DIET, SUPPLEMENTS, AND AUTISM SPECTRUM DIAGNOSES: IS THERE THERAPEUTIC VALUE?
By Judy Converse
info@nutritioncare.net

Judy Converse is a nutrition care professional

April 1, 2002 - Autism includes a spectrum of diagnoses which fall under the umbrella of pervasive developmental disorders (1). These diagnoses include Autistic Disorder, Rett’s disorder, Childhood Disintegrative Disorder, Asperger’s Disorder (ASp), and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). Impairments in social and/or communication skills, though in greatly varying degrees, are common to these diagnoses. Also noted across this spectrum are varying impairments in motor skills, cognition, and play skills (i.e., lack of imaginative play). Children falling on the spectrum often have restricted, repetitive behaviors, rigidity, or peculiar movements such as toe walking, teeth or finger clicking, rocking, or hand flapping. Seizures or mental retardation may be present as well. Diagnosis is usually made by age 3 or 4 excepting ASp, which may be diagnosed later in childhood, since verbal and cognitive skills are within normal limits in toddlerhood. AD is an especially devastating diagnosis for families, as few children with it go on to function independently as adults.

Once viewed as a form of schizophrenia caused by indifferent parenting, autism spectrum diagnoses (ASD) are now regarded as distinct and genetic in origin. But recent developments have generated debate over the possibility that autism is a systemic, treatable illness precipitated by genetic vulnerability plus an early environmental trigger (2,3). Initiating debate are the rise in ASD diagnoses in the last decade (4-6) which defies incidence for an inherited disorder; and secondly, the long-observed phenomenon that ASD children present with consistent, significant gastrointestinal, biochemical, and immune function changes, along with consistent dietary rigidities (7-31). The contention made by many parents and a growing group of physicians and nutrition care professionals is that when physical symptoms are aggressively treated, the developmental injury of autism can subside, possibly to the point of losing the diagnosis. Both issues raise objections from many who have long worked in this field, who fear that parents may be misled to believe that autism is reversible. This is a pertinent debate for nutrition care professionals with expertise in early childhood growth, gain, feeding, and special diets.

Is the rise in autism a true rise in incidence, or simply an artifact of heightened awareness and broadened diagnostic criteria? Two extensive reviews concluded that no true rise is occurring and estimated prevalence to be holding steady at roughly 5 per 10,000 (32,33). These reviews have been criticized for omitting children born since 1990, the decade in which the most severe rise and the fewest changes in diagnostic criteria occurred (34). Though broadened diagnostic criteria can account for an initial increase in incidence, it can not account for the continued and steep rise in autism throughout the last decade. Nationwide, cases have risen from some 5,000 in 1990 to 60,000 nationwide by 2000 (4). From the 1997-98 to the 1998-99 school year, the number of US children with autism receiving services under the Individuals with Disabilities Act (IDEA) rose 24%, while children with all other disabilities served under IDEA rose less than 3% (4).

Of all indicators, enrollment in IDEA programs and services due to autism diagnosis is perhaps the most practically relevant, as it represents a substantial portion of the costs which autism creates for communities. The costs of educational supports for a child with autism are high, and medical diagnosis is required for access to services. With diverse needs among students and restricted budgets, few school systems yield these costly supports without careful scrutiny of a child’s diagnosis. Only the most affected children are likely to be served. The process of diagnosis itself can take months, as it typically includes evaluations from specialists in speech, hearing, social and cognitive skills, and motor and self regulatory skills. Also, IDEA data does not reflect new diagnoses of toddlers not yet in school programs, nor diagnoses of adolescents who did not qualify for services prior to changes in DSM-IV-TR diagnostic criteria in the late 1980s. Thus IDEA data will reflect under-reporting.

This increase has received legislative scrutiny in California, where Department of Developmental Services data (35) showed that the number of persons entering the system with autism increased dramatically from 1987-1998 relative to cerebral palsy, epilepsy, and mental retardation diagnoses. The data also showed that this accelerated rate appears to be sustaining an upward trend into future years; hence a call for increased funding for school and community supports was made.

The staggering medical, emotional, and financial costs of autism have driven parents to seek new tools for better prognosis. An early monograph in this regard provided parents of affected children with information on the therapeutic use gluten and casein free diets (36). Written by a parent of an affected child who had success with a restricted diet, this book included information on the opiate theory, which holds that maldigestion of gluten and casein and their subsequent, aberrant formation of opiate like compounds (gliadomorphin and casomorphin) are responsible for much of the language delay, behavior, constipation, and dietary rigidity seen in autism (37-47). Opioid peptides are known to adversely affect neuronal development in the central nervous system (47), to affect perception, sleep, pain, cognition, and immune function (48-52), and to create perseverative behaviors (53). Remaining in question is whether excess diet sourced opiate peptides are present in ASD. Shattock (54) finds that 80% of autistic urines tested (n=1100) contain excessive gluten and casein sourced opiates.

What happens in practice? Anecdotal and clinical success with strict gluten and casein avoidance is reported (38,55-57). In my own short experience with this urinalysis, 10 of 15 ASD children tested showed excess casomorphin, gliadomorphin, or both via AAL Reference Laboratories urinary polypeptide test #6500 (66%), and have subsequently responded positively to strict dietary avoidance of these proteins based on parent report and unmeasured clinical impressions at follow up; and, of ASD children with no urinalysis prior to gluten and casein restriction (n=25), all showed a positive response to the restriction. Twenty-one have unknown outcomes due either to attrition or incomplete trial. Many parents of ASD children in my practice (n=61) defer urinary opiate testing since it is not covered by insurance. Reimbursement is withheld since not all researchers agree on the relevance of opiate peptides in autism, and because there is not agreement on diagnostic methodology. High pressure liquid chromatography (HPLC) analysis for these peptides is available from only two laboratories in the US and one in Norway (58). These opiate peptides may also be detectable with radioimmune assay (RIA) but have not been confirmed with mass spectroscopy (59).

Many providers object to gluten and casein restrictions, contending that no proof exists for the efficacy of this approach, and that it only makes children with autism less able to participate in peer or therapeutic activities which include food. Still so simple a measure is easy to test, urinalysis or no, with a strict elimination diet. Though gluten avoidance is challenging and requires substitutions across several food groups, many new food products are available for children using this approach, thanks in part to existing resources from the celiac community. Current recommendations suggest a minimum of three months of strict gluten and casein free eating before judging usefulness of the restriction (55-57,60). The restriction is complete and includes obvious as well as hidden gluten and casein (dextrose, maltose, modified food starch, caramel color, barley malt syrup, calcium caseinate, etc.). Clinical signs that may attend high urinary opiates are aphasia or poor language development; constipation or constipation mixed with wet stools; strong growth and gain or excess weight for stature; marked perseveration and rigidity; marked lack of social connectedness (61). Caveats include that supplemental B vitamins and calcium are necessary; responses will vary with degree of compliance, duration of compliance, and age at start of intervention; other unresolved gut function or food allergy issues will impede progress; and, children with high opiates may object strongly to new foods and show a lapse in behaviors or functioning at first. Anecdotally, a difficult withdrawal period is considered a harbinger of success. ASD children most accustomed to diet-sourced opiates will be most likely to eat them to exclusion, and will most likely feel great discomfort without them at first. Benefits reported to me by parents after this phase include increased alertness and awareness, increased calmness, increased words, babbling, or consonant sounds in aphasic children, increased energy for other activities, increased acceptance of new foods, and lessened constipation. Also reported to me have been spontaneous gains in potty skills. Parents have attributed this to an apparent acquisition of previously numbed sensations for eliminations, which would not be inconsistent with postulated opiate effects in ASD (62) or known effects mentioned above.

While the developmental and behavioral impacts of diet-sourced opiates in ASD are debated, still more disagreement exists over the relevance of immune responses to foods seen in ASD (22,24,28). This is doubly vexing because providers must first agree that antibody responses to foods mediated by immunoglobulins E, G, and/or A (IgG, IgE, IgA) are valid and consistently measurable, and must next accept the premise that these responses have behavioral as well as physical effects. But both these pieces of the autism puzzle remain in dispute. Building the case for their relevance is that intestinal inflammation and permeability are significantly more frequent in ASD (7-10,12,23), both of which will enhance absorption of incompletely digested peptides capable of eliciting antibody responses. IgG antibodies increase intestinal permeability (13). Also noted to be significantly greater in ASD are deficiencies of lactase, disaccharidases, and glucoamylase (9,10), which further serve to present poorly digested food for absorption.

Indeed, it is not uncommon for parents to report to me that their ASD child has never had a formed stool, but has had pale, wet, foul, gold, or mucousy stools with undigested food visible in it since eating solids. Some report 5-12 stools of this type/day beyond age 1 year. Occasional dark dry stool may be mixed in as well. Besides this type of stool, clinical signs which may accompany food intolerance are grey circles under eyes, pallor, bloating, history of or current reflux, picky poor appetite, low or low normal weight for stature, oral tactile hypersensitivity, history of or current eczema, night sweats or frequent waking, and irritability/tantrums. Classic food allergy responses mediated by IgE (causing hives or anaphylaxis) are of less interest in this scenario as parents are usually aware of these and have already omitted the triggering foods. IgG food antibody responses can be measured in blood but not on skin prick testing, and it is these which, anecdotally, appear to impact bowel function and behavior for ASD children. Typical IgG offenders in my experience are egg, soy/legumes, dairy foods, and gluten, though all kind of foods, including oils, fruits, spices, and vegetables have elicited IgG antibody responses in children I have tested via Enzyme Linked Immunoabsorbent Assay (ELISA). A greater reactivity to foods found on ELISA IgG analysis appears to positively correlate with intestinal inflammation noted on endoscopy and with wet gold stools >2/day, though this clinical impression remains untested among children in my case load.

Diets restricted across several food groups must be carefully reconstructed with adequate high biological value protein, fats, and carbohydrates. Free amino acid formulas (Pediatric EO28, Elecare) are useful when intestinal inflammation from chronic antibody response is so great that very few foods appear to be tolerated. Resolution of frequent wet stools either by restriction of offending foods, or addition of supplemental enzymes (Creon or over the counter brands) or intestinal anti-inflammatory medications (Gastrocrom, Dipentum) have also produced gains in bowel habits, potty skills, and development, per parent report to me.

Though there are some 230 physicians world wide known to be using treatments based on the premise that autism is a treatable, even reversible, systemic illness (63), no formal analysis has yet been compiled from all their current case loads, a measure which could provide invaluable insights. Meanwhile, the Autism Research Institute has maintained a database of some 25,000 ASD persons from over 60 countries which contains parent feedback on dietary tools, including supplements (63). Since these tools are available to anyone, many parents dabble with them, and use restricted diets and/or megadoses of supplements with no professional guidance. Poor outcomes can occur where parents don’t completely remove gluten and casein, don’t use a long enough trial, don’t make nutritionally or calorically adequate replacements for restricted foods, dose supplements unsafely or inappropriately, or leave intestinal inflammation, intestinal pathogens, or antigenic responses to foods unaddressed. Other concerns include mixing contraindicated medications and supplements, or stopping medications abruptly for a supplement trial.

Findings of malabsorption, enzyme deficiency, peculiar intakes, and intestinal inflammation in ASD make it plausible that micronutrient absorption or metabolism may suffer as well. Many reports in this regard exist (14-18, 64-74), and debate over therapeutic significance is equally active. Errors in metabolism of purines, metallothioneins, sulfur, glucosaminoglycans, serotonin, tryptophan, secretin, thyroid hormones, essential minerals, essential and non-essential amino acids, fatty acids, and heavy metals have been postulated or reported. Each has spurred the development of new supplement products marketed to parents of affected children. Therapeutic relevance of any one of these items is unknown without pre-treatment clinical assessment and follow up. Given that dietary rigidity and poor gut function may be present, frank nutrient deficiency is not a surprising finding in ASD. This requires assessment and treatment as one would provide for any child. Iron, vitamin A, zinc, magnesium, folate, and B vitamins have emerged as frequently marginal or deficient in ASD.

While replacing clinically deficient nutrients, B vitamins, or calcium lacking in gluten and casein free diets are obvious clinical measures, compensating for metabolic errors with nutritional supplements in ASD is a meagerly explored area of practice. Little is known about the prevalence of metabolic errors in ASD (67,68), but perhaps the most pervasively disabling one suggested to date is reported by Walsh (18) who finds that metallothioneins, the regulatory proteins for copper (Cu) and zinc (Zn), are dysfunctional in autism. Out of 503 ASD patients tested, 499 showed circulating unbound Cu at an average of four times normal levels. A similar but lesser skew of Cu:Zn has been found in assaultive young males without autism (19). This disordered metal metabolism subsequently impacts zinc-dependent enzymes in any tissue, including those responsible for gluten and casein breakdown (carboxypeptidase A, aminopeptidase). Walsh notes that disabled metallothionein metabolism will waste zinc and thus weaken immune function, heighten sensitivity to mercury, cadmium, and lead, lower gastric secretions and weaken stomach acid, lessen secretin response, and impede maturation of intestinal and brain tissues. Therapeutic suggestions include chelation of toxic metals, avoiding dietary Cu and toxic metal exposures, and adding nutrients which pomote metallothionein production (Zn, glutathione, N-acetyl cysteine, selenium, pyridoxal 5 phosphate, or vitamins A, C, D, and E).

High dose pyridoxine or pyridoxal 5 phosphate have been used for nearly four decades to counter behavioral effects and seizures in autism (69-74). Success in clinical trials is mixed (73,75) and anecdotally, roughly half of ASD children who try this supplement appear to benefit from it. Parents report increased speech, eye contact, and lessened perseverative behavior (72). Therapeutic doses start at 200 times the RDA for children age 1-4 (200-500 mg pyridoxine or 25-50 mg pyridoxal 5 phosphate) and no toxic effects are known at this dosage (76). Hyperactivity is reported by parents in some cases, which is countered with additional magnesium at up to 4 mg/kg body weight. Magnesium as well as taurine may play a role in seizure control (77,78). Taurine is used by some for ASD children at up to 1000 mg/day (79).

Therapeutic use of ascorbic acid and cis-palmitate for ASD have also been explored. A dopaminergic effect of ascorbic acid at several grams/day was postulated as the reason for its effectiveness in one trial (80); the cis isomer of vitamin A, which occurs naturally in mammalian milks, liver, and in fish oils, wins support in another, at ordinary doses (81). The trans isomer of palmitate used to supplement infant formulas, milks, and multivitamins has not shown therapeutic effecitiveness and other sources of palmitate are ideally excluded during this therapy (81). Therapeutic doses are given at or slightly above the RDA of 2500 IU/day. Ordinary cod liver oil is suitable but specially flavored cod liver oil products are now available for children to increase compliance. Beneficial effects reported to me in practice include cessation of perseverative visual behaviors (opening/closing doors, lining up trains, staring at fans or wheels), increased language, and increased sustained eye contact. Hypothetically, supplemented cis palmitate restores visual processing which has been impaired in ASD by disabled transport mechanisms for this isomer (81). Retinoid receptors critical for vision, sensory processing, language processing, and immune function are thought to regain functioning when cis palmitate is orally supplemented.

Though products exist to supplement nearly every essential nutrient and several metabolically active, non-essential compounds specifically for ASD, underlying causes for poor digestion, constipation, diarrhea, reflux, intestinal inflammation, or deficiencies should be assessed and treated before using supplements or diet restrictions (56,57,60). Overlooking this sequential analysis and treatment of clinical findings will in my experience impede progress with gluten and casein restriction and/or minimize efficacy of supplements that may be warranted. Stool analysis may reveal treatable overgrowth of detrimental gut flora such as Klebsiella, Clostridia, Bacillus, Blastocystitis, parasites, Candida parapsilosis, C. albicans, or others. These are potential sources of gut tissue injury and inflammation; they may also usurp valuable nutrients from the host and excrete organic acids capable of central nervous system effects (82). Beneficial effects have been noted with antibiotics (21) and anecdotally with antifungal medications used to rid the intestine of these microbes (60), but regression is common when medication is discontinued. Parent feedback to me following antifungal treatment has included increased alertness and language, improved bowel habits, increased calmness and happiness, leaps in potty training, and lessened rigidity in food choices.

Clinical signs of poor gut function have led to the study of secretin as a therapeutic agent for ASD (83). Secretin is released from duodenal cells upon contact with chyme and elicits release of digestive juices from the pancreas. ASD children may not release adequate secretin, due possibly to insufficient acidity of chyme or to other underlying disease. When secretin is administered during endoscopy, a dramatic "gush" of pancreatic juices - larger in volume than typically expected - has been observed in ASD children (83,84), which has led some to postulate that the pancreas is starved for secretin in ASD and compensates with increased receptor sites for this hormone. Porcine secretin is infused typically in a series of 5-8 treatments, depending on a child’s response, at 3-5 week intervals. Infusions have been anecdotally noted to elevate body temperature to a typical level (from 94oF to 98) and maintain it there for up to four weeks following infusion (59), improve bowel habits, and improve behavior and functioning in ASD children. Activation of neurons in the amygdala by secretin has also been reported (59), as has neurotransmitter activity by secretin in the cerebellum (85). The amygdala is critical for ascribing emotional value to stimuli, for comprehending facial expressions, and for allowing joint attention. Reduced activation of the amygdala in ASD has been documented (86).

Four placebo controlled studies showed statistically insignificant or no improvement from secretin infusion (87-90). These trials were limited in that they used one infusion or two rather than a series of several, and used heterogeneous patient populations with wide variations in age, gastrointestinal symptoms, and functional level. This prompted a meta-anaylsis (59,91) which pooled data from the four studies. This analysis showed a statistically significant clinical response to secretin. Larger scale, longer term trials are needed to continue informing on the therapeutic value of secretin.

Though a presumption has persisted for decades that the gastrointestinal symptoms common in autism are caused by anxiety, behavior, and mood disorders, this article presents the work of many who wonder if the reverse is true — e.g., that a disease process with distinct, treatable gastrointestinal manifestations may evolve insidiously and pervasively to create the developmental injury of autism or ASD, if neglected in infants and young children. Many strategies in nutrition care or new medical treatments which have shown therapeutic value in some ASD children are reviewed here. These require more investigation to identify potential responders and to enhance developmental outcomes for ASD children.

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