Article Summary

PSYCHIATRIC ANNALS 37:9 | SEPTEMBER 2007 639

C M E

A utism spectrum disorders (ASD) are among the most puzzling forms of develop-

mental disability. This term refers to a spectrum of pervasive developmen- tal disorders sharing defi cits in three major domains: social relatedness and interactivity, communication, and re- stricted interests and/or stereotypic or repetitive behaviors with diffi cult tran- sitions. Studies have investigated ge- netic factors, neurologic, immunologic,

Scientifi cally Unsupported Therapies in the Treatment of Young Children with

Autism Spectrum Disorders Merryl A. Schechtman, MD

1. Identify the domains of comple- mentary and alternative therapy.

2. Describe the basis for the brain-gut connection hypothesis in autism spectrum disorders.

3. Discuss sensory issues in children with autism and sensory integra- tion therapy.

Merryl A. Schechtman, MD, is Assistant

Clinical Professor of Pediatrics, Albert Ein-

stein College of Medicine, Infant Preschool

Unit, Children’s Evaluation and Rehabili-

tation Center, Rose F. Kennedy Center.

Address correspondence to: Merryl A.

Schechtman, MD, 1410 Pelham Parkway

South, Bronx, New York 10461; fax 718-

892-2296.

Dr. Schechtman has disclosed no rel-

evant fi nancial relationships.

EDUCATIONAL OBJECTIVESC M E

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and early environmental insults. ASD are lifelong, often severe disorders impacting all facets of individual, family, and community function. Re- lationships are disrupted, and socially inappropri- ate behaviors are promi- nent. Often these children do not cope well with change, making it diffi - cult for families to go out in public places. Children may become aggressive, self-injurious, or resort to self-stimulatory behaviors, which serve to calm them. Although the underlying causes of ASD have not been clarifi ed, several promising interventions have been developed utilizing behavioral techniques, educational programs, and pharmacotherapy to address the symp- toms of this disorder. The prognosis for truly normal function is guarded, even with availability of standard therapies, a factor often leading to parental des- peration and the willingness to invest in newer approaches to treatment. Ef- fective evidence-based services may also not be available or in short supply. Standard therapies may require much time to see progress, and therefore some parents may be willing to grasp at the promise of a “quick fi x.”

Scientifi cally unsupported therapies lack a foundation based on objective, controlled research, using methods standardized within biological or medi- cal science. Therapies such as these are often used either in conjunction with evidence-based medical treatments (complementary therapies) or might be used instead of the standard medical practice (alternative therapies). Use of these therapies date back to early folk medicine and are often based upon be- lief systems stemming from religious faith. Although the use of non-stan- dardized home remedies for minor ill- nesses is widespread, the emphasis in

modern-day medicine has been treat- ment that is evidence-based. There has been a growing trend toward the use of scientifi cally unsupported approaches, especially within the fi elds of chronic illness and developmental disabilities.

In 1992, the U.S. government estab- lished the National Center for Comple- mentary and Alternative Medicine (NC- CAM) through the National Institutes of Health. The NCCAM recognizes fi ve do- mains of complementary and alternative medicine: alternative medicine systems (eg, Chinese medicine), mind-body inter- ventions (eg, meditation), biologically- based medicine (eg, megavitamin ther- apy), body-based therapies (eg, sensory integration therapy), and energy therapies (eg, magnet therapy) (see Table).

The prevalence of com- plementary and alternative therapy usage in children with chronic illness, de- velopmental disabilities, and emotional problems is high.1-3 These treat- ments are often promoted commercially. They also generally lack objective, evidence-based studies to support their claims of ef-

fi cacy, often relying upon unproven the- ories with results that are usually based upon anecdotal cases. Commercial Web sites or publications, instead of peer-re- viewed, scientifi c journals, are the ve- hicles promoting the information to the public. Therapies reaching the attention of the media may then be sensational- ized, furthering their promotion. Often pediatricians fi nd themselves in a diffi cult position imposed by a parent requesting their endorsement of an unsubstantiated treatment.4 Recent studies found the use of CAM to range between 50% to 92% in the ASD population.5,6 Within the ASD population, 50% of biologically-based therapies utilized by parents involved dietary changes.7 Seventy-six percent of parents using dietary modifi cations felt

TABLE.

Types of Complementary and Alternative Medicine

Domain Examples

Alternative medicine systems Chinese medicine, acupuncture

Mind-body interventions Meditation

Biologically-based medicine Megavitamins, elimination diets

Body-based therapies Sensory integration therapy

Energy therapies Magnet therapy

SIDEBAR.

Biologically-based Therapies

Elimination diets: Feingold diet, gluten- and casein-free diet, ketogenic diet

Vitamins and supplements: Vitamins A, B6, B12, C, folate, magnesium, dimethylglycine, omega 3 fatty acids

Neurosecretory agents: Secretin, oxytocin

Famotidine (Pepcid)

Immunologically-based therapies:

Antibiotics: vancomycin

Antivirals

Antifungals based on the theory of yeast overgrowth (nystatin, fl uconazole)

Intravenous immunoglobulin G

Toxin removal: Chelation therapy based on theory of mercury toxicity

Non-biologically based treatments: Sensory integration therapy, facilitated communication therapy, auditory integration therapy, hyperbaric oxygen therapy

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•

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PSYCHIATRIC ANNALS 37:9 | SEPTEMBER 2007 641

that these had been of some benefi t for their affected child. In the category of body-based therapies, chiropractic ther- apy was most commonly used; however, there was no real reported benefi t. Vari- ous therapies were reported by parents as helpful in relaxing the child diagnosed with ASD, and these included therapeu- tic horseback therapy (hippotherapy), massage, music therapy, and sensory in- tegration therapy.

This article will focus on many of the biologically and non-biologically based alternative or complementary therapies used in the treatment of ASD (see Sidebar, page 640).

BIOLOGICALLY-BASED THERAPIES

Diets: The Brain-Gut Connection The potential relationship between

gastrointestinal symptoms and autism has been the basis of much investigation in this population. Valicenti-McDermott et al8 reported a higher than expected frequency of gastrointestinal symptoms and food selec- tivity in a sample of 50 children with ASD. Increased symptoms such as diarrhea, re- fl ux, constipation, bloating, etc., have been reported with frequencies of 9% to 50% in this popu- lation.9 Increased lev- els of serotonin, a primary gut neurotransmitter, have been found in the plasma of people with au- tism, but it is not clear that this is linked to the gastrointestinal symptoms.10

In a small, double-blinded, placebo- controlled study reviewed by Erickson,11 famotidine (Pepcid) was administered to children with ASD and gastrointesti- nal symptoms. Improved behavior was noted; however, four of the nine chil- dren noted to have behavioral improve- ment had undiagnosed gastroesophage-

al refl ux disorder, which may have been a factor in their improvement.

Dietary manipulation in the treat- ment of developmental or behavioral problems is not a new concept. The ori- gin of this practice is beyond the scope of this article. However, more recent dietary practices based upon presumed associations with nutritional excesses and defi ciencies and possible effects on behavior evolved in the 1920s, with the suggestion of excessive sugar con- sumption and the development of hy- peractivity and impulsivity. The Fein- gold diet,12 which became popularized in the 1970s, was largely based upon these theories.

In the 1970s, Panskepp13 proposed that malabsorption of casein (a milk pro- tein) and gluten (a wheat protein) might be responsible for manifestations of au- tism via altered cerebral neurotransmit- ter metabolism. The protein metabolites from milk and wheat products were

postulated to be absorbed through a “leaky gut” and to act central-

ly as endogenous opioids;

however, the relationship between opioid activity and the

development of autism remains specula- tive. The fi nding of increased peptides in the urine of children with autism14 is controversial, as is the proposal that a gluten- and casein-free diet can decrease urinary peptides, resulting in increased social interactivity among autistic chil- dren. Despite the lack of defi nitive data, the use of the gluten-/casein-free diet is widespread with many anecdotal testi- monials of its success.

Erickson11 also reviewed the use of the ketogenic diet in a small population of children with autism. Although im- proved behavior was noted, the study was not controlled. Dietary limitations, such as those imposed by selective elimination diets, may impose addition- al stress on children and their families and hypothetically may result in nutri- tional defi ciencies.

In 1998, Horvath’s report on im- proved developmental/behavioral func- tion following secretin administration to children with gastrointestinal com- plaints and symptoms of autism added to the growing number of theories of brain-gut interaction based upon gas- trointestinal proteins acting as central neuropeptides in the brain.15 However, despite the initial excitement of se- cretin as a treatment in ASD, multiple well-controlled, peer-reviewed stud- ies on more than 700 children did not bear out the treatment effects initially reported by Horvath.

In 2002, Wakefi eld16 reported a case series of endoscopic studies on children

with autism and gastrointestinal symp- toms. An increased rate of ileal lym- phonodular hyperplasia and colitis was reported. This article has since been re- tracted by almost all of the authors.

The Immune System Connection Abnormal immune function in chil-

dren with ASDs has included the fi nd- ings of increased antibodies, abnormal cytokines, antibodies to myelin basic protein, abnormal immune responses, and a reported increased prevalence of

The U.S. Institute of Medicine report ... concluded that there is no evidence linking the

MMR vaccine with autism.

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lymphonodular hyperplasia in a previ- ously diagnosed population of children with ASD.16-18 Despite suspicion of im- mune or autoimmune dysfunction in children with ASD based upon reports of increased gastrointestinal symptoms, ear infections, and allergies, no increase in the rate of either ear infections or allergic responses, has been noted.19,20 However, a recent report revealed a higher family his- tory of autoimmune disorders (rheuma- toid arthritis, celiac disease, and infl am- matory bowel disease) in a population of children with ASD and gastrointestinal symptoms who had undergone language regression, compared with those without language regression.21

IS IT VIRAL? Levy and Hyman’s 2005 review22 cited

investigational reports of evidence of early infection, chronic infl ammation, or au- toimmune disorders as possible etiologic factors in ASD. They commented that prenatal and neonatal exposure to viruses is postulated to alter brain development; however, studies of viral exposure failed to show an infl ammatory response in the brain. Antiviral agents have been proposed as a treatment strategy; however, no spe- cifi c virus has been identifi ed, and no pub- lication has addressed antiviral therapies in terms of effi cacy or safety in ASD.

In 1998, Wakefi eld16 reported on 12 cases of children with GI abnormalities and lymphonodular hyperplasia, and eight of the 12 children allegedly dem- onstrated symptoms of autism reported to develop soon after receipt of an MMR vaccination. Although Wakefi eld did not prove an actual causal connection between autism and MMR, public con- cern nonetheless exploded after this was reported on 60 Minutes. Madsen et al23 using national-registry data on autistic disorders in Denmark (a national cohort study including 537,000 children) found no association between the MMR vac- cine and the subsequent diagnosis of au- tism. In March 2004, 10 of Wakefi eld’s

co-authors published a formal retrac- tion of the suggestion of a link between MMR and autism in The Lancet.24 The U.S. Institute of Medicine report co- sponsored by the National Institutes of Health and the Centers for Disease Con- trol and Prevention concluded that there is no evidence linking the MMR vaccine with autism.25

IS IT BACTERIAL? Sandler et al26 used the antibiotic van-

comycin in a small study of 11 children with autism and diarrhea whose stools were colonized with a different clostridi- um species than controls. It was suggested that neurological symptoms might result from altered gut integrity on the basis of toxins in altered colonic fl ora. However, outcome parameters of this study were not totally blinded, and the children’s be- haviors may have improved because of improved bowel function alone.

IS IT FUNGAL? In the 1980s, anecdotal reports impli-

cated overgrowth of the yeast Candida albicans in precipitating some cases of autism. Crook27 suggested the over- growth of yeast to be secondary to anti- biotic use or ingestion of processed sug- ars. Candidal overgrowth was, however, not documented by endoscopic study.16 The yeast theory popularized the use of treatments to reduce yeast colonization, which included the use of probiotics (ac- idophilus, lactobacillus), dietary modifi - cation (reduction of refi ned sugars), and the use of antifungal agents like nystatin and fl uconazole.

IS IT PRIMARY IMMUNODEFICIENCY?

Levy and Hyman22 reviewed three small case series of ASD with equivo- cal results after intravenous immu- noglobulin G (IVIG) administration. However, because of the small risk of blood-borne infection and side effects of IVIG, they recommended that this

agent be used for diseases where there was documented benefi t.

IS IT HEAVY METAL TOXICITY? Bernard et al28 drew attention to sim-

ilarities between symptoms of autism and mercury toxicity, suggesting a con- nection between environmental sourc- es of mercury and the development of autism. However, mercury poisoning is characterized by severe movement dis- orders and peripheral nerve damage, none of which is typically found in children with ASD. Nonetheless, me- dia reports led to requests for mercury testing because of growing concerns of possible toxicity. Mercury, a heavy metal found in the environment, accu- mulates in internal organs. Therefore, blood and urine assays do not always reveal mercury exposure. Hair trace analysis, which has not been standard- ized, is not considered to be a reliable assay for mercury toxicity because of differing rates of hair growth, variable hair composition, and because sham- poos, hair products, exposure to sun, and drying all serve to leach substances from hair. Thimerosal, an ethyl-mer- cury based preservative once used in many vaccines in the United States (in- cluding the MMR vaccine), was sug- gested as a possible cause of autism in a subpopulation of immunized chil- dren. Other sources of mercury such as that contained in thermometers, mer- cury amalgams in tooth fi llings, and some fi sh came under scrutiny in the search for environmental precipitants of autism symptoms. Pregnant women were issued warnings against exces- sive fi sh consumption, and amalgam removal was even suggested. Madsen et al23 examined the use of thimerosal- containing vaccines and ASD in Den- mark, where thimerosal was removed from vaccines in 1992. This study demonstrated that despite removal of thimerosal from vaccines, the numbers of autism cases continued to rise at

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the same rate as prior to its removal. Studies of children who received heavy metal chelation failed to demonstrate improved neurodevelopmental func- tion on follow-up.29 More ominous was the documentation of two deaths in children in the United States (one of whom had autism) because of hypocalcemia and cardiac arrest after undergo- ing chelation thera- py.30 The American Academy of Pedi- atrics (AAP) and the Public Health Service published a statement in 2001 indicating the lack of a decrease in the prev- alence of autism despite the removal of thimerosal.31 Although there is no evidence for mercury’s role in causing ASD, chela- tion therapy has been utilized as a de- toxifi cation procedure, with occasion- ally disastrous results.

VITAMINS AND NUTRITIONAL SUPPLEMENTS

Nutritional supplements have also been popularized in the treatment of symptoms in children with ASD. Megavitamin ther- apy gained popularity in the 1960s with Linus Pauling’s theory linking mental ill- ness and inborn errors of metabolism.32 A variety of vitamins (vitamins A, C, B6- magnesium complex, folic acid, B12) and minerals have been advocated.

Vitamin B6-magnesium complex has been the most heavily promoted of the vitamin therapies for ASD. Vitamin B6 (pyridoxine) has been advocated because of its cofactor role in the production of the neurotransmitters: serotonin, norepi- nephrine, epinephrine, dopamine, and GABA. Magnesium may have an addi- tive effect on this. Rimland33 reported decreased behavioral outbursts in autism with vitamin B6-magnesium supple- mentation, based on more than a dozen

studies at that time, many of which were not blinded or adequately controlled. In a review of the literature in 2002, Nye and Brice34 concluded that no recom- mendation could be made for this treat- ment based upon the scant data available. Caution is advised because excessive in-

take of pyridoxine is associated with peripheral neuropathy.

Excessive magnesium concentrations are associated

with the development of seizures. Vitamin A, such as that found in

cod liver oil, is promoted as improv- ing immune function and vision in children with autism; however, no data are available. Excessive use of Vitamin A can lead to hepatotoxicity and increased intracranial pressure.

Vitamin C (ascorbic acid) was reported in one trial to decrease ste- reotypic behaviors significantly in a study of residential students with au- tism; however, this study was never replicated.35 Vitamin C in excessive doses has the potential to cause diar- rhea and renal stones.

Vitamin B12 treatment was recom- mended based upon data from a small, controlled study of 20 children with autism found to have lower plasma con- centrations of the antioxidants methio- nine, homocysteine, total glutathione, cysteine, and S-adenosylmethionine as compared with controls.36 Administra- tion of subcutaneous vitamin B12 and oral folinic acid to patients with ASD is based on the premise that these indi- viduals have compromised antioxidant defenses with an inability to detoxify

environmental contaminants. This study suggested that as plasma concentrations of the antioxidants increased, behaviors were noted to improve; however, further studies have not replicated this data.

Dimethylglycine (DMG, a nutritional supplement) is metabolized to the excit- atory neurotransmitter, glycine, within the liver. There have been reports of an old

Russian study, which suggested enhanced language skills in developmentally disabled children who were administered DMG; however, two well-controlled and blinded studies in ASD failed to demonstrate a dif- ference between DMG and placebo.37,38

Omega-3 fatty acids or polyunsatu- rated fatty acid (PUFA) 39 is a popular treatment for a variety of developmental problems including attention-defi cit/hy- peractivity disorder, dyslexia, develop- mental coordination disorder, and ASD. The results of controlled treatment trials have been mixed and are hard to inter- pret because of differing formulations of the essential fatty acids and different populations treated. Larger clinical trials are needed to corroborate the fi ndings of a few reports of improved behaviors.

Oxytocin intranasally and intrave- nously may have signifi cant positive effects on repetitive behaviors and so- cial cognition in adult autism patients; however, the signifi cance of these re- sults needs further investigation as studies on adults cannot be general- ized to children.40

Other Supplements Levy and Hyman reviewed data on

other supplements such as tryptophan,

Although there is no evidence for mercury’s role in causing ASD, chelation therapy has been

utilized as a detoxifi cation procedure, with occasionally disastrous results.

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tyrosine, cyproheptadine, D-cycloser- ine, and carnosine. There is need for additional research to support the use of these supplements.22

NONBIOLOGICAL INTERVENTIONS

Sensory Integration Therapy Ayres, an occupational therapist, pos-

tulated in 1979 that children with ASD have defi cits in the brain areas responsi- ble for processing sensory input (visual, tactile, auditory, gustatory, vestibular, and proprioceptive) and motor output.41 Sensory integration activities include jumping on trampolines, swinging, spin- ning the body, rolling the body, riding a scooter board, balance activities, appli- cation of brushes to the body, the wear- ing of weighted vests, “smooshing” a child between pads or pillows, and play- ing with textured toys. Oral motor activ- ities may be used as well. Manipulation of the environment is central to sensory integration therapy; therefore, the fabric (texture) of clothing or sheets may be changed. Labels and tags are removed from clothing, and class sizes are limited to decrease distraction. Within the class- room, a quiet corner is established to pro- vide an area with decreased stimulation. Occupational therapists commonly pro- vide sensory integration therapy, which may take place in differing venues, such as in the home or school. Anecdotal evi- dence for effi cacy of sensory integration therapy is widespread, and there is great interest in establishing an evidence-base for these therapies.

There is ongoing research evaluating the use of water therapy (aquatherapy), horseback riding (hippotherapy), music (music therapy), massage, and other therapies, which claim to calm and im- prove behavioral symptoms in children with ASD and other disabilities.

Facilitated Communication Facilitated communication (FC) refers

to an intervention utilizing either a com-

puter or typewriting device in which an- other individual, the facilitator, guides the hand of a nonverbal individual. This tech- nique was originally used to assist physi- cally disabled individuals.42 Numerous controlled and blinded studies have failed to demonstrate FC as replicable or valid. In 1998, the AAP issued a statement from the Committee on Children with Disabili- ties highlighting the lack of scientifi c data to show FC to be effective.43

Auditory Integration Training Auditory integration training (AIT)

is a technique conceived by a French ENT specialist, Dr. Guy Berard, in the 1960s. It consists of acoustically modifi ed music played to a child for 10 hours in two 30-minute sessions each day from a CD player attached to box (AIT device) that is wired to modify the signal, presumably to reduce the vol- ume for frequencies to which the child is hypersensitive. It was publicized as a method to “retrain” the auditory system in children with auditory sensitivities and became popularized by the book “The Sound of a Miracle” by Stehli.44 Gravel45 stated that there was no scien- tifi c evidence for the type of peripheral hearing abnormalities that Berard orig- inally reported. In addition, the sound pressure levels produced by some of the AIT devices were potentially unsafe. The 1998 statement of the AAP, which addressed Facilitated Communication,42 also indicated the lack of scientifi c evi- dence and potential danger of Auditory Integration Training, recommending its use in experimental protocols only.

Hyperbaric Oxygen Therapy A review of hyperbaric oxygen ther-

apy (HBOT) indicates successful use of this therapy in improving perfusion and healing in wounds (diabetes), carbon monoxide poisoning, and decompres- sion illness in sports divers.46 HBOT has been used for the treatment of cerebral palsy, fetal alcohol syndrome, traumatic

brain injury, and ischemic brain injury. It was postulated that decreased blood perfusion to several areas of the brain, in particular the temporal regions and auditory processing and language areas, correlate with many of the behaviors as- sociated in autism.47 However, scientifi c evidence is lacking for the use of HBOT in developmental disabilities.

SUMMARY Our understanding of ASD has

changed over the past decades, and di- agnostic tools have assisted in earlier identifi cation and referral for interven- tion. Appropriate intervention appears to impact positively on overall outcome for a pervasive developmental disorder for which there is currently no known cure. Novel and controversial thera- pies will come and go, and therefore physicians should familiarize them- selves with these interventions, as ad- vice about these alternative approaches will be sought. Discussions of nontra- ditional therapies should include the placebo effect, possibly undesirable, or potentially dangerous outcomes of a treatment, and the importance of scien- tifi cally sound research studies of that treatment. Addressing the use of com- plementary and alternative therapies in families with medically compromised or developmentally disabled children is crucial to providing complete care to the patient.

A note from the editors: This article originally appeared in

Pediatric Annals, a SLACK Incorporat- ed publication.

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