Definition of Disease Entity

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Definition of Disease Entity

• A group of patients with similar histories,
  symptoms,physical examination, laboratory
  findings, biopsy findings, and response to
  treatment in the absence of any other scientific
  or biologic explanation.
• Independent confirmation

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Features Common to Patients in the Autistic Group

• Similar neurologic diagnosis
• Similar symptomatology
• Similar gross pathology
• Similar histopathology
• Similar immunohistochemical pathology
• Similar response to anti-inflammatory medication
• These similarities are consistent amongst the
  majority of members of the group

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Neurologic Diagnoses

• Autism and regressive autism
• 1) Regressive autism
• 2) Plateau autism
• 3) Early onset autism
• Autistic spectrum

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Symptoms
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Symptoms

• Abdominal pain
• Diarrhea
• Constipation
• Alternating diarrhea and/or constipation
• Malodorous stool
• Growth retardation

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Photographs of diarrheal Stool
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Symptoms Abdominal Pain

• Crying
• Unexplained tantrums
• Night time wakening
• General irritability
• Vocalizing complaints
• Posturing
• Irritability just prior to bowel movement
• Hyperactivity and distractibility
• Self injurious behavior

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Photographs and videos depicting abdominal pain
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Self-Injurious Behavior
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Symptoms - Diarrhea

• 1-3 stools per day
• Soft to loose (chocolate pudding to mashed
  potato)
• Grainy
• Malodorous
• Accompanied by irritability, tantrums, or
  attempts to withhold
• Frequently visible undigested food
• Not typically bloody or mucoid (including occult
  blood)

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Symptoms - Constipation

• Infrequent stools, once every 4-10 days
• Abdominal distension
• Large caliber, often blocks the toilet
• Not typically hard or painful upon passage,
  supports concept that there exists an underlying
  inflammatory condition
• Pain and overall irritability
• Often alternating periods of constipation and
  diarrhea

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Constipation
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Symptoms - Growth

• Disproportionate number of patients plot in the
  lower 25 tile for weight at time of presentation
• Many patients are gt90th tile at presentation

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Physical Examination

• Weight for age generally in lower 25 tile
• Abdominal distension
• Hyperactive bowel sounds
• Tymponitic abdomen
• Difficult to assess presence of tenderness
• Occasional extraintestinal manifestations

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Evaluation

• complete blood count, erythrocyte sedimentation
  rate, chemistries, celiac titers, thyroid
  function, inflammatory bowel disease serology,
  stool cultures, ova/parasites, hemoccult
• Diet review(eg. carbohydrates, sorbitol, fruit
  juices)
• Gluten and casein free diet
• Colonoscopy and biopsy. EGD in those patients
  experiencing perceived abdominal pain

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Laboratory Findings

• The most striking observation in regards to tests
  of the blood and stool is their normalcy.
• Despite the intensity and chronicity of the above
  symptoms, traditional markers of bowel
  inflammation and inflammatory bowel disease are
  absent, as are known stool pathogens.
• We have noted a consistent pattern of abnormally
  elevated
• 1) gliadin IgG antibody.
• 2) thrombocytosis (clustered in top 25 of
  normal or
• elevated).
• 3) Inflammatory bowel disease serology

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Tissue Findings
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Wireless Capsule Endoscopy
Normal small bowel
Erythema
Erythemaapthoid ulcers
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Immunohistochemistry and Molecular Pathology
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Treatment

• Dietary restriction
• 5 ASA anti-inflammatory agents
• Prednisone
• 6-Mercaptopurine
• Cromolyn Sodium
• Singulair
• Objective measures of response to treatment
  (frequency, consistency, pain, irritability,
  odor, growth)
• Dietary restriction

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We do not yet know whether treatment with
anti-inflammatory drugs results in improvement of
microscopic histopathology or in
behavioral/functional/cognitive improvement of
autistic parameters.
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Additional Clinical Observations Supporting the
Concept of Bowel Inflammation

• Parental reports of improvement in bowel symptoms
  while on gluten/casein free diet
• Parental reports of transient improvement in
  bowel symptoms in the days following secretin
  administration
• Parental reports of improvement in bowel symptoms
  while on pancreatic enzymes
• Parental reports of unexpected calm and mellow
  mood and behavior on day prior to colonoscopy
  when child is placed on a diet limited to clear
  fluids ONLY
• Wide array of endoscopic findings in both the
  lower and upper gastrointestinal tract (see
  following slides)

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Esophageal Ulcerations
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Esophageal Eosinophilia and Lymphonodularity
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Esophageal Nodularity and Esophagitis
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Gastric Ulcerations
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Duodenal Ulcerations
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Data Summary - January 2006

• 143 consecutive ASD patients who underwent
  colonoscopy for chronic gastrointestinal symptoms
• 78 had diarrhea
• 59 had abdominal pain
• 15 had growth failure
• 73 had ileocolitis
• LNH predicted colitis
• Inflammation was most likely to occur in younger
  patients

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In summary

• All the criteria needed for defining a disease
  state are met
• Similar histories, symptoms, physical exam,
  laboratory tests, biopsy readings, and response
  to treatment
• Independent confirmation of previously reported
  findings

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Question

• What is causing this inflammation and lymph node
  enlargement?

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• Wake Forest University School of Medicine
• PERSISTENT ILEAL MEASLES VIRUS IN A LARGE COHORT
  OF REGRESSIVE AUTISTIC CHILDREN WITH ILEOCOLITIS
  AND LYMPHONODULAR HYPERPLASIA REVISITATION OF AN
  EARLIER STUDY
• S. Walker, K. Hepner, J. Segal, A. Krigsman
• Background Autistic enterocolitis, consisting of
  a nonspecific ileocolitis coupled with
  ileocolonic lymphonodular hyperplasia (LNH), was
  first introduced as a new, potentially
  virus-induced disease entity eight years ago in a
  group of ASD children with developmental
  regression.Objectives The primary objective of
  this study was to examine ileal biopsy tissue in
  a large cohort of pediatric patients who carry a
  diagnosis of regressive autism and whose chronic
  gastrointestinal symptoms warranted diagnostic
  endoscopic evaluation, for evidence of measles
  virus RNA.Methods Patients who had been
  diagnosed with autism and who were referred to a
  pediatric gastroenterologist for evaluation of
  chronic GI symptoms were eligible to participate
  in this IRB approved study. For each patient,
  medical histories, vaccination records,
  histopathology reports, and ileocolonoscopic
  biopsy tissue were available for evaluation.
  Terminal ileum (TI) biopsy tissue was assayed by
  RT-PCR for the presence of measles virus RNA and
  PCR-positive samples were sequenced.Results
  Medical and clinical data have been collected for
  gt275 patients who fit the study inclusion
  criteria. PCR analysis on TI biopsy tissue from
  an initial 82 patients showed that 70 (85) were
  positive for the F gene amplicon. Fourteen have
  been verified by DNA sequence and an additional
  56 amplicons are being sequenced now. Work is
  ongoing to assay the remaining specimens (200)
  and to identify and assay relevant control tissue
  samples. Conclusions Preliminary results from
  this large cohort of pediatric autistic patients
  with chronic GI symptoms confirm earlier findings
  of measles virus RNA in the terminal ileum and
  support an association between measles virus and
  ileocolitis /LNH. Sponsors ARI NAA
  individual donations