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.ravenintellections.com/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
Teresa
Binstock
Researcher
in Developmental & Behavioral Neuroanatomy
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