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Complementary and Alternative Medicine ASD

Source: Levy Se and Hyman SL. Novel Treatments for Autistic Spectrum Disorders. MRDD Research Reviews. 2005; 11: 131-142.

This review addresses both complementary and alternative medicine (CAM) therapies and conventional medical therapies (CMT) that have not been accepted as mainstream clinical practice.

Immune Modulation Therapies

Gastrointestinal Tract Function Therapies

Neurotransmitter Regulation Therapies

Non-Biological Therapies

IMMUNE MODULATION THERAPIES

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Rationale:

Symptoms of autism may be the result of brain damage caused by autoimmunity, primary/secondary immune deficiency, or immunologic response to infections.

  • Some children with autism have antibodies directed toward endothelial cells, neurofilaments, and myelin basic protein
  • Brain development in mouse models is altered by prenatal/neonatal exposure to novel viruses and by maternal immune response to viral infection in utero
  • Increased rates of autoimmune disorders have been reported in families of children with autism
  • Some children with autism have altered immune function, indicated by decreased natural killer cell cytotoxicity, altered CD4 and CD8, and lower levels of Th1 cells, IL2, IFN-ä, and TNF-á

Intravenous Immunoglobulins (IVIG)

Evidence:

Three case series:

  • Open trial with 10 children – subjective improvement with treatment and worsening after discontinuation of treatment
  • Trial with 10 children – 5 did not improve, 4 had mild improvement in attention
  • Trial with 7 children – no improvement over 6 months

Known/potential side effects:

  • Small risk for blood-borne infection (derived from human plasma)
  • Rare:
    • Renal tubular acidosis
    • Thromboembolic events
    • Aseptic meningitis
    • Rash

Antiviral agents (i.e. valacyclovir)

Evidence:

No peer-reviewed publications assessing safety/efficacy of antiviral agents in children with ASD

Known/potential side effects:

  • Bone marrow suppression
  • Nausea
  • Headache
  • Dizziness
  • Abdominal pain
  • Depression

Chelating agents (i.e. dimercaptosuccinic acid [DMSA], mud baths, dietary fiber supplements)

Rationale:

Belief that it is necessary to remove mercury (from childhood vaccinations) stored in the body.

Evidence:

There are no peer-reviewed publications assessing safety/efficacy of chelating agents in children with ASD.

Known/potential side effects (DMSA):

  • Renal toxicity
  • Hepatic toxicity

GASTROINTESTINAL TRACT FUNCTION THERAPIES

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Rationale:

  • Reports of high frequency of gastrointestinal symptoms (diarrhea, constipation, and gastroesophageal reflux) in children with ASD
  • Early developmental genes that have been associated with autism are expressed in the brain and the intestine
  • People with autism and their relatives have been consistently found to have increased levels of plasma serotonin, the primary neurotransmitter that functions in the enteric nervous system
  • Viral exposure may lead to immune response in the colon and consequent altered permeability (“leaky gut”)
  • Case series found that children with ASD and gastrointestinal symptoms had an increased rate of ileal lymphoid nodular hyperplasia and evidence of colitis and gastroesophageal reflux

Digestive enzymes

Rationale:

Proteins are malabsorbed/incompletely broken down, leading to the presence of toxic compounds called “exorphins” in the gastrointestinal tract. Frequently used despite lack of evidence and potential side effects.

Evidence:

One open clinical trial with EnzymAidTM (formulated combination of enzymes) and acidophilus (probiotic agent)

  • 46 subjects, 40% consuming gluten/casein free diet
  • 37% of subjects dropped out of trial (cited reasons: personal issues, lack of palatability of preparation, and behavioral/medical side effects [~15%])
  • Positive trends in outcome measures were observed, but observers were not blinded

Probiotics (i.e. acidophilus and lactobacillus), antifungal agents (i.e. fluconazole), “yeast-free diet”

Rationale:

Symptoms of autism are caused by an overgrowth of yeast (candida) in the intestine as a result of antibiotic use, immune alteration, or ingestion of processed sugars/other foods that increase yeast growth. It is hypothesized that yeast overgrowth causes negative effects via toxic metabolites, negative impacts on the absorptive ability of the intestinal membrane, or epiphenomenon.

Evidence:

  • There is no evidence that typical antibiotic use can lead to intestinal candida infections in individuals with normal immune systems.
  • A case report of two children with autistic features found that they had Krebs cycle intermediates of potentially fungal origin in their urine.
  • Despite the fact that there have been no peer-reviewed clinical trials of these therapies, they are frequently used.

Known/potential side effects

Antifungal agents

  • Liver toxicity
  • Exfoliative dermatitis
  • Diarrhea

Gluten-free/Casein-free diet

Rationale:

Children with ASD have a “leaky gut” and cannot completely breakdown gluten and casein. Peptide fragments are absorbed (gliadinomorphins from barley, rye, oats, and wheat and casomorphins from dairy products) and act as endogenous opioids.

Evidence:

  • There is some evidence of elevated urinary peptides related to gluten and casein in children with ASD.
  • One randomized study with 20 children found that development was significantly better after one year for children on the diet versus the controls.
  • In general, implementation of gluten and casein-free diets is widespread, with many reports of success in the nonscientific literature.

Known/potential side effects:

  • Children’s nutritional status may be adversely affected by dietary restriction
  • Diet can be expensive and stressful to implement

Specific Carbohydrate DietTM (SCD)

Rationale:

Children with ASD have a “leaky gut” and cannot completely breakdown carbohydrates. This diet focuses on providing monosaccharides versus disaccharides and polysaccharides. It was originally developed for individuals with celiac disease.

Evidence:

There are no peer-reviewed publications assessing safety/efficacy of the SCD in children with ASD.

Known/potential side effects:

  • Children’s nutritional status may be adversely affected by dietary restriction
  • Diet can be expensive and stressful to implement

Antibiotic Therapy

Rationale:

Alterations in the intestinal flora lead to changes in the integrity of the intestinal lining and toxins that precipitate the symptoms of ASD.

Evidence:

  • Some studies show that children with autism have intestinal colonization with different clostridium species compared to children without autism
  • 11 children with ASD and a history of behavioral regression and diarrhea were given oral vancomycin; blinded videotape evaluations and non-blinded behavior/communication assessments demonstrated significant improvement in 8 of the children

Known/potential side effects:

  • Colitis

NEUROTRANSMITTER REGULATIONS THERAPIES

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Rationale:

Dietary supplements (including vitamins, minerals and herbs) provide substrates or cofactors that can compensate for biochemical deficits and improve neurotransmitter function.

Vitamin C

Rationale:

Vitamin C is a cofactor in the conversion of tyrosine to dopamine and tryptophan to 5-HT.

Evidence:

  • 30-week double blind, placebo controlled trial showed positive results in decreasing stereotyped behavior

Known/potential side effects (high dose):

  • Gastrointestinal upset
  • Kidney stones

Folic acid

Rationale:

Folate is a cofactor in the methylation reactions involved in catecholamine synthesis and metabolism.

Evidence:

No peer-reviewed studies have examined the efficacy/safety of folic acid supplementation in children with ASD.

Vitamin B6 (pyridoxine) with magnesium

Rationale:

Vitamin B6 is involved in the synthesis of the neurotransmitters norepinephrine, serotonin, dopamine, histamine, epinephrine and GABA.

Evidence:

  • Most studies are surveys or open label
  • Double-blind clinical trials with small samples sizes did not show positive effects on autism symptoms for low or high dose B6

Note: Most commonly used supplements for autism in Autism Research Institute survey of parents

Known/potential side effects (high dose)

  • Peripheral neuropathy

Vitamin B12

Rationale:

Children with autism have an impaired antioxidant defense system, leading to an inability to detoxify environmental contaminants and consequent neurodevelopmental harm.

Evidence:

20 children with autism were compared to 33 controls

  • Children with autism had lower plasma concentrations of methionine, S-adenosylmethionine, homocysteine, cystathionine, cysteine and higher concentrations of adenosine, oxidized glutathione, and S adenosylhomocysteine compared to controls (no dietary/medical history taken)
  • These laboratory measures were normalized in children with autism after treatment with oral folic acid and subcutaneous B12; subjective improvement in behavior was also noted

Note: Vitamin B12 is found only in animal products and may need to be supplemented in vegans. Individuals with celiac disease may also need vitamin B12 supplementation.

Known/potential side effects:

  • None known.

Dimethylglycine (DMG)

Rationale:

DMG is metabolized to glycine, an excitatory neurotransmitter, in the liver. It may also act to enhance the immune system.

Evidence:

  • Two double-blind, placebo-controlled studies (n = 10 and n = 37) demonstrated no significant effect of DMG compared to placebo on clinical rating scales or behavior
  • There were no peer-reviewed studies examining the effects of trimethylglycine (a related supplement) on children with ASD

Note: Second most commonly used supplement for autism in Autism Research Institute survey of parents

Known/potential side effects:

  • During one of the studies, a child became hyperactive on DMG and the supplement was discontinued

D-cycloserine

Rationale:

Glutaminergic neurotransmission (GABA receptors and the GABA system) may be involved in ASD. GABA is an inhibitory neurotransmitter in the cerebral cortex. D-cycloserine is a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) glutamate receptor.

Evidence:

  • Adults with schizophrenia treated with D-cycloserine and a neuroleptic showed decreased disruptive symptoms
  • 10 subjects (ages 5-27) with ASD were given doses of d-cycloserine (3 different levels) after a two-week single-blind placebo lead-in phase; on the highest dose, subjects showed statistically significant improvement in social withdrawal

Known/potential side effects:

  • Two subjects experienced motor tics and increased echolalia during the trial

Tryptophan

Rationale:

Abnormalities in serotonin metabolism have been documented in individuals with ASD. Tryptophan is a precursor of serotonin (5-hydroxytryptophan). Tryptophan depletion has been documented in conjunction with significant deterioration in patients with ASD.

Evidence:

  • Differences in peripheral metabolism of 5-hydroxytryptophan after an oral challenge were demonstrated in a study with 18 adolescents with autism and 20 controls

Known/potential side effects:

  • In the past, contaminated commercial tryptophan supplements have caused Eosinophilia myalgia syndrome

Tyrosine

Rationale:

Tyrosine is a precursor for catecholamines (dopamine, norepinephrine, and epinephrine).

Evidence:

There are no peer-reviewed studies on the effects of tyrosine in individuals with ASD.

L-carnosine

Rationale:

Glutaminergic neurotransmission (GABA receptors and the GABA system) may be involved in ASD. Carnosine is a dipeptide (histadine and alanine) that acts on GABA receptors in the frontal lobe.

Evidence:

  • An 8-week open trial of 800 mg of L-carnosine in 31 children with autism demonstrated improvement on socialization and receptive vocabulary measures; many confounders, including educational interventions, placebo effect, and improved seizure management were not taken into account

Cyproheptadine (Periactin™)

Rationale:

Elevated blood levels of 5-HT have been associated with increased platelet serotonin levels. Cyproheptadine is a 5-HT2 receptor antagonist with antipsychotic action.

Evidence:

  • 40 children (ages 3-11) with severely disruptive behavior symptoms were given oral cyproheptadine, haloperidol or placebo in an 8-week double-blind, placebo-controlled trial; children given cyproheptadine/haloperidol had better outcomes on the Aberrant Behavior Checklist-Community and the Childhood Autism Rating Scale (CARS)

Known/potential side effects:

  • Sleepiness
  • Increased appetite

Oxytocin

Rationale:

Oxytocin is a neuropeptide released from the posterior pituitary gland that has cognitive, behavioral and social effects. Children with ASD have low plasma oxytocin level and atypical oxytocin.

Evidence:

  • Oxytocin-deficient animal models have demonstrated improved social function and behavior after administration of oxytocin directly into the amygdale/intracerbroventricula.
  • In a crossover study, 15 adults with ASD were given parenteral synthetic oxytocin and placebo; the number and type of repetitive behaviors decreased when subjects were taking oxytocin

Essential fatty acids

Rationale:

Essential fatty acids are structural components of neuron cell membranes. They are metabolized to prostaglandins, prostacyclins and leukotrienes.

Evidence:

  • Case reports provide anecdotal evidence of improvement in children with ASD following essential fatty acid supplementation.
  • There are no clinical studies on the effects of essential fatty acid supplementation in children with ASD.

Known/potential side effects:

  • Increased bleeding times
  • Potential mercury contamination in commercial supplements

NON-BIOLOGICAL THERAPIES

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Rationale:

The underlying neural architecture of the brain can be changed by non-biological means.

Auditory Integration Training (AIT)

Children are repeatedly exposed to altered sounds through a set of earphones.

Rationale:

Auditory perception deficits can compound language disorders in individuals with ASD. Many children with ASD are sensitive to sounds. It may be possible to retrain the ear and central listening mechanism.

Evidence:

  • Difficult to assess effect because of concurrent therapies
  • Studies including placebo (sham listening procedure) have not demonstrated beneficial effects of AIT for children with ASD
  • The American Academy of Pediatrics does not currently endorse AIT

Behavioral Optometry

A combination of lenses and visual training exercises are used to remediate vision problems.

Rationale:

Visual scrutiny and inspection at the periphery of the visual field are two stereotyped behaviors observed in individuals with autism.

Evidence:

  • Subjective improvements in behavior reported with the use of prism lenses.
  • The American Academy of Pediatrics does not currently endorse behavioral optometry.

Craniosacral Manipulation

The practitioner uses light touch to apply pressure to points along the craniosacral axis to restore proper cerebrospinal fluid flow within the cranium and spinal cord.

Rationale:

Normal function of the nervous system depends on the flow of cerebrospinal fluid within the cranium and spinal cord. If the flow is disrupted, it affects cranial rhythm and leads to abnormal function.

Evidence:

  • There have been anecdotal reports of improved behavior in individuals with ASD following craniosacral manipulation.
  • No peer-reviewed articles on the use of craniosacral therapy in individuals with ASD are available.
  • Review articles have concluded that there is little scientific basis for craniosacral therapy; interobserver reliabilities are low.
  • The touch and circumstances of the therapy may cause behavioral effects.

Facilitated Communication

Nonverbal individuals are physically guided through the use of a computer or other device designed for communication by a facilitator. It is different from augmentative communication in that a facilitator is involved.

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