UCSF Osher Center for Integrative Medicine

What are these kids taking? An Integrative Approach to Autism Sanford C. Newmark M.D.

Pediatric Integrative

Neurodevelopmental Clinic

Disclosure

No one involved in the planning or presentation of this activity has any relevant

financial relationships with a commercial interest to disclose.

Autism

A Neurodevelopmental Syndrome characterized by:

Difficulty with communication and interaction with other people.

Restricted interests and repetitive behaviors Symptoms that hurt the person’s ability to

function properly in school, work, and other areas of life

The Autism “Epidemic” •  Prevalence in the 1960’s 5-6/10,000

•  CDC Prevalence now 1 in 59 or 147/10,000 (recent study 1 in 40)

•  Much of increase in prevalence likely due to better surveillance and awareness, and looser definition of autism.

Autism 1 in 68 children

What Causes Autism?

•  Autism is a Phenotype Defined by a set of observable behaviors – Communication Deficits – Deficits in social interaction – Repetitive behaviors

•  This may represent very different genetics, epigenetics and physiologies

Genetic Predisposition + Environmental Influences

Autism

Genetic Predisposition

Environmental Influences

Prenatal Perinatal Postnatal Toxin Exposure Prematurity Toxin Exposure Medication use C-section Antibiotics Maternal Illness Nutritional Deficiencies Nutritional Deficiencies

Autism

Can toxic exposures cause Autism?

•  Compared: level of environmentally released mercury with special education and autism students

•  for each 1000 lb. of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism.

•  Health Place. 2006 Jun;12(2):203-9

Risk of Autism – Fetal Pesticide Exposure - California

•  465 autistic children, 7000 controls •  Calculated pesticide exposure weeks 1

through 8 of gestation Risk of autism was 6x as great for

mothers living within 500 meters of highest pesticide application

Roberts EHP 2007

Autism – Pesticide Risk & Folic Acid

CHARGE Study – 296 autism + controls Compared to those with Folic Acid intake > 800 Mcg •  ORs for the combination of low FA and indoor pesticide

exposure was 2.1 •  ORs for the combination of low FA and regular pregnancy

exposure to pet pesticides was 3.9 •  ORs for the combination of low FA and regular pregnancy

exposure to outdoor sprays and foggers was 4.1 Schmidt Environ Health Perspect; 2017

Genetic Predisposition

Environmental Influences Epigenetics

Prenatal Perinatal PostNatal Toxin Exposure Prematurity Toxin Exposure Medication use C-section Antibiotics Maternal Illness Nutritional Deficiencies Nutritional Deficiencies

Autism

Conventional Paradigm-Brain Disorder

•  Genetically based, hard wired brain disorder.

•  The genes affect the brain, and the brain affects the behaviors.

•  A “static encephalopathy.” A brain condition with limited capacity for change

Old Paradigm

Genetics + Environment

Brain Disorder Treatment = Therapy

Problems with Brain Disorder Model

•  Does not explain why children with autism have the following problems:

•  Gastrointestinal abnormalities •  Chronic inflammation •  Metabolic abnormalities •  Abnormal Immunity •  Allergic problems •  Nutritional Deficiencies •  Mitochondrial Deficiencies

New Paradigm

Genetics + Environment

Physiological and Epigenetic Changes Affecting Multiple Systems Including the Brain

Autism

Genetic Predisposition

Environmental Influences – Prenatal Perinatal

Postnatal GI disturbances Metabolic derangement Allergy Nutritional Deficiencies Oxidative stress Abnormal immunity Inflammation

Autism

Why is this Important?

•  Because, if autism is an ongoing systemic disease in which immune and metabolic and allergic abnormalities affect the brain,

•  Then we may be able to treat the abnormalities, improve brain function, and improve the core symptoms of autism.

Neuroglial activation and neuroinflammation in the brain of patients with autism.

•  We demonstrate an active neuroinflammatory process in the cerebral cortex, white matter, and notably in cerebellum of autistic patients.

•  Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues.

•  CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.

•  Ann Neurol. 2005 Jan;57(1):67-81.

“... Could it be that dysregulation from immune or biochemical or other metabolic or infectious problems can have an impact across the blood brain barrier and affect brain function?” •  “We are asking if autism is a

dynamic, or even a metabolic encephalopathy, …a metabolic disturbance of the ways the cells can function in the brain. (Martha Herbert)

A Systemic Disease Affecting Brain Function?

Gastrointestinal Symptoms in Autism Spectrum

Disorder: A Meta-analysis

•  Odds ratio for GI symptoms 4.2

•  Odd ratio for diarrhea 3.6

•  Odds ratio for constipation 3.9

•  Odds ratio for abdominal pain 2.5

•  Pediatrics 2014

GI Abnormalities in Children with Autism

•  Not only do these children have symptoms, but many have significant bowel pathology of various types.

36 children with autism and GI Sx

•  Grade I or II reflux esophagitis in 25 (69.4%). •  Chronic gastritis in 15(42%) •  Chronic duodenitis in 24(67%). •  Often, these children are nonverbal, and

cannot tell you they are in pain.

Journal of Pediatrics. 1999 Nov.

“Leaky Gut” – Increased Intestinal Permeability

•  Intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders.

•  Altered intestinal permeability 9 of 21 (43%) autistic patients, 0 of 40 ( 0%) controls. D'Eufemia P. et. Al. . Acta Paediatrica., 1996

Leaky Gut – Intestinal Permeability

•  Abnormal Intestinal Permeability Autism (36.7%) Relatives (21.2%) Normal subjects (4.8%)

•  “The IPT alterations found in first-degree relatives suggest the presence of an intestinal (tight-junction linked) hereditary factor in the families of subjects with autism”

J Pediatr Gastroenterol Nutr. 2010 Jul 28

Abnormal Gut Flora

•  A number of studies have shown abnormal gut flora in autism

•  Increased clostridia species •  Decreased levels of Bifidobacteria (a beneficial probiotic) •  Distinct and less diverse gut microbial populations •  “Taken together, autism and accompanying GI symptoms were

characterized by distinct and less diverse gut microbial compositions with lower levels of Prevotella, Coprococcus, and unclassified Veillonellaceae.”

•  PLOS One 2013

Treating Autistic Mice??

•  “Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors.”

•  Cell 155, 1–13, December 19, 2013

Creating Autistic Mice

•  Transplant of gut microbiota from human donors with autism into germ-free mice.

•  Colonization with ASD microbiota is sufficient to induce hallmark autistic behaviors.

•  The brains of mice colonized with ASD microbiota display alternative splicing of ASD-relevant genes.

•  Cell 177, May 30, 2019

•  Cell 155, 1–13, December 19, 2013

Fecal Microbial Transplant - Autism

•  18 subjects: Autism and moderate to severe GI symptoms

•  FMT (Fetal Microbial Transplant) Standardized human gut microbiota > 99% bacteria

•  8 weeks – delivered orally or rectally •  Results – some improvement in GI and

Autism Symptoms •  Weakness – small, unblinded. Microbiome 2017

Immune Dysregulation in Autism

•  Review of 39 studies strongly suggest a proinflammatory state in ASD as compared to controls,

•  Pro-inflammatory Cytokines increased -– several up-regulated in brain itself

•  TNFa, IL-6, and IL-17a have all been increased in children with ASD.

•  Low levels Natural Killer cells •  Deficiencies in Regulator T-cells •  Several studies indicate role of maternal anti-fetal

autoantibodies

Autoimmunity •  IgG anti-brain autoantibodies

27% with ASD, 2% controls

•  IgM anti-brain autoantibodies 36% with ASD

0% of controls

•  In another study 69% had anti- caudate antibodies

•  Journal of Pediatrics., 1999

Significance of Autoantibodies

•  …” elevated levels (of autoantibodies),, may be representative of a continuous cycle of immune activation and antibody production, potentially resulting in the generation of pathogenic autoantibodies”.

•  Wills 2007

Mitochondrial Dysfunction Autism

•  14 of 69 abnormal plasma lactate •  Muscle Biopsy-5 of 11 patients definite mitochondrial disorder •  Overall 7.2% of autistic patients mitochondrial disorder Presence in general population 0.01%.

•  Other studies similar results

•  Developmental Medicine & Child Neurology 2005

Autism and Oxidative Stress •  Children with autism have significantly higher

concentrations of SAH(S-adenosylhomocysteine), adenosine, and oxidized glutathione

•  Children with autism have an impaired capacity for methylation, one of the most important metabolic functions in our body. This leads to oxidative stress and other problems

•  Janes SJ., Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism American Journal of Clinical Nutrition. 80(6):1611-7, 2004 Dec

Conventional Treatment: Behaviorally Based Therapies

•  Intensive Behavioral Modification (ABA) •  Speech therapy, •  Physical therapy •  Occupational therapy •  Sensory integration therapy

Conventional Treatment of Autism

•  Medications are generally not effective in treating the core symptoms of autism, but can help with certain behavioral symptoms. (Explosiveness, hyperactivity, anxiety)

•  Often significant side-effects

“Alternative” or Biomedical Treatment of Autism

•  In 2006 74% of families of children with Autistic Spectrum Disorder were using some type of CAM therapy.

•  54% of families used biologically based therapies, including modified diets, vitamins minerals, and other nutritional supplements.

•  (Hanson 2006)

“Alternative” or Biomedical Treatment of Autism

Gluten-free casein-free diet – other diets Vitamin and mineral supplementation Omega-3 Fatty Acids Probiotics Methylcobolamin and Folinic acid Oxytocin glutathione Chelation therapy Treatment of yeast and parasitic infections Treatment viral illnesses Hyperbaric Oxygen

I.M – A 4 year-old with Autism

•  4 y.o. - classic autism Severe language delay, Stereotypic behaviors, Poor social interaction

•  Chronic diarrhea

•  2 years conventional therapy

I.M.- A 4 year-old with Autism -2

•  Gluten-free casein free diet. •  Omega-3 fatty acid supplementation. •  Probiotics.

I.M.- A 4 year-old with Autism -3

At 1-month f/u: Stools completely normalized. Child more ‘awake’. Less obsessive, More words, Increased eye contact.

Noticed by therapists and relatives as well as mom.

I.M.- 2 Years Later

•  Speaking in sentences. Can tell a story about school

•  Much less hyperactive •  Much better eye contact •  Able to be mainstreamed in school. •  Autism still present

Food Allergies-GFCF Diet •  10 matched pairs of children with autism

randomized to GFCF diet or control for 1 year •  Autistic behaviors evaluated compared to

matched controls Post intervention, the diet group had a mean autistic trait score of 5.60 (compared to the control group mean score of 11.20)

•  However other studies have shown no efficacy

•  Nutritional Neuroscience. 2002

GFCF Diet

•  Eliminate all Gluten and Casein for at least 60 days

•  Can see dramatic changes not just in the gut but in autistic behaviors (in some children only)

•  IgG food testing - Controversial •  Other diets include Specific

Carbohydrate Diet, Low Phenol Diet,

Omega-3 Fatty Acids and Autism

•  Omega-3 Fatty Acids are crucial to normal brain function

•  Children with autism have 20-30% less PRBC Omega-3 Fatty Acids than children without autism.

O-3’s and Autism: Meta-Analysis

•  6 randomized trials – total of 194 patients •  Mild, but significant improvements in

–  Hyperactivity –  Lethargy –  Stereotypy

No significant differences emerged between supplementation of omega-3 fatty acids and placebo in global assessment of functioning

Neuropsychiatry Dis Treat. 2017 Oct 4;13:2531-2543

Autism and Vitamin D •  Prenatal Deficiency of Vitamin D increases rates of

autism •  Meta-analysis 2015 – serum levels in autism lower

than controls •  Vitamin D -Neurosteroid -active in brain development,

having effects on cellular proliferation, differentiation, calcium signaling, neurotrophic and neuroprotective action

•  Two open label trials found high dose vitamin D improves the core symptoms of autism in about 75% of autistic children.

Other Vitamins and Minerals

•  Zinc highly Associated with autism. Some evidence of a low zinc copper ratio (but no good treatment studies)

•  Low iron also associated with autism. •  Multivitamin Supplement with high

levels of B Vitamins have shown effect

Methylcobolamin – Methyl B12

•  RDBPCT The primary outcome measure – Outcome better in treatment group, 95% CI 1.2-0.2, p = 0.005).Given by sq injection q 3 days

•  From parent surveys and clinical experience one of most effective biomedical treatments

•  Predicated on fact that autistic children unable to Methylate vitamin B-12, leading to deficiency in glutathione production.

. Hendren J Child Adol Psychopharm2016 Nov;26(9):774-783

Folinic Acid & Autism •  Metabolically active form of Folic Acid (Leucovorin) •  RDBPCT – 48 children with autism – 2mg/kg/day

Folinic acid •  Significant improvement in verbal communication

on all standardized measures.

•  Even larger improvement in those who are “Folate Receptor Autoantibody Positive (These receptors prevent folate from crossing blood brain barrier)

Probiotics

•  Stabilize the Immune System •  Help Fix leaky gut •  Decrease Allergy •  Decrease Infection •  Eliminate Toxic Bacteria •  No good studies show effectiveness

of Probiotics for autism

Broccoli and Autism

•  DBRPCT 29 13-21 year olds •  Received placebo or Broccoli sprout

extract (sulforaphane) for 18 weeks •  Showed significant improvement

compared to placebo on 3 standardized autism scales (ABC, SRS, CGI) P<0.01values less for all

Broccoli and Autism – Why? •  Dietary sulforaphane, of recognized low toxicity, was

selected for its capacity to reverse abnormalities that have been associated with ASD, including:

•  oxidative stress, lower antioxidant capacity, depressed glutathione synthesis

•  reduced mitochondrial function •  oxidative phosphorylation, •  increased lipid peroxidation •  neuroinflammmation.

Cannabis for Autism •  Clinically can be extremely helpful – especially with

rage attacks and anxiety •  Only very preliminary research •  THC/CBD Ratio Important – Pure CBD unlikely to be

effective •  No researched dosing guidelines – start small and

increase slowly. •  Results can be dramatic

Oxytocin for Autism

•  Oxytocin – the “social hormone” •  MRI study showed oxytocin increased

activity in brain associated with processing social information

•  Autistic adults recognized emotions better, better speech recognition

•  Research has substantiated improvement in some children

•  Vasopressin now being studied

Chelation Therapy •  First, determining which, if any, children with autism

have a heavy metal problem is not simple •  If there is, some use a “chelating agent”, like DMSA,

which pulls the metal out of the tissues and into the urine

•  This takes many months- there are some risks. •  Some recent research suggests pectin may be

effective and safe. •  Many families employ various types of chelation

therapy. Important to ask

Hyperbaric Oxygen Therapy

•  Children go into a pressure tank with high Oxygen concentrations

•  Takes 40 or more sessions •  Very time consuming and expensive •  One randomized study found modest

gains, another no improvement

Is treatment justified given lack of hard evidence?

•  In autism biomedical treatment is not substituted for other treatment.

•  Early treatment is essential •  Therefore using safe treatments, even

without hard evidence, seems justified •  If 10% of children had a significant

response would it be worth it?

Dangers of Biomedical Treatment

•  Highly limited diets – weight loss, possible vitamin and mineral deficiencies

•  Vitamin or mineral toxicity – rare but can happen – too many supplements

•  Chelation therapy – can be dangerous, especially IV

•  Off label use pharmaceutical medications

Sleep

•  Sleep is crucially important for optimum behavior and performance

•  Many children with autism do not sleep well

•  Rule out sleep apnea

Sleep – How can you help?

•  Sleep hygiene •  Behavioral techniques •  Melatonin - Begin with 0.5 mg, can

work up to 5 mg •  5-HTP – Begin with 50 mg. Can

increase to 200 mg •  Medications if necessary

Bottom Line

Approaching autism as an ongoing systemic disease affecting the brain:

explains the strong evidence of autoimmune, allergic and metabolic abnormalities in autism

and the striking, although preliminary, evidence of significant changes in some children with autism when these abnormalities are treated.

My Recommendations?

•  Continue the conventional therapies that seem to be helpful.

•  Always ask what alternative or “biomedical” therapies are being used

•  Consider beginning some of the safer Biomedical Treatments outlined above, or referring to a physician skilled in thee treatments.

Simple Steps

•  Trial of gluten and Casein Free Diet in Those interested

•  Check CBC, ferritin, zinc, Vitamin D – treat where indicated

•  Begin Fish Oil •  Begin Autism Targeted Multivitamin and

probiotic •  Make sure sleep problems are treated •  Refer for more in depth treatment as needed