9a. Excerpts from CDC's in-house conference: Thimerosal sequelae
http://www.nationalautismassociation.org/library/IOM%20Simpsonwood%20in%20bold.pdf
9b. Blaylock R, MD. The thimerosal coverup – a thorough delineation of CDC, FDA knowledge about thimerosal circa 1999.
http://sydney.indymedia.org/front.php3?article_id=45874&group=webcast
10a. House Subcommittee Hearing transcripts: Truth Revealed: New Scientific Discoveries Regarding Mercury in Medicine and Autism. September 08, 2004
http://reform.house.gov/WHR/Hearings/EventSingle.aspx?EventID=1311
10b. Testimony of Lyn Redwood, RN, MSN; President; Safeminds
http://reform.house.gov/UploadedFiles/Testimony Redwood.pdf
10c. Analysis and critique of the CDC's handling of the thimerosal exposure assessment based on Vaccine Safety Datalink (VSD) information. Safeminds, 2003.
http://www.momsonamissionforautism.org/index/VSD.SafeMinds.critique.pdf
10d. NoMercury.org – an information resource about thimerosal
http://www.nomercury.org/
11. Verstraeten T, Davis RL, DeStefano F et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics. 2003 Nov;112(5):1039-48. Erratum in: Pediatrics. 2004 Jan;113(1):184.
12. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med 2003 228(6):660-4 PMID 12773696
"We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders."
13. Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003 6(2):97-102 PMID 14534046
"The [thimerosal] dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other."
14. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 01.
15. Geier MR, Geier DA. Autism and thimerosal-containing vaccines: analysis of the Vaccine Adverse Events Reporting System (VAERS). IOM presentation, Feb 9, 2004.
Slides: http://www.iom.edu/view.asp?id=18392
Audio: http://www.iom.edu/view.asp?id=19120
16. Geier & Geier. Parents' worries about thimerosal in vaccines are well founded!
http://pediatrics.aappublications.org/cgi/eletters/112/6/1394
[An excellent summary & rebuttal of pro-thimerosal articles.]
17. Baskin DS et al. Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci. 2003 Aug;74(2):361-8. Epub 2003 May 28. PMID: 12773768
18. David Baskin, M.D. Relation of Neurotoxic Effects of Thimerosal to Autism. IOM presentation, Feb 9, 2004. Audio only: http://www.iom.edu/view.asp?id=19124
19. Pichichero ME et al. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet. 2002 30;360(9347):1737-41. PMID 12480426
"Interpretation: Administration of vaccines containing thiomersal does not seem to raise blood concentrations of mercury above safe values in infants." [But see cite 20]
20. Waly M et al. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70. PMID: 14745455
"Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury [at nanomolar levels described by Pichichero et al), aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins."
21. Richard C. Deth, Ph.D. Effects of Mercury on Methionine Synthase: Implications for Disordered Methylation in Autism Defeat Autism Now! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/RichardDeth.htm
22a. Mady Hornig, M.D Etiologic factors and pathogenesis of autism: evidence from clinical studies and animal models. IOM presentation Feb 9 2004 Audio only: http://www.iom.edu/view.asp?id=19108
22b. Mady Hornig, PhD: Testimony to House Subcommittee Sept 8 2004
http://reform.house.gov/UploadedFiles/Testimony Hornig.pdf
23. Westphal GA et al. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8. PMID: 11007341
24: Muller M et al. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal. Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81. PMID: 11556154
25. Westphal GA et al. Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes. Arch Toxicol. 2003 Jan;77(1):50-5. Epub 2002 Nov 06. PMID: 12491041
26. Havarinasab S et al. Dose-response study of thimerosal-induced murine systemic autoimmunity. Toxicol Appl Pharmacol. 2004 194(2):169-79. PMID: 14736497
"The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury."
27. Vojdani A, Pangborn JB et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99. PMID: 14611720
28. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol. 2003 Jul-Aug;22(4):277-85. PMID: 12933322
"Hair mercury levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a significant difference. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively."
29. Boyd Haley, Ph.D. Reduced Levels of Mercury in First Baby Haircuts of Autistic Children. IOM presentation, Feb 9 2004.
Slides: http://www.iom.edu/view.asp?id=18394
Audio: http://www.iom.edu/view.asp?id=19128
30: Boyd Haley, Ph.D. Nucleotides and Mercury Defeat Autism Now! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/Haley.htm
31. L-W. Hu et al. "Neutron Activation Analysis of Hair Samples for the Identification of Autism", Transactions of the American Nuclear Society, Vol. 89, November 16-20, 2003.
32. Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of mercury poisoning. Med Hypotheses. 2001 Apr;56(4):462-71. PMID: 11339848
33. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry. 2002;7 Suppl 2:S42-3. PMID: 12142947
34. Excerpts from CDC's in-house conference: Thimerosal sequelae
http://www.nationalautismassociation.org/library/IOM%20Simpsonwood%20in%20bold.pdf
35. Congressman, Dr. Weldon's letter to the CDC director, available at:
http://momsonamissionforautism.org/Autism_Central/Dr_Weldon_Responds.shtml
36a. IOM presentation of Congressman Dave Weldon, M.D.
http://www.nationalautismassociation.org/pdf/Weldon.pdf
36b. Doctors must prescribe without all the facts. Dr. Darshak Sanghavi, Children's Hospital and Harvard Medical School. sanghavi@post.harvard.edu October 12, 2004
http://www.boston.com/news/globe/.../doctors_must_prescribe_without_all_the_facts/
Intestinal pathologies
37. D'Eufemia P et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996 Sep;85(9):1076-9. PMID: 8888921
"We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls."
38. Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28. PMID: 12608733
39. Mercer ME, Holder MD. Food cravings, endogenous opioid peptides, and food intake: a review. Appetite. 1997 Dec;29(3):325-52. PMID: 9468764
40a. Lucarelli S et al. Food allergy and infantile autism. Panminerva Med. 1995 Sep;37(3):137-41. PMID: 8869369
"The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We also looked for immunological signs of food allergy in autistic patients on a free choice diet. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of these antibodies were significantly higher than those of a control group which consisted of 20 healthy children."
40b. Iacono G et al. Chronic constipation as a symptom of cow milk allergy. J Pediatr. 1995 Jan;126(1):34-9. PMID: 7815220
"Twenty-seven consecutive infants (mean age, 20.6 months) with chronic "idiopathic" constipation were studied to investigate the possible relation between constipation and cow milk protein allergy (CMPA). The infants were initially observed on an unrestricted diet, and the number of stools per day was recorded. Subsequently the infants were put on a diet free of cow milk protein (CMP) for two periods of 1 month each, separated by two challenges with CMP. During the CMP-free diet, there was a resolution of symptoms in 21 patients; during the two consecutive challenges, constipation reappeared within 48 to 72 hours. In another six patients the CMP-free diet did not lead to improvement of constipation. Only four of the patients who improved on the CMP-free diet had concomitant symptoms of suspected CMPA, but a medical history of CMPA was found in 15 of the 21 patients cured and in only one of the six patients whose condition had not improved (p < 0.05); in addition, in 15 of the 21 cured patients, results of one or more laboratory tests (specific IgE, IgG, anti-beta-lactoglobulin, circulating eosinophils) were positive at the time of diagnosis, indicating hypersensitivity, compared with one of the six patients whose condition did not improve (p < 0.05). The endoscopic and histologic findings at the time of diagnosis showed proctitis with monocytic infiltration in two patients cured with the CMP-free diet; after 1 month on this diet, they were completely normal. We conclude that constipation in infants may have an allergic pathogenesis."
40c. Iacono G et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med. 1998 Oct 15;339(16):1100-4. PMID: 9770556
BACKGROUND: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. METHODS: We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for two weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. RESULTS: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cow's milk had a response. In all 44 children with a response, the response was confirmed with a double-blind challenge with cow's milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P=0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P<0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P=0.008), and signs of hypersensitivity, such as specific IgE antibodies to cow's-milk antigens (31 of 44 vs. 4 of 21, P<0.001). CONCLUSIONS: In young children, chronic constipation can be a manifestation of intolerance of cow's milk.
41. Arnold GL et al. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord 2003 33(4):449-54. PMID: 12959424
"No amino acid profile specific to autism was identified. However, children with autism had more essential amino acid deficiencies consistent with poor protein nutrition than an age/gender matched control group. There was a trend for children with autism who were on restricted diets to have an increased prevalence of essential amino acid deficiencies and lower plasma levels of essential acids including the neurotransmitter precursors tyrosine and tryptophan than both controls and children with autism on unrestricted diets."
42. Chauhan V et al. Alteration in amino-glycerophospholipids levels in the plasma of children with autism: a potential biochemical diagnostic marker. Life Sci 2004 Feb 13;74(13):1635-43. PMID: 14738907
"the levels of AGP [amino-glycerophospholipids] were found to be significantly increased in the plasma of children with autism as compared to their non-autistic normal siblings."
43. Knivsber AM et al. Reports on dietary intervention in autistic disorders. Nutr Neurosci. 2001;4(1):25-37. PMID: 11842874
"…Gluten and/or casein free diet has been implemented to reduce autistic behaviour, in addition to special education, since early in the eighties. Over the last twelve years various studies on this dietary intervention have been published in addition to anecdotal, parental reports. The scientific studies include both groups of participants as well as single cases, and beneficial results are reported in all, but one study. While some studies are based on urinary peptide abnormalities, others are not. The reported results are, however, more or less identical; reduction of autistic behaviour, increased social and communicative skills, and reappearance of autistic traits after the diet has been broken."
44. Karyn Seroussi -- Dietary Intervention for Autism Defeat Autism Now! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/KarynSeroussi.htm
45. ARI's Parent Ratings Data
Parent Ratings for Autism HTML
Parent Ratings for Autism PDF
Parent Ratings for Aspergers HTML
Parent Ratings for Aspergers PDF
46: Wakefield AJ et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 28;351(9103):637-41. PMID: 9500320
47: Ashwood P et al. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003 Nov;23(6):504-17. PMID: 15031638
"At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet.The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases."
48: Wakefield AJ. Enterocolitis, autism and measles virus. Mol Psychiatry. 2002;7 Suppl 2:S44-6. PMID: 12142948
49: Wakefield AJ. The gut-brain axis in childhood developmental disorders. J Pediatr Gastroenterol Nutr. 2002 May-Jun;34 Suppl 1:S14-7. PMID: 12082381
50. Binstock T. Anterior insular cortex: linking intestinal pathology and brain function in autism-spectrum subgroups. Med Hypotheses 2001 57(6):714-7. PMID: 11918432
"Numerous parents and some physicians report that an autistic child's attention and language improve in response to treatments which eliminate certain dietary antigens and/or which improve intestinal health. For at least some autism-spectrum children, the link between intestinal pathology, attention, and language may derive from shared neuroanatomic pathways within the anterior insular cortex (aIC); from a neurotrophic virus such as herpes simplex (HSV) migrating within afferents to the insular cortex; and/or from synaptic exhaustion in the aIC as induced by chronically inappropriate neuronal activity in the enteric nervous system and/or its vagal efferents."
51: Torrente F et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375-82, 334.
PMID: 11986981
"Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion."
52. Uhlmann V et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Mol Pathol. 2002 Apr;55(2):84-90. PMID: 11950955
"AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis… RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder."
53. Wakefield AJ et al. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.Aliment Pharmacol Ther 2002 16(4):663-74. PMID 11929383
54. Furlano RI et al. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001 Mar;138(3):366-72. PMID: 11241044
"OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism."
55. O'Leary JJ et al. Measles virus and autism. Lancet. 2000 Aug 26;356(9231):772. PMID: 11085720
56. Wakefield AJ et al. Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95. PMID: 11007230
"OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders."
60. Wakefield AJ, Montgomery SM. Autism, viral infection and measles-mumps-rubella vaccination. Isr Med Assoc J. 1999 Nov;1(3):183-7. PMID: 10731332
61. Wakefield AJ. MMR vaccination and autism. Lancet. 1999 Sep 11;354(9182):949-50. PMID: 10489978
62a. Horvath K et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999 Nov;135(5):559-63. PMID: 10547242
"OBJECTIVES: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. RESULTS: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function… CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients…"
62b. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002 Jun;4(3):251-8. PMID: 12010627
63. Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002 Oct;14(5):583-7. PMID: 12352252
"High prevalence of histologic abnormalities in the esophagus, stomach, small intestine and colon, and dysfunction of liver conjugation capacity and intestinal permeability were reported. Three surveys conducted in the United States described high prevalence of gastrointestinal symptoms in children with autistic disorder. Treatment of the digestive problems may have positive effects on their behavior."
64. Quigley EM, Hurley D. Autism and the gastrointestinal tract. Am J Gastroenterol. 2000 Sep;95(9):2154-6. PMID: 11007210
65. Tim Buie, M.D. Presentation at 2003 Defeat Autism Now!, Philadelphia.
http://64.202.182.52/powerpoint/dan2003/TimothyBuie.htm
MV in PBMCs, as variant SSPE
66. Kawashima H et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000 Apr;45(4):723-9. PMID 10759242
"One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation."
67. Jeff Bradstreet, M.D. A Case-control Study of Mercury Burden in Children with Autistic Disorders and Measles Virus Genomic RNA in Cerebrospinal Fluid in Children with Regressive Autism. IOM presentation, Feb 9, 2004.
Slides: http://www.iom.edu/view.asp?id=18578
Audio: http://www.iom.edu/view.asp?id=19130
68. 48a: Valsamakis A et al. Altered virulence of vaccine strains of measles virus after prolonged replication in human tissue. J Virol. 1999 73(10): 8791-7. PMID 10482633
http://jvi.asm.org/cgi/reprint/73/10/8791.pdf
69. Binstock T. Intra-monocyte pathogens delineate autism subgroups. Med Hypotheses. 2001 Apr;56(4):523-31. PMID 11339860
70. Garg RK. Subacute sclerosing panencephalitis.Postgrad Med J. 2002 Feb;78(916):63-70. PMID 11807185.
71. Neuroprogressive disease of post-infectious origin: a review of a resurging subacute sclerosing panencephalitis (SSPE). Ment Retard Dev Disabil Res Rev. 2001;7(3):217-25. PMID: 11553938
72. Gascon GG. Subacute sclerosing panencephalitis. Semin Pediatr Neurol. 1996 Dec;3(4):260-9. PMID: 8969008
MMR additional miscellany
73. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 01. PMID: 14976450
"These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile."
74. Vijendra K. Singh, Ph.D. Autism, Vaccines, and Immune Reactions. IOM presentation, Feb 9, 2004.
Audio only: http://www.iom.edu/view.asp?id=19132
75. Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr Neurol. 2003 Apr;28(4):292-4. PMID: 12849883
"Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed that the antibody was directed against a protein of approximately 74 kd molecular weight. The antibody to this antigen was found in 83% of autistic children but not in normal children or siblings of autistic children. Thus autistic children have a hyperimmune response to measles virus, which in the absence of a wild type of measles infection might be a sign of an abnormal immune reaction to the vaccine strain or virus reactivation."
76. Singh VK et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64. PMID 12145534
"Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism."
77. Singh VK et al. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998 89(1):105-8. PMID: 9756729
"Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism."
vMV, MV & immunity
78. Hussey GD et al. The effect of Edmonston-Zagreb and Schwarz measles vaccines on immune response in infants. J Infect Dis. 1996 Jun; 173(6): 1320-6 PMID: 8648203
The effects of measles immunization on immune responses in infants and the roles of vaccine strain and age of immunization are not known. Eighty-eight children were immunized at 6 or 9 months of age with the Edmonston-Zagreb (EZ) or Schwarz (SW6, SW9) strain of measles vaccine… Therefore, measles immunization resulted in suppression of lymphoproliferation, which was most evident in infants with the highest antibody responses and most immune activation."
79. Auwaerter PG et al. Changes within T cell receptor V beta subsets in infants following measles vaccination. John Hopkins University School of Medicine, Baltimore, MD 21287, USA. Clin Immunol Immunopathol 1996 79(2): 163-70. PMID: 8620622
"Measles produces immune suppression which contributes to an increased susceptibility to other infections. These data suggest that [vaccinal and wild-type] measles virus may affect immune responses in part by altering the T cell receptor repertoire."
80. Schneider-Schaulies S, ter Meulen V. Triggering of and interference with immune activation: interactions of measles virus with monocytes and dendritic cells. Viral Immunol. 2002;15(3):417-28. PMID: 12479392
81. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med 1997;186:813-23
82. Sonoda S, Nakayama T. Detection of measles virus genome in lymphocytes from asymptomatic healthy children. J Med Virol 2001 65(2):381-7 PMID: 11536248
"In 83 individuals immunized with measles vaccine, the vaccine strain genome was detected in 10 (71.4%) of 14 recipients whose PBMC were obtained within 2 months of vaccination."
83. Valsamakis A et al. Strains of measles vaccine differ in their ability to replicate in an damage human thymus. J Infect Dis. 2001 Feb 1; 183(3): 498-502. Johns Hopkins University, Baltimore, Maryland, USA. PMID: 11133383
[Question: How would the thymic-damage findings be exacerbated if tested tissues were selected to represent humans with excessively increased susceptibility, eg, an infant with persisting colic and/or persisting otitis?]
MV & Vitamin A
84. Yalcin SS et al. The effect of live measles vaccines on serum vitamin A levels in healthy children. Acta Paediatr Jpn. 1998 Aug; 40(4): 345-9. PMID: 9745778
"Serum retinol levels have been shown to be depressed during measles infection. This study aims to demonstrate whether there is any decrease in serum vitamin A level following immunization with live viral vaccine and its relation with vaccine seroconversion in children with measles. Since many children receive measles vaccine alone or in combination with measles-mumps-rubella vaccine, we studied serum vitamin A levels and antibody levels in healthy, well-nourished children before and after immunization with monovalent and combined live attenuated measles vaccine… CONCLUSION: Serum vitamin A levels are reduced following vaccination with monovalent and combined live attenuated measles vaccines."
85. Vitamin A administered with measles vaccine to nine-month-old infants does not reduce vaccine immunogenicity. J Nutr. 1999 Aug; 129(8): 1569-73. PMID 10419992
http://www.nutrition.org/cgi/reprint/129/8/1569.pdf
"Among malnourished infants, the geometric mean titer was significantly greater in the vitamin A group compared to the placebo group (ratio of geometric means, 1.57; 95% confidence interval, 1. 18-2.0), but seroconversion rates did not differ."
[Comment: note the theoretical implication that malourished children may have lower cell-mediated immunity and thus generate increased antibody immunity. This is consistent with immunity lab-data in many autistic children.]
86. Yalcin SS, Yurdakok K. Sex-specific differences in serum vitamin A values after measles immunization. Pediatr Infect Dis J. 1999 Aug; 18(8): 747-8. PMID 10462357
87. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc 1999 58(3): 719-27. PMID 10604208
"…vitamin A and related retinoids play a major role in immunity, including expression of mucins and keratins, lymphopoiesis, apoptosis, cytokine expression, production of antibody, and the function of neutrophils, natural killer cells, monocytes or macrophages, T lymphocytes and B lymphocytes. Recent clinical trials suggest that vitamin A supplementation reduces morbidity and mortality in different infectious diseases, such as measles, diarrhoeal disease, measles-related pneumonia, human immunodeficiency virus infection and malaria. Immune responses vary considerably during different infections, and the available data suggest that the modulation of immune function by vitamin A may also vary widely, depending on the type of infection and immune responses involved."
88. Molina EL, Patel JA. A to Z: vitamin A and zinc, the miracle duo. Indian J Pediatr. 1996 63(4): 427-31. PMID 10832460
"Dietary micronutrients such as vitamins and trace minerals are known modulators of host immune responses against common pathogens. In this respect, vitamin A and zinc have recently received increased attention. Several in vivo and in vitro studies suggest that vitamin A may be a critical player in the mucosal immune responses in the respiratory and gastrointestinal tracts, particularly in undernourished children. The effect may be mediated primarily by stabilization of the membrane of mucosal epithelial cells, as well as enhanced leukocyte functions. The beneficial effect of vitamin A therapy in reducing measles-associated morbidity and mortality suggests its crucial role in defenses against viral pathogens. Zinc is also known affect leukocyte functions such as phagocytosis and T-lymphocyte-mediated immune responses… Dietary supplementation or therapeutic treatment with vitamin A and zinc may be a cheap yet effective means of preventing or treating infections in highly susceptible populations. Additional studies, however, are required to better define the types of pathogens and the specific human populations that may benefit from such therapy."
88b. Chandra RK, Wadhwa M. Nutritional modulation of intestinal mucosal immunity. Immunol Invest. 1989 Jan-May;18(1-4):119-26. PMID: 2659508
"Protein-energy malnutrition results in an increased risk of gastrointestinal infection. This can be attributed in part to impaired immune responses. Cell-mediated immunity is decreased as judged by reduced number and function of thymus-dependent lymphocytes, impaired delayed cutaneous hypersensitivity reactions, and decreased production of lymphokines. Concentration of secretory IgA is reduced and there are fewer intraepithelial lymphocytes. Antibody responses following viral vaccine administration are reduced and there is decrease in natural killer cell activity. In addition, the number of bacteria binding to epithelial cells is increased. These changes are observed also in certain selected nutrient deficiencies, such as that of vitamin A. It is suggested that impaired systemic and mucosal immunity contributes to the increased frequency and severity of intestinal infections seen in undernourished individuals."
88c. Lie C et al. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. Eur J Clin Nutr. 1993 Feb;47(2):88-96. PMID: 8436094
"One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year."
88d. Sarkar J et al. Vitamin A is required for regulation of polymeric immunoglobulin receptor (pIgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cell line. J Nutr. 1998 Jul;128(7):1063-9. PMID: 9649586
"The secretory immunoglobulin A (IgA) antibody response to infections of mucosal surfaces requires transport of IgA from the basal to apical surface of mucosal epithelial cells by a specific transport protein, the polymeric immunoglobulin receptor (pIgR). We have tested the hypothesis that the vitamin A metabolite all-trans retinoic acid (RA) is required for the regulation of pIgR expression by the cytokines interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in HT-29 cells… These data indicate that RA strongly interacts with IL-4 and IFN-gamma to regulate pIgR expression in HT-29 cells, suggesting that vitamin A may be required for proper in vivo regulation of IgA transport in response to mucosal infections."
88e. Nikawa T et al. Vitamin A prevents the decline in immunoglobulin A and Th2 cytokine levels in small intestinal mucosa of protein-malnourished mice. J Nutr 1999 129(5):934-41. PMID: 10222382
"These results suggest that large oral supplements of vitamin A may preserve mucosal IgA level during protein malnutrition, possibly by stimulating Th2 cytokine production and thereby, inducing resistance against infection."
88f. Aukrust P et al. pal.aukrust@klinmed.uio.no Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses. Eur J Clin Invest. 2000 30(3):252-9. PMID: 10692003
"BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI… CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.
88g. Bjersing JL et al. jan.bjersing@immuno.gu.se Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin Exp Immunol. 2002 Dec;130(3):404-8. PMID: 12452829
"Child mortality in diarrhoeal disease is increased significantly by vitamin A deficiency in poor countries. The pathological mechanisms are not known in detail. However, in this paper we report that vitamin A-deficient Wistar rats had much reduced IgA+ plasma cells in the ileal lamina propria (eightfold reduction from 470 cells/mm(2), P = 0.009), as well as a prominent reduction of CD4+ cells in the parafollicular regions of ileal Peyer's patches (reduction from 7200 to 105 cells/mm(2), P = 0.009). IL-2Ralpha-chain (CD25) positive lymphocytes in the ileal Peyer's patches were also reduced significantly in vitamin A deficiency (from 1400 to 300 cells/mm(2), P = 0.009). The density of CD8 cells tended to be increased relative to the control animals (from 5100 to 6000 cells/mm(2), not statistically significant). In conclusion, the marked decrease of lamina propria IgA+ plasma cells may be one cause of the high diarrhoeal mortality in vitamin A deficiency. This, in turn, appears to be related to reduced numbers of activated or regulatory CD4+ T cells in Peyer's patches.
88h. Kim JY, Chung BH. Effects of combination dietary conjugated linoleic acid with vitamin A (retinol) and selenium on the response of the immunoglobulin production in mice. J Vet Sci. 2003 Apr;4(1):103-8. PMID: 12819373
"The dietary effect of conjugated linoleic acid (CLA) on the response of the immunoglobulin (serum and tissue) production in Balb/C mice was examined at three doses: 0 %(control), 0.5% and 1.5%. The combination effects of CLA with vitamin ADE or selenium also were investigated. CLA at 0.5% increased serum immunoglobulin A, G, mesenteric lymph node (MHN) and gut luminal IgA (secretory IgA) levels. However, 1.5% CLA decreased SIgG slightly. CLA both alone and combined with vitamin ADE and selenium did not affect serum IgE. The levels of immunoglobulin concentration in the 0.5% CLA group were higher than those in the 1.5% CLA group. The level of serum IgG in 1.5% CLA combined with selenium was maintained at the same level as that of control. It is considered that overdoses of CLA (1.5%) even depressed the production of immunoglobulin but selenium and/or vitamin inhibited this activity to a certain extent.In this study, dietary CLA increased immunoglobulin production in a dose-dependent manner. Vitamin ADE and Selenium combined with CLA also increased the immunoglobulin production response except serum IgE.
89. D'Souza RM, D'Souza R. Vitamin A for preventing secondary infections in children with measles—a systematic review. J Trop Pediatr. 2002 48(2):72-7. PMID 12022432
90. D'Souza RM, D'Souza R. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2002;(1):CD001479. PMID 11869601
"REVIEWER'S CONCLUSIONS: Although we did not find evidence that a single dose of 200,000 IU of vitamin A per day was associated with reduced mortality among children with measles, there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality. The effect was greater in children under the age of two years."
91. Madhulika et al. Vitamin A supplementation in post-measles complications. J Trop Pediatr. 1994 Oct;40(5):305-7. PMID 7807628.
The case fatality rate was 16 per cent in those who received VIT.A, while the same was 32 per cent in those who did not receive Vit.A (P < 0.02)."
92. Hussey GD, Klein M. Routine high-dose vitamin A therapy for children hospitalized with measles. J Trop Pediatr. 1993 39(6):342-5. PMID 8133555
Measles is without specific therapy and remains important globally as a cause of childhood death. In controlled studies, high-dose vitamin A therapy (Hi-VAT)—with 400,000 IU vitamin A--has been demonstrated to markedly reduce measles-associated morbidity and mortality."
93. Butler JC et al. Measles severity and serum retinol (vitamin A) concentration among children in the United States. Pediatrics. 1993 Jun;91(6):1176-81. PMID 8502524
94. Bluhm DP, Summers RS. Plasma vitamin A levels in measles and malnourished pediatric patients and their implications in therapeutics. J Trop Pediatr 1993 39(3):179-82. PMID 8326539
This study has shown that there is a high incidence of baseline hyporetinaemia in these patients. The mean retinol plasma levels return to within normal limits after 8 days of either routine treatment or vitamin A supplementation."
95. Ogaro FO et al. Effect of vitamin A on diarrhoeal and respiratory complications of measles. Trop Geogr Med. 1993;45(6):283-6. PMID 8116059
"These findings, along with those from three other trials in Africa, suggest that high dose vitamin A reduces the severity of complications during measles."
96. Coutsoudis A et al. Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J. 1992 11(3):203-9. PMID 1565535
These findings reinforce results from animal studies that show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation."
97. Frieden TR et al. Vitamin A levels and severity of measles. New York City. Am J Dis Child. 1992 Feb;146(2):182-6. PMID 1285727
Recent studies show that vitamin A levels decrease during measles and that vitamin A therapy can improve measles outcome in children in the developing world. Vitamin A levels of children with measles have not been studied in developed countries. We therefore measured vitamin A levels in 89 children with measles younger than 2 years and in a reference group in New York City, NY. Vitamin A levels in children with measles ranged from 0.42 to 3.0 mumol/L; 20 (22%) were low. Children with low levels were more likely to have fever at a temperature of 40 degrees C or higher (68% vs 44%), to have fever for 7 days or more (54% vs 23%), and to be hospitalized (55% vs 30%). Children with low vitamin A levels had lower measles-specific antibody levels. No child in the reference group had a low vitamin A level. Our data show that many children younger than 2 years in New York City have low vitamin A levels when ill with measles, and that such children seem to have lower measles-specific antibody levels and increased morbidity. Clinicians may wish to consider vitamin A therapy for children younger than 2 years with severe measles…"
MV in PBMCs, as variant SSPE
66. Kawashima H et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000 Apr;45(4):723-9. PMID 10759242
"One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation."
67. Jeff Bradstreet, M.D. A Case-control Study of Mercury Burden in Children with Autistic Disorders and Measles Virus Genomic RNA in Cerebrospinal Fluid in Children with Regressive Autism. IOM presentation, Feb 9, 2004.
Slides: http://www.iom.edu/view.asp?id=18578
Audio: http://www.iom.edu/view.asp?id=19130
68. 48a: Valsamakis A et al. Altered virulence of vaccine strains of measles virus after prolonged replication in human tissue. J Virol. 1999 73(10): 8791-7. PMID 10482633
http://jvi.asm.org/cgi/reprint/73/10/8791.pdf
69. Binstock T. Intra-monocyte pathogens delineate autism subgroups. Med Hypotheses. 2001 Apr;56(4):523-31. PMID 11339860
70. Garg RK. Subacute sclerosing panencephalitis.Postgrad Med J. 2002 Feb;78(916):63-70. PMID 11807185.
71. Neuroprogressive disease of post-infectious origin: a review of a resurging subacute sclerosing panencephalitis (SSPE). Ment Retard Dev Disabil Res Rev. 2001;7(3):217-25. PMID: 11553938
72. Gascon GG. Subacute sclerosing panencephalitis. Semin Pediatr Neurol. 1996 Dec;3(4):260-9. PMID: 8969008
MMR additional miscellany
73. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 01. PMID: 14976450
"These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile."
74. Vijendra K. Singh, Ph.D. Autism, Vaccines, and Immune Reactions. IOM presentation, Feb 9, 2004.
Audio only: http://www.iom.edu/view.asp?id=19132
75. Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr Neurol. 2003 Apr;28(4):292-4. PMID: 12849883
"Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed that the antibody was directed against a protein of approximately 74 kd molecular weight. The antibody to this antigen was found in 83% of autistic children but not in normal children or siblings of autistic children. Thus autistic children have a hyperimmune response to measles virus, which in the absence of a wild type of measles infection might be a sign of an abnormal immune reaction to the vaccine strain or virus reactivation."
76. Singh VK et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64. PMID 12145534
"Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism."
77. Singh VK et al. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998 89(1):105-8. PMID: 9756729
"Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism."
vMV, MV & immunity
78. Hussey GD et al. The effect of Edmonston-Zagreb and Schwarz measles vaccines on immune response in infants. J Infect Dis. 1996 Jun; 173(6): 1320-6 PMID: 8648203
The effects of measles immunization on immune responses in infants and the roles of vaccine strain and age of immunization are not known. Eighty-eight children were immunized at 6 or 9 months of age with the Edmonston-Zagreb (EZ) or Schwarz (SW6, SW9) strain of measles vaccine… Therefore, measles immunization resulted in suppression of lymphoproliferation, which was most evident in infants with the highest antibody responses and most immune activation."
79. Auwaerter PG et al. Changes within T cell receptor V beta subsets in infants following measles vaccination. John Hopkins University School of Medicine, Baltimore, MD 21287, USA. Clin Immunol Immunopathol 1996 79(2): 163-70. PMID: 8620622
"Measles produces immune suppression which contributes to an increased susceptibility to other infections. These data suggest that [vaccinal and wild-type] measles virus may affect immune responses in part by altering the T cell receptor repertoire."
80. Schneider-Schaulies S, ter Meulen V. Triggering of and interference with immune activation: interactions of measles virus with monocytes and dendritic cells. Viral Immunol. 2002;15(3):417-28. PMID: 12479392
81. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med 1997;186:813-23
82. Sonoda S, Nakayama T. Detection of measles virus genome in lymphocytes from asymptomatic healthy children. J Med Virol 2001 65(2):381-7 PMID: 11536248
"In 83 individuals immunized with measles vaccine, the vaccine strain genome was detected in 10 (71.4%) of 14 recipients whose PBMC were obtained within 2 months of vaccination."
83. Valsamakis A et al. Strains of measles vaccine differ in their ability to replicate in an damage human thymus. J Infect Dis. 2001 Feb 1; 183(3): 498-502. Johns Hopkins University, Baltimore, Maryland, USA. PMID: 11133383
[Question: How would the thymic-damage findings be exacerbated if tested tissues were selected to represent humans with excessively increased susceptibility, eg, an infant with persisting colic and/or persisting otitis?]
MV & Vitamin A
84. Yalcin SS et al. The effect of live measles vaccines on serum vitamin A levels in healthy children. Acta Paediatr Jpn. 1998 Aug; 40(4): 345-9. PMID: 9745778
"Serum retinol levels have been shown to be depressed during measles infection. This study aims to demonstrate whether there is any decrease in serum vitamin A level following immunization with live viral vaccine and its relation with vaccine seroconversion in children with measles. Since many children receive measles vaccine alone or in combination with measles-mumps-rubella vaccine, we studied serum vitamin A levels and antibody levels in healthy, well-nourished children before and after immunization with monovalent and combined live attenuated measles vaccine… CONCLUSION: Serum vitamin A levels are reduced following vaccination with monovalent and combined live attenuated measles vaccines."
85. Vitamin A administered with measles vaccine to nine-month-old infants does not reduce vaccine immunogenicity. J Nutr. 1999 Aug; 129(8): 1569-73. PMID 10419992
http://www.nutrition.org/cgi/reprint/129/8/1569.pdf
"Among malnourished infants, the geometric mean titer was significantly greater in the vitamin A group compared to the placebo group (ratio of geometric means, 1.57; 95% confidence interval, 1. 18-2.0), but seroconversion rates did not differ."
[Comment: note the theoretical implication that malourished children may have lower cell-mediated immunity and thus generate increased antibody immunity. This is consistent with immunity lab-data in many autistic children.]
86. Yalcin SS, Yurdakok K. Sex-specific differences in serum vitamin A values after measles immunization. Pediatr Infect Dis J. 1999 Aug; 18(8): 747-8. PMID 10462357
87. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc 1999 58(3): 719-27. PMID 10604208
"…vitamin A and related retinoids play a major role in immunity, including expression of mucins and keratins, lymphopoiesis, apoptosis, cytokine expression, production of antibody, and the function of neutrophils, natural killer cells, monocytes or macrophages, T lymphocytes and B lymphocytes. Recent clinical trials suggest that vitamin A supplementation reduces morbidity and mortality in different infectious diseases, such as measles, diarrhoeal disease, measles-related pneumonia, human immunodeficiency virus infection and malaria. Immune responses vary considerably during different infections, and the available data suggest that the modulation of immune function by vitamin A may also vary widely, depending on the type of infection and immune responses involved."
88. Molina EL, Patel JA. A to Z: vitamin A and zinc, the miracle duo. Indian J Pediatr. 1996 63(4): 427-31. PMID 10832460
"Dietary micronutrients such as vitamins and trace minerals are known modulators of host immune responses against common pathogens. In this respect, vitamin A and zinc have recently received increased attention. Several in vivo and in vitro studies suggest that vitamin A may be a critical player in the mucosal immune responses in the respiratory and gastrointestinal tracts, particularly in undernourished children. The effect may be mediated primarily by stabilization of the membrane of mucosal epithelial cells, as well as enhanced leukocyte functions. The beneficial effect of vitamin A therapy in reducing measles-associated morbidity and mortality suggests its crucial role in defenses against viral pathogens. Zinc is also known affect leukocyte functions such as phagocytosis and T-lymphocyte-mediated immune responses… Dietary supplementation or therapeutic treatment with vitamin A and zinc may be a cheap yet effective means of preventing or treating infections in highly susceptible populations. Additional studies, however, are required to better define the types of pathogens and the specific human populations that may benefit from such therapy."
88b. Chandra RK, Wadhwa M. Nutritional modulation of intestinal mucosal immunity. Immunol Invest. 1989 Jan-May;18(1-4):119-26. PMID: 2659508
"Protein-energy malnutrition results in an increased risk of gastrointestinal infection. This can be attributed in part to impaired immune responses. Cell-mediated immunity is decreased as judged by reduced number and function of thymus-dependent lymphocytes, impaired delayed cutaneous hypersensitivity reactions, and decreased production of lymphokines. Concentration of secretory IgA is reduced and there are fewer intraepithelial lymphocytes. Antibody responses following viral vaccine administration are reduced and there is decrease in natural killer cell activity. In addition, the number of bacteria binding to epithelial cells is increased. These changes are observed also in certain selected nutrient deficiencies, such as that of vitamin A. It is suggested that impaired systemic and mucosal immunity contributes to the increased frequency and severity of intestinal infections seen in undernourished individuals."
88c. Lie C et al. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. Eur J Clin Nutr. 1993 Feb;47(2):88-96. PMID: 8436094
"One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year."
88d. Sarkar J et al. Vitamin A is required for regulation of polymeric immunoglobulin receptor (pIgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cell line. J Nutr. 1998 Jul;128(7):1063-9. PMID: 9649586
"The secretory immunoglobulin A (IgA) antibody response to infections of mucosal surfaces requires transport of IgA from the basal to apical surface of mucosal epithelial cells by a specific transport protein, the polymeric immunoglobulin receptor (pIgR). We have tested the hypothesis that the vitamin A metabolite all-trans retinoic acid (RA) is required for the regulation of pIgR expression by the cytokines interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in HT-29 cells… These data indicate that RA strongly interacts with IL-4 and IFN-gamma to regulate pIgR expression in HT-29 cells, suggesting that vitamin A may be required for proper in vivo regulation of IgA transport in response to mucosal infections."
88e. Nikawa T et al. Vitamin A prevents the decline in immunoglobulin A and Th2 cytokine levels in small intestinal mucosa of protein-malnourished mice. J Nutr 1999 129(5):934-41. PMID: 10222382
"These results suggest that large oral supplements of vitamin A may preserve mucosal IgA level during protein malnutrition, possibly by stimulating Th2 cytokine production and thereby, inducing resistance against infection."
88f. Aukrust P et al. pal.aukrust@klinmed.uio.no Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses. Eur J Clin Invest. 2000 30(3):252-9. PMID: 10692003
"BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI… CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.
88g. Bjersing JL et al. jan.bjersing@immuno.gu.se Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin Exp Immunol. 2002 Dec;130(3):404-8. PMID: 12452829
"Child mortality in diarrhoeal disease is increased significantly by vitamin A deficiency in poor countries. The pathological mechanisms are not known in detail. However, in this paper we report that vitamin A-deficient Wistar rats had much reduced IgA+ plasma cells in the ileal lamina propria (eightfold reduction from 470 cells/mm(2), P = 0.009), as well as a prominent reduction of CD4+ cells in the parafollicular regions of ileal Peyer's patches (reduction from 7200 to 105 cells/mm(2), P = 0.009). IL-2Ralpha-chain (CD25) positive lymphocytes in the ileal Peyer's patches were also reduced significantly in vitamin A deficiency (from 1400 to 300 cells/mm(2), P = 0.009). The density of CD8 cells tended to be increased relative to the control animals (from 5100 to 6000 cells/mm(2), not statistically significant). In conclusion, the marked decrease of lamina propria IgA+ plasma cells may be one cause of the high diarrhoeal mortality in vitamin A deficiency. This, in turn, appears to be related to reduced numbers of activated or regulatory CD4+ T cells in Peyer's patches.
88h. Kim JY, Chung BH. Effects of combination dietary conjugated linoleic acid with vitamin A (retinol) and selenium on the response of the immunoglobulin production in mice. J Vet Sci. 2003 Apr;4(1):103-8. PMID: 12819373
"The dietary effect of conjugated linoleic acid (CLA) on the response of the immunoglobulin (serum and tissue) production in Balb/C mice was examined at three doses: 0 %(control), 0.5% and 1.5%. The combination effects of CLA with vitamin ADE or selenium also were investigated. CLA at 0.5% increased serum immunoglobulin A, G, mesenteric lymph node (MHN) and gut luminal IgA (secretory IgA) levels. However, 1.5% CLA decreased SIgG slightly. CLA both alone and combined with vitamin ADE and selenium did not affect serum IgE. The levels of immunoglobulin concentration in the 0.5% CLA group were higher than those in the 1.5% CLA group. The level of serum IgG in 1.5% CLA combined with selenium was maintained at the same level as that of control. It is considered that overdoses of CLA (1.5%) even depressed the production of immunoglobulin but selenium and/or vitamin inhibited this activity to a certain extent.In this study, dietary CLA increased immunoglobulin production in a dose-dependent manner. Vitamin ADE and Selenium combined with CLA also increased the immunoglobulin production response except serum IgE.
89. D'Souza RM, D'Souza R. Vitamin A for preventing secondary infections in children with measles—a systematic review. J Trop Pediatr. 2002 48(2):72-7. PMID 12022432
90. D'Souza RM, D'Souza R. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2002;(1):CD001479. PMID 11869601
"REVIEWER'S CONCLUSIONS: Although we did not find evidence that a single dose of 200,000 IU of vitamin A per day was associated with reduced mortality among children with measles, there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality. The effect was greater in children under the age of two years."
91. Madhulika et al. Vitamin A supplementation in post-measles complications. J Trop Pediatr. 1994 Oct;40(5):305-7. PMID 7807628.
The case fatality rate was 16 per cent in those who received VIT.A, while the same was 32 per cent in those who did not receive Vit.A (P < 0.02)."
92. Hussey GD, Klein M. Routine high-dose vitamin A therapy for children hospitalized with measles. J Trop Pediatr. 1993 39(6):342-5. PMID 8133555
Measles is without specific therapy and remains important globally as a cause of childhood death. In controlled studies, high-dose vitamin A therapy (Hi-VAT)—with 400,000 IU vitamin A--has been demonstrated to markedly reduce measles-associated morbidity and mortality."
93. Butler JC et al. Measles severity and serum retinol (vitamin A) concentration among children in the United States. Pediatrics. 1993 Jun;91(6):1176-81. PMID 8502524
94. Bluhm DP, Summers RS. Plasma vitamin A levels in measles and malnourished pediatric patients and their implications in therapeutics. J Trop Pediatr 1993 39(3):179-82. PMID 8326539
This study has shown that there is a high incidence of baseline hyporetinaemia in these patients. The mean retinol plasma levels return to within normal limits after 8 days of either routine treatment or vitamin A supplementation."
95. Ogaro FO et al. Effect of vitamin A on diarrhoeal and respiratory complications of measles. Trop Geogr Med. 1993;45(6):283-6. PMID 8116059
"These findings, along with those from three other trials in Africa, suggest that high dose vitamin A reduces the severity of complications during measles."
96. Coutsoudis A et al. Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J. 1992 11(3):203-9. PMID 1565535
These findings reinforce results from animal studies that show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation."
97. Frieden TR et al. Vitamin A levels and severity of measles. New York City. Am J Dis Child. 1992 Feb;146(2):182-6. PMID 1285727
Recent studies show that vitamin A levels decrease during measles and that vitamin A therapy can improve measles outcome in children in the developing world. Vitamin A levels of children with measles have not been studied in developed countries. We therefore measured vitamin A levels in 89 children with measles younger than 2 years and in a reference group in New York City, NY. Vitamin A levels in children with measles ranged from 0.42 to 3.0 mumol/L; 20 (22%) were low. Children with low levels were more likely to have fever at a temperature of 40 degrees C or higher (68% vs 44%), to have fever for 7 days or more (54% vs 23%), and to be hospitalized (55% vs 30%). Children with low vitamin A levels had lower measles-specific antibody levels. No child in the reference group had a low vitamin A level. Our data show that many children younger than 2 years in New York City have low vitamin A levels when ill with measles, and that such children seem to have lower measles-specific antibody levels and increased morbidity. Clinicians may wish to consider vitamin A therapy for children younger than 2 years with severe measles…"
Viruses in autism
195. Ghaziuddin M et al. Autistic symptoms following herpes encephalitis. Eur Child Adolesc Psychiatry. 2002 Jun;11(3):142-6. PMID: 12369775
"Autism is a childhood onset neurodevelopmental disorder characterized by reciprocal social deficits, communication impairment, and rigid ritualistic interests, with the onset almost always before three years of age. Although the etiology of the disorder is strongly influenced by genes, environmental factors are also important. In this context, several reports have described its association with known medical conditions, including infections affecting the central nervous system. In this report, we describe an 11-year-old Asian youngster who developed the symptoms of autism following an episode of herpes encephalitis. In contrast to previous similar reports, imaging studies suggested a predominant involvement of the frontal lobes. At follow-up after three years, he continued to show the core deficits of autism. This case further supports the role of environmental factors, such as infections, in the etiology of autism, and suggests that in a minority of cases, autistic symptoms can develop in later childhood.
196. Gillberg IC. Autistic syndrome with onset at age 31 years: herpes encephalitis as a possible model for childhood autism. Dev Med Child Neurol. 1991 Oct;33(10):920-4. PMID: 1743418
197. DeLong GR et al. Acquired reversible autistic syndrome in acute encephalopathic illness in children. Arch Neurol. 1981 Mar;38(3):191-4. PMID: 6162440
"In seeking the neurologic substrate of the autistic syndrome of childhood, previous studies have implicated the medial temporal lobe or the ring of mesolimbic cortex located in the mesial frontal and temporal lobes. During an acute encephalopathic illness, a clinical picture developed in three children that was consistent with infantile autism. This development was reversible. It was differentiated from acquired epileptic aphasia, and the language disorder was differentiated aphasia. One child has rises in serum herpes simplex titers, and a computerized tomographic (CT) scan revealed an extensive lesion of the temporal lobes, predominantly on the left. The other two, with similar clinical syndromes, had normal CT scans, and no etiologic agent was defined. These cases are examples of an acquired and reversible autistic syndrome in childhood, emphasizing the clinical similarities to bilateral medial temporal lobe disease as described in man, including the Kluver-Bucy syndrome seen in postencephalitic as well as postsurgical states.
198. Gillberg C. Onset at age 14 of a typical autistic syndrome. A case report of a girl with herpes simplex encephalitis. J Autism Dev Disord. 1986 Sep;16(3):369-75. PMID: 3558293
199. Stubbs EG et al. Autism and congenital cytomegalovirus. J Autism Dev Disord. 1984 Jun;14(2):183-9. PMID: 6086566
200. Ivarsson SA et al. Autism as one of several disabilities in two children with congenital cytomegalovirus infection. Neuropediatrics. 1990 May;21(2):102-3. PMID: 2163029
201. McLachlan RS et al. Treatment of Rasmussen's syndrome with ganciclovir. Neurology. 1996 Oct;47(4):925-8. PMID: 8857720
"Since cytomegalovirus (CMV) has been implicated in the pathogenesis of Rasmussen's syndrome, we treated four patients with ganciclovir, a potent anti-CMV drug. A 7-year-old girl with seizures escalating to 60/day over 3 months despite triple antiepileptic drug therapy became seizure-free 5 days after initiation of treatment with no recurrence at 1.5 years follow-up. Focal neurologic signs, cognitive function, and the EEG returned to normal. Two patients treated 34 and 72 months after disease onset in association with epilepsy surgery had a reduction in seizures and one had no response. CMV genome was detected in the brains of two of the three patients in whom it was assessed. The response to antiviral therapy supports a viral etiology for chronic encephalitis of Rasmussen. If the disease is suspected, treatment with ganciclovir should be considered as early as possible.
202. Domachowske JB et al. Acute manifestations and neurologic sequelae of Epstein-Barr virus encephalitis in children. Pediatr Infect Dis J. 1996 Oct;15(10):871-5. PMID: 8895918
BACKGROUND: Complications of Epstein-Barr virus (EBV) infection are diverse and include a number of neurologic manifestations such as meningitis, meningoencephalitis, cerebellitis, cranial neuritis and others. In general encephalitis caused by EBV in pediatric patients has been considered a self-limited illness with few or no sequelae. METHODS: Charts were reviewed from all patients < 18 years of age admitted to or discharged from the State University of New York Health Science Center at Syracuse between 1982 and 1992 with a diagnosis of encephalitis or meningo- encephalitis. Eleven cases of EBV encephalitis diagnosed during a 10-year period were reviewed to characterize the clinical and laboratory findings in the acute setting and the extent of neurologic sequelae on follow-up. RESULTS: Acute neurologic manifestations were diverse and included combative behavior (55%), seizures (36%), headache (36%) and evidence of focal involvement (27%). Classic findings of infectious mononucleosis were noted infrequently; 18% each had pharyngitis, adenopathy, positive heterophile antibody tests or atypical lymphocytosis. Two patients (18%) had abnormal neuroimaging studies, one in the acute stage and the other at the time of follow-up. Seven patients (64%) had abnormal electroencephalograms (EEGs) in the acute setting; of these three had persistent abnormalities on follow-up. Forty percent developed persistent neurologic abnormalities including global impairment, perseverative autistic-like behavior and persistent left upper extremity paresis. CONCLUSIONS: Classic signs, symptoms and laboratory findings in infectious mononucleosis may be absent in Epstein-Barr virus encephalitis. Neurologic sequelae occur in a substantial number of patients.
203. Caruso JM et al. Persistent preceding focal neurologic deficits in children with chronic Epstein-Barr virus encephalitis. J Child Neurol. 2000 Dec;15(12):791-6. PMID: 11198493
"Epstein-Barr virus encephalitis is a self-limiting disease with few sequelae. Persistence of neurologic deficits prior to and after the acute illness has yet to be described in children. We describe five children with persistent cognitive and focal neurologic deficits due to chronic Epstein-Barr virus encephalitis with various T2-weighted magnetic resonance imaging abnormalities. Clinical features were a 9-year-old boy with aphasia and apraxia, an 11-year-old girl with impulsivity and inappropriate behavior, a 17-year-old boy with deterioration of cognitive skills and judgment, a 5-year-old boy with complex-partial seizures, and a 6-year-old girl with obsessive-compulsive behavior. All patients had elevated serum Epstein-Barr virus titers for acute infection, with cerebrospinal fluid polymerase chain reaction positive for Epstein-Barr virus in four patients. Three children were treated with methylprednisolone with minimal improvement without changes on magnetic resonance imaging. Epstein-Barr virus encephalitis can present with chronic and insidious neurologic symptoms and should be considered in the differential diagnosis of children with acute or chronic neurologic illness of unknown etiology."
Probiotics
204. Erdeve O et al. The probiotic effect of Saccharomyces boulardii in a pediatric age group. J Trop Pediatr. 2004 Aug;50(4):234-6. PMID: 15357564
"The aim of this study was to determine the efficacy of S. boulardii in diarrhea associated with commonly used antibiotics such as sulbactam-ampicillin (SAM) and azithromycin (AZT). Four hundred and sixty-six patients were assigned to four different groups as follows: group 1:117 patients receiving SAM alone; group 2:117 patients receiving SAM and S. boulardii, group 3:105 patients receiving AZT alone; group 4:127 patients receiving AZT and S. boulardii. Antibiotic-associated diarrhea was seen in 42 of the 222 patients (18.9 per cent) receiving an antibiotic without the probiotic, and in 14 of the 244 patients (5.7 per cent) who received both the probiotic and the antibiotic (p < 0.05). In the group receiving SAM where S. boulardii use was found to be significant, the use of S. boulardii decreased the diarrhea rate from 32.3 to 11.4 per cent in the 1-5 years age group (p < 0.05). This is a pioneering study investigating combined antibiotic and probiotic use in pediatric diarrhea patients."
205. Gill HS, Guarner F. Probiotics and human health: a clinical perspective. Postgrad Med J. 2004 Sep;80(947):516-26. PMID: 15356352
"There is unequivocal evidence that administration of probiotics could be effective in the treatment of acute infectious diarrhoea in children and the prevention of antibiotic associated diarrhoea and nosocomial/community acquired diarrhoea. Encouraging evidence is also emerging for the effectiveness of probiotics in the prevention and management of pouchitis and paediatric atopic diseases, and the prevention of postoperative infections. There is also strong evidence that certain probiotic strains are able to enhance immune function, especially in subjects with less than adequate immune function such as the elderly. Efficacy of probiotics in the prevention of traveller's diarrhoea, sepsis associated with severe acute pancreatitis, and cancers, the management of ulcerative colitis, and lowering of blood cholesterol remains unproven. In addition to firm evidence of efficacy (for a range of conditions), major gaps exist in our knowledge regarding the mechanisms by which probiotics modulate various physiological functions and the optimum dose, frequency, and duration of treatment for different probiotic strains."
206. Kruis W. Antibiotics and probiotics in inflammatory bowel disease. Aliment Pharmacol Ther. 2004 Oct;20 Suppl 4:75-8. PMID: 15352898
"Summary Treatment with antibiotics in inflammatory bowel disease has a long tradition and is widely used. The indications for antibiotic therapy are wide ranging, from specific situations such as abscesses or fistulae, to patients with severe disease (as an unspecific 'protective' measure), and to address the hypothesis that the enteric flora as a whole, or specific microorganisms such as mycobacteria, are involved in the pathogenesis of inflammatory bowel disease. The best-studied single antibiotic compound is metronidazole. However, overall, the scientific basis for the use of antibiotics is limited, which may reflect a lack of interest from sponsors within the pharmaceutical industry. Despite this weak evidence base, antibiotics are a globally established therapeutic tool in inflammatory bowel disease. Growing evidence from human and animal studies points towards a pivotal pathogenetic role of intestinal bacteria in inflammatory bowel disease. In view of these experimental findings, clinical trials have been undertaken to elucidate the therapeutic effects of probiotics in inflammatory bowel disease. Probiotics are viable nonpathogenic microorganisms which confer health benefits to the host by improving the microbial balance of the indigenous microflora. So far, of the many candidates, one specific strain (Escherichia coli Nissle 1917) and a mixture of eight different bacteria have demonstrated convincing therapeutic efficacy in controlled studies. Maintenance therapy in ulcerative colitis and prevention therapy, as well as the treatment of pouchitis, have emerged as areas in which probiotic therapy offers a valid therapeutic alternative to current treatments. Further investigations may detect additional clinically effective probiotics and other clinical indications."
207. Fedorak RN, Madsen KL. Probiotics and the management of inflammatory bowel disease. Inflamm Bowel Dis. 2004 May;10(3):286-99. PMID: 15290926
"The demonstration that immune and epithelial cells can discriminate between different microbial species has extended our understanding of the actions of probiotics beyond simple barrier and antimicrobial concepts. Several probiotic mechanisms of action, relative to inflammatory bowel disease, have been elucidated: (1) competitive exclusion, whereby probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium; (2) immunomodulation and/or stimulation of an immune response of gut-associated lymphoid and epithelial cells; (3) antimicrobial activity and suppression of pathogen growth; (4) enhancement of barrier function; and (5) induction of T cell apoptosis in the mucosal immune compartment. The unraveling of these mechanisms of action has led to new support for the use of probiotics in the management of clinical inflammatory bowel disease. Though level 1 evidence now supports the therapeutic use of probiotics in the treatment of postoperative pouchitis, only levels 2 and 3 evidence is currently available in support of the use of probiotics in the treatment of ulcerative colitis and Crohn's disease. Nevertheless, one significant and consistent finding has emerged during the course of research in the past year: not all probiotic bacteria have similar therapeutic effects. Rigorously designed, controlled clinical trials are vital to investigate the unresolved issues related to efficacy, dose, duration of use, single or multi-strain formulation, and the concomitant use of prebiotics, synbiotics, or antibiotics."
208. Nardone G, Rocco A. Probiotics: a potential target for the prevention and treatment of steatohepatitis. J Clin Gastroenterol. 2004 Jul;38(6 Suppl):S121-2. PMID: 15220676
"The accumulation of fat in hepatocytes with a necroinflammatory component-steatohepatitis-that may or may not have associated fibrosis is becoming a frequent lesion. Although steatohepatitis is currently recognized to be a leading cause of cryptogenic cirrhosis, the pathogenesis has not been fully elucidated. Among the various factors implicated, intestinal bacterial overgrowth may play a role. Indeed, various rat models of intestinal bacterial overgrowth have been associated with liver lesions similar to NASH, and bacterial overgrowth has been observed significantly more often in patients with NASH compared with control subjects. The authors discuss the relationship among intestinal bacterial overgrowth, steatohepatitis development, and probiotic treatment."
209. Saggioro A. Probiotics in the treatment of irritable bowel syndrome. J Clin Gastroenterol. 2004 Jul;38(6 Suppl):S104-6. PMID: 15220671
"Irritable Bowel Syndrome (IBS) may be diagnosed on the presence of symptoms, according to Rome II criteria and some studies have shown that abnormal colonic fermentation may be an important factor in the development of symptoms in some patients with IBS. Since the fermentations of substrates by the intestinal flora may play a key role in the use of probiotics in the treatment of IBS, fifty patients (24 males, 26 females), mean age 40 years (range = 26-64 years) with IBS, according to Rome II criteria, were enrolled into the study after informed consensus. Patients were randomly assigned to receive either the active preparation containing Lactobacillus Plantarum LP0 1 and Bifidocterium Breve BR0 both at a concentration of 5 x 10 CFU/ml, or placebo powder containing starch identical to the study product, for 4 weeks. To evaluate treatment efficacy two different scores were considered: Pain score in different abdominal locations after treatment decreased in probiotics group of 38% versus 18% (P < 0.05) of placebo group after 14 days and of 52% versus 11% (P < 0.001) after 28 days. The severity score of characteristic IBD symptoms significantly decreased in probiotic group versus placebo group after 14 days 49.6% versus 9.9% (P < 0.001) and these data were confirmed after 28 days (44.4% versus 8.5%, P < 0.001). In conclusion, short-term therapy with Lactobacillus PlantarumLP0 1 and Bifidocterium Breve BR0 may be considered a promising approach to the therapy for IBS."
210. Di Stefano M et al. Probiotics and functional abdominal bloating. J Clin Gastroenterol. 2004 Jul;38(6 Suppl):S102-3. PMID: 15220670
"Functional abdominal bloating is a condition dominated by a feeling of abdominal fullness or bloating and without sufficient criteria for another functional gastrointestinal disorder. The currently used therapeutic approaches aim to reduce the volume of intestinal gas, thus increasing intestinal gas elimination or reducing its production. Some promising results have been obtained by the use of prokinetics, such as tegaserod and Prostigmine, and by the use of nonabsorbable antibiotics, such as rifaximin. Another therapeutic approach is represented by the administration of probiotics to modify the composition of colonic flora and thus the production of intestinal gas. The authors recently studied the effect of LGG, which proved to be more effective than placebo in reducing the severity of symptoms."
211. Isolauri E. Dietary modification of atopic disease: Use of probiotics in the prevention of atopic dermatitis. Curr Allergy Asthma Rep. 2004 Jul;4(4):270-5. PMID: 15175140
"The increased prevalence of atopic diseases, atopic dermatitis, allergic rhinitis, and asthma has been described as an epidemic. New approaches in the fight against allergic diseases are called for, the target being the persistence of the atopic T helper 2-skewed immune responder pattern beyond infancy. Atopic dermatitis, the earliest of these conditions, might act as a portal for the development of IgE-mediated atopic manifestations. Abundant evidence implies that specific strains selected from the healthy gut microbiota exhibit powerful antipathogenic and anti-inflammatory capabilities, and several targets for the probiotic approach have emerged in atopic dermatitis: degradation/structural modification of enteral antigens, normalization of the properties of aberrant indigenous microbiota and of gut barrier functions, regulation of the secretion of inflammatory mediators, and promotion of the development of the immune system. Better understanding of the effects of different probiotic strains and deeper insight into the mechanisms of the heterogeneous manifestations of atopic disease are needed for the validation of specific strains carrying anti-allergic potential."
212. Cross ML. Immune-signalling by orally-delivered probiotic bacteria: effects on common mucosal immunoresponses and protection at distal mucosal sites. Int J Immunopathol Pharmacol. 2004 May-Aug;17(2):127-34. PMID: 15171813
"Probiotics--orally-delivered preparations of non-pathogenic bacterial cells--have been reported to increase anti-microbial protection in the gastrointestinal tract environment, and offer a safe and effective non-pharmaceutical means for combating infectious diseases and certain other pathologies. There is also an increasing body of evidence to suggest that immunostimulation by probiotic bacteria in the gut can enhance immune protection at distal mucosal sites, such as the urogenital and respiratory tracts. This review summarises the current information, from both clinical and animal model studies, of a role for orally-delivered probiotics in modulating mucosal immunoresponses and protection at distal sites. While it is clear that probiotics hold promise in this area, research that is targeted toward identifying the mechanism driving stimulation of the common mucosal immune system, as well as patterns of mucosal tissue homing by immunocytes following probiotic-mediated signalling in the gut, is strongly encouraged."
213. Drakes M et al. Bacterial probiotic modulation of dendritic cells. Infect Immun. 2004 Jun;72(6):3299-309 PMID: 15155633
"Intestinal dendritic cells are continually exposed to ingested microorganisms and high concentrations of endogenous bacterial flora. These cells can be activated by infectious agents and other stimuli to induce T-cell responses and to produce chemokines which recruit other cells to the local environment. Bacterial probiotics are of increasing use against intestinal disorders such as inflammatory bowel disease. They act as nonpathogenic stimuli within the gut to regain immunologic quiescence. This study was designed to determine the ability of a bacterial probiotic cocktail VSL#3 to alter cell surface antigen expression and cytokine production in bone marrow-derived dendritic cell-enriched populations. Cell surface phenotype was monitored by monoclonal fluorescent antibody staining, and cytokine levels were quantitated by enzyme-linked immunosorbent assay. High-dose probiotic upregulated the expression of C80, CD86, CD40, and major histocompatibility complex class II I-Ad. Neither B7-DC or B7RP-1 was augmented after low-dose probiotic or Lactobacillus casei treatment, but B7RP-1 showed increased expression on dendritic cells stimulated with the gram-negative bacterium Escherichia coli. Functional studies showed that probiotic did not enhance the ability of dendritic cells to induce allogeneic T-cell proliferation, as was observed for E. coli. Substantial enhancement of interleukin-10 release was observed in dendritic cell-enriched culture supernatants after 3 days of probiotic stimulation. These results demonstrate that probiotics possess the ability to modulate dendritic cell surface phenotype and cytokine release in granulocyte-macrophage colony-stimulating factor-stimulated bone marrow-derived dendritic cells. Regulation of dendritic cell cytokines by probiotics may contribute to the benefit of these molecules in treatment of intestinal diseases."
Immune impairments in autism
214. Warren RP et al. Brief report: immunoglobulin A deficiency in a subset of autistic subjects. J Autism Dev Disord. 1997 Apr;27(2):187-92. PMID: 9105969
215. Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol. 1996 Jul;67(2):97-102. PMID: 8765331
216. Immunogenetic studies in autism and related disorders.Mol Chem Neuropathol. 1996 May-Aug;28(1-3):77-81. PMID: 8871944
217. Elevated serotonin levels in autism: association with the major histocompatibility complex. Neuropsychobiology. 1996;34(2):72-5. PMID: 8904735
218. Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology. 1995;32(3):120-3. PMID: 8544967
219. DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology. 1995;31(2):53-7. PMID: 7760985
220. Decreased plasma concentrations of the C4B complement protein in autism. Arch Pediatr Adolesc Med. 1994 Feb;148(2):180-3. PMID: 8118537
221. Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol. 1991 Mar;83(3):438-40. PMID: 2004485
222. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry. 1987 May;26(3):333-5. PMID: 3597287
223. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986 Jun;16(2):189-97. PMID: 2941410
Methylcobalamin miscellany
225. Intestinal absorption and concurrent chemical changes of methylcobalamin. J Lab Clin Med. 1973 Apr;81(4):557-67. PMID: 4696188
226. Detection of malabsorption of vitamin B12 due to gastric or intestinal dysfunction. Semin Nucl Med. 1972 Jul;2(3):220-34. PMID: 4625601
227. Vitamin B 12 malabsorption in chronic pancreatic insufficiency. N Engl J Med 1971 Mar 25;284(12):627-32. PMID: 5547614
228. Complex of intrinsic factor and B12 in human ileum during vitamin B12 absorption. Am J Physiol. 1968 Apr;214(4):832-5. PMID: 5642944
229. The binding of methylcobalamin and vitamin-B 12 coenzyme. S Afr Med J. 1970 May 2;44(18):537-9. PMID: 5445924
230. Competition between bacteria and intrinsic factor for vitamin B 12: implications for vitamin B 12 malabsorption in intestinal bacterial overgrowth. Gastroenterology. 1972 Feb;62(2):255-60. PMID: 4629318
231. Effect of small intestinal bacteria on intrinsic factor and the vitamin B 12-intrinsic factor complex. Scand J Gastroenterol. 1971;6(8):707-13.
232. Correction of cobalamin malabsorption in pancreatic insufficiency with a cobalamin analogue that binds with high affinity to R protein but not to intrinsic factor. In vivo evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. J Clin Invest. 1978 Jun;61(6):1628-34. PMID: 659618
233. Absorption studies in patients with Crohn's disease and in patients with ulcerative colitis. Acta Med Scand. 1971 Nov;190(5):407-10. PMID: 5149268
234. Production of vitamin B 12 analogues in patients with small-bowel bacterial overgrowth. Ann Intern Med. 1977 Nov;87(5):546-51. PMID: 921081
Thus bacterial production of cobamides, both de novo and from ingested CN-Cbl
bound to intrinsic factor, occurs in humans with bacterial overgrowth states and results in a significant loss of vitamin B12 to the host."
[B12 lab result may indicate extreme high, a false positive in some cases]
235. Current concepts of cobalamin (vitamin B12) absorption and malabsorption. J Clin Gastroenterol. 1980 Sep;2(3):287-97. PMID: 7005313
236. The effect of intrinsic factor proteins on the methylating activity of CH3-B12 coenzyme. Bull Acad Pol Sci Biol. 1975;23(6):361-4. PMID: 1164687
237. James Neubrander, M.D. -- Biochemical Context and Clinical Use of Methyl B12 Defeat Autism Now! 2003 Philadelphia http://64.202.182.52/powerpoint/dan2003/Neubrander.htm
238. James Neubrander, M.D. -- Case presentation of Children with Autism Spectrum Disorder Defeat Autism Now! 2003 Philadelphia http://64.202.182.52/powerpoint/dan2003/JamesNeubrander.htm
239. James Neubrander, M.D. -- Biochemical Context And Clinical Use Of Vitamin B12. Defeat Autism Now! 2004, Washington, D.C.
240. Walsh WJ et al. Reduced violent behavior following biochemical therapy. Physiol Behav. 2004 Oct 15;82(5):835-9. Pfeiffer Treatment CenterWarrenville, IL 60555 PMID: 15451647
"Reduced violent behavior following biochemical therapy. We conducted an outcome study to measure the effectiveness of biochemical therapy for 207 consecutive patients presenting with a diagnosed behavior disorder. The treatment protocols were based on clinical evaluation and our past experience in the treatment of 8000 patients with behavior disorders at the Pfeiffer Treatment Center (PTC) over a 10-year period. Each test subject was screened for chemical imbalances previously found in high incidence in this population, including metal-metabolism disorders, methylation abnormalities, disordered pyrrole chemistry, heavy-metal overload, glucose dyscontrol, and malabsorption. The clinical procedure included a medical history, assay of 90 biochemical factors, and a physical examination. Standardized treatment protocols were applied for each imbalance that was identified. The frequencies of physical assaults and destructive episodes were determined using a standardized behavior scale before and after treatment, with follow-up ranging from 4 to 8 months. RESULTS: Seventy-six percent of the test subjects achieved compliance during the treatment period. The remaining 24% were reported to have discontinued the therapy. A reduced frequency of assaults was reported by 92% of the compliant assaultive patients, with 58% achieving elimination of the behavior. A total of 88% of compliant destructive patients exhibited a reduced frequency of destructive incidents and 53% achieved elimination of the behavior. Statistical significance was found for reduced frequency of assaults (t=7.74, p<0.001) and destructive incidents (t= 8.77, p<0.001). The results of this outcome study strongly suggest that individualized biochemical therapy may be efficacious in achieving behavioral improvements in this patient population.
Epileptiform pattern in autism
241: Nasr JT et al. The Electroencephalogram in Children with Developmental Dysphasia. Epilepsy Behav. 2001 Apr;2(2):115-118. PMID: 12609193
Speech and language delay is a common developmental or acquired disorder. It can be a feature of the autistic spectrum, and if regression of language coincides with epilepsy, the diagnosis of Landau-Kleffner syndrome is considered. Slow acquisition of language without regression is called developmental dysphasia. A retrospective review of clinical and electroencephalographic (including video electroencephalographic) data on 138 children with speech/language delay, seen in a year's time, is presented. The electroencephalogram (EEG) was abnormal in 61% of children with a history of language regression. The EEG was abnormal in
only 15% of children with developmental language disorder, most of whom also had clinical seizures. The difference between the two groups was highly significant (P = 0.004). Therefore obtaining an EEG in children with regression of language, especially if a history of clinical seizures is elicited, is indicated.
242. Wheless JW et al. Language dysfunction in epileptic conditions. Semin Pediatr Neurol. 2002 Sep;9(3):218-28. PMID: 12350043
Epilepsy may disrupt brain functions necessary for language development by its associated intellectual disabilities or directly as a consequence of the seizure disorder. Additionally, in recent years, there has been increasing recognition of the association of epileptiform electroencephalogram (EEG) abnormalities with language disorders and autism spectrum disorders. Any process that impairs language function has long-term consequences for academic, social, and occupational adjustments in children and adolescents with epilepsy. Furthermore, impairments in specific language abilities can impact memory and learning abilities. This article reviews interictal language function in children and adults with epilepsy; epilepsy surgery and language outcome; and language disorders associated with abnormal EEGs. The relationship between epilepsy and language function is complicated as the neuroanatomic circuits common to both overlap. We demonstrate how magnetoencephalography (MEG) offers the ability to analyze the relationship of language, EEG abnormalities, and epilepsy.
243. Hrdlicka M et al. Not EEG abnormalities but epilepsy is associated with autistic regression and mental functioning in childhood autism. Eur Child Adolesc Psychiatry. 2004 13(4):209-13.
The aim of the study was to investigate the potential association of epilepsy and EEG abnormalities with autistic regression and mental retardation. We examined a group of 77 autistic children (61 boys, 16 girls) with an average age of 9.1 +/- 5.3 years. Clinical interview, neurological examination focused on the evaluation of epilepsy, IQ testing, and 21-channel EEG (including night sleep EEG recording) were performed. Normal EEGs were observed in 44.4% of the patients, non-epileptiform abnormal EEGs in 17.5%, and abnormal EEGs with epileptiform discharges in 38.1% of the patients. Epilepsy was found in 22.1% of the subjects. A history of regression was reported in 25.8% of the patients, 54.8% of the sample had abnormal development during the first year of life, and 79.7% of the patients were mentally retarded. Autistic regression was significantly more frequent in patients with epilepsy than in non-epileptic patients (p = 0.003). Abnormal development during the first year of life was significantly associated with epileptiform EEG abnormalities (p = 0.014). Epilepsy correlated significantly with mental retardation (p = 0.001). Although the biological basis and possible causal relationships of these associations remain to be explained, they may point to different subgroups of patients with autistic spectrum disorders.
244. McVicar KA, Shinnar S. Landau-Kleffner syndrome, electrical status epilepticus in slow wave sleep, and language regression in children. Ment Retard Dev Disabil Res Rev. 2004;10(2):144-9. PMID: 15362173
The Landau-Kleffner syndrome (LKS) and electrical status epilepticus in slow wave sleep (ESES) are rare childhood-onset epileptic encephalopathies in which loss of language skills occurs in the context of an epileptiform EEG activated in sleep. Although in LKS the loss of function is limited to language, in ESES there is a wider spectrum of cognitive impairment. The two syndromes are distinct but have some overlap. The relationship between the epileptiform EEG abnormalities and the loss of cognitive function remains controversial, even in LKS which is the most widely accepted as an acquired epileptic aphasia. Language regression also occurs in younger children, frequently in the context of a more global autistic regression. Many of these children have epileptiform EEGs. The term autistic regression with epileptiform EEG has been proposed for these children. Whether these children are part of an extended LKS spectrum is very controversial, because there are differences in age of onset, clinical phenotype, and EEG findings. An understanding of the available data on clinical characteristics, EEG findings, pathology, prognosis, and treatment of these syndromes is essential for further progress in this area.
245. Tharp BR. Epileptic encephalopathies and their relationship to developmental disorders: Do spikes cause autism? Ment Retard Dev Disabil Res Rev. 2004;10(2):132-4.
Epileptic encephalopathies are progressive clinical and electroencephalographic syndromes where deterioration is thought to be caused by frequent seizures and abundant EEG epileptiform activity. Seizures occur in approximately 10-15% of children with pervasive developmental disorders (PDD) and 8-10% have epileptiform EEG abnormalities without seizures. Thirty percent of children with PDD have regression of social behavior and language at 2-3 years of age. Some authors speculate that the regression is caused by epileptiform activity even in the absence of overt clinical seizures ("autism with epileptic regression") and suggest that elimination of the epileptiform activity, either medically or surgically, should lead to improvement in behavior. This review examines the data showing that interictal epileptiform discharges are associated with transient clinical dysfunction and discusses the implications of these observations for autistic behavioral abnormalities. The results of resective surgery, vagal nerve stimulation, and multiple subpial transaction on children with autism and epileptiform EEG abnormalities are also discussed. I conclude that there is no evidence that interictal discharges per se cause (or contribute to) the complex behavioral phenotype of autism. There is no justification to support the use of anticonvulsant medication or surgery in children with PDD
without seizures; that is, there is no evidence that treatment to eliminate EEG spikes will have a therapeutic effect on the behavioral abnormalities of PDD and autism.
246. Chez MG et al. Frequency of EEG abnormalities in age-matched siblings of autistic children with abnormal sleep EEG patterns. Epilepsy Behav. 2004 Apr;5(2):159-62. PMID: 15123015
Epileptiform activity in sleep has been described even in the absence of clinical seizures in 43-68% of patients with autistic spectrum disorders (ASDs). Genetic factors may play a significant role in the frequency of epilepsy, yet the frequency in normal age-matched controls is unknown. We studied overnight ambulatory electroencephalograms (EEGs) in 12 nonepileptic, nonautistic children with a sibling with both ASDs and an abnormal EEG. EEG studies were read and described independently by two pediatric epileptologists; 10 were normal studies and 2 were abnormal. The occurrence of abnormal EEGs in our sample (16.6%) was lower than the reported occurrence in children with ASDs. Further, the two abnormal EEGs were of types typically found in childhood and were different from those found in the ASD-affected siblings. The lack of similarity between sibling EEGs suggests that genetic factors alone do not explain the higher frequency of EEG abnormalities reported in ASDs.
Amino acids & epileptiform activity
247. Park YD. The effects of vagus nerve stimulation therapy on patients with intractable
seizures and either Landau-Kleffner syndrome or autism. Epilepsy Behav. 2003 Jun;4(3):286-90. PMID: 12791330
Acquired and developmental comorbid conditions, including language and behavioral disorders, are often associated with epilepsy. Although the relationship between these disorders is not fully understood, their close association may indicate that they share common features, suggesting that these conditions may respond to the same therapies. Not only has vagus nerve stimulation (VNS) therapy been proven to reduce the frequency of pharmacoresistant seizures in epilepsy patients, but preliminary studies also indicate that VNS therapy may improve neurocognitive performance. On the basis of these findings, we hypothesized that VNS therapy would improve the quality of life of patients with either Landau-Kleffner syndrome (LKS) or autism, independent of its effects on seizures. Data were retrospectively queried from the VNS therapy patient outcome registry (Cyberonics, Inc; Houston, TX, USA). A constant cohort of 6 LKS patients and 59 autistic patients were identified. Among the LKS patients, 3 patients at 6 months experienced at least a 50% reduction in seizure frequency as compared with baseline. Physicians reported quality-of-life improvements in all areas assessed for at least 3 of the 6 children. More than half of the patients with autism (58%) experienced at least a 50% reduction in seizure frequency at 12 months. Improvements in all areas of quality of life monitored were reported for most patients, particularly for alertness (76% at 12 months). Although these preliminary findings are encouraging, a prospective study using standardized measurement tools specific to these disorders and a longer-term follow-up are necessary to better gauge the efficacy of VNS therapy among these patient populations.
248. El Idrissi A et al. Prevention of epileptic seizures by taurine. Adv Exp Med Biol. 2003;526:515-25. PMID: 12908638
249. Dufour F et al. Modulation of absence seizures by branched-chain amino acids: correlation with brain amino acid concentrations. Neurosci Res. 2001 Jul;40(3):255-63. PMID: 11448517
250. Borowicz KK et al. Two essential amino acids, L-lysine and L-histidine, in five types of experimental seizures. Pol J Pharmacol. 2000 Sep-Oct;52(5):345-52. PMID: 11334226
L-Lysine (250-2,000 mg/kg) and L-histidine (1,000-2,000 mg/kg) significantly raised the electroconvulsive threshold. D-Histidine (1,000 mg/kg) was completely ineffective in this regard. Both amino acids were generally inactive in pentetrazole-, picrotoxin- and aminophylline-induced seizures, though L-histidine (2,500 mg/kg) significantly reduced the number of mice with clonic convulsions in the pentetrazole test. Also, L-lysine (2,500 and 3,000 mg/kg) significantly diminished mortality rate in aminophylline-induced seizures. In addition, L-lysine (2,500-3,000 mg/kg) and L-histidine (2,000-2,500 mg/kg) delayed the onset of aminophylline- and picrotoxin-evoked convulsions. L-Lysine and L-histidine (both up to 1,000 mg/kg) did not affect amygdala-kindled seizures in rats. The results indicate that some of indispensable amino acids may play a role in the inhibitory transmission in the central nervous system. A possibility arises that appropriate diet may be an important supportive factor in the treatment of some epileptic patients, probably suffering from generalized tonic-clonic seizures.
251. Kirchner A et al. Effects of taurine and glycine on epileptiform activity induced by removal of Mg2+ in combined rat entorhinal cortex-hippocampal slices. Epilepsia. 2003 Sep;44(9):1145-52. PMID: 12919385
PURPOSE: The imbalance between neuronal inhibition and excitation contributes to epileptogenesis. Inhibition in the central nervous system (CNS) is mediated by gamma-aminobutyric acid (GABA) and glycine. Recent studies indicate the expression of glycine receptor (GlyR) in hippocampus and neocortex. However, the function of GlyR in these regions is not clarified completely. The aim of this study was to investigate whether the GlyR agonists glycine and taurine promote an anticonvulsive effect…. Likewise glycine, after an initial proconvulsant effect, suppressed epileptiform discharges. CONCLUSIONS: These findings show that GlyR agonists, in particular taurine, could serve as potential anticonvulsants and suggest an important role of GlyR in cortical function and dysfunction.
252. Gietzen DW et al. Indispensable amino acid deficiency and increased seizure susceptibility in rats. Am J Physiol. 1996 Jul;271(1 Pt 2):R18-24. PMID: 8760199
Repeated subthreshold stimulation of limbic brain areas increases seizure susceptibility in experimental models of epilepsy. In addition, acute dietary indispensable amino acid (IAA) deficiency activates the anterior piriform cortex (APC), a seizure-prone limbic brain area in the rat. Based on these two findings, we hypothesized that activation of the APC by chronic exposure to IAA-deficient diets might increase seizure susceptibility. Several nonessential amino acid neurotransmitters are important in seizures, but deficiencies of nontransmitter IAAs have not been well studied in seizure models. In four trials, we made injections of pentylenetetrazole intraperitoneally or of bicuculline into the APC in histidine-, isoleucine-, or threonine-deficient rats and controls. Increased susceptibility to seizures in the deficient animals was observed as increased severity of the seizures, decreased threshold for the dose of the chemostimulant and time to seizure, or a combination thereof. Pair-fed controls showed that this effect was not due to an energy deficit. This novel but robust finding suggests that IAA deficiency may increase vulnerability to seizures by repeated activation of the APC.
253. Hammen A et al. A paradoxical rise of neonatal seizures after treatment with vitamin B6. Eur J Paediatr Neurol. 1998;2(6):319-22. PMID: 10727199
We report the case of a newborn with intractable epileptic seizures developing a paradoxical rise of seizure frequency and electroencephalogram alterations after administration of vitamin B6. We have been unable to determine the aetiology of this disorder. In a newborn presenting with drug-resistant epileptic seizures, the first therapeutic option remains the application of intravenous pyridoxine, but the physician should be aware of the risk of an increase in seizure frequency.
Autism Treatment Evaluation Checklist (ATEC)
254. Autism Treatment Evaluation Checklist (ATEC)
Internet Scoring Program
http://www.autismeval.com/ari-atec/index.html
New Autism Epidemiology Study
whole article free online
http://www.publichealthreports.org/article/PIIS0033354904001347/abstract
http://download.journals.elsevierhealth.com/pdfs/journals/0033-3549/PIIS0033354904001347.pdf
255. Blaxil MF. What's going on? The question of time trends in autism. Public Health Reports 119.6. 536-551 (November 2004)
Synopsis: Increases in the reported prevalence of autism and autistic spectrum disorders in recent years have fueled concern over possible environmental causes. The author reviews the available survey literature and finds evidence of large increases in prevalence in both the United States and the United Kingdom that cannot be explained by changes in diagnostic criteria or improvements in case ascertainment. Incomplete ascertainment of autism cases in young child populations is the largest source of predictable bias in prevalence surveys; however, this bias has, if anything, worked against the detection of an upward trend in recent surveys. Comparison of autism rates by year of birth for specific geographies provides the strongest basis for trend assessment. Such comparisons show large recent increases in rates of autism and autistic spectrum disorders in both the U.S. and the U.K. Reported rates of autism in the United States increased from ,3 per 10,000 children in the 1970s to .30 per 10,000 children in the 1990s, a 10-fold increase. In the United Kingdom, autism rates rose from ,10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s. Reported rates for the full spectrum of autistic disorders rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000 range in the two countries. A precautionary approach suggests that the rising incidence of autism should be a matter of urgent public concern.
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