Autistic spectrum disorders (ASD) are diagnosed with increasing frequency in children under 3 years of age. 1,2 The clinical diagnosis is supported by identification of core deficits in communication, social reciprocity, and repetitive behaviors, 3 even in young children. 4,5 Although there is much we do not know about the natural history of symptoms in preschool children, the diagnosis of ASD is typically stable in 2- to 3-year-old children. 5 The emphasis on early diagnosis and referral for treatment is based on studies that suggest that intensive services begun before age 3 might be associated with better academic and behavioral outcome at school age. 6–8 With increasingly rapid access to scientific and anecdotal information in the electronic and print media, families often formulate opinions about possible interventions that are not among those conventionally suggested by their child's treatment team. A strong belief in a treatment that is considered alternative or complementary or alternative medicine (CAM) may change the professional dynamic between professional and parent. This article reviews some of the common CAM treatments used to address symptoms of ASD and discusses strategies that professionals may use in assessing the validity and safety of new CAM treatments that emerge.
CONVENTIONAL TREATMENT RECOMMENDATIONS
Most experts will agree that the best first line of treatment is an intensive, coordinated program of special education, developmental therapies, and behavior management. 9,10 A developmentally appropriate intervention program, with a language-based curriculum for promotion of communication and social skills, is essential to promote progress. This program should include intensive speech-language therapy, with consideration for possible support with augmentative or total communication. If the child has sensory intolerance that causes behavioral dyscontrol, strategies employed by occupational therapists can be incorporated into the program to enhance functional abilities and sensory tolerance. Last, the program should incorporate an intensive behavioral intervention approach to enhance the acquisition of language and social behaviors.
Programmatic application of techniques of applied behavior analysis including discrete trial instruction has demonstrated improvements in skill acquisition and function. 6,11 Home and educational programs using DIR (developmental, individual-difference, relationship-based) approach, also known as “floor time,” have been advocated for reinforcement of communication and play skills in naturalistic settings. 12 Other curricula, such as the TEACCH approach, 13 provide an individualized educational program that is structured to address the deficits of children with ASD. Although center-based programs utilizing developmental curricula have been traditional sources of intervention and have much anecdotal support, few objective data have been collected to demonstrate efficacy. 9,10 Medication remains a small part of the treatment in the preschool-age child. For symptoms such as inattention, hyperactivity, impulsivity, severe aggression, sleep disorders, and others, a trial of medication may be a helpful adjunct to a behavioral program 14,15 that has been carefully devised to address these problem behaviors. Medication will not treat the core symptoms of autism.
A recent policy statement from the American Academy of Pediatrics 16 outlined the role of the pediatrician in the diagnosis and management of ASD in children. Therapists and educators are in a unique position to influence families who may be pursuing a range of treatments. They may be able to guide families to seek medical assistance and avoid serious side effects or complications if they are cognizant of the basis, benefit, and harm of popular treatments. The American Academy of Pediatrics' recommendations include use of specific screening tools, referral for audiologic and speech-language evaluation, and involvement in early intervention and developmental therapy services. Physicians are urged to become familiar with popular alternative treatments and approach the issue objectively and compassionately. This is good advice for educators and therapists as well.
It is the job of medical, educational, and other professionals serving infants and young children to educate families to review critically promises of cure or treatment. Families should pursue standard treatments before considering other ones. Careful analysis of treatment claims should extend to the treatments used in conventional intervention programs as well, since there are often limited outcome data to justify recommendations for the conventional treatments offered. 17 Since developmental disorders such as ASD have nonspecific treatments for unclear etiologies, many families seek answers that provide more hope or definitive promise of cure. 18,19 Families should be taught to become informed consumers and to review critically the validity of proposed treatments. They should look for scientific evidence of benefit, potential health risk, and financial or time cost of all treatments.
Investigators 11 in a study of intensive behavioral treatments for young children with autism surveyed families to identify what other approaches they were employing. Out of 121 families working closely with treatment teams, 56% had used sensory integration therapies, 50% had tried elimination diets, and 61% had tried vitamin supplements. A subset of families was interviewed regarding their choices of additional therapies. All of those using diets and vitamins had obtained their information from other parents or from literature related to ASD. The original assessment teams were the source of the recommendation for speech-language therapy. Therapists outside the treatment team recommended sensory integration.
Since CAM treatment is in such frequent use by families with children with disabilities, the American Academy of Pediatrics 20 recently issued a position statement. This statement advises pediatricians to be supportive of families in their search for treatment, careful in their interpretation of claims from non-peer-reviewed sources, and watchful over the child, being alert for potential side effects.
Some of the CAM treatments have been subjected to scientific, unbiased study; however, most claims are based on anecdotal reports or subjective case series. Young children with ASD may respond to educational and therapeutic interventions in a dramatic fashion. The disorder is not static, so studies of efficacy must be carefully designed to eliminate confounding factors of treatment and time effects. Further, the effect of placebo cannot be discounted. 21 To be confident that an intervention is effective, a study must include random assignment of comparable subjects to different treatments, measure outcome variables using valid measures, and employ consistent doses/treatments across subjects. 22
There are two different types of CAM treatments: biologic and nonbiologic. Biologic agents either can be bought over the counter by families or administered by a physician. It is helpful to consider them in three categories as listed in Table 1. The nonbiologic treatments are novel approaches to existing therapies; they are provided by a therapist or may be self-administered by the family or child.
Several different vitamins and vitamin preparations are in common use. In most instances they are not potentially harmful. Many children receive a combination of vitamin B6 (pyridoxine) and magnesium supplementation, with a high dose of B6 (at one to two times the Recommended Dietary Allowance). A few controlled scientific studies have shown some short-term benefits, but most refute claims of behavioral improvement. 23,24 Several studies have shown some symptomatic benefit, but are compromised by methodologic problems. A double-blind, placebo controlled study could not corroborate the prior findings. 24 Potential side effects include peripheral neuropathy and arrhythmia from magnesium overdose. 18
Vitamin C is not as commonly used, but offers some promise. A small study 25 showed decreased stereotypic behaviors with treatment, but this study needs to be duplicated. Few side effects are noted. Dimethylglycine (DMG) was not found to be beneficial in a small case series. 26
Vitamin A treatment is based on the assumption that some children with ASD are vulnerable to the impact of mercury exposure and that vitamin A supplementation can change this vulnerability. This is based on the hypothesis that genetically at-risk children are predisposed by G-alpha protein defect. It is assumed by proponents of that theory that live measles vaccine depletes stores of vitamin A, resulting in metabolic changes and precipitating behavior changes in children with ASD. 27 Supplementing with natural forms of vitamin A (such as cod liver oil) is purported to improve immune and visual function. No data are available about effectiveness. There are multiple serious side effects from overdose, including pseudotumor cerebrii (increased pressure around the brain). Overdose during pregnancy may result in fetal loss and deformity or damage.
Secretin is a hormone found in the gastrointestinal tract that helps control digestion. Its use for children with ASD came to attention after publicity in 1998 on a national television show. The show highlighted a case report in the medical literature 28 about three children with ASD who improved 5 weeks after secretin administration. These children had decreased gastrointestinal symptoms and improved behavior. Since then multiple evidence-based scientific studies have failed to confirm the claims of dramatic improvement in the symptoms. 29–33 Despite objective data disproving an association in their individual child, many families who participated in well-designed, double-blind controlled trials have continued with secretin treatments. 21 Potential adverse side effects include immunologic or allergic response to repeated administration of foreign protein and seizures. To date, there are several hundred children with autism who have had careful assessment of response to a double-blind administration of secretin with no statistically significant benefit. Families who wish to pursue this therapy may be best served in controlled trials.
Some families have explored ingestion of alkaline salts in an effort to provide natural secretion of secretin and other gastrointestinal peptides. 18 Alkaline salts are potentially harmful to the liver. No studies of safety or efficacy have been completed, and there is potential risk in altering the body's natural acid-base homeostasis.
Bethanecol is a medication used in gastrointestinal disorders such as gastroesophageal reflux. Some clinicians feel it is a pancreatic stimulant and has an effect similar to secretin. One non-peer-reviewed source 34 reports that children's symptoms improved after treatment with a combination of vitamin A in cod liver oil and bethanecol. No published results of controlled studies are available.
Pepcid (famotidine) is an antacid that has been used because of earlier reports of effectiveness in treatment of symptoms of schizophrenia. 18 One report 35 suggested its use in autism, but no controlled studies have been completed in children with ASD. There is, however, extensive experience with famotidine for symptoms of gastroesophageal reflux in children.
Many investigators have suggested that ASD may be caused by a dysfunction of the immune system. There are many reports of abnormalities in the number and types of antibodies, immunoglobulins, lymphocytes, and proteins in the central nervous system. 36,37 Laboratory studies showing differences in measurements of immune markers (eg, elevated or decreased immunoglobulin levels or antibody response to viruses) have been used as justification for treatment with intravenous immunoglobulins (IVIGs) or antiviral medications. Controlled studies of IVIG treatment do not document significant improvement. 38,39
Although there are anecdotal reports of children with ASD treated with antiviral medications typically reserved for documented systemic viral infections, there are no data on safety or efficacy. It is known that prenatal brain damage from rubella infection during gestation may lead to ASD. It is plausible that other viruses also might infect the brain prenatally and cause the types of pathologic findings frequently seen in the brains of people with autism. 40 However, no such virus has yet been identified. Immune response to common childhood viruses may not be specific for central nervous system infection, and do not imply causality. 27,41 The literature to date does not support the use of IVIG or antiviral treatments outside of research protocols.
It has been hypothesized that in children with ASD gastrointestinal dysfunction leads to overgrowth of bacteria in the gut. The theory describes possible yeast overgrowth, primary dysfunction of the immune system, and/or antibiotic overuse. One treatment includes use of probiotic therapy, where bacteria living in the gastrointestinal tract are replaced with other benign organisms such as acidophilus (found in yogurt) or treated with antibiotics such as vancomycin, which eliminate a large number of gut bacteria. A case report on an Internet Listserve of several children treated in an open label trial of vancomycin precipitated great interest in this treatment. There have been no controlled scientific studies. Vancomycin has several serious side effects including colitis-like inflammation and development of bacteria that are resistant to this potent antibiotic. In many hospitals, the infectious disease specialist must be consulted if this antibiotic is prescribed in order to regulate the possibility of creating immune bacteria.
Another theory of causation of autism involves yeast overgrowth in the gastrointestinal tract due to excessive treatment with antibiotics. The hypothesis suggests that overgrowth of candida or yeast, which produces toxins, acts centrally on the nervous system to produce the symptoms of autism. The initial evidence for this was circumstantial, 42 with documentation of substances related to Kreb's metabolic cycle intermediates in the urine of two brothers who developed symptoms of ASD with intermittent motor findings. Proposed treatment of yeast overgrowth would include lengthy courses of nystatin, Diflucan, and other medications. Stool cultures may be used as an endpoint of treatment, but it is not clear if this is a valid endpoint, as there are no data about how commonly yeast would be found in large numbers of children who are asymptomatic. Horvath et al 43 did not demonstrate yeast in samples taken from the small intestines of children with ASD at the time of endoscopy. These medications have possible side effects of liver toxicity and anemia. Dietary means of discouraging yeast overgrowth have been proposed, 44 but have not been examined for efficacy in clinical trials.
Diet or additives
The idea of dietary treatment of ASD is appealing to many people. Since many families report gastrointestinal symptoms (constipation, diarrhea, and extreme dietary selectivity), this seems like a logical source of treatment. In theory, many view it as a noninvasive, nontoxic means of providing treatment. The theory behind the efficacy of dietary treatment in ASD, particularly the gluten-free/casein-free diet, is the opioid excess theory. In short, this theory states that children with ASD have impaired function and permeability of the gastrointestinal system (“leaky gut syndrome”). Because of this dysfunction, fragments of wheat (gluten) or milk (casein) are not well absorbed. These fragments theoretically function as endogenous neuropeptides, or chemical transmitters that affect brain function. 18,45,46 This theory, the common history of gastrointestinal symptoms, and reports of effectiveness of gluten-free diet have led investigators to question whether celiac disease is more common in children with ASD. 47 There are conflicting reports of laboratory studies to confirm gluten sensitivity in children with ASD. Further controlled studies of diagnostic evaluations for celiac disease and impact of gluten-free diet need to be done.
The gluten-free/casein-free diet may be the most commonly used non-medication treatment attempted, although many families may not implement the diet correctly with total elimination of gluten and casein. Anecdotal reports and the lay press describe remarkable improvement with implementation of the diet. Since so many children do have gastrointestinal symptoms, and many parents report changes in affect and attention, it is hard to disregard the claims. However, the studies that have attempted to demonstrate efficacy of this diet have been flawed. Study problems have included lack of valid outcome measures, presence of confounding treatments, and no placebo controls or challenges. 45,46,48 There are two, single-case methodology reports that were published more than 20 years ago, 49,50 Case series 48 have had multiple confounding factors.
Since information on the diet has appeared extensively in the media and popular press, many families undertake this diet without professional guidance or nutritional support. There may be real risks in decreased calcium and vitamin D intake in young children in whom the most abundant source of these nutrients is cow milk. 51 There have been two recent case reports of children without autism who were diagnosed as having protein malnutrition after being maintained on rice- or soy-based beverages by health-conscious parents without being provided an alternate protein source. 52 Protein sufficiency may be tenuous in children with ASD given their food preferences, which is further compromised by additional limitations. 53,54 Young children can have a nutritionally adequate diet that is milk and wheat free. Nutritional consultation is indicated, and monitoring by the primary care provider is essential.
Other approaches have included administration of essential fatty acids (EFAs) such as flaxseed oil. The justification for this treatment is extrapolated from limited data related to children with attention deficit/hyperactivity disorder (ADHD). 56 Supplementation with EFAs is commonly used in an effort to enhance attention. This has not been assessed specifically in children with ASD.
Chelation is one of the more recent treatments that has reached popularity without adequate scientific scrutiny. Chelation involves the administration of a chemical (by mouth or through an intravenous catheter) for the purpose of binding up and removing from the blood potentially toxic heavy metals such as iron, mercury, lead, and others. The theory supporting chelation suggests that heavy metal intoxication, especially mercury, is responsible for the regressive form of autism. The source of mercury is felt to be thimerosal, the preservative in immunizations. Protocols for chelation treatment in children with ASD have been proposed and are being implemented by practitioners without benefit of controlled scientific study of their efficacy for changes in symptoms of ASD. Recent studies 57,58 have not confirmed chelation's efficacy in producing changes in developmental function in children with documented lead intoxication. The chemicals used for chelation (eg, DMSA) are not approved by the Food and Drug Administration for treatment of autism. They are potentially dangerous, with side effects of liver and kidney toxicity, potential severe electrolyte and fluid imbalance, and hypersensitivity.
Many families and clinicians believe that mercury toxicity through exposure in immunizations is a cause of autism. The belief that symptoms of mercury toxicity from dietary or industrial sources might mirror symptoms of ASD has resulted in concerns about the safety of the use of inorganic mercury in the form of thimerosal as a stabilizer in multi-use vials of hepatitis and diphtheria-pertussis-tetanus (DPT) vaccines (see above section on chelation).
Exposure to organic mercury from maternal whale meat ingestion in the Faroe Islands has been associated with language delays in children. 59 However, similar doses in the Seychelles from maternal ingestion of fish did not produce identifiable developmental disabilities. 60 A record review of weight and thimerosal exposure in a large cohort of children in a vaccine monitoring program did not show an association with ASD. 61 A weak association with language delays was noted, however. 61
Analysis of the existing literature did not support evidence of harm at the doses of thimerosal found in vaccines. 62 Steps are being taken for removal of thimerosal from most vaccines. A report evaluating the putative association of thimerosal and autism will be published in the near future by the Institute of Medicine.
Allegations have been made that the measles-mumps-rubella (MMR) vaccine administration predated onset of behavioral regression in children with ASD and gastrointestinal symptoms. 63 Wakefield et al 62 theorized that changes seen due to autistic enterocolitis, including changes in intestinal permeability, were secondary to viral infection from the vaccine invading the gut or perhaps altering the permeability to potential neurotoxins. This hypothesis led to a popular belief that administration of monovalent MMR vaccines, rather than the trivalent vaccine, would not increase risk of ASD. Proponents of this theory believe that simultaneous administration might lead to persistent infection or alteration of the clinical and immune response to the antigens. Review of the scientific evidence does not support an association at a population level between ASD and MMR. 27,61 There has been no change in the existing dosage schedule of childhood vaccines based on these allegations.
A number of noninvasive or nonbiologic treatments also have come into common use. The popularity of each varies by time and geographic location, despite a dearth of well-controlled, evidence-based studies to support or refute their efficacy. The treatments include auditory integration, facilitated communication, craniosacral manipulation, and others.
The goal of auditory integration is to decrease sensitivity to sound by systematic exposure to altered music by headphones. A well-designed study described in a recent position paper 63 of the American Academy of Pediatrics did not confirm positive effects, and the academy does not endorse this treatment. It is possible that some aspect of the treatment may be effective for some aspect of ASD in a subset of individuals. Existing research does not permit that level of analysis.
The initial positive results of facilitated communication, the use of a communication device with physical contact but not conscious guidance from a familiar person, have not been confirmed when examined in a blinded fashion. Facilitated communication was initially proposed in the 1980s. Effects seen in children have been subsequently shown to be a function of activities of the facilitator. 64
Craniosacral manipulation is a type of manipulation done by chiropractors, physical therapists, and occupational therapists trained in the technique. Advocates purport that by massage of the skull they can alter the flow of cerebrospinal fluid and effect behavioral change. No scientific treatment data are available to confirm proposed benefits. 9
Interactive metronome is a theoretical treatment. It involves use of a musical metronome to alter the timing of information presented to children to enhance concentration and vigilance. No studies of children have been completed. Some preliminary positive results were reported at a conference, based on some results seen in children with ADHD. 64
There are many factors that contribute to parents' choices of treatment for children with ASD. Some of those choices may not include or may interfere with traditional early intervention services. All professionals involved in the therapeutic management of children with ASD need to be aware of all the available options. Professionals caring for infants and young children provide very intense services. They spend many hours with children with ASD and their families. They have the opportunity to observe subtle behavioral effects and may be in a position to assist parents in objectively assessing the results of treatments chosen. The placebo effect also may involve members of the therapy team, so it is important to use objective data when possible. Educational and therapeutic teams that have frequent contact with a young child may be the first to notice side effects of CAM treatments and, as child advocates, can serve an important role in counseling families regarding timely medical consultation. Just as pediatricians have been advised to have an open mind regarding the possible efficacy of CAM treatments while supporting the well-being of the child, other professionals working with families and young children have the same directive.
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