Biomedical Individuality and Effective Treatment Strategies ...Presentation Transcript
ASI Conference – Oct 2008
Anju I. Usman, M.D.
True Health Medical Center
Environmental Toxicity And Heavy Metal Burden Genetics Biologic and Immunological Triggers Autism Timing Biomedical Causation Theories and the Web of Interactions Heavy Metal Overload Oxidative Stress Gut Dysfunction Immune Dysregulation Inflammation
Dietary and Nutritional Factors
Heavy Metal Overload
Depletion of reduced Glutathione
Immune System Dysregulation
The above lead to chronic smoldering inflammation in the body and brain
Pro-inflammatory Factors in the Gut (Ashwood, Jyonuchi)
Pro-inflammatory Cytokines in the Brain
MCP-1, TGF beta-1 (Vargas,Pardo, 2005)
Abnormal EEG, Seizure activity
Microglial Activation and perivascular inflammation
Autoantibodies to neural antigens (Connolly, 1999)
Myelin basic protein and Neuronal Axonal Filament Protein Antibodies (Gupta, 1996 /Singh, 1997)
History and Physical Examination
Address Gastrointestinal Health
Treat underlying Immune Issues and Inflammation
Support Detoxification/Mitochondrial Pathways
Heavy Metal/Chemical Detoxification
Intensity of Symptoms = Intensity of Treatment Educational and Behavioral Therapies Environmental Controls Dietary Interventions Nutrient Therapies Gastrointestinal Health Immune Issues and Inflammation Promotion of Natural Detox and Mitochondria Pharmaceutical Detox and other Drug therapy Hyperbaric Oxygen Therapy
Casein/gluten peptides are broken down by DPPIV. This enzyme can be disabled by toxic metals and yeast.
High levels of opioid peptides (gliadorphin and caseomorphine) found in urine of autistics. (Reichelt, 1997)
Casein-free, Gluten-free diet may be an effective intervention (Whiteley,1999)
Presently NIH study underway
Casein – protein from all dairy products
Caseomorphine= undigested casein peptide, has an opiate effect on the brain
Gluten – protein found in wheat, rye, oat, barley, malt, spelt
Gliadorphin= partially digested gluten peptide, has an opiate effect on the brain
Urinary Peptides can be measured
Jyonouchi H et al (2002) Neuropsychobiology 46 qq
Croonenberghs J et al (2002) Neuropsychobiology 45
Ashwood P et al (2004) J Clin Immuno 24: 664-673
Jyonouchi H et al (2005) Neuropsychobiology 51: 77-85
It remains unclear how and when microglia and astroglia become activated in the brains of patients with autism. Glial responses in autism may be part of intrinsic, or primary, reactions that result from disturbances in glial function or neuronal-glial interactions during brain development. They may also be secondary, resulting from unknown disturbances (such as infections or toxins) in prenatal or postnatal CNS development. Nevertheless, the findings of this study highlight the existence of neuroimmunological processes in autism and provide a setting for new research approaches to the diagnosis and treatment of this debilitating neurological disorder.
The Neuroscientist, Volume 11, Number 5, 2005. Martha Herbert, MD, PhD ,
"neuroinflammation appears to be present in autistic brain tissue from childhood through adulthood." Dr. Herbert suggests that chronic disease or an external environmental source (like heavy metals) may be causing the inflammation. Excerpt: " Oxidative stress, brain inflammation, and microgliosis have been much documented in association with toxic exposures including various heavy metals.. .the awareness that the brain as well as medical conditions of children with autism may be conditioned by chronic biomedical abnormalities such as inflammation opens the possibility that meaningful biomedical interventions may be possible well past the window of maximal neuroplasticity in early childhood because the basis for assuming that all deficits can be attributed to fixed early developmental alterations in neural architecture has now been undermined.
“ The brains of children with neurological disorders are experiencing severe oxidative stress and inflammation, suggesting an environmental cause.
Monosodium Glutamate (MSG)
Modified Food Starch
Peas, Mushrooms, Tomatoes
Rosemary, Lemon Balm
Skull Cap, Chamomile
Excitotoxins = Substances that cause an excess of excitatory neurotransmission in the brain. If inhibitory neurotransmission is lacking, chronic inflammation in the brain may result.
2007 study in The Lancet examined the effect of artificial coloring and preservatives on hyperactive behavior in children. After consuming an additive-free diet for six weeks, the children were given either a placebo beverage or one containing a mix of additives in two-week intervals. In the additive group, hyperactive behaviors increased.
The study caused many pediatricians to rethink their skepticism about a link between diet and A.D.H.D. “The overall findings of the study are clear and require that even we skeptics, who have long doubted parental claims of the effects of various foods on the behavior of their children, admit we might have been wrong,” reported a February issue of AAP Grand Rounds, a publication of the American Academy of Pediatrics.
Inadequate antioxidant status is a major pathway for inflammation.
Various free rdicals (ROS), including superoxide, peroxide, hydroxyl and peroxynitrite, are generated through the inflammatory prostaglandin/leukotriene pathways.
These free radicals can damage or destroy virtually every cellular biomolecule: proteins, fatty acids, phospholipids, glycoproteins, even DNA, leading to cell injury or death.
vitamins C and E are the two most important nutritional antioxidants.
Vitamin C, E, alpha-lipoic acid, Co Q10 and NADH act as a team.
One of the many ways excitotoxins damage neurons
is to prevent the intracellular formation of glutathione.
Rosemary Waring found low Sulfate levels in ASD. Low Sulfation leads to poor detoxification of Phenols.
PST Enzyme helps to detox Phenolic Substances from the body
Common Phenolic Substances
Salicylates (grapes, apples, strawberries)
Biologic Agents (yeast)
Pesticides, Herbicides, Perfumes
Lack of sulfation may manifest as hyperactivity, stimming, lax ligaments, red cheeks and red ears.
Pyridoxal 5-Phosphate is a co-factor
Epsom Salts/Magnesium Sulfate Baths may help
Casein-free/Gluten-free /Diet Trial for 3-6 months.
Avoid sugar and refined starch, replace with whole grains
Maximize antioxidants and phytonutrients.
Limit processed and preserved foods; organic is best.
Limit intake of phenolics (apples, grapes, strawberries…).
Drink plenty of filtered water.
Never microwave in plastics or Styrofoam, do not store food in plastic or foil, or cook on Teflon coated pans.
Add good fats (olive, coconut, flax). Avoid hydrogenated and trans fats and esterified fats.
Buy hormone-free, antibiotic-free, organic meat and eggs.
Add fermented foods (coconut kefir, kombucha,…).
Dietary Detours CF/GF Diet Persistent Gut Issues Hyperactivity/Stimming Specific Carbohydrate Diet Body Ecology Diet Low Oxalate Diet Avoid Excitotoxins Low Phenolic/Feingold Diet Low Copper Diet Elimination/Rotation Diet Elimination/Rotation Diet
Ames BN (2002) High dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km) : relevance to genetic disease and polymorphisms. Am J Clin Nutr 75: 616-658
Vieth R (2001) Vitamin D nutrition and its potential health benefits for bone, cancer and other conditions. J Nutr & environmental med 11: 275-291.
Fernstom JD ( 2000) Can Nutritional Supplements modify brain function? Am J Clin nutr 71: 1669S-1673S.
Ames BN (2004) A role for supplements in optimizing health : the metabolic tune-up. Arch Biochem Biophys 421: 227-234
Dr. Bernie Rimland – Autism Research Institute http://www.autismwebsite.com/ARI/treatment/b6studies.htm Studies of High Dosage Vitamin B6 (and often with Magnesium) in Autistic Children and Adults, 1965 - 2005 Twenty-one of twenty-two studies yielded positive results, including 13 double-blind placebo-controlled trials; even minor adverse effects rarely were seen. http://www.autismwebsite.com/ARI/dan/scientificfoundations.htm Compilation of Studies Supporting the Biomedical Approach Scientific Foundations of a Biomedical Approach to ASD
Pyridoxal 5-phosphate (P5P) active form of vitamin B6
Conversion of B6 to P5P requires: ATP, Mg, Zn, Vit B2
Used by 112 enzymes
Decarboxylation ( L-Dopa to Dopamine, 5HTP to Serotonin, Glutamic Acid to GABA)
Methylation also helps with the production and metabolism of Dopamine, Serotonin, Norepinephrine and Epinephrine.
Shown to help cognitive ability, abstract thinking, attention, focus, awareness, language, behavior, OCD, anxiety, ….(Neubrander, 2004).
No test for methylB12 deficiency.
Consider 3 month trial.
Side effects – increased energy, hyperactivity, agitation, stimming.
Protocol 75 mcg/kg subcutaneous injection
every 3 rd day
Parents give the preservative-free,
methyl B12 injections themselves.
Essential fatty acids, DHA and human brain development Indian J.Pediatr Mar 2005
Infants of mothers supplemented with EFAs and DHA had higher mental processing, psychomotor scores, and eye-hand coordination. EFAs may prevent ADHD in preschoolers.
Long chain polyunsaturated fatty acids in childhood developmental and psychiatric disorders Lipids Dec 2004
LC-PUFA help with childhood behavior and learning difficulties.
Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo-controlled Pilot Study
EFA helped with hyperactivity and sterotypy in ASD children.
Essential Fats are fats that your body can not manufacture. They need to be consumed.
These fats are essential for neuronal transmission, cell to cell communication, normalizing excitation, maintaining skin, hair, joint structure, and minimizing inflammation.
Fish, Flax, Seaweed
Safflower, Sunflower, Corn,
Borage, Evening Primrose
Olive, Avocado, Coconut
Calcium 200-1000mg per day
Methyl B12 injections
Vitamin C 500-1500mg/day
Vitamin E 200-800 IU/day
Vitamin A 2500-15,000iu/day
Vitamin D 2000 IU/day
Glutathione 200mg per day
Melatonin 1-3 mg/day
Omega 3 EFA 1000mg
Daily bowel movements are a goal.
Add digestive enzymes with meals.
Start high potency probiotics (acidophilus and bifidus) or probiotic containing foods.
Start treatment for dysbiosis depending on symptoms and labs.
Check for high ammonia , treat accordingly.
If persistent symptoms:
Eliminate disaccharides from diet for 3-6 months
Specific Carbohydrate Diet (SCD)
Consider referral to knowledgeable GI specialist
Consider trial of IV or nasal Secretin.
Treat with natural anti-inflammatories.
Comprehensive Metabolic Panel
Intracellular Minerals and Metals
Urine Essential Minerals
Essential Fatty Acids
Plasma cysteine, sulfate, rGSH
Urine Organic Acids Test (OATS)
T lymphocyte Panel
Natural Killer Cell Activity
Anti MBP Ab
Anti NAFP Ab
IgG Food Ab Panel
Genomics – SNPs
Urine/ Fecal Toxic Metals
Urinary 8-OH Guanosine
These agents create inflammation, free radicals and oxidative stress.
Some of these biologic agents produce neurotoxins and excitotoxins and other toxic by-products.
Some agents increase cell membrane permeability.
Our body may produce antibodies to these agents. These antibodies may cross react with our own tissue creating an autoimmune reaction. This is called molecular mimicry.
Clostridia produce toxins (propionic acid) and enzymes that create severe gut inflammation, produce watery diarrhea, and can cause behavior changes.
American Journal of Biochemistry and Biotechnology 4 (2): 146-166, 2008
Derrick F. MacFabe
Innate neuroinflammatory changes, increased oxidative stress and disorders of glutathione metabolism may be involved in the pathophysiology of autism spectrum disorders (ASD). Propionic acid (PPA) is a dietary and gut bacterial short chain fatty acid which can produce brain and behavioral changes reminiscent of ASD following intraventricular infusion in rats treatment day, specific brain regions were assessed for neuroinflammatory or oxidative stress markers. ..
Immunohistochemical analyses revealed reactive astrogliosis (GFAP), activated microglia (CD68,Iba1) without apoptotic cell loss (Caspase 3’ and NeuN) in hippocampus and white matter (external capsule) of PPA treated rats. Biomarkers of protein and lipid peroxidation, total glutathione (GSH) as well as the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) were examined in brain homogenates. Some brain regions of PPA treated animals (neocortex, hippocampus, thalamus, striatum) showed increased lipid and protein oxidation accompanied by decreased total GSH in neocortex. Catalase activity was decreased in most brain regions of PPA treated animals suggestive of reduced antioxidant enzymatic activity. GPx and GR activity was relatively unaffected by PPA treatment while GST was increased, perhaps indicating involvement of GSH in the removal of PPA or related catabolites. Impairments in GSH and catalase levels may render CNS cells more susceptible to oxidative stress from a variety of toxic insults. Overall, these findings are consistent with those found in ASD patients and further support intraventricular PPA administration as an animal model of ASD.
Very foul stools
Mucus in stools
Severe diarrhea following antibiotic use
Probiotics, High Potency single strain
Frequent diaper rash
History of frequent antibiotics
Limit carbs, sugar, yeast
Nystatin, Amphotericin B
Grapefruit Seed Extract
Oil of Oregano, Pau d’Arco
Garlic, Samento, …
Worse at full moon
Picking, biting, licking, itching, grinding
J Neurosci Res. 2007 Apr;85(5):1143-8.
Evidence for Mycoplasma ssp., Chlamydia pneunomiae, and human herpes virus-6 coinfections in the blood of patients with autistic spectrum disorders.
Nicolson GL , Gan R , Nicolson NL , Haier J .
We examined the blood of 48 patients from central and southern California diagnosed with autistic spectrum disorders (ASD) by using forensic polymerase chain reaction and found that a large subset (28/48 or 58.3%) of patients showed evidence of Mycoplasma spp. infections compared with two of 45 (4.7%) age-matched control subjects (odds ratio = 13.8, P < 0.001). Because ASD patients have a high prevalence of one or more Mycoplasma spp. and sometimes show evidence of infections with Chlamydia pneumoniae, we examined ASD patients for other infections. Also, the presence of one or more systemic infections may predispose ASD patients to other infections, so we examined the prevalence of C. pneumoniae (4/48 or 8.3% positive, odds ratio = 5.6, P < 0.01) and human herpes virus-6 (HHV-6, 14/48 or 29.2%, odds ratio = 4.5, P < 0.01) coinfections in ASD patients. We found that Mycoplasma-positive and -negative ASD patients had similar percentages of C. pneumoniae and HHV-6 infections, suggesting that such infections occur independently in ASD patients. Control subjects also had low rates of C. pneumoniae (1/48 or 2.1%) and HHV-6 (4/48 or 8.3%) infections, and there were no coinfections in control subjects. The results indicate that a large subset of ASD patients shows evidence of bacterial and/or viral infections (odds ratio = 16.5, P < 0.001). The significance of these infections in ASD is discussed in terms of appropriate treatment. (c) 2007 Wiley-Liss, Inc. PMID: 17265454 [PubMed - indexed for MEDLINE]
The Association between Tick-Borne Infections, Lyme Borreliosis and Autism Spectrum Disorders
Robert C Bransfield, MD
A Lyme Induced Autism Foundation conference was held in June 2007 in Irvine, California to explore the association between infectious diseases, tick-borne infections, including Lyme Borreliosis ( Borrelia burgdorferi ) and autism spectrum disorders. There are multiple cases of mothers with Lyme disease and children with autism spectrum disorders; significant fetal neurological abnormalities associated with tick-borne diseases; improvement in autistic symptoms in some autism spectrum disorder patients from antibiotic treatment; similarities between the clinical manifestations of tick-borne diseases and autism spectrum disorder regarding pathophysiology, treatment responses, immune reactivity, temporal lobe pathology, and brain imaging data.
Pilot studies of autism spectrum disorder patients demonstrate positive reactivity for Borrelia burgdorferi at 22% (Vojdani) and 26% (Lyme Induced Autism Foundation) and 58% for Mycoplasma ( including M. fermentans and M. pneumoniae ), 8% for Chlamydia pneumoniae and 29% for Human Herpes Virus-6 (Nicolson). In addition, geographical patterns of a greater incidence of autism spectrum disorders approximate regions that are more endemic for tick-borne diseases.
It is hypothesized that chronic infectious diseases, including tick-borne infections such as Borrelia burgdorferi may have direct effects, promote other infections and create a weakened, sensitized and immunologically vulnerable state during fetal development and infancy leading to increased vulnerability for developing autism spectrum disorders.
Frequent strep infections
Frequent bacterial infections
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 [PubMed - indexed for MEDLINE]
DeLong GR, Bean SC, Brown FR 3rd .
Acquired reversible autistic syndrome in acute encephalopathic illness in children.
Brief report: autistic disorder in three children with cytomegalovirus infection.
J Autism Dev Disord. 2004 Oct;34(5):583-6. PMID: 15628611
Poor Eye Contact
History of Regression after MMR or other live viruses
Olive Leaf Extract, Elderberry
High Dose Vitamin A
Low Dose Naltrexone
Mol Pathol. 2002 Apr;55(2):84-90.
Potential viral pathogenic mechanism for new variant inflammatory bowel disease.
Uhlmann V , Martin CM , Sheils O , Pilkington L , Silva I , Killalea A , Murch SB , Walker-Smith J , Thomson M , Wakefield AJ , O'Leary JJ .
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. METHODS: Formalin fixed, paraffin wax embedded and fresh frozen biopsies from the terminal ileum were examined from affected children and histological normal controls. The measles virus Fusion (F) and Haemagglutinin (H) genes were detected by TaqMan reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody. 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.
Healing the New Childhood Epidemics (Autism, ADHD, Asthma and Allergies, Ken Bock MD
Autism: Effective Biomedical Treatments , Pangborn and Baker
Children with Starving Brains , Jaquelyn McCandless MD
Special Diets for Special Kids , Lisa Lewis
Evidence of Harm , David Kirby
Excitotoxins, the Taste that Kills , Russel Blaylock MD