By Mary Kay Floeter, MD, PhD
As the nationwide H1N1 flu vaccination program gets underway, neurologists have been asked by the Centers for Disease Control (CDC), in partnership with the Academy, to report all cases of Guillain-Barre syndrome (GBS) to determine if there is an increased incidence of GBS following vaccination. Information on the H1N1 flu vaccine, and instructions on how to report cases of GBS to the CDC's Vaccine Adverse Event Reporting System (VAERs), can be found on the AAN.com's GBS Monitoring Toolkit page.
Because neurologists are typically involved in making a diagnosis of GBS, it is worth looking back at the 1976 vaccination program for swine flu that gave rise to the current national vaccine safety program, to see what was known at the time, and the questions that still remain, which might be amenable to current methods of investigation.
After an outbreak of swine flu among military personnel at Fort Dix, NJ, a nationwide National Influenza Immunization Program was rolled out in the fall of 1976. Over a 10-week period about 45 million persons were vaccinated for swine flu. But on December 16 of that year, a moratorium on further vaccinations was declared because of the unusual number of reports of GBS occurring in the weeks following vaccination.
The CDC asked all state health departments to participate in a national surveillance program to report all cases of GBS, and approximately 1,100 cases were reported through early 1977. The initial reports of the incidence of GBS following swine flu vaccination were high—leading to calculations that vaccination produced a seven- to eight-fold increased risk of GBS. However, these numbers were criticized on two key points: whether patients who probably had other conditions were included, and the appropriate figure to use for the estimated baseline incidence of GBS.
Following a court order, a panel of academic experts was convened in 1981 to review the data reported. This panel included one neurologist, Maurice Victor, MD, and their report was published in the American Journal of Epidemiology ("An epidemiologic and clinical evaluation of Guillain-Barre? syndrome reported in association with the administration of swine influenza vaccines." Am J Epidemiol. 1984 Jun;119(6):841-79). Only a limited dataset was available under the court order. After excluding cases outside the time window of vaccination, there were 944 adult cases of GBS that the panel reviewed. Of these, 504 cases had received swine flu vaccinations, and 440 cases were unvaccinated. Cases of GBS were classified as "extensive" or "limited" according to the extent of motor and respiratory involvement, clinical characteristics such as progression and pattern, and supportive diagnostic information such as cerebrospinal fluid (CSF) findings or examinations by neurologists. The onset of symptoms in the vaccinated "extensive" cases showed a clear peak beginning during the first days after vaccination, rising to a maximum by the end of the second week, with a smoothly declining curve over the next six weeks. "Limited" cases, which were fewer in number, had a less clear-cut onset in relationship to the timing of vaccination.
The panel found that deciding which estimate to use for the baseline incidence of GBS was not simple. There was concern that the number of unvaccinated cases of GBS reported could represent a bias, such as an increased alertness and thoroughness of reporting. In the literature, there was good agreement between population-based studies from Olmstead County, Minnesota, and from Michigan, and these were used to provide a baseline estimate for "extensive" and "limited" GBS that was actually higher than the incidence in the unvaccinated cases. Using the unvaccinated cases as the low estimate and the Minnesota/Michigan cases as a high estimate, the relative risk of "extensive" GBS after swine flu vaccination was estimated to range from 3.96 to 7.75.
Since 1976, changes have been made in methods and quality control for production of vaccines. The CDC's Vaccine Adverse Event Reporting System (VAERS) has not found an increased incidence of GBS with seasonal flu vaccinations since it was instituted in 1990. The 1976 flu season's data indicate that, if GBS were to occur after vaccination, the onset would likely be within two weeks. From the scientific point of view, it is still not clear what led to the increased incidence of GBS in 1976.
Since that time, we have gained a much greater understanding of the immune-mediated nature of GBS. In some cases particular gangliosides or carbohydrate moieties have been identified as the targets of auto-antibodies. In a few situations, such as GBS following Campylobacter jejuni infection, these antibodies appear to arise from molecular mimicry with antigens on the pathogen. Host susceptibility and genetic factors may also play a role. Although GBS following H1N1 vaccine is unlikely, determining the target of antibodies would be a useful piece of the puzzle that clinicians could contribute to better understanding causes of GBS.
For additional information on the signs and symptoms of GBS and treatment of GBS, two excellent resources are the webinar conducted in October 2009 by Ted M. Burns, MD, and Orly Avitzur, MD, MBA, FAAN, which can be downloaded from AAN.com, and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) podcast by Richard L. Hughes, MD, FAAN.
Within the past 24 months, Dr. Floeter served on the editorial board of Muscle and Nerve. She is a government employee in the Intramural Clinical Program of the National Institutes of Neurological Disorders and Stroke, NIH, DHHS, which funds her research.