Sometimes wishing does not make it so. Parents of autistic children began calling Melvin Heyman, MD, chief of pediatric gastroenterology at the University of California, San Francisco in 1998. They were full of hope about reports that secretin, a hormone produced in the intestines and used in a diagnostic procedure, might improve their children's ability to talk and interact with others. To test that concept, Heyman and clinical research fellow Jenifer Lightdale, MD, teamed with autism experts from UCSF's Langley Porter Psychiatric Institute to perform objective tests of language and behavior before and after administering secretin. The results were reported May 13, 2000 at the Pediatric Academic Societies/American Academy of Pediatrics meeting in Boston. Twenty autistic children, aged 3-6, received formal language testing before infusion with secretin and in four follow-up tests in ensuing weeks. No child showed significant changes in either receptive or expressive language. "Beginning in 1998, a worldwide storm of reports on the internet, plus stories in the Wall Street Journal and on Dateline NBC, have described secretin as potentially a true treatment for children with autism," said Lightdale. "Our study and one other were the first to test objectively whether this was so. We began the study because we were concerned that parents and health care providers did not have sufficient scientific information to evaluate secretin's potential effects."
Both studies had negative results. However, the researchers reported that some parents from both study groups indicated they still would use the drug for their children.
Lightdale conducted the UCSF study under Heyman's supervision. Their co-investigators were UCSF-LPPI autism experts Bryna S. Siegel, PhD, Glen R. Elliott, MD, PhD, Cathy Hayer, MA, and Christopher Lind-White, MD. Lightdale is now a postdoctoral fellow in pediatric gastroenterology at Children's Hospital Boston.
Heyman said that parents' excitement about secretin were first stirred by 1998 stories of a mother who said that her son showed improvements in autistic symptoms after he was given secretin during a diagnostic test for diarrhea. Dateline NBC profiled the mother and her son. The Wall Street Journal described an entrepreneur, the father of two autistic children, who founded a pharmaceutical company and obtained the license for synthetic secretin to ensure a supply of the drug to treat autism. An article in the Journal of the Association of Academic Minority Physicians described the first boy, as well as two other children who reportedly showed increased alertness, eye contact and expressive language within days after receiving a single dose of the hormone. The article described marked improvements in language over a short time, and reported effects lasting up to five weeks.
"After word of these observations spread, UCSF's gastrointestinal service was inundated with calls from parents asking for secretin infusions, often as many as 30 per day," Heyman said. Eventually, more than 2,000 called from Northern California and around the country. "The need for research to see whether the drug was effective was accentuated by reports from autism interest groups that thousands of children had begun receiving secretin in repeated doses," Heyman said. Some web entrepreneurs charged inflated prices to give secretin to autistic children. In some cases the drug was administered in unproven ways, such as by mouth or through the skin using a solvent called DMSO.
Siegel, who is associate adjunct professor of psychiatry at UCSF, has worked with autistic children and their families for 25 years. She defined autism as a syndrome that begins in the first few years of life, involving severe deficits in social and communication skills. It affects the child's ability to process incoming information from the social and physical worlds, to interact with others and to use language. The cause is not known and, to date, there is no proven cure. However, for some autistic children, behavioral interventions can markedly improve language and social skills. For older individuals, medications sometimes can help ease obsessive behaviors.
Heyman said that secretin is a hormone that stimulates the pancreas to increase production of digestive fluids. It is approved as a diagnostic drug, to show whether the pancreas is impaired in its ability to respond to stimulation, since that can cause chronic diarrhea and other disorders. Secretin has no known therapeutic use, and few known side effects, though one version of the drug has been associated with allergic and anaphylactic reactions. It has not been tested for safety or efficacy in children, either in a single-dose or as a long-term medication.
Lightdale's study looked at autistic children who were near the same age and were given a similar intravenous dose of secretin to the three children described in the 1998 journal article. Each child in the UCSF study was tested before the infusion with secretin and again in sessions one, two, three and five weeks after infusion. Each child was given a standardized test called the Preschool Language Scale - 3, and was videotaped during play and scored for specific behaviors characteristic of autism.
The PLS-3 test was objectively scored and indicated no quantifiable changes either in the way children understood language, or the way they were able to use words and gestures to express themselves. The videotaped behavior tests were scored using criteria in the test manual, by three independent reviewers who never met the children and were not told which week of the study a given test represented. The latter results will be published at a later date. A true, dramatic change in skills and behavior would have been a surprising result after a dose of a drug, said Siegel. "The claims made for this drug do not hold up well to any neuro-developmental model of how new skills are acquired," she said. "Language ability depends on changes in the brain as the child goes through activities that stimulate the acquisition of vocabulary and grammar structure. The child has to develop a two year old's language ability to go on and learn to speak like a three year old. A pill can't do that for him."
Eighteen sets of parents in the study filled out a survey afterwards about their child's condition. In contrast to the results observed by the study authors, 15 sets of parents indicated that they felt their child had moderate to significant improvements in language skills following the secretin infusion. The UCSF results are similar to those of another study, reported in December, 1999 in the New England Journal of Medicine, by researchers at the University of North Carolina. They studied children aged 3 - 14 who had either autism or a similar condition, pervasive developmental disorder. They administered secretin to half and placebo to the rest. The UNC researchers found no significant effect of secretin - in fact, the children who received the placebo showed slightly greater improvement on behavior tests. However, a majority of parents, including those whose children received placebo, retained their interest in using secretin even after they were told the results.
How to explain the difference between objective test scores and parents' perceptions? "This is a very good example of placebo effect," said Siegel. "By definition, the placebo can be expected to cure whatever ails you. In the studies of secretin, these parents saw differences in eye contact, in attention, in use of words - any activity that seemed like an improvement was attributed to the drug."
"Hope is essential when you care for a child with a chronic disability and there is no definitive treatment," Siegel said. "But sometimes hope lets people believe more than they truly can count on. It can be a roller-coaster that, in the end, is just another source of strain."
REPORTERS' NOTES:
To contact Jenifer Lightdale, call Susan Craig at Children's Hospital Boston News Service, 617-355-6420 craig_s@tch.harvard.edu
To contact Melvin Heyman or Bryna Siegel, call Janet Basu at UCSF News Services, 415-476-2557
jbasu@pubaff.ucsf.edu
RE THE PAS/AAP MEETING:
For the first time in their histories, the Pediatric Academic Societies (PAS) and the American Academy of Pediatrics (AAP) are sponsoring a joint meeting to discuss the health of children in North America and beyond. Significant scientific and clinical advances will be presented, touching topics such as gene therapy, environmental impacts on health, the status of care for neonates, the mental health of children, and advances in treating chronic diseases.
Pressroom contacts, May 12-16: Hynes Convention Center, Room 106, Boston, 617-954-2521