Ketogenic Diet Therapy for Autism Spectrum Disorder
Condition: Autism Spectrum Disorder
MeSH terms: Autistic Disorder; Autism Spectrum Disorder; Child Development Disorders, Pervasive
Study type: Interventional

Summary: 
      This study will assess the effectiveness of the ketogenic diet (high-fat, low-carbohydrate,
      and moderate protein) in treating autism spectrum disorder (ASD). Three study groups will be
      comprised of children (2-21 years of age) based on whether or not they have ASD and receive
      the ketogenic diet - ASD/ketogenic diet, ASD/non-ketogenic diet, and non-ASD/non-ketogenic
      diet.
    

Detailed description: 
      Recent studies have shown that the ketogenic diet (high-fat, low-carbohydrate, and moderate
      protein; induce a shift from the primary metabolism of glucose to ketones) or Modified-Atkins
      diet may be effective in treating autism. Research on the Black and Tan BRachyury (BTBR)
      T+tf/J mouse strain, characterized by an autism-like behavioral phenotype, has demonstrated
      the efficacy of a ketogenic diet in improving autism. Although, modified diets, such as the
      Feingold diet, low-sugar diet, or gluten-free diet, have shown behavioral improvements in
      patients with Attention Deficit Hyperactivity Disorder (ADHD), the ketogenic diet has not
      been studied in autism spectrum disorder (ASD) despite the high incidence of ADHD
      comorbidity. The findings from only one prospective, pilot study have been published, which
      reported significant behavioral improvement in all 18 autistic subjects after six months
      (assessed at intervals of four weeks on the diet and two weeks diet-free) on the ketogenic
      diet. Clearly, the ketogenic and other modified diets as promising treatments for ASD have
      been understudied. Additional clinical research is necessary to establish the ketogenic diet
      as a safe, effective treatment alternative for children with ASD.

      This proposed research project will involve an ethnically diverse sample (varied genetic
      background and environmental exposure) to assess the efficacy of the ketogenic diet as a
      therapeutic intervention, and to understand its beneficial effects in children with ASD. The
      investigators anticipate that noteworthy findings will contribute to the sparse literature on
      ASD and effective dietary interventions and prompt future research collaborations with
      investigators from other medical centers and/or academic institutions. Funding for future
      research appears promising considering that ketogenic therapies are also a novel method for
      the treatment of a variety of disorders, including other neurodevelopmental disorders,
      diabetes, migraine headaches, brain tumors, multiple sclerosis, and obesity.

      In addition, the investigators propose to also examine the potential changes in blood
      composition and intestinal (gut) microbiome in children with (without) ASD who are treated
      (not treated) with the ketogenic diet in light of the effect on their ASD symptomatology. The
      relationship between the gastrointestinal tract and the central nervous system has garnered
      increasing interest in the research community. The gut-brain interface describes a
      bidirectional relationship in which the central nervous system influences the gut and vice
      versa. Little is known about the mechanisms behind anecdotal reports of dietary success in
      humans, but it is suspected that alterations in gut microflora are involved. Mulle et al.
      (2013) postulated that the connection between the gut microbiome and ASD may be either the
      direct cause or as indirect consequence of atypical patterns of feeding and nutrition.
      Similarly, diet patterns, including the ketogenic diet, impact nutrient availability and thus
      indirectly modulate the gut microbiome. Multiple studies have confirmed differences in levels
      of gut commensals and overall metabolite profiles in fecal and urinary samples from healthy
      children compared to children with ASD, potentially as a result of changes in the microbiome.
      In the maternal immune activation mouse model of ASD, Hsiao et al. (2013) reported that
      probiotic treatment with B. fragilis could correct behavioral abnormalities and metabolomics
      profile typified in ASD and ameliorate ASD-relevant GI barrier deficits in mice. Sandler et
      al. (2000) demonstrated that oral vancomycin treatment showed short-term improvements in
      children with regressive-onset autism, suggesting that alterations in gut bacteria profile,
      in this case with antibiotic therapy, may improve autistic behavior. Studies of the gut
      microbiome in children with ASD may elucidate the role of diet and the alterations in
      gastrointestinal microbes related to ASD. As a result of these data, novel treatments may be
      discovered.

      The specific aims of this study are:

      Aim 1. To evaluate the effect of the ketogenic diet on the core symptoms of autism. The
      following instruments will be used to measure core autistic symptoms: a) Autism Diagnostic
      Observation Schedule - Second Edition (ADOS-2); b) Asperger Syndrome Diagnostic Scale (ASDS);
      c) Childhood Autism Rating Scale (CARS-2); d) Gilliam Autism Rating Scale (GARS-3); e) Social
      Responsiveness Scale - Second Edition (SRS-2); f) Diagnostic and Statistical Manual IV Text
      Revision (DSM-IV-TR) and DSM-V ASD criteria; g) Standardized social & intelligence tests (if
      available, administered by child's school); and h) Vanderbilt ADHD Diagnostic Teacher Rating
      Scale Forms (Vanderbilt).

      Hypothesis: Participants who have ASD/on the ketogenic diet will have significantly lessened
      core autistic symptoms than those that have ASD/not on the ketogenic diet, between baseline
      to three and six months after the dietary intervention is initiated.

      Aim 2. In anticipation of significant changes in core autistic symptomatology, to examine the
      effects of the ketogenic diet on the (a) number and dosage of medications used for behavioral
      management, (b) number of lab tests ordered for behavioral management, (c) number of
      emergency room or hospital visits for behavioral management, and (d) subject/family
      satisfaction with the ketogenic diet.

      Hypothesis: The number (and/or dosage) of medications, lab tests ordered, and emergency room
      or hospital visits for behavioral management will decrease, and participant/family
      satisfaction will be high for participants who have ASD/on the ketogenic diet than those who
      have ASD/not on the ketogenic diet, between baseline to three and six months after the
      dietary intervention is initiated.

      Aim 3. To compare differences and/or changes in (a) biochemical profiles as defined from
      blood and stool (gut or fecal microbiome) specimen samples and (b) serum and urine ketone
      levels.

      Hypothesis: Participants who have ASD/on the ketogenic diet will have notably different
      biochemical profiles and significantly higher serum/urine ketone levels than those who have
      ASD/not on the ketogenic diet and typically developing controls on a regular diet, between
      baseline to three and six months after the dietary intervention is initiated.

      The investigators anticipate that the KD will be effective in treating ASD, and further an
      understanding of dietary patterns and gastrointestinal alterations in ASD. Noteworthy
      findings will contribute to the sparse literature on the association between dietary
      intervention and neurodevelopmental disorders, and assist with obtaining future funding for
      higher-level clinical trials involving collaborative research with other medical centers and
      academic institutions. These initiatives, the investigators believe, are necessary to
      establish the KD as a novel, safe alternative to effectively treat patients with ASD.
    

Intervention name(s): Ketogenic Diet
Intervention type(s): Other
Intervention description(s): Dietary
Other intervention name(s): Classic Ketogenic Diet; Shriner's Ketogenic Diet; Non-Ketogenic Diet
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Autism; Autism Spectrum Disorder; Ketogenic Diet; Biochemical Profiles