Marker Helps Identify Children at Risk for Obsessive-Compulsive Disorder Following Streptococcal Infections

A biological marker may identify children at risk for developing obsessive-compulsive disorder (OCD) after having an untreated streptococcal bacteria infection, according to scientists from The Rockefeller University and the National Institute of Mental Health (NIMH). The discovery will help improve the understanding of the disease process of OCD and related tic disorders such as Tourette’s syndrome.

“The marker should enhance the diagnosis of patients and aid in the development of treatments that address the biological basis of the obsessive-compulsive disorder,” says senior author John Zabriskie, M.D., associate professor and head of the Laboratory of Clinical Microbiology and Immunology at Rockefeller. Zabriskie, Susan Swedo, M.D., of NIMH, and their colleagues published their findings in the January American Journal of Psychiatry.

OCD, once considered to have only a psychological basis, is a biological disorder involving the nervous system. OCD patients have recurrent, unwanted thoughts such as anxiety about contamination or being hurt and have uncontrolled repetitive rituals including hand washing, cleaning, checking or counting. The rituals provide only temporary relief.

Often chronic and relapsing, OCD typically begins in early childhood or adolescence. OCD annually occurs in about 3.9 million people in the United States, about 2 percent of the population, according to the NIMH, part of the U.S. federal government’s National Institutes of Health. NIMH reports that the OCD-related social and economic costs in the United States tally $8.4 billion, nearly 6 percent of the country’s yearly total mental health care costs.

“Studies suggest that a variety of things–genetic susceptibility, an imbalance of the brain’s messenger chemicals or a dysfunction of part of the brain–can cause the childhood onset of OCD,” explains Swedo, first author of the study and chief of the Section on Behavioral Pediatrics at NIMH. “This study indicates there may be another cause: some children are predisposed to developing OCD and tic disorders after an infection with the streptococcal bacteria. The marker we have newly identified should help us recognize a majority of these children.”

Streptococcal bacteria are the most common disease-causing bacteria in people. One type, group A b-hemolytic, can cause strep throat, middle-ear infections, pneumonia and rheumatic fever. Because a variant of rheumatic fever, Sydenham’s chorea or St. Vitus’ dance, features neurological problems that result in involuntary movements or tics, Swedo and her colleagues examined children to explore the connection between the bacteria and the disease.

The studies revealed a group of children who abruptly and dramatically develop OCD or Tourette’s syndrome after b-hemolytic streptococcal infections. Tourette’s syndrome can involve the making of noises or use of foul language, but like Sydenham’s chorea also features neurological problems that result in involuntary movements or tics. The tic behaviors arise from malfunctions in part of the brain called the basal ganglia.

The researchers suggest that it is the immune system’s abnormal reaction to the streptococcal bacteria that triggers the disorders in at-risk children. The concept that OCD might be a streptococcal induced autoimmune reaction to brain antigens had its foundations in work performed by Zabriskie, Gunnar Husby, M.D., and Ralph C. Williams, M.D., in the late 1970s in which they demonstrated a cross reaction between streptococcal antigens and brain antigens. Normally, during an infection, the immune system recognizes proteins called antigens on the outer surface of the bacteria and responds by manufacturing antibodies. The antibodies adhere to the antigens and flag certain white blood cells to destroy the bacteria.

However, in OCD, scientists suggest that after infection, the antibodies to the bacteria may make their way to the healthy brain, falsely leading an attack on the basal ganglia. This autoimmune malfunction disrupts normal brain activity and triggers OCD. Based on their work in children, the investigators designated children with OCD, Tourette’s syndrome or tics that arise after a streptococcal infection as PANDAS, an acronym for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

To hunt for a way to identify PANDAS, the researchers turned to a known marker that predicts people at risk for developing rheumatic fever: a protein found on the surface of the immune system’s B cells. Zabriskie and colleagues at The Rockefeller University Hospital first identified the protein when hunting for a genetic clue to explain why rheumatic fever tends to occur more frequently in certain families.

“We suspect that that everyone has the gene for this B cell surface protein but in most healthy people the gene is not very active and only a small amount, from none to 4 percent, of the protein is made. However, in individuals more susceptible to rheumatic fever, the gene is not correctly regulated and antigen is made at levels of up to 30 percent. We consider any expression level of 12 percent or greater to be a positive test of a person at risk,” explains Zabriskie.

To look for the B cell protein, Zabriskie and coinvestigators at Rockefeller developed a monoclonal antibody, D8/17, that binds to the protein. They then adapted D8/17 for use as the screening test in the current study. The researchers examined the blood of a group of 27 PANDAS children, finding that 85 percent (23) had the marker. In a group of nine children with Sydenham’s chorea, 89 percent (eight) had positive tests, while in a group of 24 healthy children, only 17 percent (four) had the marker. Furthermore, the PANDAS and Sydenham’s chorea children had significantly higher average counts of the cells bearing the marker. The children ranged in age from 5 to 14 years.

“If, through further investigations, the D8/17 marker proves reliable in identifying PANDAS-susceptible individuals then it may be possible to provide preventative therapies to at-risk individuals and prevent the onset of some cases of OCD and Tourette’s syndrome,” says Zabriskie.

The researchers now are examining the B cell surface protein to determine its exact structure and its role in the autoimmune dysfunction that results in OCD. They also are testing therapies for OCD including plasma pheresis, the replacement of blood to remove the harmful antibodies and halt the autoimmune attack.

Zabriskie and Swedo’s coauthors include at NIMH Henrietta L. Leonard, M.D., Barbara B. Mittleman, M.D., Albert J. Allen, M.D., Ph.D., Judith L. Rapoport, M.D., Sara P. Dow and Melissa E. Kanter and at Rockefeller Floresta Chapman. NIMH supported the research. Callisto Pharmaceuticals based in New York, N.Y., has licensed the technology for the D8/17 test from Rockefeller.