are available to guide the evaluation. For this reason, primary care physicians, psychiatrists, psychologists, pediatricians, and gastroenterologists may need to work together to improve the evaluation and treatment of gastrointestinal symptoms in individuals with ASDs.
Statement 7
For a person with an ASD who presents for treatment of a problem behavior, the care provider should consider the possibility that a gastrointestinal symptom, particularly pain, is a setting event, that is, a factor that increases the likelihood that serious problem behavior (eg, self-injury, aggression) may be exhibited. Sudden and unexplained behavioral change can be the hallmark of underlying pain or discomfort. Behavioral treatment may be initiated as the possible concurrent medical illness is being investigated, diagnosed (or excluded), and treated, but the behavioral treatment should not substitute for medical investigation. The behavioral treatment plan should be developed, implemented, and changed as needed in collaboration with the medical caregivers who are leading the medical investigation.
Clinical practice guidelines for the management of ASDs have not included routine consideration of potential gastrointestinal problems.1,3–5 As previously noted, for individuals with ASDs, symptoms associated with gastrointestinal disorders, especially pain, may function as setting events for problem behaviors.34 In this context, a setting event is any gastrointestinal symptom that influences how a person will respond to a given environment. For example, the presence of pain (a gastrointestinal setting event) can result in simple daily tasks and routines being perceived by the child as much more aversive than would be the case if the child were healthy and free of pain. As a consequence, these tasks and routines now trigger bouts of severe problem behavior as the child attempts to escape from the now-aversive situation. Once the gastrointestinal condition has been treated successfully, it is likely that pain will diminish, the situation will be perceived as less aversive, and the child will, therefore, no longer be motivated to engage in problem behavior. A review of both gastrointestinal symptoms and behaviors clinically associated with gastrointestinal problems (see Tables 2 and 3), along with other potential sources of pain and discomfort (such as ear, dental, urologic, musculoskeletal, and cutaneous problems), should be incorporated into the clinical behavioral assessment.
The presence of gastrointestinal symptoms and/or related behaviors (Table 3), regardless of whether they are clearly temporally related to problem behavior, should be considered a strong and urgent indication for medical investigation. Clinical judgment will determine if medical investigation should precede or occur concurrently with behavioral and/or psychopharmacologic intervention; the latter, however, should never substitute for medical investigation. Clearly, reliable biomarkers of gastrointestinal function are needed to identify those individuals who are highly likely to have conditions that may respond to medical or surgical intervention. Until such biomarkers are shown to be helpful, clinicians with expertise in both medical and behavioral interventions should work together on an integrated care plan.
Recognition that abdominal pain and discomfort can function as a setting event has important implications for the treatment of problem behavior.15 First, time-consuming behavioral treatments that address only psychosocial triggers and consequences for problem behavior may likely be ineffective. Behavioral treatments that promote means of communication in the affected individual may be more effective. For example, it would be extremely useful, from the standpoint of medical diagnosis, to teach a child to identify the location and type of pain that he or she is currently experiencing.35 Second, the individual can be taught skills for coping with task demands appropriately during moments of pain or discomfort, and psychosocial environments that have become aversive because of gastrointestinal pain can be restructured to attenuate their aversive properties.36,37 Third, if the gastrointestinal disorder is recognized and medical treatment is effective, the problem behaviors may diminish. When abdominal pain or discomfort is a setting event, psychotropic medications are likely to be ineffective and may even aggravate the problem if they have adverse gastrointestinal effects.
Statement 8
Education of caregivers and health care providers is necessary to impart knowledge of how to recognize typical and atypical signs and symptoms of gastrointestinal disorders in individuals with ASDs.
The clinical presentation of gastrointestinal disorders in individuals with ASDs may differ from that of individuals with typical development. For example, behavioral alterations can complicate the diagnosis of GERD in persons with compromised communication skills. Expert clinicians have observed that aggressive and self-injurious behavior may be the primary clinical manifestations of GERD in individuals with ASDs, but these symptoms are frequently attributed to nonmedical causes. As a result, manifestations may go unrecognized as signs and symptoms of GERD and, importantly, may go untreated. Caregivers should be informed about atypical manifestations of gastrointestinal disorders. Greater awareness of this association by health care providers may result in these conditions being diagnosed and treated in more affected individuals. Additional research is needed to evaluate the usefulness of adding behavior to screening for gastrointestinal problems in persons with ASDs.
Educational programs designed to increase awareness of medical conditions that can go unrecognized because of atypical symptom presentation should be a priority at meetings of professional societies such as the American Academy of Pediatrics, American Academy of Family Physicians, and National Association of Pediatric Nurse Practitioners.
Statement 9
Pediatricians and other primary care providers should be alert to potential nutritional problems in patients with ASDs. Evaluation by a nutritionist who is familiar with nutrition support for individuals with ASDs is recommended if caregivers raise concern about the patient's diet or if the patient exhibits selectivity of intake or is on a restricted diet.
Nutritional deficiencies have been reported in patients with ASDs, which is not surprising because of the narrow food preferences of many affected individuals and/or purported therapeutic diets that might be nutritionally inadequate. In a study of 36 children with ASDs, regardless of unrestricted or restricted diet, essential amino acid deficiencies consistent with poor protein nutrition occurred more frequently than in age- and gender-matched controls.38 Low dietary intake of calcium and vitamin D and iron deficiency have been implicated in compromised bone development and sleep disturbances, respectively, in children with ASDs receiving an unrestricted or restricted diet.39,40 Resources for general nutritional guidance are available that may be helpful for families.41–43
Statement 10
Primary care nutritional assessment for each person with an ASD should include (1) weight for height or BMI, (2) weight for age, (3) height for age, and (3) any marked changes in growth rate (percentiles over time).
It is recommended that pediatricians routinely monitor anthropometry as part of the evaluation of children with ASDs. Abnormalities in nutritional status (wasting, stunting) or changes in growth rate should alert the clinician to inadequate growth and the possibility of inadequate caloric intake or poor nutritional quality of the diet, malabsorption, or maldigestion. Any child whose growth is of concern should be referred to a nutritionist, preferably one who is familiar with nutritional support for individuals with ASDs.
In addition to nutritional inadequacy, children with ASDs have the potential to be obese. In a retrospective review of charts from 1992 to 2003 in children aged 3 to 18 years with ASDs, the prevalence rates of at risk for overweight (BMI 85th percentile) and overweight (BMI 95th percentile) were 35.7% and 19.0%, respectively.44 These prevalence data are similar to rates in children aged 6 to 19 years in the general population of 31.0% and 16.0% for at risk for overweight and overweight, respectively, in 1999–2002.45 However, children with ASDs in the 12- to 19-year age range were reported to have 80% and 50% rates of being at risk for overweight and overweight, respectively, compared with 30.9% and 16.1%, respectively, in the general population.44
Statement 11
Anecdotal reports have suggested that there may be a subgroup of individuals with ASDs who respond to dietary intervention. Additional data are needed before pediatricians and other professionals can recommend specific dietary modifications.
Dietary modifications such as removal of milk for symptoms of lactose intolerance may be approached empirically, as with any other pediatric patient with consistent symptoms. The data on the value of specific diets being effective in the treatment of individuals with ASDs are difficult to assess. Many dietary modifications are believed to have a beneficial outcome, although placebo effects are likely to be high in this setting. The few studies in the literature are difficult to interpret without adequate control groups.
Statement 12
Available research data do not support the use of a casein-free diet, a gluten-free diet, or combined gluten-free, casein-free (GFCF) diet as a primary treatment for individuals with ASDs.
Few studies have examined the effects of a casein-free diet, a gluten-free diet, or combined GFCF diet on the behavior of individuals with ASDs. To our knowledge, only 1 double-blind placebo-controlled study has been published to date.46
In this double-blind crossover trial of GFCF or typical diet in 15 children with ASDs, there were no differences in measures of severity of ASD symptoms, communication, social responsiveness, and urinary peptide levels after 12 weeks.46 Nevertheless, after being informed of the results, 9 parents wanted to continue the diet and reported positive subjective clinical changes while their child was on the GFCF diet. Study limitations included the small sample size and heterogeneity, concerns about compliance and possible dietary infractions by study subjects, and lack of a direct observational outcome measure.
Parents need information to help plan a balanced diet within the restrictions imposed by the chosen diet. Given the real hardships associated with implementation of a strict GFCF diet, additional studies are needed to assess risk factors and possible markers that identify individuals who might benefit from these diets. The panel emphasized that parents and care providers should agree on objective measures, which ideally are to be evaluated by blinded observers, to assess the intervention effect as well as a reasonable time frame before embarking on restrictive or unusual diets. The current literature does not permit a recommendation as to the length of a trial of dietary intervention. In the absence of data, any trial will need to be long enough to ensure that variability in behavior is not responsible for the perceived diet response.
Statement 13
For patients with ASDs, a detailed history should be obtained to identify potential associations between allergen exposure and gastrointestinal and/or behavioral symptoms.
It has been estimated that 25% to 65% of children in westernized societies have evidence of allergen sensitization, with food allergy present in 6% to 8% of infants and young children and 4% of adolescents and adults. It is assumed that a similar proportion of children with ASDs exhibit allergic disorders.47–49 Table 5 lists symptoms associated with immune-mediated gastrointestinal food allergies as well as suggested diagnostic approaches.50 The patient's parents, teachers, or other caretakers are an important source of information, because they are in a position to observe an association between exposure and the person's response.
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