Considering Biomedical and Alternative Treatments for Autism

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Considering Biomedical and Alternative Treatments
for Autism

• Robert L. Hendren, DO
• Professor of Psychiatry
• Exec. Director, M.I.N.D. Institute
• Chief, Child and Adolescent Psychiatry
• UC Davis

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Evidence-Based Intervention Strategies

• Behavioral - ABA (Applied Behavioral Analysis)
• TEACCH (Treatment, Education of Autistic
  Communication Handicapped Children)
• Pivotal Response Training (Koegel)
• Incidental Teaching Approach
• Developmental, Individual-Difference
  Relationship-Based model (Greenspan)

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Less Evidence-Based Educational Interventions for
ASD and LD

• Lindamood-Bell
• - develop sensory cognitive processes
• - concept symbol imagery, visual motor
• skills
• Daily Life Therapy
• - Higashi School in Japan
• - Self esteem, exercise, rhythm, music, arts

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Less Evidence-Based Interventions for ASD and LD

• Computer Programs
• Fast ForWord - slows sounds then speeds up
• Earobics - auditory attention, phenomic id and
  awareness.
• Train Time - receptive expressive language and
  attention
• Facilitated communication - supports typing at
  keyboard

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Less Evidence-Based Interventions for ASD and LD

• Speech Language Therapy
• PECS (Picture Exchange Communication System)
• Communication books
• Augmentative Communication Devices

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Less Evidence-Based Treatments for Behavioral
Disorders in Children

• Melatonin for sleep
• Atypical antipsychotics
• SSRIs
• Creatin (apraxic language)

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Anecdotal Evidence-Based Non-Biological
Interventions for ASD and LD

• Auditory Integration Training
• Bernard Method - dampen hypersensitive
  frequencies
• Tomatis Method Mozart and Gregorian chants as
  sound stimulation
• SAMONAS - classical music and sounds of nature
• Rhythmic Entertainment Intervention - drum beats
• Music Therapy

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Anecdotal Evidence-Based Interventions for ASD
and LD

• Doman/Delacato Method - normalize sensory
  system
• Craniosacral Therapy - free restrictions of
  motion and normalize rhythm
• Hyperbaric Oxygen Therapy regenerate neurons
  (series of 3 cases Rossignol, 2006 one small
  double-blind placebo controlled study)
• EEG Biofeedback correct EEG abnormalities

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What Causes Autism?

• First hit - Genetic neurodevelopmental
  vulnerability
• Second hit - environmental toxicant or
  stressor plus compromised immune system
• Third hit - Restricted development

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Biomedical Approach to Autism

• Is autism a disease of the brain or a disease of
  the bodys metabolism that affects the brain?
• Seizures
• GI symptoms
• Regressive autism
• Is autism caused by environmental stressors plus
  immune deficiency?

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Types of Biomedical/CAM (modified from Levy
Hyman 2003, 2007)

• Neurotransmitter production or release (DMG,
  B6/Mg, Vit C, Omega 3, St. Johns Wort)
• Food Sensitivities and Gastrointestinal Function
  (GF/CF, Secretin, digestive enzymes, Pepcid,
  antibiotics)
• Putative immune mechanism or modulators
  (antifungals, IV Ig, vit A/Cod liver oil)
• Potential heavy metal toxin removal (chelation,
  DMSA or DMRA)
• Methylation (methylcobalamine, folinic acid)
• Non-biological (craniosacral manipulation,
  transcranial magnetic stimulation)

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M.I.N.D. Translational Model -Mechanisms and
Trajectories

• Immune function and strengthening
• Oxidative stress assessment and correction
• Inflammatory processes assessment and reduction
• Nutritional assessment and correction
• Early targeted behavioral intervention

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Current Translational Research at the M.I.N.D.
Institute

• Immunology Oral IgG, Actos
• Oxidative Stress - Methyl B12
• Inflammation HBOT
• Lipid metabolism - Omega 3 fatty acid
• Behavioral/ mirror neurons early intervention
• Biomarkers - Pharmacogenetics and genomics,
  cytokines, MRI

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B6 / Magnesium

• Rationale
• Proposed to effect the folinic acid pathway and
  increase glutathione. Many people with autism are
  reported to have impaired metabolism of
  adenosylhomocysteine, adenosine, and
  methylcobalamin, such that homocysteine formation
  and methionine synthase processes are deficient.
• Evidence
• Twenty-two studies are reported by Rimland, some
  controlled, on use of pyridoxine or pyridoxine
  with pyridoxal 5-phospate in autism. Twenty-one
  had positive outcomes. Those that used magnesium
  in conjunction had the most positive outcomes.
  However, one double-blind, placebo controlled
  study with 10 children was negative (Findling,
  1997).
• May work better in adults.

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B6 / Magnesium

• Procedure
• 30mg/kg per day of B6 and 10mg/kg per day of Mg
  but maybe low
• Greater clinical improvement is realized by
  successful treatment with (injectible)
  methylcobalamin or oral trimethlglycine
  (betaine).
• Safety
• Excessive doses of B6 may cause peripheral
  neuropathy and Mg may cause arrhythmia. Increased
  hyperactivity to the point of hypomania is
  reported.
• Promise
• Recent Cochrane review concluded studies not
  adequate to comment on efficacy (Nye, 2002).
  Meta-analysis of 12 studies suggest it may be a
  promising adjunct (Pfeiffer, 1995) but there
  are no recent studies.

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Folinic Acid

• Rationale
• Folates are involved in the synthesis of
  neucleotides from purines, indirectly with
  synthesis of transfer RNA and as methyl donor to
  create methylcobalamin. Folinic acid is more
  metabolically active (Kelly, 1998).
• Evidence
• One case report (Moretti, 2005)
• Procedure
• Not recommended to be used alone. Suggested as
  add on to methylcobalimine (James, 2004). 400-800
  mcg twice a day
• Safety
• Promise

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Vitamin A / Cod Liver Oil

• Rationale facilitates immune response by
  modulation of G-protein function in cell membrane
• Evidence
• Anecdotal reports are positive (Megson, 2000)
  and an older, double-blind study reported
  improved sensory motor scores (Heeley, 1996)
• Procedure
• Safety Toxicities include pseudotumor cerbri,
  skin rash, and hepatomeglia
• Promise

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Omega 3 Fatty Acids (DHA)

• Rationale
• Low levels reported in autism and other
  disorders (ADHD, Tourettes, Bipolar).
  Antioxidant that helps with immune regulation.
  May affect neurotransmitters and prostaglandins
• Evidence none for autism but some for ADHD,
  Tourettes and Bipolar
• Procedure
• Low dose of no benefit.
• Often combined with cod liver oil.
• Suppliers Eskimo 3, Nordic naturals, Omega
  Brite, Vital nutrients, Omega 6 has lowest
  mercury and less fish taste.
• Safety No known side effects

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Casein-Free, Gluten-Free Diet

• Rationale
• Protein breakdown products from milk
  (casomorphin) and grains (gliadomorphin) cause
  inflammation in the stomach and gut, allowing
  leakage of opioid-like compounds, altering
  immunity and inhibiting CNS maturation.
• Evidence
• Modest evidence for opioid theory based on GI
  symptoms and celiac disease.
• Debate about whether children with autism have
  more GI symptoms than typically developing
  children.
• Evidence that children with autism have altered
  immunity.

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Casein-Free, Gluten-Free Diet

• Evidence (Cont.)
• May need to be on diet for at least 8 months to
  see benefit.
• Treatment results inconsistent
• Recent review found only one small study
  demonstrating benefit for a select group was
  reliable (Millward, 2004 Knivsberg, 2002).
• Parent reports to ARI various gluten, casein and
  gluten casein restricted diets help 46-63 of
  individuals with autism, with 2-4 reporting
  worsening of behaviors.
• Procedure
• Very difficult to implement due to limitations
  in foods and taste

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Other Dietary Modification

• Rationale
• Lactose intolerance per lactase deficiency as
  reported by Kushak and Buie, Mass General
  Childrens Hospital.
• Maltose intolerance- Kushak and Buie
• Sucrose-isomaltose (and palatinose) intolerance
  Kushak and Buie.
• Safety for all Dietary Modification
• Dietary inadequacy (calcium, vitamin D, protein)
  if restrictions not balanced. Often requires
  strong motivation from parents.
• Promise
• It may be that subgroups of children have
  sensitivity. Trial should be considered with
  motivated parents.

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Secretin

• Rationale vasoactive gut peptide
• Evidence
• Initial report of benefit in three cases
  (Horvath, 1998)
• No reports of group or individual effects to
  support the efficacy. Families may choose to
  continue Secretin even when notified their child
  did not receive the treatment in a blinded study.
• Procedure Multiple IV Secretin treatments
• Safety No known risks
• Promise Maybe for a very select group

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Digestive Enzymes

• Rationale
• Based on a gut-brain connection associated with
  autism (Reichelt, 1981 Horvath, 1999 Wakefield,
  2002). Use of a comprehensive digestive enzyme
  with meals to aid digestion of all exorphin
  peptides and disaccharides.
• Evidence
• No published reports.
• Through not tabulated by ARI, usage trials by
  Kirkman Labs and Klaire Labs resulted in 40-60
  of tested children showing improvement
  worsening (beyond a 10-day period) occurred in
  about one in 40 (2.5).
• Proposed to improve self-stimulation and
  stereotypies, aggression, GI symptoms,
  socialization, and hyperactivity.

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Digestive Enzymes

• Procedure
• Plant derived enzymes may be best, but animal
  derived enzymes are more accepted. Labs who make
  these are Klaire, Kirkman, ITI and Houston.
• Amount of digestive enzymes to be taken depends
  on the size and content of the meal, not the
  subjects size or weight. Only one enzyme complex
  has isomaltase-palatinase activity as well as
  peptidases, amylases, and other disaccharidases
  (Kirkman Laboratories). Other enzyme
  formulations contain the requisite peptidases
  (including DPP4), amylase, and some
  disaccharidases.
• Safety
• Not an invasive modality as it only requires
  swallowing one or two capsules (or opened capsule
  contents) at the beginning of each meal.
• Exorphin withdrawal and dysbiotic flora die off
  periods can occur with all digestive aids in some
  individuals with autism.
• Ulceration and gastritis is reported.
• Promise
• Difficult to predict who will respond favorably
  or not. Easy to do and relatively safe.

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Antibiotics, Probiotics

• Rationale
• Individuals with autism are reported to have
  more bacterial dysbiosis in the intestinal tract
  and mouth/throat than controls. Antibiotics may
  worsen or improve ASD (Manev, 2001)
• Evidence
• One small, poorly designed study suggested
  transient benefit for 8 out of 10 children with
  regressive autism with vancomycin (Sandler et
  al., 2000)
• Testimonial evidence - coordinated use of
  probiotics significantly increases clinical
  success in normalizing gut flora (Brudnak, 2002).
  
• Safety - Superinfection or resistance with
  long-term use of antibiotics.

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Antifungals

• Rationale
• Too much Candida in sensitive individuals.
  However, excessive yeast/fungal overgrowths have
  not been found. Improvements are reported with
  antifungals even with no overgrowth (Shaw et al.,
  1995) leading some to say it is something in the
  medication rather than the yeast killing
  properties that is of benefit.
• Evidence
• According to ARI report, use of antifungals
  helps up to 51 (Diflucan, n215) with lower
  success percentages for other antifungals and
  some antibiotics. Adverse reactions or worsening
  are 5-7 for antifungals and higher for
  antibiotics.
• Safety
• Superinfection or resistance with long-term use
  of antifungals.

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Intravenous Immunoglobin G

• Rationale ASD and immune dysfunction
  (Zimmerman, 2000 Krause, 2002)
• Evidence growing for immune dysfunction
  (Croonenberghs, 2002)
• Subjective improvement in open trials (Gupta,
  1996 Wank, 2002). One negative open study
  (DelGiudice-Asch, 1999)
• Procedure IV IG
• Safety small risk for aseptic meningitis,
  renal failure or infection
• Promise

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Heavy Metal Chelation (DMSA, DMRA)

• Rationale
• The treatment is targeted at tissue-sequestered
  mercury based on lead and other heavy metal
  detoxification.
• Evidence
• None found in literature. Of all the drug, diet,
  and nutritional therapies listed on the ARI
  Survey, detoxification is reported to help the
  highest percentage of individuals with autism
  (71) and it worsened only 3, the second
  lowest percentage.
• Procedure
• Detoxification involves courses of oral DMSA
  (2,3 dimercaptosuccinic acid) with periodic
  elemental analysis of urine from subjects and
  controls.
• To be successful, detoxification treatment
  requires two prerequisite treatments that must be
  successful clearing the gut of harmful
  dysbiotic flora, and bolstering metabolism with
  essential nutrients so that the individual can
  tolerate detoxification.
• Screen for precursors and seizures.
• Supplement for zinc deficiency and cistine.

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Heavy Metal Chelation (DMSA, DMRA)

• Safety
• It is controversial, and the IOM recently warned
  of unspecified risks. Renal and hepatic
  toxicity is possible with oral agents. Most
  common side effects are diarrhea and fatigue.
  Less common side effects include abnormal CBC,
  LFTs and mineral abnormalities. Seizures have
  also been reported. Reports of sulfer smell,
  regression, GI symptoms and rash
• Promise
• While it was felt to be a helpful treatment by
  skilled practitioners, it is very complicated and
  was felt to be too complicated for an
  experimental study. An open label study is being
  developed at ASU. See ARI website for discussion
  and protocol.

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Methylcobalamine (methyl B12)

• Evidence
• James (2004) reports abnormal methylation in
  children with autism normalized with methyl B12
  but not clinical rating were done.
• Various clinicians report improvement in 40 to
  90 of individuals.
• Procedure
• Administered subcutaneously in the buttocks at a
  dosage of 64.5 mg/kg every 3 days for 6 weeks
  (Hopewell and Wellness Labs)
• Safety
• Minor trauma from SubQ injections
• Promise
• Ranked 1 by the group as holding promise and
  lending itself to a clinical trial. Clinical
  trial at MIND Institute for children 2 to 7.

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Subject Enrollment Status
72 (21/29) Chose to Enter the Extension Study
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Group Response CARS
Lower Scores Indicate Improvement
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Group Response SBV
Higher Scores Indicate Improvement
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Group Response ABC
Lower Scores Indicate Improvement
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Responder Subgroup
Subgroup of 9 (31) Responders to Behavioral
Measures Responder Subgroup Also Showed
Significantly Improved Plasma Glutathione
Responder classification based on clinically
significant improvement on the CGI and at least
two additional behavioral measures. Clinical
significance on these measures was determined by
an improvement of at least 1 point on the CGI, 10
points on the PIA-CV and CBCL, 5 points on the
PPVT, MCDI, and ABC, and 2 points on the CARS.
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Responder Subgroup CGI
Lower Scores Indicate Improvement
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Blood Analysis in Responders

• Plasma GSH/GSSG in responder subgroup
• p0.097 for baseline compared to placebo
• p0.002 for baseline compared to active
• p0.025 for active compared to placebo
• Plasma GSH in responder subgroup
• p0.311 for baseline compared to placebo
• p0.002 for baseline compared to active
• p0.002 for active compared to placebo

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Others

• Pepcid (famotidine) H-2 antagonist 3
  children improved in double-blind trial (Linday)
• Rivastigmine cholinesterase inhibitor improves
  language and behavior in open label study (Chez,
  2004)
• Galantamine may enhance expressive language in
  adults with ASD (Hertzman, 2003)
• Memantine (Nemenda) glutamate receptor, used
  of Alzheimers
• Transsulferation - Abnormalities of
  sulfoxidation and sulfation affecting the
  stability of catecholamine neurotransmitters,
  impairing integrity of gut wall and heightening
  sensitivity to pollutants.
• Creatin
• Valtrex (acyclovar) antiviral or effect on
  purine

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Pharmacogenomics of Risperdal Tx (Hendren Sharp)
Preliminary Data
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Biomedical Treatments (Adams JB, ARI, 2007)

• Improve diet
• Food allergies
• GF/CF diet
• Vitamin/Mineral Supplements (Adams 2004)
• Essential Fatty Acids (Amminger, 2006)

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Biomedical Treatments (cont)

• Gut Treatments antifungals, probiotics,
  digestive enzymes
• Amino acids, Melatonin, Thyroid supplements,
  sulfation
• Glutathione, methyl B12
• Chelation
• Immune system regulation (IVIG, Actos, LD
  Naltrexone)

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