New Act by Congress Gives Boost to Autism Research
February 2007, Vol. XXIV, No. 2
The passage and signing in December of the Combating Autism Act (S. 843), which authorizes $945 million over 5 years for research, screening, intervention, and education on autism spectrum disorders (ASD) and developmental disabilities, has been hailed by the advocacy group Cure Autism Now (CAN) as a “federal declaration of war on the epidemic of autism,” a disorder that affects 1 in 166 children. 1 Yet, some battles are already under way at NIMH's Intramural Research Program, with patient recruitment proceeding for 3 major autism studies.
In a press statement, Jonathan Shestack, father of an autistic child and cofounder of CAN, a large private funding organization for autism research, said S. 843 (now Public Law 109-416) “creates a congressionally mandated road map for a federal assault on autism, including requirements for strategic planning, budget transparency, congressional oversight, and a substantial role for parents of children with autism in the federal decision-making process.”
Key provisions of the law, subject to the availability of appropriations, call for the following:
The NIMH studies on the NIH campus in Bethesda, Md, are the first products of a new, integrated focus on autism. One study, “Clinical and Immunological Investigations of Sub-types of Autism,” seeks to learn more about autism and its subtypes. “It is actually two studies in one,” said Susan Swedo, MD, chief of NIMH's Pediatrics and Developmental Neuropsychiatry Branch.
The first is a study of regressive versus nonregressive autism to determine whether there is an immune or other systemic trigger of children's neurologic regression, she said. It involves 50 children with idiopathic autism and regression, 50 children with idiopathic autism and no history of regression, 25 children with Rett syndrome, and 50 healthy children. The age range of all 4 groups is between 12 months and 48 months at first visit.
The second component to the study, Swedo said, is part of the Autism Phenome Project, a pilot investigation being conducted in collaboration with David Amaral, PhD, Beneto Foundation Professor and director of research at the M.I.N.D. Institute at the University of California, Davis. Between the 2 sites, the pilot phase of the phenome study involves 50 to 100 children with autism, 50 children with developmental delays, and 50 to 100 children without disorders. The purpose is to identify clinically meaningful subtypes of autism, which could lead to better understanding of the etiology and pathophysiology of the disorder.
Increasingly, researchers are considering that autism may be multiple disorders. The regressive subtype is well characterized, Swedo said, although there is some debate about how common it is. The reports vary from indicating that as few as 10% to as many as 40% of children with autism have a pattern of regression.
With regressive autism, Swedo explained, you have a history of the child developing typically until age 12 to 18 months with appropriate development of language and social skills and then the child loses words and social skills and begins to look indistinguishable from children who have had autistic symptoms from birth or early on.“Some investigators have found that the regressive subtype actually has a worse prognosis,” she said.
To explain the regression, Swedo said that the research team's working hypothesis is that there are environmental triggers or perhaps genetic aberrations that are expressed at this particular point in the child's development. One possibility based on Swedo's work with obsessive-compulsive disorder and the pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections subgroup is that regressive autism develops following a viral or bacterial infection that triggers an autoimmune response and neuropsychiatric symptoms.
The phenome study includes questions related to a child's exposure to environmental toxins and household products; neuroimaging (structural MRI); and biomarkers; as well as very careful behavioral, neurologic (eg, via electroencephalograms administered while the child sleeps in the hospital overnight), and physical assessments. “The children will be monitored every 6 months to a year until they are age 5, and then intermittently after that time” to examine the validity of their diagnosis and how their symptom course evolves over time, Swedo added.
In another small-scale intramural study, Treatment of Childhood Regressive Autism With Minocycline: An Anti-Inflammatory Agent Active Within the CNS, NIMH researchers are examining the use of the antibiotic minocycline (Dynacin, Minocin, Myrac) in children aged 3 to 12 years with regressive autism.
“We are using minocycline, a tetracycline derivative, not for its effectiveness as an antibiotic but rather for its ability to modulate the immune system,” Swedo said. “It has fairly specific effects on NF-kappa B and therefore inhibits the initiation of the cascade that leads to inflammation. Published data from the Johns Hopkins group [2,3] demonstrate that brains of individuals with autism have evidence of chronic neuroinflammation. We hope that by stopping that process, the children will be able to recover some of their skills. We are conducting an open-label trial in 10 children and are accepting referrals. If the results are encouraging, we will do a placebo-controlled trial in a larger cohort of subjects.”
Asked about other pharmacologic approaches being investigated at NIMH, Swedo responded, “We have a few in [the] pipeline, but it is premature to talk about them. Eric Hollander, MD, has been doing some work with oxytocin, reported at the American College of Neuropsychopharmacology's annual meeting.”
Hollander, chairman of psychiatry at the Mt Sinai School of Medicine in New York and director of the Seaver and New York Autism Center of Exellence, and Jennifer Bartz, PhD, found that pitocin (synthetic oxytocin), administered intravenously or nasally, may have significant positive effects in adults with autism. Oxytocin, a hormone that is best known for activity during birth and lactation, is also a brain neurotransmitter involved in social recognition and bonding.
The third NIMH study, “Mercury Chelation to Treat Autism,” seeks to address whether chelation therapy can be helpful for autism. The chelation study is a placebo-controlled trial that involves use of meso-2,3-dimercaptosuccinic acid (DMSA, succimer), an orally adminstered chelating agent that binds to all metals including mercury and lead but also to some beneficial metals, such as zinc and iron, according to Swedo. DMSA is commonly used to treat autism, with some surveys estimating that 1 in 12 children with autism has undergone chelation, although it has never been tested in a controlled study and there is no proof that it helps children with the disorder. Support for its use is based on single-case reports of benefits of chelation with DMSA.
Children aged 4 to 10 years in whom autism, Asperger disorder, or pervasive child developmental disorders have been diagnosed; who weigh at least 33 lb; who have detectable, but not toxic, levels of mercury or lead in the blood; and who have not previously received chelation therapy may be eligible for this study.
“The chelation study is based on the hypothesis that mercury toxicity is responsible for at least some cases of autism,” Swedo said. She explained that extensive controversy surrounds the issue of mercury toxicity in autism. The Institute of Medicine (IOM) conducted a comprehensive study of the question of whether thimerosal, an ethylmercury-based compound used previously in the United States as a vaccine preservative for routine childhood immunizations, contributed to the apparent increase in the prevalence of ASDs. 4 The IOM panel concluded that there was no evidence for an association, but the report has been dismissed by some parents who report “toxic mercury levels” among their affected children and who have observed benefits of open-label DMSA administration.
To answer the question in a controlled fashion, the NIMH will enroll about 120 children in the chelation study, with half randomized to placebo and half to DMSA. The trial will last for 6 months, and researchers are enrolling participants now. “We would love to receive referrals,” Swedo said, adding that psychiatrists can find out more by going to www.clinicaltrials.gov or by contacting Lorraine Lougee, LCSW, research coordinator. Lougee's e-mail address is LougeeL@intra.nimh.nih.gov.
Incidence and prevalence
Because of recurrent questions about whether autism is increasing, Swedo was asked about incidence and prevalence. “We have absolutely no data on incidence,” she said. “We can say the disorder appears to be more prevalent now than it has been reported in the past. However, there was a major change in diagnostic criteria and case-finding methods, so it is unclear [whether] it represents a true change in rates of affected individuals. . . . The CDC is conducting several studies currently to address that question.”
There is increasing agreement on what true autism is, using the Autism Diagnostic Observational Schedule, a semistructured observational scale developed to assess social interaction, communication, and play in persons suspected of having autism, and the Autism Diagnostic Interview, Swedo said.
“Those 2 give you nice, reliable cutoffs where you can say a child has autism, is on the autism spectrum, or is developing typically. Including children on the autism spectrum will increase apparent prevalence rates,” Swedo said. “The figure of 1 in 166 children having autism was recently confirmed in a CDC study that reviewed school records and confirmed the diagnosis from medical records. But the study included all children with an ASD as having ‘autism'-this included not only severely affected individuals with full-blown autism but also those with a pervasive developmental disorder not otherwise specified and those with Asperger disorder, a condition [that] is not as impairing.”
“In order to determine the true prevalence of autism and to know whether there is an ‘epidemic' as some have asserted,” Swedo continued, “we need to have better data about the current prevalence of autism and related disorders and then compare those data with comparable data from previous studies. The CDC is conducting surveillance studies at a number of US sites, and the NIH is sponsoring longitudinal investigations here and abroad to address those questions.”
References1. Centers for Disease Control and Prevention. How common are autism spectrum disorders (ASD)? Available at: http://www.cdc.gov/ncbddd/autism/asd_common.htm. Accessed January 5, 2007.
2. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17:485-495.
3. Vargas DL, Nascimbene C, Krishnan C, et al. Neuroglial activation and neuroinflammation in the brain of patients with autism [published correction appears in Ann Neurol. 2005;57:304]. Ann Neurol. 2005;57:67-81.
4. Board on Health Promotion and Disease Prevention, Institute of Medicine. Immunization Safety Review: Vaccines and Autism (2004). Available at: http://www.nap.edu/books/030909237X/html/1.html. Accessed January 5, 2007.