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  1. 1. BIOMEDICAL GASTROINTESTINAL PATHOLOGY IN AUTISM SPECTRUM DISORDERS: THE VENEZUELAN EXPERIENCE By Lenny G. González, MD R Lenny González, MD, specializes ecent studies in the medical sleep disorders, and other behavioral in pediatric gastroenterology and literature have confirmed that disturbances. The problem of physical nutrition and is a member of the staff gastrointestinal (GI) symptoms symptoms such as abdominal pain being of SOVENIA (Venezuelan Society of are common in patients with autism interpreted simply as aberrant behaviors Autistic Children). Her focus is on spectrum disorders (ASD). In two is particularly problematic in children the diagnosis and treatment of GI prospective studies, GI symptoms were who are nonverbal and who have serious pathology in children with autism present in 80% and 70% of autistic difficulties expressing themselves.10 and children with developmental children, respectively.1 In contrast with Detailed case histories often provide delays. Dr. Gonzalez sees children the ASD group in the latter study, evidence of abdominal colic and from all over South America and has Valicenti-McDermott et al. reported GI sleep disorders during the nursing performed intestinal endospcopies symptoms in only 28% of neurotypical stage and frequent infections of the on more than 956 children with controls.1,2,10 Retrospective studies upper respiratory tract (such as otitis autism. She has collaborated with that rely only upon review of the and tonsillitis) and GI tract caused Thoughtful House and Dr. Andrew children’s existing clinical records are by bacterial, viral, parasitic, or yeast Wakefield in Austin, Texas, where likely to underestimate the true size infections. Affected children are often she investigated the histological of the problem since these records hypersensitive to sounds, light, flavors, findings of gastrointestinal mucosa rarely document GI symptoms. The smells, and clothing labels. In addition, of patients and diagnosed infections inadequacy of this approach means that there is often a history of intolerance and immune system disorders. She is it is impossible to determine whether to certain foods containing gluten and actively involved in the Defeat Autism symptoms were not present or, more casein as well as indicators of food Now! Conference. In addition, she likely, that the clinician just failed to allergies.5-7 has presented her findings in most document them. On the other hand, Children with autism often present Latin American countries. She is prospective studies that systematically with GI and extra-intestinal symptoms. dedicated to education, research, and ask about the presence or absence The digestive symptoms include support for families with children who of specific symptoms provide a much abdominal pain, pyrosis (heartburn), have autism and/or gastrointestinal more accurate picture of the size of the chronic diarrhea, flatulence, drooling diseases. problem. or excessive salivation, vomiting, regurgitations, weight loss, rumination, Clinical manifestations of GI disease bruxism (teeth grinding), irritability, in ASD children dysentery, constipation, and fecal Physical symptoms in ASD children impaction. During symptomatic are often misinterpreted as just episodes, periods of irritability, autistic behaviors. In our experience, insomnia, and auto-aggressive behaviors symptoms of what turns out to be GI are observed. In ASD children, it is distress often present as inexplicable common to observe abnormal toileting irritability, aggressive or auto-aggressive patterns. Diarrhea and constipation are (self-injurious) behaviors, discomfort, common, and constipation can coexist 74 THE AUTISM FILE | | REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 32 2009
  2. 2. One explanation might be that part of the neurological disability in children with autism results from absorption across an inflamed intestinal lining of molecules that are toxic to the developing brain. with episodes of diarrhea. In the case barrier that restricts the contents of referred to as intestinal dysbiosis. Several of diarrhea, the stools are semi-liquid, the gut from getting into the blood investigators have found evidence of very fetid with mucus and undigested stream. It it is composed of cells with this imbalance in autistic children. A food; sometimes they can have a sandy/ absorptive surfaces (the brush border) good example of a pathogenic (disease- grainy consistency and other times that interact with the contents of the causing) bacterium is Clostridium difficile. show blood. Diarrhea is one of the most lumen. Between these cells are gates This organism is a common cause of common symptoms as reported in the called tight junctions, the integrity severe colitis that occurs when broad- studies of D’Eufemia, Torrente, Horvath, of which is important in preventing spectrum oral antibiotics have killed Wakefield, Furlano, and Sabrá. This has noxious substances from entering the off the beneficial gut bacteria and been our experience in Venezuela, also.14 bloodstream without passing directly have allowed this antibiotic-resistant The extra-intestinal problems through the cells.10 opportunistic organism to overgrow and experienced by our ASD children with One explanation might be that part cause inflammation.10 GI symptoms include respiratory, of the neurological disability in children The gut-brain connection is neurological, and dermatological with autism results from absorption recognized as playing a role in the disorders. These include frequent across an inflamed intestinal lining neurological complications of a number coughing (often dry), upper respiratory of molecules that are toxic to the of gastrointestinal diseases. Symptoms tract infections, skin rashes, eczema, developing brain.10-14 Inflammation of like constipation, pain, or abdominal atopic dermatitis, seborrheic dermatitis, the intestinal wall can be induced by distension are reported by adults with and itching. diverse causes such as food allergy, degenerative disorders of the central The most common clinical signs are use of antibiotics and non-steroidal nervous system like Parkinson’s disease, 4 Dennie Morgan infraorbital skin folds anti-inflammatory drugs, infection, while parents of autistic children report (caused by edema or fluid collecting or by enzymatic insufficiency, similar symptoms, although the precise in areas of inflammation), dark circles mycotoxins from yeast/fungi, gluten, nature of any link between the gut and under the eyes, long eyelashes, casein, chemical additives, colorings, the brain is unknown. abdominal distension, halitosis, perianal preservatives, malabsorption of erythema (diaper rash), anal fissures, proteins, heavy metal intoxications, and Ileo-colonoscopy and autistic dry skin, angular cheilosis (sore cracks pesticides.3-6 enterocolitis at the corners of the lips), and greenish The integrity of the intestinal wall also In 1998, a team of doctors at the Royal anterior rinorrhea (runny nose). plays an important role in the adequate Free Hospital in London reported the There are also alterations in the stool absorption of nutrients and the exclusion results of ileocolonoscopies on 12 consistency, color, and smell (excessively of potentially harmful toxins, bacteria, children who presented with autism offensive) as well as the presence of allergens, and peptides coming from and GI symptoms. In a series of papers, mucus or blood, food remains, and certain foods. In our experience, food Wakefield and colleagues described a visible fat (often semi-liquid, acidic, components such as gluten and casein new variant of intestinal inflammatory excessively fetid, greasy feces, with can provoke the behavioral abnormalities disease, which was named autistic mucus and/or blood). characteristic of autism 4 , possibly when enterocolitis. The disease is characterized they enter the systemic circulation. by mild-to-moderate chronic patchy Etiopathogenesis Increased intestinal permeability (leaky inflammation of the mucosa and Recent studies of ASD children gut) may be the link that explains the lymphoid nodular hyperplasia (LNH) report chronic inflammation of the association of autism with an abnormal (swelling of the lymph glands) in the gastrointestinal tract that may be intestinal immune response, multiple bowel lining. Visible features suggestive present anywhere from the esophagus food allergies, dysbiosis, fungal of inflammatory bowel disease included down to the rectum: this inflammation overgrowth (Candida albicans), as well the red halo sign – an expression of may well explain the GI symptoms and as with micronutrient deficiencies.4,5 pre-ulcerative reddening around the at least some of the behaviors.18-15, 35-40 Probably due to GI inflammation and swollen lymphoid tissues – typically Several theories have been proposed abnormal immune function, children located at the terminal ileum, potentially for how deterioration in gastrointestinal with autism may have increased levels extending to involve the whole colon, function might influence neurological of harmful bowel organisms. Frequent loss of vascular pattern, and mucosal functioning. The epithelial cell layer antibiotic use in the first years of life can granularity, erythema (redness), and that lines the GI mucosa forms a also contribute to the chronic imbalance, ulceration. When compared with ISSUE 32 2009 REPRINTED WITH PERMISSION © THE AUTISM FILE | | THE AUTISM FILE 75
  3. 3. BIOMEDICAL neurotypical children, including those Reflux Esophagitis (Endoscopy) Reflux Esophagitis (Biopsy) with ulcerative colitis (a well described inflammatory bowel disease), the findings suggested a novel disease process.14 In the UK study and in our own experience, these abnormal findings are more frequent in autistic children than in developmentally normal children with GI symptoms. The only exception was ulceration, which was uncommon in both groups. The biopsies from the children with autism showed reactive LNH in 88.5% of the children compared with only 29% of children with ulcerative colitis, and 0.0% in the control group without IBD. In many cases, the researchers also saw infiltration of Figure 1: (a) endoscopic image typical of reflux esophagitis (b) matches the 4 histological inflammatory cells like neutrophils criteria for diagnosis of reflux esophagitis. (pus cells) and lymphocytes (chronic inflammatory cells) in the epithelium of lower gastrointestinal inflammation mucosa in autistic children is being the bowel mucosa. Active neutrophilic have been found to different degrees studied in the search for an association inflammation in the ileum was present of severity;6 the relationship, if any, between the histological changes and in 8% of the children with autism and between the severity of the bowel the etiopathogenesis of autism. in none of the non-inflammatory bowel inflammation and the autistic features disease controls. Chronic lymphocytic is not yet known. Using techniques that Upper gastrointestinal endoscopy inflammation in the colon was present identify specific immune cell types, Based upon our experience, we stress the in 88% of the autistic cases, 4% of the under the microscope these investigators importance of a full examination of the controls, and 100% of ulcerative colitis have shown characteristic patchy GI tract in symptomatic children with any cases. inflammation in many ASD children degree or type of ASD, to include upper In our published study of 45 ASD including a pronounced infiltrate of GI endoscopy (esophagus, stomach and, children and 57 developmentally normal CD4, CD8, gamma delta T cells and duodenum). The literature supports controls presenting for GI assessment, antibody producing plasma cells. The the existence of upper gastrointestinal chronic inflammation and LNH in the inflammatory response is different from disease in these children.3-15 In our colon and ileum was present in 100% that seen in IBD (inflammatory bowel Venezuelan series,13 we found that 88% of the autistic cases compared with disease) patients and in the normal of the patients had reflux esophagitis, 66.66% of the controls, reflecting a controls. The inflammation was more 55% had nonspecific gastritis due to high background rate of infectious localized to the epithelium and basement Helicobacter pylori, 52% of ASD children enterocolitis in Venezuelan children membranes (superficial layers) of the gut had Giardia intestinalis infection, (see below.)13 Since then, other studies mucosa than that which is commonly and 37% had chronic unspecific carried out in the United States, Brazil, seen in classic IBD.34-38 inflammation of the small intestine. Italy, and Venezuela have confirmed Intestinal symptoms are not necessary This was in addition to the findings of the finding of inflammation and LNH in for the presence of intestinal disease. colitis with LNH (69%), of which 11% ASD.10-14, 29 An increase in intestinal permeability had eosinophilic colitis, and 100% of the in patients with ASD who were not children presented chronic inflammation Immune profiling of the intestinal symptomatic from the GI perspective and lymphoid nodular hyperplasia (LNH) disease in ASD and who had no other evidence of GI of the terminal ileum. Furlano (2001), Torrente (2002), illness was described by D’Eufemia in and Ashwood (2004) have described 1996 8 and in 1998-2000. Wakefield Esophagus immune abnormalities and abnormal and colleagues suggest the association Over the past decade, the expanding cytokine profiles in the intestine of inflammatory intestinal chronic body of literature on esophageal of ASD children with GI symptoms. disease and autism from an analysis physiology and pathology has led to Cytokines are chemical messengers that of ileal and colonic biopsies where the the perception that the esophagus is communicate between cells to increase frequent presence of LNH and unspecific an immunologically active organ. It or decrease the activity of the immune colitis are evidenced.9-15 Currently, the can respond to a variety of stimuli by system. In ASD children, upper and structure and function of the digestive augmenting certain immunological 76 THE AUTISM FILE | | REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 32 2009
  4. 4. defenses, including recruitment and have it in their stomach characteristically Endoscopic Image of Duodenum activation of eosinophils – immune have a very obvious nodular gastritis. cells involved in allergic responses. (Figure 4) We observed chronic H. Esophageal pathology is common in pylori-associated gastritis in 55.6% of the Venezuelan children with ASD (in our children with autism and 33.3% in the study, degrees of esophagitis were controls, compared with active chronic described according to the guidelines gastritis without H. pylori in 33.33% of of the European and American Society the children with autism and 2.56% of of Pediatric Gastroenterology and the controls. This compares with a finding Nutrition. 11,12). One of the most of gastritis in 15 of 36 ASD children by common visual findings in eosinophilic Horvath et al. in US children.14 esophagitis is linear streaks of nodular (When assessing stomach pathology, mucosa. Eosinophilic esophagitis is a we used the Sydney System for common pathology in ASD children and classification and grading of gastritis14 Figure 2: nodular duodenal bulb is defined as an increase in the number and a raised eosinophil count as one of eosinophils seen microscopically per greater than 20 cells per HPF). high-power field (HPF). For eosinophils, One of the characteristic lesions we see the normal range in the esophagus is in the stomach is reactive gastropathy, between 0-2 cells/HPF. In eosinophilic which can be associated with the reflux of esophagitis associated with various food bile into the stomach from the duodenum. allergic disorders, we often see 20 cells/ Endoscopic findings include congestion, HPF or more.14, 24, 40, 41 enanthema (an eruption on the mucus Reflux esophagitis, in which stomach membrane of the stomach), erythema acid moves back up into the lower (reddening), micro- and macro-nodularity esophagus, is also common. Visually in the body and antrum, ulcers, and biliary this is indicated by esophageal rings, reflux as a result of hypomotility (reduced mucosal erythema, linear ulcers, and peristalsis) moving food from the antrum erosive esophagitis when damage from of the stomach into the duodenum. One Figure 3: lymphoid accumulations cumulus the acid reflux is extreme. The finding observation in affected children is that in the esophagical mucosa of a 4-year-old is confirmed by biopsy. (Figure 1) In they have very distended bellies. child with diagnosis of severe autism. our series, the most frequent diagnosis was reflux esophagitis that was present Small Bowel in 89% of the children with autism The small bowel is the duodenum, the Stomach compared with 49% in the control group, jejunum, and the ileum. It is the longest with a significant difference between the part of the bowel, and it is important groups of p<0.001.14 A neurotypical child because it is where the body absorbs with esophageal pathology as described calories and nutrients. Currently, the small above would complain bitterly; for the bowel can be visualized using capsule nonverbal child, drawing attention to endoscopy, but, other than the very first the source of their distress is particularly and last parts of the small intestine it is challenging, and doctors should retain a not routinely accessible to biopsy. We high index of suspicion.40 sometimes find celiac disease in children with autism, but it is surprisingly rare, Stomach considering that this group is exceedingly Our experience with gastric disease in sensitive to gluten. Because celiac disease Figure 4: corresponds to image of gastric Venezuela is somewhat different from can only be diagnosed with certainty while antrum where nodularity (stony antrum) can the experience of others since we have the child is ingesting gluten, it is critical be seen, characteristic of the infection by a high rate of infection with H. pylori to obtain baseline celiac antibodies before Helicobacter pylori. in children. H. pylori can be a painful beginning a gluten-free diet in order to bacterial infection, and children who confidently exclude celiac disease. Since then, other studies carried out in the United States, Brazil, Italy, and Venezuela have confirmed the finding of inflammation and LNH in ASD. ISSUE 32 2009 REPRINTED WITH PERMISSION © THE AUTISM FILE | | THE AUTISM FILE 77
  5. 5. BIOMEDICAL Treatment gluten and casein, among others (because The diagnosis and treatment of these may result in an immune/allergic gastrointestinal disease in children with response that may exacerbate any intestinal autism involves an exhaustive assessment inflammation) and strengthen their immune that includes a detailed case history and system throughout with the treatment of physical examination, investigation of any IgA secretory deficiency. the macroscopic characteristics of the All of the intestinal lesions, damage, or stool, laboratory testing, a complete stool abnormalities are potentially treatable.Many analysis, a search for intestinal infections to children respond very well to combinations include parasites, Campylobacter jejuni and of the following: of a restricted diet, Clostridium difficile, and a fungal culture. anti-inflammatory medication, probiotics, Treatment is designed to reduce damage antibiotics, antifungals, and digestive and inflammation of the gastrointestinal enzymes, among other things. There is mucosa, diminish intestinal permeability, correlation between the treatment of GI improve nutrient intake and micronutrient disease and improved cognitive functions, Figure 5: histologic specimen with absorption, and treat any associated decreased self-aggressiveness, and eosinophilic gastritis infection(s). In addition, the children improvements in attention, visual contact, should avoid proteins in the diet such as and sleep disorders. Colitis with LNH In summary, particular attention should be paid to: 1. Nutritional intervention (e.g., gluten-free/casein-free diet and appropriate supplementation) 2. Treatment of gastroesophageal reflux disease (GERD) 3. Treatment of eosinophilic esophagitis 4. Management of gastritis with or without Helycobacter pylori infection 5. Treatment of constipation29 6. Management of pancreatic insufficiency30 Figure 6: image where total loss of normal 7. Antifungal treatment characteristics of the colon can be observed. 8. Probiotics, prebiotics (foods that support beneficial bacteria), fermented foods31, 32 9. Treatment of other infections including Clostridium difficile, intestinal Histological image of Ileum parasites such as protozoarians and helminths, and other bacteria including ECEP, Klebsiella pneumoniae, Citrobacter feundii, Enterobacter cloacae, Pseudomona aeruginosa, Proteus mirabilis, Aspergillus, Trichosporum and Geotrichum sp, among others. Conclusions Our experience of Venezuelan children with ASD is that most have GI symptoms that may not be immediately evident or may not be obviously related to intestinal distress. The absence of obvious GI symptoms does not mean an absence of the disease. There may be chronic inflammation anywhere from the esophagus down to the rectum that may be seen even in asymptomatic patients; the GI evaluation is an essential part of the investigation protocol in ASD. In our experience, treating GI disease is consistently associated with Figure 7: eosinophilic colitis at 10X in a improved cognitive functions, decreased self-aggressiveness, better attention, improved child with severe autism. eye contact, and decreased sleep disorders. In our experience, treating GI disease is consistently associated with improved cognitive functions, decreased self-aggressiveness, better attention, improved eye contact, and decreased sleep disorders. 78 THE AUTISM FILE | | REPRINTED WITH PERMISSION © THE AUTISM FILE ISSUE 32 2009
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Possible autoimmune enteropathy enteroscopy: Another piece in the jigsaw of 15 Wakefield AJ., Murch SH., Anthony A., found in autistic children. The Lancet this gut-brain syndrome. AMJ Gatroenterol et al. Ileal lymphoid nodular hyperplasia, 2002;359:1674. 2005 Letters to the editor. ISSUE 32 2009 REPRINTED WITH PERMISSION © THE AUTISM FILE | | THE AUTISM FILE 79