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Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 26, 2009
A recently published study about bone development in autistic children (1) makes preliminary but noteworthy points about exclusion diets and their ramifications. Importantly, many autism parents report that their autistic child improves in response to a food-elimination diet, with gluten free (GF) and/or casein free (CF) being among the most common (2). Working with clinicians, some parents purchase food-hypersensitivity assays that further guide trials with an elimination diet. The diets of autistic children are increasingly studied (eg, 3-5), and the various findings suggest a lack of proof for the efficacy of GFCF diets (6), even as a majority of parents (N > 2500) report the GF and/or CF diet to have beneficial effects in their autistic child (2).
ARI's Parent Ratings data don't differentiate between GF and CF diets, but most parents who responded (66% of > 2500) found an exclusion diet to be helpful, whereas 3% reported adverse effects, and 31% of parents perceived no effect of a GF and/or CF diet (2). These diets had a ratio of 19 to 1 when comparing children who improved versus children whose symptoms worsened. Further support for the relevance of elimination diets is suggested by the findings of Jyonouchi and colleagues, who have documented food-related immune irregularities in children with autism (eg, 7-9).
The gap between autism-diet findings (eg, 6) and parents' practical experience (2) may derive from methodologies used in traditional medical research, wherein group comparisons and statistical manipulations of data predominate, with double-blind, placebo studies virtually considered to be sanctified. However, "single-subject research" (eg, 10-12) may be more effective for evaluating elimination diets in specific autistic children. The clinician's office and the child's home may be better settings than study facilities located on university campuses.
Given the background sketched above, clinicians and parents are encouraged to peruse Hediger et al 2008, "Reduced bone cortical thickness in boys with autism or autism spectrum disorder" (1). The study's findings are accompanied by insights having significance for clinicians who evaluate and treat autistic children.
"The effect of casein-free diets was pronounced over these ages ([4-8 yrs] Table 4). The adjusted BCT [bone cortical thickness] of boys on casein-free diets were lower, compared with the BCT of those on unrestricted diets (p < .05). Adjusting for height, boys on casein-free diets had average BCT % deviations of –18.9 ± 3.7%, almost twice that of boys on unrestricted diets (–10.5 ± 1.3%, p < .04), although it should be noted that even for boys on unrestricted diets the % deviation was still highly significantly different from zero (p < .001). There was no mitigating effect of calcium-containing supplement use." (1; p852)
Note that autistic children not on a CF diet had bone atypicality. The discussion by Hediger et al is well written and thorough. Many possible factors influencing bone development are considered, including but not limited to adrenarche and to gastrointestinal and hormonal irregularities common in autistic children (eg, 13-16). The roles of sunshine, daily activities, and vitamin D are mentioned (1).
"...although a low dietary intake of calcium and vitamin D from dairy sources appeared to be a significant factor limiting bone development in our study, it is probable that physical inactivity and/or lack of sunlight exposure also contributed [to the BCT finding]."
The researchers make clear that despite a large body of anecdotal information about positive effects of elimination diets, a major "double-blind, placebo control" study of restricted diet in autism (3) had negative findings, which (as mentioned above) may be derive from study design.
Hediger et al close with sound counsel:
"Parents and health care practitioners consider these diets to be at worst innocuous and without significant adverse consequences. In light of these findings [about reduced BCT], the potential for decreased bone development and its effect on fracture risk in these children should be considered when evaluating the risk-to-benefit ratio in treating autism or ASD with a casein-free diet. Our results also suggest that dietary intakes and bone development should be monitored in children who are put on a casein-free diet." (2).
Indeed, clinicians treating autistic children ought not presume that CF diets are without ramifications. And, as Hediger et al have described, autistic children not on a CF diet also tend to have atypical bone development. Many factors are involved, not only those mentioned hereinabove.
Substantive letters of response to this brief critique of Hediger et al and supported by citations will be considered for posting.
References:
1. Reduced bone cortical thickness in boys with autism or autism spectrum disorder.
Hediger ML et al. J Autism Dev Disord. 2008 May;38(5):848-56.
National Institute of Child Health and Human Development
Bethesda, MD 20892-7510, USA.
Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4-8 years. Second metacarpal bone cortical thickness (BCT), measured on hand-wrist radiographs, and % deviations in BCT from reference medians were derived. BCT increased with age, but % deviations evidenced a progressive fall-off (p = .02): +3.1 +/- 4.7%, -6.5 +/- 4.0%, -16.6 +/- 3.4%, -19.4 +/- 3.7%,-24.1 +/- 4.4%, at ages 4-8, respectively, adjusting for height. The 12% of the boys on casein-free diets had an overall % deviation of -18.9 +/- 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (-10.5 +/- 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001). Our data suggest that the bone development of autistic boys should be monitored as part of routine care, especially if they are on casein-free diets.
2. Parent Ratings
http://www.autism.com/treatable/form34qr.htm
3. The gluten-free, casein-free diet in autism: results of a preliminary double blind clinical trial.
Elder JH et al. J Autism Dev Disord. 2006 Apr;36(3):413-20.
This study tested the efficacy of a gluten-free and casein-free (GFCF) diet in treating autism using a randomized, double blind repeated measures crossover design. The sample included 15 children aged 2-16 years with autism spectrum disorder. Data on autistic symptoms and urinary peptide levels were collected in the subjects' homes over the 12 weeks that they were on the diet. Group data indicated no statistically significant findings even though several parents reported improvement in their children. Although preliminary, this study demonstrates how a controlled clinical trial of the GFCF diet can be conducted, and suggests directions for future research.
4. Dietary intake and parents' perception of mealtime behaviors in preschool-age children with autism spectrum disorder and in typically developing children.
Lockner DW et al. J Am Diet Assoc. 2008 Aug;108(8):1360-3.
University of New Mexico, Albuquerque, NM 87131
Parents of children with autism spectrum disorder (ASD) frequently report that their children have selective eating behaviors and refuse many foods, which could result in inadequate nutrient intake. This preliminary cross-sectional descriptive study investigated dietary intake and parents' reported perception of food behaviors of 20 3- to 5-year-old children with ASD. Twenty typically developing children matched for sex, age, and ethnicity were also studied as a case-control comparison. Nutrient intake determined from 3-day food records was adjusted for day-to-day variation to determine the estimate of usual intake distribution for the two groups. This distribution was compared with the Estimated Average Requirement or Adequate Intake recommendations. The reported food behaviors and use of vitamin or mineral supplements were compared for matched pairs using the exact McNemar test. Nutrient intake was similar for both groups of children, with the majority of children consuming more than the recommended amounts for most nutrients. Nutrients least likely to be consumed in recommended amounts were vitamin A, vitamin E, fiber, and calcium. Children with ASD were more likely to consume vitamin/mineral supplements than typically developing children. Compared with parents of typically developing children, parents of children with ASD were more likely to report that their children were picky eaters and resisted trying new foods, and they were less likely to describe their children as healthy eaters or that they eat a variety of foods. Despite the similar and generally adequate nutrient intake for the 40 children in this study, parents of children with ASD had more negative perceptions of their children's dietary behaviors.
5. Does nutritional intake differ between children with autism spectrum disorders and children with typical development?
Herndon AC et al. J Autism Dev Disord. 2009 Feb;39(2):212-22. Epub 2008 Jul 4.
University of Colorado Denver, School of Medicine, Aurora, CO 80045
Consumption of macro- and micronutrients and food group servings by children with autism spectrum disorders (ASDs; n = 46) and typical development (n = 31) were compared using 3-day diet records. Children with ASDs consumed significantly more vitamin B6 and E and non-dairy protein servings, less calcium, and fewer dairy servings (p < .05). The significantly lower dairy serving intake persisted after controlling for child age and sex and parental dietary restrictions, and excluding children on the gluten-free casein-free (GFCF) diet. Large proportions of children in both groups did not meet national recommendations for daily intake of fiber, calcium, iron, vitamin E, and vitamin D.
6. Gluten- and casein-free diets for autistic spectrum disorder.
Millward C et al. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498.
BACKGROUND: It has been suggested that peptides from gluten and casein may have a role in the origins of autism and that the physiology and psychology of autism might be explained by excessive opioid activity linked to these peptides. Research has reported abnormal levels of peptides in the urine and cerebrospinal fluid of people with autism. OBJECTIVES: To determine the efficacy of gluten and/or casein free diets as an intervention to improve behaviour, cognitive and social functioning in individuals with autism. SEARCH STRATEGY: The following electronic databases were searched: CENTRAL(The Cochrane Library Issue 2, 2007), MEDLINE (1966 to April 2007), PsycINFO (1971 to April 2007), EMBASE (1974 to April 2007), CINAHL (1982 to April 2007), ERIC (1965 to 2007), LILACS (1982 to April 2007), and the National Research register 2007 (Issue1). Review bibliographies were also examined to identify potential trials. SELECTION CRITERIA: All randomised controlled trials (RCT) involving programmes which eliminated gluten, casein or both gluten and casein from the diets of individuals diagnosed with an autistic spectrum disorder. DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were assessed to determine inclusion by two independent authors The included trials did not share common outcome measures and therefore no meta-analysis was possible. Data are presented in narrative form. MAIN RESULTS: Two small RCTs were identified (n = 35). No meta-analysis was possible. There were only three significant treatment effects in favour of the diet intervention: overall autistic traits, mean difference (MD) = -5.60 (95% CI -9.02 to -2.18), z = 3.21, p=0.001 (Knivsberg 2002) ; social isolation, MD = -3.20 (95% CI -5.20 to 1.20), z = 3.14, p = 0.002) and overall ability to communicate and interact, MD = 1.70 (95% CI 0.50 to 2.90), z = 2.77, p = 0.006) (Knivsberg 2003). In addition three outcomes showed no significant difference between the treatment and control group and we were unable to calculate mean differences for ten outcomes because the data were skewed. No outcomes were reported for disbenefits including harms. AUTHORS' CONCLUSIONS: Research has shown of high rates of use of complementary and alternative therapies (CAM) for children with autism inc. luding gluten and/or casein exclusion diets. Current evidence for efficacy of these diets is poor. Large scale, good quality randomised controlled trials are needed.
7. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder.
Jyonouchi H et al. Neuropsychobiology. 2002;46(2):76-84.
Department of Pediatrics, University of Minnesota
OBJECTIVES: Children with autism spectrum disorder (ASD) frequently reveal various gastrointestinal (GI) symptoms that may resolve with an elimination diet along with apparent improvement of some of the behavioral symptoms. Evidence suggests that ASD may be accompanied by aberrant (inflammatory) innate immune responses. This may predispose ASD children to sensitization to common dietary proteins (DP), leading to GI inflammation and aggravation of some behavioral symptoms. METHODS: We measured IFN-gamma, IL-5, and TNF-alpha production against representative DPs [gliadin, cow's milk protein (CMP), and soy] by peripheral blood mononuclear cells (PBMCs) from ASD and control children [those with DP intolerance (DPI), ASD siblings, and healthy unrelated children]. We evaluated the results in association with proinflammatory and counter-regulatory cytokine production with endotoxin (LPS), a microbial product of intestinal flora and a surrogate stimulant for innate immune responses. RESULTS: ASD PBMCs produced elevated IFN-gamma and TNF-alpha, but not IL-5 with common DPs at high frequency as observed in DPI PBMCs. ASD PBMCs revealed increased proinflammatory cytokine responses with LPS at high frequency with positive correlation between proinflammatory cytokine production with LPS and IFN-gamma and TNF-alpha production against DPs. Such correlation was less evident in DPI PBMCs. CONCLUSION: Immune reactivity to DPs may be associated with apparent DPI and GI inflammation in ASD children that may be partly associated with aberrant innate immune response against endotoxin, a product of the gut bacteria.
8. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention.
Jyonouchi H et al. Neuropsychobiology. 2005;51(2):77-85.
Department of Pediatrics, New Jersey Medical School
OBJECTIVE: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. METHODS: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-alpha, IL-1beta, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. RESULTS: ASD and NFH PBMCs produced higher levels of TNF-alpha with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-alpha levels produced with LPS and those with cow's milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(-) ASD PBMCs with LPS. GI(+) ASD but not GI(-) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(-) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities.
9. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders.
Jyonouchi H et al. J Pediatr. 2005 May;146(5):605-10.
Department of Pediatrics, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases
New Jersey Medical School/UMDNJ Newark, NJ 07101-1709
OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.
10. Use of the single subject design for practice based primary care research.
Janosky JE. Postgrad Med J. 2005 Sep;81(959):549-51. {free online}
http://pmj.bmj.com/cgi/content/full/81/959/549
The use of a single subject research design is proposed for practice based primary care research. An overview of the rationale of the design, an introduction to the methodology, strengths, limitations, a sample of recent literature citations, a working example, and possible clinical applications are presented.
11. Case studies, single-subject research, and N of 1 randomized trials: comparisons and contrasts.
Backman CL, Harris SR. Am J Phys Med Rehabil. 1999 Mar-Apr;78(2):170-6.
Case studies, single-subject research designs, and N of 1 randomized clinical trials are methods of scientific inquiry applied to an individual or small group of individuals. A case study is a form of descriptive research that seeks to identify explanatory patterns for phenomena and generates hypotheses for future research. Single-subject research designs provide a quasi-experimental approach to investigating causal relationships between independent and dependent variables. They are characterized by repeated measures of an observable and clinically relevant target behavior throughout at least one pretreatment (baseline) and intervention phase. The N of 1 clinical trial is similar to the single-subject research design through its use of repeated measures over time but also borrows principles from the conduct of large, randomized controlled trials. Typically, the N of 1 trial compares a therapeutic procedure with placebo or compares two treatments by administering the two conditions in a predetermined random order. Neither the subject nor the clinician is aware of the treatment condition in any given period of time. All three approaches are relatively easy to integrate into clinical practice and are useful for documenting individualized outcomes and providing evidence in support of rehabilitation interventions.
12. Single-subject experimental designs: a practical research alternative for practicing physicians.
Marvel MK, Amodei N. Fam Pract Res J. 1992 Jun;12(2):109-21.
Single-subject research designs offer a viable alternative to the more customary group-comparison designs. The flexibility and practicality of these designs make them particularly well suited for practicing family physicians interested in testing their clinical hunches. Three designs are described that are feasible in a practice setting: ABAB (reversal), multiple-baseline, and the alternating treatment design. Either visual inspection or statistical approaches can be used to evaluate these designs. By being aware of their limitations and by following simple practical steps, the practicing physician can use these designs to improve care of individual patients while simultaneously contributing to our general knowledge.
13. Elevated levels of growth-related hormones in autism and autism spectrum disorder.
Mills JL et al. Clin Endocrinol (Oxf). 2007 Aug;67(2):230-7.
National Institute of Child Health and Human Development, Bethesda MD
OBJECTIVE: Children with autism are known to have larger head circumferences; whether they are above average in height and weight is less clear. Moreover, little is known about growth-related hormone levels in children with autism. We investigated whether children with autism were taller and heavier, and whether they had higher levels of growth-related hormones than control children did. DESIGN: A case-control study design was employed. PATIENTS: Boys with autism spectrum disorder (ASD) or autism (n = 71) and age-matched control boys (n = 59) were evaluated at Cincinnati Children's Hospital. MEASUREMENTS: Height, weight and head circumference were measured. Blood samples were assayed for IGF-1 and 2, IGFBP-3, growth hormone binding protein (GHBP) and for dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). RESULTS: Subjects with autism/ASD had significantly (P = 0.03) greater head circumferences (mean z-score 1.24, SD 1.35) than controls (mean z-score 0.78, SD 0.93). Subjects with autism also had significantly (P = 0.01) greater weights (mean z-score 0.91, SD 1.13) than controls (mean z-score 0.41, SD 1.11). Height did not differ significantly between groups (P = 0.65); subjects with autism/ASD had significantly (P = 0.003) higher body mass indices (BMI) (mean z-score 0.85, SD 1.19) than controls (mean z-score 0.24, SD 1.17). Levels of IGF-1, IGF-2, IGFBP-3 and GHBP in the group with autism/ASD were all significantly higher (all P < or = 0.0001) than in controls. CONCLUSIONS: Children with autism/ASD had significantly higher levels of many growth-related hormones: IGF-1, IGF-2, IGFBP-3 and GHBP. These findings could help explain the significantly larger head circumferences and higher weights and BMIs seen in these subjects. Future studies should examine the potential role of growth-related hormones in the pathophysiology of autism.
14. Fetal testosterone and autistic traits.
Auyeung B et al. Br J Psychol. 2009 Feb;100(Pt 1):1-22.
University of Cambridge, Cambridge, UK
Studies of amniotic testosterone in humans suggest that fetal testosterone (fT) is related to specific (but not all) sexually dimorphic aspects of cognition and behaviour. It has also been suggested that autism may be an extreme manifestation of some male-typical traits, both in terms of cognition and neuroanatomy. In this paper, we examine the possibility of a link between autistic traits and fT levels measured in amniotic fluid during routine amniocentesis. Two instruments measuring number of autistic traits (the Childhood Autism Spectrum Test (CAST) and the Child Autism Spectrum Quotient (AQ-Child)) were completed by these women about their children (N=235), ages 6-10 years. Intelligence Quotient (IQ) was measured in a subset of these children (N=74). fT levels were positively associated with higher scores on the CAST and AQ-Child. This relationship was seen within sex as well as when the sexes were combined, suggesting this is an effect of fT rather than of sex per se. No relationships were found between overall IQ and the predictor variables, or between IQ and CAST or AQ-Child. These findings are consistent with the hypothesis that prenatal androgen exposure is related to children exhibiting more autistic traits. These results need to be followed up in a much larger sample to test if clinical cases of ASC have elevated fT.
15. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression.
Valicenti-McDermott MD et al. Pediatr Neurol. 2008 Dec;39(6):392-8.
Few studies have compared gastrointestinal problems in children with an autism spectrum disorder with and without a history of language regression. A cross-sectional study was conducted with structured interviews in 100 children with autism spectrum disorder, using a gastrointestinal questionnaire and a familial autoimmune questionnaire. By parental report, children with language regression more frequently exhibited an abnormal stool pattern (40% vs 12%, P = 0.006) and had an increased family history of celiac disease or inflammatory bowel disease (24% vs 0%, P = 0.001) and of rheumatoid arthritis (30% vs 11%, P = 0.03). Among 35 children with a family history of autoimmune disease, an abnormal stool pattern was reported more frequently in those with language regression (78% vs 15%, P = 0.001) than in those without. An association was observed between children with language regression, a family history of autoimmune disease, and gastrointestinal symptoms. Additional studies are needed to examine a possible shared autoimmune process.
16: Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders.
Levy SE et al. Biol Psychiatry. 2007 Feb 15;61(4):492-7. Epub 2007 Jan 3.
BACKGROUND: Gastrointestinal (GI) symptoms and abnormalities in stool consistency are frequently reported by parents of children with autism spectrum disorders (ASD). The purpose of this study was to 1) describe dietary intake of a cohort of children with ASD compared with normative data and 2) determine whether GI symptoms and stool consistency are related to dietary intake. METHODS: Data from diet diaries of children (3-8 years) with ASD (n = 62) were analyzed by a registered pediatric dietician to compare to RDA standards for total calories, protein, carbohydrate, and fat. Dietary intake was correlated with descriptors of stool consistency using cumulative logistic regression methods. RESULTS: Intake of calories, carbohydrates, and fat were in the average range; protein intake was increased (211% of RDA). Reported frequency of GI abnormalities, including abnormal stool consistency (e.g., bulky or loose), was increased (54%). No statistically significant relationships between stool consistency and dietary intake were observed. CONCLUSIONS: In this sample, there was a high rate of reported gastrointestinal symptoms, despite lack of medical causes. Intake was adequate for calories and carbohydrates and increased for protein. The children did not exhibit excessive carbohydrate intake. There was no association of nutrient intake to changes in stool consistency.
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