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A review of gluten- and casein-free diets for treatment of autism: 2005–2015

Authors Elder J, Kreider C, Schaefer N, de Laosa M

Received 15 July 2015

Accepted for publication 28 September 2015

Published 1 December 2015 Volume 2015:7 Pages 87—101

DOI https://doi.org/10.2147/NDS.S74718

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Elizabeth Steels

Peer reviewer comments 2

Editor who approved publication: Dr Gary Johanning


Video abstract presented by JH Elder.

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Jennifer Harrison Elder,1 Consuelo Maun Kreider,2 Nancy M Schaefer,3 Mary B de Laosa4

1Department of Family and Community Health Nursing Science, 2Department of Occupational Therapy, 3Health Science Center Library, 4Department of Psychology, University of Florida, Gainesville, FL, USA

Background: The gluten-free, casein-free (GFCF) diet is heralded by strong anecdotal parental reports to greatly improve and even "cure" symptoms of autism spectrum disorders (ASDs). Yet, to date, little conclusive empirical evidence exists supporting its use.
Objective: The purpose of this paper is to provide an overview of the state of the recent evidence regarding the use of GFCF diet for treatment of individuals with ASD.
Methods: Five database providers (PubMed, Web of Knowledge, EBSCO, ProQuest, and WorldCat) were used to search 19 databases, yielding a total of 491 articles that were published through February 2015. Peer-reviewed articles published between January 2005 and February 2015 were included for review if study participants were identified as having ASD and if the study investigated the effects of the GFCF diet on ASD behaviors or the relationship between the diet and these behaviors.
Results: Evaluation of search results yielded eleven reviews, seven group experimental studies including five randomized controlled trials, five case reports, and four group observational studies published during the last 10 years. These studies represent a marked increase in the number of reported studies as well as increased scientific rigor in investigation of GFCF diets in ASD.
Conclusion: While strong empirical support for the GFCF diet in ASD is currently lacking, studies point to the need for identifying subsets of individuals (eg, those with documented gastrointestinal abnormalities) who may be the best responders to the GFCF diet. Identifying these subsets is critically needed to enhance rigor in this research area. Until rigorous research supporting the use of GFCF diet is reported, clinicians should continue to use caution and consider several factors when advising regarding implementation of the GFCF diet for individuals with ASD.

Keywords: GFCF diet, autism spectrum disorders, review, gluten free, casein free, dietary intervention


 

Introduction

Autism, or the broader category of autism spectrum disorder (ASD), continues to pose challenges in determining the most efficacious and effective treatment approaches for managing associated social, communication, behavioral, and developmental symptoms.1 First described in a 1943 case report by Kanner,2 interventional approaches for autism have been the subject of a vast number of clinical reports and case studies; less common are rigorous intervention trials. Recently, the thinking about ASD has expanded from a solely psychiatric condition to a multisystem inflammatory disorder that includes systemic inflammation of the gastrointestinal (GI) tract impacting the brain, immune system, and metabolism.3

One popular treatment for addressing possible systemic inflammation is the gluten-free, casein-free (GFCF) diet, heralded by strong anecdotal parental reports of greatly improved4 and even “cured” symptoms of ASD, such that the child no longer meets criteria for ASD.5 The GFCF diet was first identified for use in schizophrenia,6 where a possible genetic defect may contribute to what has been referred to as a “leaky gut”, resulting in an overload of gluten (from wheat) and casein (from dairy). It is posited that this overload causes high peptide levels, which may produce an opioid-type effect that manifests in the behavioral symptoms commonly seen in ASD.7 Others speculate that many individuals with ASD may have undiagnosed gastric conditions and sensitivities that are caused or aggravated by the ingestion of casein and gluten. This discomfort, or even severe pain in some cases, may result in externalizing behaviors (eg, tantrums, screaming, and aggression) and inattention to tasks due to the distraction because of the pain.

Several systematic reviews814 of GFCF studies have focused on the few existing intervention studies and reported inconclusive results.814 However, as Kanner2 noted in his case report, a thorough review must address case studies as well as reports of clinical trials to produce a “full view of the landscape” of what is currently known about the GFCF diet. Such comprehensiveness is needed to assist families and clinical professionals in making informed decisions about implementing the GFCF diet and can identify specific directions for future research.

The purpose of this paper is to provide an overview of the state of the recent evidence regarding the use of GFCF diet for treatment of individuals with ASD as needed for directing future research and advancing clinical practice recommendations. As such, we reviewed the scientific literature published between January 2005 and February 2015 and have organized our review into four sections: summaries of review articles, group experimental intervention studies including randomized clinical trials, case reports, and group observational studies.

Methods

We began our review with a scoping search of the literature in order to gain a broad overview of the existing relevant literature. Table 1 details our search strategies, which were constructed by the third author, a research librarian. Nineteen databases from five database providers (PubMed, Web of Knowledge, EBSCO, ProQuest, and WorldCat) were searched via subject headings and keywords, with the latter truncated and/or phrase searched to capture various forms of gluten, casein, GFCF diet, autism, ASD, and Asperger’s syndrome. Search efforts yielded a total of 491 articles. Removal of duplicates and non-English articles left 290 potential articles, whose titles (and abstracts when needed) were independently screened by two members of the research team. Additional screening was conducted for 1) publication date prior to 2005; 2) publication type, such as commentary, letter to the editor, book chapter, or thesis/dissertation; 3) publication in nonpeer reviewed periodical; 4) main topics unrelated to gluten- or casein-restricted diet; 5) main topics unrelated to ASD; 6) non-ASD research participants; and/or 7) non-English publications. Full texts of the remaining 61 publications were read and sorted by article type (ie, review, experimental, case, group observational). Review articles focusing on GFCF diet in ASD were retained; all remaining articles were read for major focus on use of GFCF diet in ASD. Backward searches of references in the eleven included review articles yielded one additional published abstract, resulting in the 27 publications included in our review. At each step of the article reduction process, two researchers discussed discrepancies in their independent evaluations until consensus was reached; when needed, a third member of the research team assisted with deliberations.

Table 1 Search strategies used
Abbreviations: AB, abstract; ASC, autism spectrum condition; ASSIA, Applied Social Sciences Index and Abstracts; ASD, autism spectrum disorder; CINAHL, cumulative index to nursing and allied health literature; DE, descriptor; ERIC, Educational Resources Information Center; GFCF, gluten-free, casein-free; GFD, gluten-free diet; MH, subject heading; TI, title

Review articles, intervention studies, case reports, and group observational studies were included if the study participants were identified as having ASD, and the study investigated either the effects of the GFCF diet on ASD behaviors or the relationship between the diet and behaviors of individuals with ASD. All articles included for review were published in peer-reviewed, English-language journals between January 2005 and February 2015. Studies were excluded if they did not focus on GFCF diet in ASD. However, because of the paucity of randomized controlled trials (RCTs) reported in the literature and because of the study’s rigor, we chose to include the one double-blind RCT reported via published abstract15 (no other published abstracts reported on a RCT testing GFCF diets in ASD).

Results

Reviews

A total of eleven review articles814,1619 from ten research groups were included in this review and are summarized in Table 2. Hereafter, we will refer to these eleven review articles as ten reviews because one review article was written as an addendum11 of the group’s review that was published in the prior year.10 These authors reviewed a RCT reported in 2010 by Whiteley et al,20 which was published shortly after the original review was released. Notably, six1214,1719 of the ten reviews were published during the last 2 years of our review period; of these six reviews, five13,14,1719 reported on multidimensional considerations (eg, safety, adherence to evidence-based practice standards, diet allergies), informing the use of GFCF diets in the treatment of ASD.

Table 2 Review articles
Abbreviations: AB, 2 phase study where A phase is the baseline phase and B phase is the intervention phase; ASD, autism spectrum disorder; GF, gluten-free only; GFCF, gluten-free, casein-free; EBP, evidence-based practice; GI, gastrointestinal; RCT, randomized controlled trial.

Of the ten reviews, two9,12 limited their review to RCTs. remaining reviews included uncontrolled studies, group descriptive/observational studies, and case reports in addition to RCTs. The most rigorous review of the GFCF diet in ASD is a 2008 Cochrane Review by Millward et al.9 They identified only two small RCTs (n=35), which rendered a meta-analysis impossible. The authors concluded that despite the evidence of high use of this diet as well as other complementary and alternative medicines, insufficient evidence exists to support its efficacy. The review of GFCF diet studies conducted by Mulloy et al10 identified 14 reports published over the 30 years, 1977–2007. These studies greatly varied in quality and scope; most lacked adequate control measures, and sample sizes ranged from one individual to a group of 30. These authors used preestablished criteria to judge the evidence as suggestive, preponderant, or conclusive; they found no studies providing conclusive level evidence and only three studies providing preponderant level evidence. In the most recent (2014) synthesis of the literature, Marí-Bauset et al14 reviewed a total of 32 studies of various designs published between 1971 and 2012, of which 24 reported on effectiveness of GFCF diet in the treatment of ASD and 8 reported on the safety of the diet. Despite the breadth of evidence reviewed, these authors found the evidence supporting the effectiveness and safety of GFCF diets for treatment of ASD to remain limited and weak.

Group experimental studies

A total of seven group experimental studies4,15,2024 testing the effect of GFCF diet in ASD were included for review, of which six were prospective studies4,15,2023 and one24 a retrospective analysis of data from one4 of the six prospective studies. Of the six prospective studies, two were double-blind RCTs.4,15 Two studies20,21 used a single-blind RCT design in which the parents provided the child’s food, while study personnel supported them with dietary guidance. Two studies22,23 used an uncontrolled design to investigate the effect of GF-only, CF-only, and GFCF diet conditions (three separate interventions) on children’s behaviors using non-blinded assessments of specific behaviors in the three intervention groups. Of the group experimental studies included for review, only two15,21 restricted the age span of participants to an age range spanning ≤2 years; the remaining studies allowed study sample age ranges of up to 18 years. Additionally, only one study20 tested an intervention that lasted longer than 3 months. Notably, this was the only study that reported statistically significant improvements in the GFCF diet group using blinded assessment. No other studies using blinded assessment found group differences for the GFCF diet. However, one study4 did note positive anecdotal reports for some participants on the GFCF diet. Table 3 summarizes the seven group experimental studies included in our review.

Table 3 Group experimental studies
Abbreviations: ADHD-IV, Attention-deficit hyperactivity disorder – IV rating scale; ADOS, Autism Diagnostic Observation Schedule; AGS, American Guidance Service; ASD, autism spectrum disorder; CARS, Childhood Autism Rating Scale; CF, casein-free only; ECOS, Ecological Communication Orientation Scale; GARS, Gilliam Autism Rating Scale; GF, gluten-free only; GFCF, gluten-free, casein-free; ICD, International Classification of Diseases; PDD, pervasive developmental delay; RFRLRS, Ritvo-Freeman Real Life Rating Scale; RCT, randomized controlled trial; VABS, Vineland Adaptive Behavior Scale.

Case reports

A total of five case reports5,2528 were reviewed and are summarized in Table 4. Of these five cases, one employed a quasi-experimental design. Irvin25 utilized a ABAB (2-phase design where A1 is the baseline, B1 is the introduction of intervention, A2 is the withdrawal of intervention, and B2 is the reintroduction of intervention) reversal design and measured the frequency of problem behaviors in a controlled setting while on and off the GFCF diet. No significant reduction in problem behaviors was found while the child was on the GFCF diet as compared to a regular diet. However, the remaining four case reports described positive changes in cognitive, behavioral, and language symptoms of the children with ASD following implementation of the GFCF diet. Additionally, in these four cases,5,2628 parents reported positive results, such as improved language and cognitive development and satisfaction with the overall changes in their child. Three5,26,27 of the five case reports noted that the GFCF diet improved the child’s communication skills and cognitive scores so drastically that the children eventually no longer met the diagnostic criteria for ASD. Most notable among the five case reports reviewed was the presence of preexisting GI symptoms in the four cases,5,2628 reporting improvement in ASD-related symptoms after the implementation of the GFCF diet.

Table 4 Case reports
Note: ABAB: 2-phase design where A1 is the baseline, B1 is the introduction of intervention, A2 is the withdrawal of intervention, and B2 is the reintroduction of intervention.
Abbreviations: ASD, autism spectrum disorder; CAM, complementary and alternative medicines; CHARGE, coloboma, heart defect, atresia choanae, retarded growth and development, genital abnormality, and ear abnormality; GFCF, gluten-free, casein-free.

Group observational studies

Four group observational studies2932 were reviewed that contribute evidence informing more nuanced aspects of future GFCF diet trials; these studies are summarized in Table 5. An observational study by Patel and Curtis29 incorporated pre- and posttesting of ten children who received a comprehensive, multifaceted treatment regime, which for some children included a GFCF diet. These authors reported improved behavioral, social, motor, and GI symptoms after 3–6 months. In a survey of 293 parents of children with ASD on a GFCF diet, Pennesi and Klein30 found greatest improvements in the subgroups of children with GI symptoms, allergy symptoms, and those on the GFCF diet for longer than 6 months. In a post hoc analysis of the ScanBrit trial data, Pedersen et al31 reported that children with the strongest probability of being a responder to GFCF diet after 12 months were those aged 7–9 years, who had clinically significant attention deficit hyperactivity disorder – IV (ADHD-IV) scores.

Table 5 Group observational studies
Abbreviations: ADHD, attention deficit hyperactivity disorder; ADHD-IV, ADHD rating scale IV; ADOS, Autism Diagnostic Observation Schedule; AS, Asperger’s syndrome; ASD, autism spectrum disorder; CARS, Childhood Autism Rating Scale; CDD, childhood disintegrative disorder; FFQ, Food Frequency Questionnaire; GI, gastrointestinal; GFCF, gluten-free, casein-free; GSRS, Gastrointestinal Symptoms Rating Scale; HFA, high functioning autism; PDD, pervasive developmental delay; PDD-NOS, pervasive developmental delay – not otherwise specified; RS, Rett syndrome; VABS, Vineland Adaptive Behavior Scale.

Discussion

Our review of the recent literature on gluten- and/or casein-restricted diets for the treatment of ASD yielded eleven reviews, seven group experimental studies, including five RCTs, five case reports, and four group observational studies published during the last 10 years (January 2005 through February 2015). As previously mentioned, the earliest reports within the literature on gluten- and/or casein-restricted diets in ASD have been case studies, with gradual movement toward more rigorous research over the last 10 years. Perhaps this review’s strongest contribution to the literature informing GFCF dietary interventions in ASD is the contextual overview of the scientific literature published during the past 10 years. Of the reviews included in our study, the review conducted by Marí-Bauset et al14 included the largest number of primary (nonreview) studies informing on the effect of gluten- and/or casein-restricted diets in the treatment of individuals with ASD (n=24). Of its 24 relevant studies, 4 (16%) were published in the 1970s, 10 (42%) were published in the 12-year span of 1990 and 2002, and the remaining 10 studies (42%) were published during the 7-year period of 2005 through 2012. This observation, in conjunction with the number of reviews focusing on GFCF in ASD published in 2012 and 2013 (six of ten included in our review) indicates an increased interest in GFCF treatments for ASD over the past 10 years. Researchers’ collective understanding of the questions at hand has refined to reflect an incomplete but multifaceted understanding of gluten- and/or casein-restricted diets in the treatment of ASD. Some studies point to a child’s age at diet introduction,31 while others suggest duration of diet20,30 as well as possible food sensitivities and allergies1012,14,18 as potential factors impacting efficacy of GFCF diet in ASD. Others note physiological abnormalities in ASD that may help to elucidate potential responders.3337 These findings are highly significant and similar to our conclusions about the state of the science related to the GFCF intervention in ASD.

Limitations

Findings were limited by our specific question investigating the current state of evidence regarding the use of the GFCF dietary intervention in ASD. That is, we were seeking information about results of the GFCF diet itself and not necessarily what patient characteristics might suggest the best responders. As a result, only eight studies included for review contributed evidence as to who may be the best responders to a GFCF diet for treatment of ASD.1012,14,18,20,30,31

Future direction: targeting subgroups of likely responders

The recent literature indicates a need for future GFCF diet trials to target likely responders. Case report descriptions of positive effects in the four (of five) cases included in our study reporting GI symptoms are consistent with conclusions drawn from reviews published between January 2005 and February 2015. Specifically, Mulloy et al10,11 and Marí-Bauset et al14 recommended consideration of the GFCF diet only when food allergy and/or sensitivities have been diagnosed. In their reviews of the scientific literature, Dosman et al,18 Hurwitz,12 and Mari-Bauset et al14 recommended screening for celiac disease and/or food allergies prior to implementation of the GFCF diet. Conclusions drawn in at least two reviews,13,17 analysis of two clinical trials,15,20 and one observational cross-sectional study30 suggest the existence of a subgroup of responders to GFCF dietary interventions. Empirically derived information suggestive of subgroups that may be responsive to GFCF dietary interventions has only recently come to light and has not yet been incorporated into the published clinical trials included in our review.

Summary

Despite its lack of empirical validation, there is enough interest in the GFCF diet that the treatment strategy remains widely used with individuals with ASD. The GFCF diet serves as a strong exemplar of science lagging behind in its ability to inform the practices of a community of interest. Some reasons for this paucity of empirical support are discussed in the reviewed literature and include challenges related to conducting clinical trials that must ensure dietary compliance and experimental blinding in naturalistic, day-to-day settings and interactions. In short, well-controlled GFCF dietary trials are difficult to conduct but remain desperately needed in order to inform clinical treatment decisions. Further concerted efforts must be made to identify subsets of individuals (eg, those with documented GI abnormalities) who may be the best GFCF diet “responders”. Finally, until such evidence is available, clinicians should advise those wishing to implement the GFCF diet that it is not likely to be a “miraculous cure” as some claim. As such, clinicians should use caution and consider a number of factors, such as the individual’s overall nutritional status as well as potential added family burden related to cost and time commitments, when advising regarding implementation of the GFCF diet for individuals with ASD.

Acknowledgments

The authors acknowledge Caroline S Mikaiel for assistance with initial data analysis. This work was supported in part by the National Institutes of Health – National Center for Medical and Rehabilitation Research (NICHD) and the National Institute for Neurological Disorders and Stroke under grant number K12 HD055929. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions

JHE, CMK, and NMS contributed to the literature search. CMK, NMS, and MBD contributed to the data collection. All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.


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