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Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report
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- TABLE 1
GRADE System Definitions
Type of Evidence Quality of Evidence High: evidence based on randomized, controlled trials High quality: additional research is very unlikely to change our confidence in the estimate of effect. Low: evidence based on observational studies Moderate quality: additional research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Very low: any other evidence Low quality: additional research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: Any estimate of effect is very uncertain. Critiques (review articles and editorials) are ineligible for assessment by the GRADE system of evaluation.
Adapted with permission from BMJ Publishing Group Ltd from Atkins D, Best D, Briss PA, et al; GRADE Working Group. BMJ. 2004;328(7454):1490.
- TABLE 2
Behaviors That May Be Markers of Abdominal Pain or Discomfort in Individuals With ASDs
Vocal Behaviors Motor Behaviorsa Changes in Overall State Frequent clearing of throat, swallowing, tics, etc Facial grimacing Sleep disturbances: difficulty getting to sleep, difficulty staying asleep Screaming Gritting teeth Increased irritability (exaggerated responses to stimulation) Sobbing “for no reason at all” Wincing Noncompliance with demands that typically elicit an appropriate response (oppositional behavior) Sighing, whining Constant eating/drinking/swallowing (“grazing” behavior) Moaning, groaning Mouthing behaviors: chewing on clothes (shirt sleeve cuff, neck of shirt, etc), pica Delayed echolalia that includes reference to pain or stomach (eg, child says, “Does your tummy hurt?” echoing what mother may have said to child in the past) Application of pressure to abdomen: leaning abdomen against or over furniture or kitchen sink, pressing hands into abdomen, rubbing abdomen Direct verbalizations (eg, child says “tummy hurts” or says “ouch,” “ow,” “hurts,” or “bad” while pointing to abdomen) Tapping behavior: finger tapping on throat Any unusual posturing, which may appear as individual postures or in various combinations: jaw thrust, neck torsion, arching of back, odd arm positioning, rotational distortions of torso/trunk, sensitivity to being touched in abdominal area/flinching Agitation: pacing, jumping up and down Unexplained increase in repetitive behaviors Self-injurious behaviors: biting, hits/slaps face, head-banging, unexplained increase in self-injury Aggression: onset of, or increase in, aggressive behavior A functional behavioral assessment would be useful in interpreting these behaviors.
↵a Motor behaviors also may be markers of pain or discomfort arising in other parts of the body.
- TABLE 3
Diagnostic Evaluation of Gastrointestinal Symptoms and Disorders in Individuals With ASDs
Symptom Possible Associated Gastrointestinal Disorder Definition Diagnostic Evaluations to Be Considered Sleep disturbance GERD Parental/provider report (1) Diagnostic trial of proton-pump inhibitor; (2) pH probe, EGD Self-injurious behavior, tantrums, aggression, oppositional behavior Constipation, GERD, gastritis, intestinal inflammation Parental/provider report (1) Abdominal radiograph; (2) diagnostic trial of proton-pump inhibitor or PEG 3350; (3) pH probe, EGD, colonoscopy Chronic diarrhea Malabsorption, maldigestion ≥3 loose stools daily for >2 wk (1) Stool analysis for occult blood, enteric pathogens, ova/parasites (Giardia or Cryptosporidium), Clostridium difficile; (2) consider PEG 3350 if overflow diarrhea is a possibility; (3) lactose breath test (or measure lactase-specific activity), EGD, colonoscopy Straining to pass stool, hard or infrequent stool Constipation ≤2 hard stools per week (Bristol stool score) (1) Abdominal radiograph to look for fecal impaction; (2) diagnostic trial of PEG 3350 Perceived abdominal discomfort: pressing abdomen, holding abdomen and crying, problem behaviors related to meals Constipation, GERD, intestinal inflammation, malabsorption, maldigestion (1) Diagnostic trial of proton-pump inhibitor or PEG 3350; (2) abdominal radiograph; (3) lactose breath test (or measure lactase-specific activity); (4) pH probe, EGD, colonoscopy Flatulence and/or bloating Constipation, lactose intolerance, enteric infection with Giardia or Cryptosporidium (1) Abdominal radiograph; (2) diagnostic trial of PEG 3350 or lactose restriction; (3) lactose breath test or EGD (measure lactase-specific activity) Any or all of the above FAP, IBS FAP: abdominal pain without demonstrable evidence of anatomic, metabolic, infectious, inflammatory, neoplastic, or other pathologic condition (1) Behavioral soothing; (2) diet enhancements with fruits, fiber, sufficient fluids; (3) increase in routines for sleep and toilet time IBS: FAP associated with alteration in bowel movements EGD indicates esophagogastroduodenoscopy; PEG, polyethylene glycol.
- TABLE 4
Prevalence of Gastrointestinal Symptoms in Individuals With ASDs
Source Overall Prevalence Prevalence of Specific Disorders Sample Size Sample Characteristics Control Comments Black et al16 (2002) 9% with gastrointestinal disease (vs 9%)a — 96 Children with later diagnosis of ASD 449 children matched for age, gender, practice, and index date (date of first recorded diagnosis of ASD) Nested case-control study; UK General Practice Database (N = 211 480; general practitioner records of recurrent gastrointestinal symptoms) Taylor et al17 (2002) 17% with chronic bowel symptoms (lasting ≥3 mo) 8.9% chronic constipation; 4.0% diarrhea; 1.5% constipation and diarrhea 473 278 children with childhood ASDs plus 195 with atypical ASDs — Electronic disability registries in 5 London health districts and special school and child psychiatry records; clinical notes supplemented by family questionnaires Fombonne and Chakrabarti18 (2001) 18.8% with gastrointestinal symptoms 9.4% constipation; 5.2% abdominal pain; 5.2% bloody stools; 3.1% diarrhea 96 Post-MMR sample of children referred for developmental problem to local child development center who received PDD diagnosis (26 with ASDs, 56 with atypical ASDs, 1 with Asperger syndrome) — Part of UK epidemiologic survey of PDD; gastrointestinal symptom occurrence assessed by community pediatrician alone or with parent questionnaire Nikolov et al19 (2009) 23% with moderateb or severec gastrointestinal problems, primarily constipation and diarrhea 2% with >1 moderateb or severec gastrointestinal problem 172 Children with PDDs (88% with diagnosis of ASDs, 8% with PDD-NOS, 4% with Asperger syndrome); 145 boys, 27 girls; mean age: 8.3 ± 2.6 y (range: 5–17 y) — Children enrolled in 1 of 2 multisite randomized clinical trials conducted by the RUPP Autism Network; presence of gastrointestinal disorder determined by medical history and/or interview with primary caretaker using screening questionnaire Molloy and Manning-Courtney20 (2003) 24% with ≥1 chronic gastrointestinal symptom 12% chronic diarrhea; 9% chronic constipation; 7% chronic reflux/vomiting; 2% abdominal pain; 2% gaseousness 137 General population of children with ASDs attending autism clinic and not referred to gastroenterologist for assessment of gastrointestinal symptoms — Single-site study Ming et al21 (2008) 59% with gastrointestinal dysfunctionb Of the 94 (59%) with gastrointestinal dysfunction: 38% diarrhea or unformed stools; 28% constipation; 19% GER 160 Children with ASDs referred to and consecutively evaluated at autism center; all had validated complete history (medical and psychiatric disorder records) — Prevalence based on retrospective chart review and clinical intake forms completed by caregivers Valicenti-McDermott et al22 (2006) 70% with ≥1 lifetime gastrointestinal symptom (vs 28% in typically developing subjects [P < .001] and 42% in subjects with other developmental disorders [P = .03]) 44% chronic constipation (vs 16% [P = .023] and 38%); 28% fecal encopresis (vs 2% [P = .00] and 12% [P = .012]); 18% frequent vomiting (vs 0% [P = .008 and 8%); 18% abnormal stool patternb (vs 4% [P = .039] and 2% [P = .021]) 50 Children with ASDs aged 1–18 y followed in pediatric neurology and developmental pediatrics programs, private practices, or clinics at 2 urban centers 2 control groups matched for age, gender, and ethnicity: 50 children with typical development and 50 with other developmental disorders Cross-sectional study in which lifetime prevalence rates were determined by structured interviews Horvath and Perman13 (2002) 84.1% had ≥1 gastrointestinal symptom (vs 31.2% [P < .0001]); 41.1% had ≥4 gastrointestinal symptoms (vs 5%) 44% abdominal discomfort (vs 9%); 54% gaseousness (vs 19%); 34% bloating (vs 5%); 24% belching (vs 9%); 16% reflux (vs 5%) 412 Children with ASD diagnosis attending autism clinics in 2 cities in northeastern US 43 healthy aged-matched siblings Questionnaires to patients at autism clinic, supplemented by interviews with parents of 116 of 412 patients Parracho et al23 (2005) 91.4% (vs 25% in siblings and 0% in unrelated healthy children [P < .05] vs all controls) 75.6% diarrhea; 55.2% gaseousness; 46.6% abdominal pain; 44.8% constipation; 43.0% abnormal feces 58 Children with ASDs aged 3–16 y Two control groups: 12 siblings without ASDs and 10 unrelated healthy children Data obtained by questionnaire Lightdale et al24 (2001) 50% loose stools or diarrhea; ∼50% bloating, flatulence; 33% abdominal pain 500 Children with ASDs Parental reports Afzal et al25 (2003) — 36% moderate or severe constipation (vs 10% [P = .011]); 54.4% moderate or severe rectosigmoid loading (vs 24.1% [P < .01]) 103 Children aged ≤18 y with formal ASD diagnosis who were referred to tertiary pediatric gastroenterology service 29 consecutive children without ASDs referred to emergency department, most with abdominal pain Retrospective study of abdominal radiographs GER indicates gastroesophageal reflux; MMR, measles, mumps, and rubella; RUPP, Research Units on Pediatric Psychopharmacology.
↵a Chronic inflammation of gastrointestinal tract (eg, ulcerative colitis and regional enteritis), celiac disease, food intolerance, and recurrent gastrointestinal symptoms (eg, diarrhea, colic, or vomiting 3 times in 6 months).
↵b Gastrointestinal problem was moderate when it caused some impairment or required intervention to prevent likely impairment.
↵c Gastrointestinal problem was severe when it caused impairment and required intervention.
d Chronic gastrointestinal dysfunction defined as diarrhea or unformed stools, constipation, gastroesophageal reflux, or bloating persisting for an estimate of >6 months.
e More than 4 weeks of daily painless recurrent passage of ≥3 large unformed stools.
- TABLE 5
Symptoms Associated With Immune-Mediated Gastrointestinal Food Allergies and Suggested Diagnostic Approaches
Disorder Mechanism Symptoms Diagnostic Approach Pollen-food allergy syndrome (oral allergy syndrome) IgE mediated Mild pruritus, tingling, and/or angioedema of the lips, palate, tongue, or oropharynx; occasional sensation of tightness in the throat and rarely systemic symptoms Clinical history and positive SPT responses to relevant food proteins (prick-plus-prick method); ± oral challenge: positive with fresh food, negative with cooked food Gastrointestinal “anaphylaxis” IgE mediated Rapid onset of nausea, abdominal pain, cramps, vomiting, and/or diarrhea; other target organ responses (ie, skin, respiratory tract) often involved Clinical history and positive SPT responses or RAST results; ± oral challenge Allergic eosinophilic esophagitis IgE mediated and/or cell mediated GER or excessive spitting up or emesis, dysphagia, intermittent abdominal pain, irritability, sleep disturbance, failure to respond to conventional antireflux medications Clinical history, SPTs, endoscopy and biopsy, elimination diet, and challenge Allergic eosinophilic gastroenteritis IgE mediated and/or cell mediated Recurrent abdominal pain, irritability, early satiety, intermittent vomiting, FTT and/or weight loss, peripheral blood eosinophilia (in 50%) Clinical history, SPTs, endoscopy and biopsy, elimination diet, and challenge Food protein–induced proctocolitis Cell mediated Gross or occult blood in stool; typically thriving; usually presents in first few months of life Negative SPT responses; elimination of food protein → clearing of most bleeding in 72 h; ± endoscopy and biopsy; challenge induces bleeding within 72 h Food protein–induced enterocolitis Cell mediated Protracted vomiting and diarrhea (± blood) not infrequently with dehydration; abdominal distention; FTT; vomiting typically delayed 1–3 hours after feeding Negative SPT responses; elimination of food protein → clearing of symptoms in 24–72 h; challenge → recurrent vomiting within 1–2 h, ∼15% have hypotension Food protein–induced enteropathy celiac disease (gluten-sensitive enteropathy) Cell mediated Diarrhea or steatorrhea, abdominal distention and flatulence, weight loss or FTT, ± nausea and vomiting, oral ulcers Endoscopy with biopsy of duodenum while on a gluten-containing diet; IgA; tissue transglutaminase; antiendomysial antibody; if IgA deficient, IgG tissue transglutaminase should be measured FTT, failure to thrive; GER, gastroesophageal reflux; Ig, immunoglobulin; RAST, radioallergosorbent test; SPT, skin-prick test.
Adapted from with permission from the American Academy of Allergy Asthma & Immunology from Sampson HA. J Allergy Clin Immunol. 2003;111(2 suppl):S540–S547.
- TABLE 6
Key Take-Away Messages
Individuals with ASDs whose families report gastrointestinal symptoms warrant a thorough gastrointestinal evaluation. All of the common gastrointestinal conditions encountered by individuals with typical neurologic development are also present in individuals with ASDs. The communication impairments characteristic of ASDs may lead to unusual presentations of gastrointestinal disorders, including sleep disturbances and problem behaviors. Caregivers and health care professionals should be alert to the presentation of atypical signs of common gastrointestinal disorders in patients with ASDs. If a person with an ASD is on a restricted diet, professional supervision can help to identify and treat nutritional inadequacy. Integrating behavioral and biomedical approaches can be advantageous in conceptualizing the role of pain as a setting event for problem behavior, facilitating diagnosis, and addressing residual pain symptoms to enhance quality of life. Genetic assays should be included as part of the data to be collected in research protocols. At present, there are inadequate data to establish a causal role for intestinal inflammation, increased intestinal permeability, immunologic abnormalities, or food allergies in ASDs. - TABLE 7
Areas in Need of New Knowledge
Research Objective Recommendation Statement No. Determine prevalence of gastrointestinal disorders in individuals with ASDs Prospective multicenter studies; population-based studies; subjects with well-documented diagnosis of ASD by accepted classification methods; use of validated instruments and outcome measures 3 Develop screen for gastrointestinal disorders in individuals with ASDs that can be used by primary care and other providers Prospective multicenter studies; validation by gastrointestinal specialists 2, 7 Identify behaviors associated with gastrointestinal pain/distress in persons with ASDs Prospective multicenter studies; evaluation of behavioral items as useful additions to screens for gastrointestinal problems in persons with ASDs; inclusion of treatment-responsive measures of behavior in research trials of treatments for gastrointestinal problems 2, 7 Evaluate whether dietary restriction is efficacious for individuals with ASDs Adequately powered randomized, controlled trial 11 Identify role of abnormal gastrointestinal permeability in neuropsychiatric manifestations of ASDs Prospective studies; properly powered and controlled 5 Determine relationship of immune dysfunction to clinical symptoms that present in patients with ASDs Well-defined studies; large sample sets; age-matched and geographically matched controls; extensive analysis of immune function 17 Determine if alteration in gut microflora is associated with either gastrointestinal or neurobehavioral symptoms in patients with ASDs Use high through-put molecular approaches to identify and quantify microbial species; selection criteria to control for antimicrobial exposure and diet 19 Clarify underlying pathophysiology and clinical aspects of ASDs Detailed description of phenotype (biological, clinical, and behavioral features) of study subjects 20 Characterize genotype of individuals with ASDs and gastrointestinal disorders Include genetic testing for all study subjects; conduct studies in subjects with well-defined genetic syndromes with high rates of ASDs 21, 22 Identify genetic mutations that may be possible underlying causes of ASDs Obtain blood samples from study subjects for banking of DNA 23
Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report
