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Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
March 23, 2009
The frequency of autism has increased and is accurately considered an epidemic (1). In the early 1970s., the rate was 1 in 10,000. In the early 1980s. the rate had increased to more than 1 per 2500. In recent years, the rate of autism-spectrum disorders is even higher and is now estimated at 1 per 150 children, with some states and the U.S. military reporting even higher rates. Although better diagnosis and other factors account for a small percentage of autism's increased prevalence, most of the increased rate is actual (1).
Although the Hertz-Piccioto et al prevalence study focused upon California (1), which uses accurate diagnostic criteria, the rate of children with autism or other autism-spectrum disorders (ASDs) is increasing nationally, even internationally. An important question arises: Have medical schools and other conduits of physician-training (eg, CME, primary journals) prepared physicians not only to diagnose and treat autism and other ASDs but also - and this is equally important - to diagnose and treat pathologies associated with autism and the other ASDs (2-5)?
Three recently published, peer-reviewed articles (6-8) provide preliminary answers regarding treatment. Findings in these articles are augmented by more than 30 years of treatment-efficacy data collected and made available by the Autism Research Institute (9). Each of these four sources is considered separately in this brief review. As we shall see, complementary and alternative medicine (CAM) plays a growing role in autism treatments (6,8), and various CAM-related treatments are reported to be more efficacious than are pharmaceutical palliatives (9). Note that no specific therapeutic works for all autistic children. There is much inter-child variation in what works and what doesn't. Thorough medical histories and lab data (per child) are important. Each treatment modality may become contraindicated for a specific child (9).
A. Drs. Golnik and Ireland at the University of Minnesota conducted an extensive survey of physicians in regard to how they treat autistic patients (7). Consider several statements from the study's abstract: "Previous studies suggest over half of children with autism are using complementary alternative medicine (CAM)... Physicians encouraged multi-vitamins (49%), essential fatty acids (25%), melatonin (25%) and probiotics (19%) and discouraged withholding immunizations (76%), chelation (61%), anti-infectives (57%), delaying immunizations (55%) and secretin (43%)... Physicians encouraging CAM were more likely to desire CAM training, inquire about CAM use, be female, be younger, and report greater autism visits, autism education and CAM knowledge."
Given these findings, a physician reading this page would be well served to read the Parent Ratings of treatment efficacy as compiled by Autism Research Institute (9). Intriguingly, many so-called CAM-treatments have higher got-better/got-worse ratio than do traditional pharmaceuticals (9). Perhaps not surprising is that there are gaps between what's taught in medical school and what parents know to be working and not working for their specific, very individual child. Noteworthy are data-based observations presented in Golnik and Ireland's Table 3. Physicians were more likely to encourage CAM therapeutics if the doctors had received medical school autism training, had received residency autism training, had received continuing medical education autism training, or had a friend or relative with autism (7; p5).
B. In a related analysis reported separately, Golnik, Ireland, and Borowsky surveyed"physicians' perspectives on primary care for children with autism"(8). Findings presented in this study merit special attention. Quotes from the abstract are informative:
"Physicians reported significantly lower overall self-perceived competency, a greater need for primary care improvement, and a greater desire for education for children with autism compared with both children with other neurodevelopmental conditions and those with chronic/complex medical conditions.
"The following barriers to providing primary care were endorsed as greater for children with autism: lack of care coordination, reimbursement and physician education, family skeptical of traditional medicine and vaccines, and patients using complementary alternative medicine."
Important in this summary are hints of divergent belief systems. Many but certainly not all parents of autistic children are skeptical of traditional medicine, know that various CAM-related treatments are helpful for their child (9), and believe that vaccinations injure some children. At least some evidence supports each of these attitudes and beliefs. For instance, Bernadine Healy, M.D., former NIH director, and Duane Alexander, M.D., NICHD director, have each stated that epidemiologic studies seeming to "prove" that vaccines don't cause some cases of autism have lacked power and design adequate for identifying subgroups with increased susceptibility for having a significant and lasting adverse reaction (10-11). Furthermore and despite misleading news headlines, the U.S. Vaccine Court has ruled that autism and PDD (one of the ASDs) can be induced by vaccinations (12). But let's set aside this contentious issue and return to the role of traditional- and CAM-therapeutics for children with an ASD.
C. Since 1967 the Autism Research Institute has compiled and shared Parent Ratings of treatment efficacy for pharmaceuticals, supplements, and diets (9). Although some scientists might belittle such data, many of treatments have substantial numbers of reports. Furthermore, empiric observations of what works and what doesn't is an integral part of contemporary medical practice, as when a physician says to a patient, Try this, if it doesn't work, we'll try something else. Physicians are encouraged to peruse ARI's Parent Ratings data http://www.autism.com/treatable/form34qr.htm. Data presented on that url can inform a physician otherwise uncomfortable in treating children with autism (9).
D. News reports often describe autism as a "mystery" and fail to mention pollutants and susceptibility. Indeed, a growing number of studies describe findings implicating environmental pollutants and both genetic and metabolic biomarkers of susceptibility (eg, D'Amelio et al 2005; Windham et al 2006; Palmer RF et al 2006, 2009).
A recent review by Zecavati and Spence is entitled "Neurometabolic Disorders and Dysfunction in Autism" (10). Each of the researchers is with the NIH. Their review summarizes known metabolic problems associated with autism and proceeds to discuss important advances, especially in regard to a) mitochrondrial dysfunction as different from the classical mitochondrial disorders, b) clinical signs associated with methylation-related pathways, and c) treatments that target glutathione- and methylation-related pathways. The paper offers a section entitled, "Diagnosis, Testing, and Treatment", which includes statements such as:
"...mild cases of metabolic disease may go undiagnosed or become masked by other comorbid conditions. Certainly, most children with autism do not see metabolic specialists, and some of the red flags for metabolic conditions could easily go unnoticed. Discovery of some of these disorders in even a small percentage of patients with autism could majorly benefit the individual patient and provide a better understanding of the underlying pathophysiology
of autism in some cases."
"...it remains important to tailor the diagnostic evaluation to the individual patient, and practitioners must rely heavily on clinical judgment in deciding which tests to order."
"Tests likely to diagnose the more common neurometabolic disorders include plasma amino acids, urine organic acids, plasma ammonia, lactate/pyruvate, and the acylcarnitine profile. Table 1 lists signs, symptoms, and medical comorbidities that may yield clues to disorders that could be used as red flags for further specific testing."
E. Parents have long described regressions and various pathologies in their autistic child. In recent years, researchers have begun to document these phenomena (eg, 13-16). Clinically useful biomarkers are becoming described (eg, 17-20).
Conclusion: The epidemics of autism and other autism-spectrum disorders are prompting an increasing number of families to seek physician-guided treatment. Two recent studies by Golnik and her colleagues describe a wide range of treatments offered by physicians. Ironically, there was a trend wherein physicians who received autism training in medical school or residency were more likely to use therapeutics often labeled as "complimentary and alternative". The irony is furthered by patterns in treatment-efficacy data compiled by the Autism Research Institute (9). Physicians wanting more information are encouraged to read studies summarized in this review and to obtain several of the citation-filled books that describe advances in diagnosis and treatment of autism-spectrum children (21).
References
1. The rise in autism and the role of age at diagnosis.
Hertz-Picciotto I, Delwiche L.Epidemiology. 2009 Jan;20(1):84-90.
BACKGROUND: Autism prevalence in California, based on individuals eligible for state-funded services, rose throughout the 1990s. The extent to which this trend is explained by changes in age at diagnosis or inclusion of milder cases has not been previously evaluated. METHODS: Autism cases were identified from 1990 through 2006 in databases of the California Department of Developmental Services, which coordinates services for individuals with specific developmental disorders. The main outcomes were population incident cases younger than age 10 years for each quarter, cumulative incidence by age and birth year, age-specific incidence rates stratified by birth year, and proportions of diagnoses by age across birth years. RESULTS: Autism incidence in children rose throughout the period. Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence rates increased most steeply for 2- and 3-year olds. The proportion diagnosed by age 5 years increased only slightly, from 54% for 1990 births to 61% for 1996 births. Changing age at diagnosis can explain a 12% increase, and inclusion of milder cases, a 56% increase. CONCLUSIONS: Autism incidence in California shows no sign yet of plateauing. Younger ages at diagnosis, differential migration, changes in diagnostic criteria, and inclusion of milder cases do not fully explain the observed increases. Other artifacts have yet to be quantified, and as a result, the extent to which the continued rise represents a true increase in the occurrence of autism remains unclear.
2. Autism spectrum disorders: concurrent clinical disorders.
Xue Ming et al. J Child Neurol. 2008 Jan;23(1):6-13.
Individuals with autism spectrum disorder are heterogeneous in clinical presentation, concurrent disorders, and developmental outcomes. This study characterized the clinical co-occurrences and potential subgroups in 160 children with autism spectrum disorders who presented to The Autism Center between 1999 and 2003. Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors. Sleep disorders were associated with gastrointestinal dysfunction (P < .05) and mood disorders (P < .01). Food intolerance was associated with gastrointestinal dysfunction (P = .001). Subjects with mood disorder tended to develop aggressive or self-injurious behaviors (P < .05). Developmental regression was not associated with increased co-occurrence of medical or psychiatric disorders. Medical co-occurrence did not present as a risk factor for psychiatric co-occurrence, and vice versa. These results showed a high prevalence of multiple medical and psychiatric co-occurrences. There may be common pathophysiologic mechanisms resulting in clinical subgroups of autism spectrum disorders. Recognition of the co-occurrence of concurrent disorders may provide insight into the therapeutic strategy.
3. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease.
Valicenti-McDermott M et al. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36.
This is a cross-sectional study that compares lifetime prevalence of gastrointestinal (GI) symptoms in children with autistic spectrum disorders (ASDs) and children with typical development and with other developmental disabilities (DDs) and examines the association of GI symptoms with a family history of autoimmune disease. A structured interview was performed in 50 children with ASD and 2 control groups matched for age, sex, and ethnicity-50 with typical development and 50 with other DDs. Seventy-four percent were boys with a mean age of 7.6 years (SD, +/-3.6). A history of GI symptoms was elicited in 70% of children with ASD compared with 28% of children with typical development (p <.001) and 42% of children with DD (p =.03). Abnormal stool pattern was more common in children with ASD (18%) than controls (typical development: 4%, p =.039; DD: 2%, p =.021). Food selectivity was also higher in children with ASD (60%) compared with those with typical development (22%, p =.001) and DD (36%, p =.023). Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms. In the multivariate analysis, autism (adjusted odds ratio (OR), 3.8; 95% confidence interval (CI), 1.7-11.2) and food selectivity (adjusted OR, 4.1; 95% CI, 1.8-9.1) were associated with GI symptoms. Children with ASD have a higher rate of GI symptoms than children with either typical development or other DDs. In this study, there was no association between a family history of autoimmune disease and GI symptoms in children with ASD.
4. Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions.
Campbell DB et al. Pediatrics. 2009 Mar;123(3):1018-24.
OBJECTIVE: In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder-associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions. PATIENTS AND METHODS: Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder-associated MET promoter variant rs1858830 were determined. Family-based association test and chi(2) analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions. RESULTS: In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. chi(2) analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls. CONCLUSION: These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.
5. Discerning the Mauve Factor, Part 1.
McGinnis WR et al. Altern Ther Health Med. 2008 Mar-Apr;14(2):40-50.
"Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL). Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL. Heightened HPL excretion classically associates with emotional stress, which in turn is known to associate with oxidative stress. For this review, markers for nutritional status and for oxidative stress were examined in relationship to urinary HPL. In cohorts with mixed diagnoses, 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001). Above-normal HPL excretion corresponded to subnormal vitamin B6 activity and subnormal zinc with remarkable consistency. HPL correlated inversely with plasma glutathione and red-cell catalase, and correlated directly with plasma nitric oxide (P < .0001). Thus, besides implying proportionate needs for vitamin B6 and zinc, HPL is a promising biomarker for oxidative stress. HPL is known to cause non-erythroid heme depression, which lowers zinc, increases nitric oxide, and increases oxidative stress. Administration of prednisone reportedly provoked HPL excretion in animals. Since adrenocorticoid (and catecholamine) stress hormones mediate intestinal permeability, urinary HPL examined in relationship to urinary indicans, presumptive marker for intestinal permeability. Urinary HPL associated with higher levels of indicans (P < .0001). Antibiotics reportedly reduce HPL in urine, suggesting an enterobic role in production. Potentially, gut is a reservoir for HPL or its precursor, and stress-related changes in intestinal permeability mediate systemic and urinary concentrations.
6. Complementary Alternative Medicine for Children with Autism: A Physician Survey.
Golnik AE, Ireland M.J Autism Dev Disord. 2009 Mar 11. [Epub ahead of print]
http://www.springerlink.com/content/304v264707075381/
Previous studies suggest over half of children with autism are using complementary alternative medicine (CAM). In this study, physicians responded (n = 539, 19% response rate) to a survey regarding CAM use in children with autism. Physicians encouraged multi-vitamins (49%), essential fatty acids (25%), melatonin (25%) and probiotics (19%) and discouraged withholding immunizations (76%), chelation (61%), anti-infectives (57%), delaying immunizations (55%) and secretin (43%). Physicians encouraging CAM were more likely to desire CAM training, inquire about CAM use, be female, be younger, and report greater autism visits, autism education and CAM knowledge. Physicians were more likely to desire CAM training, inquire about CAM and view CAM as a challenge for children with autism compared to children with other neurodevelopmental and chronic/complex conditions.
7. Medical homes for children with autism: a physician survey.
Golnik A, Ireland M, Borowsky IW.Pediatrics. 2009 Mar;123(3):966-71.
http://pediatrics.aappublications.org/cgi/content/abstract/123/3/966
BACKGROUND: Primary care physicians can enhance the health and quality of life of children with autism by providing high-quality and comprehensive primary care. OBJECTIVE: To explore physicians' perspectives on primary care for children with autism. METHODS: National mail and e-mail surveys were sent to a random sample of 2325 general pediatricians and 775 family physicians from April 2007 to October 2007. RESULTS: The response rate was 19%. Physicians reported significantly lower overall self-perceived competency, a greater need for primary care improvement, and a greater desire for education for children with autism compared with both children with other neurodevelopmental conditions and those with chronic/complex medical conditions. The following barriers to providing primary care were endorsed as greater for children with autism: lack of care coordination, reimbursement and physician education, family skeptical of traditional medicine and vaccines, and patients using complementary alternative medicine. Adjusting for key demographic variables, predictors of both higher perceived autism competency and encouraging an empirically supported therapy, applied behavior analysis, included having a greater number of autism patient visits, having a friend or relative with autism, and previous training about autism. CONCLUSIONS: Primary care physicians report a lack of self-perceived competency, a desire for education, and a need for improvement in primary care for children with autism. Physician education is needed to improve primary care for children with autism. Practice parameters and models of care should address physician-reported barriers to care.
PMID: 19255027
8. Neurometabolic disorders and dysfunction in autism spectrum disorders.
Zecavati N, Spence SJ.
Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health.
Curr Neurol Neurosci Rep. 2009 Mar;9(2):129-36.
http://www.generationrescue.org/pdf/Zecavati-2009-NIH-report-on-metabolic-basis-of-autism.pdf
The cause of autism remains largely unknown because it is likely multifactorial, arising from the interaction of biologic, genetic, and environmental factors. The specific role of metabolic abnormalities also is largely unknown, but current research may provide insight into the pathophysiologic underpinnings of autism, at least in some patients. We review a number of known neurometabolic disorders identified as having an autistic phenotype. We also discuss the possible involvement of mitochondrial disorders and dysfunction as well as a theory regarding an increased vulnerability to oxidative stress, by which various environmental toxins produce metabolic alterations that impair normal cellular function. Finally, we review various strategies for metabolic work-up and treatment. Accurate diagnosis of neurometabolic disorders and a broader understanding of underlying metabolic disturbance even in the absence of known disease have important implications both for individual patients and for research into the etiology of autism.
9. Parent Ratings of Behavorial Effects of Biomedical Interventions [pharmaceuticals, supplements, diets]
http://www.autism.com/treatable/form34qr.htm
10. Fighting the Autism-Vaccine War
By Bernadine Healy, M.D. [former director of NIH]
http://health.usnews.com/articles/health/brain-and-behavior/2008/04/10/fighting-the-autism-vaccine-war.html
11. Duane Alexander. M.D., NICHD director.
As quoted in: NIH Agency Head: Vaccine-Autism Research is "Legitimate" - by David Kirby
http://www.huffingtonpost.com/david-kirby/nih-agency-head-vaccine-a_b_170034.html
12. Vaccine Court rulings, eg:
a. Hanna Poling, vaccination cocktail induced mitochondria dysfunction & regression into autism
http://adventuresinautism.blogspot.com/2008/03/spinning-hannah-poling-case.html
b. MMR and regression into PDD
http://www.huffingtonpost.com/robert-f-kennedy-jr-and-david-kirby/vaccine-court-autism-deba_b_169673.html
13: Regression in autism: prevalence and associated factors in the CHARGE Study.
Hansen RL et al. Ambul Pediatr. 2008 Jan-Feb;8(1):25-31.
"The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes."
14: Distinct genetic risk based on association of MET in families with co-occurring autism and gastrointestinal conditions.
Campbell DB et al. Pediatrics. 2009 Mar;123(3):1018-24.
"These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction."
15. Discerning the Mauve factor, Part 2.
McGinnis WR et al. Altern Ther Health Med. 2008 May-Jun;14(3):56-62.
16. Autism spectrum disorders: concurrent clinical disorders.
Xue Ming et al. J Child Neurol. 2008 Jan;23(1):6-13.
http://jcn.sagepub.com/cgi/reprint/23/1/6
"Medical and psychiatric co-occurrences included sleep disorders, epilepsy, food intolerance, gastrointestinal dysfunction, mood disorder, and aggressive and self-injurious behaviors."
17. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders.
Faber S et al. Biomarkers. 2009 Mar 11:1-10.
http://www.informaworld.com/smpp/content~db=all?content=10.1080/13547500902783747
"The frequency of zinc deficiency, copper toxicity and low zinc/copper in children with autism spectrum disorders (ASDs) may indicate decrement in metallothionein system functioning. A retrospective review of plasma zinc, serum copper and zinc/copper was performed on data from 230 children with autistic disorder, pervasive developmental disorder-NOS and Asperger's syndrome. The entire cohort's mean zinc level was 77.2 mug dl(-1), mean copper level was 131.5 mug dl(-1), and mean Zn/Cu was 0.608, which was below the 0.7 cut-off of the lowest 2.5% of healthy children. The plasma zinc/serum copper ratio may be a biomarker of heavy metal, particularly mercury, toxicity in children with ASDs."
18. Biomarkers of environmental toxicity and susceptibility in autism.
Geier DA et al. J Neurol Sci. 2008 Sep 24.
"The urinary porphyrin and CARS score correlations observed among study participants suggest that mercury intoxication is significantly associated with autistic symptoms. The transsulfuration abnormalities observed among study participants indicate that mercury intoxication was associated with increased oxidative stress and decreased detoxification capacity."
19. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism.
James SJ et al. Am J Clin Nutr. 2004 Dec;80(6):1611-7
http://www.ajcn.org/cgi/content/full/80/6/1611
20. Porphyrinuria in childhood autistic disorder: implications for environmental toxicity.
Nataf R et al. Toxicol Appl Pharmacol. 2006 Jul 15;214(2):99-108.
"Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's."
21. Citation-supported books helpful for clinicians
http://www.generationrescue.org/reading.html
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