The mean age at vaccination was 41 (SD 25); and this did not differ between those with and without epilepsy (data not shown). Most vaccinations in people with epilepsy were done at ages 25-74, while the vaccinations in those without epilepsy were more evenly distributed over ages, except for those over 75 in whom there were fewer vaccinations (table 1). There was a fairly even distribution between sexes in the two cohorts. The number of seizures by calendar time was fairly evenly distributed over the whole period, with a clear dip at the end of 2009/beginning of 2010.
Table 1 Frequency and incidence rates of seizures per 1000 person years among vaccinated population with and without previous epileptic seizures, by sex, age group, and study period
Five people with epilepsy died within the 90 day period after the last vaccination (median age 57.6, SD 24). In all of these people, death occurred more than one month after the seizure. Two people died within a fortnight after vaccination. Two people without epilepsy died within the study period (aged 77 and 85).
Incidence rate of seizures
We calculated incidence rates of seizures for both cohorts. The incidence rate of epileptic seizures in the cohort with epilepsy was 249 per 1000 person years in the control period before vaccination and slightly lower in the control period after vaccination (229 per 1000 person years) (table 1). In the two risk periods the incidence rate was 258 (day 1-7) and 253 (day 8-30), respectively, per 1000 person years, while it was highest in the buffer period just before vaccination (313 per 1000 person years). The confidence intervals, however, overlapped between periods.
In the cohort without epilepsy the incidence of seizures was considerably lower (range 0.6-1.1 per 1000 person years in the various periods) (table 1). There was a significant increasing incidence trend over the study period in this cohort (P<0.002).
Self controlled case series analysis
In the main analysis we examined the incidence rate of seizures in the day 1-7 risk period and in the day 8-30 risk period compared with the overall incidence rate in the two control periods before and after vaccination separately for the subcohorts of people with recorded epilepsy and people without recorded epilepsy. For those with epilepsy and seizures there was no increase in risk in the first risk period (day 1-7; relative incidence 1.01, 95% confidence interval 0.74 to 1.39) or in the second risk period (day 8-30; 1.00, 0.83 to 1.21) (table 2). For those without epilepsy but with seizures, there was a non-significant decrease in risk in the first risk period (0.67, 0.27 to 1.65) and no significant increase in risk in the second risk period (1.11, 0.73 to 1.70) (table 2).
Table 2 Relative incidence of seizures in risk periods compared with control period (day 90-31 before vaccination and day 31-90 after vaccination) for people with epilepsy and with seizures (n=738) and for people without epilepsy but with seizures (n=121) (more ...)
We carried several sensitivity analyses to control for robustness of the main analysis. In one sensitivity analysis we included the buffer period (30-1 days before vaccination) in the model. For those with epilepsy and seizures, there was a significant risk increase during the buffer period compared with the control periods (relative incidence 1.33, 95% confidence interval 1.14 to 1.56), while for those without epilepsy but with seizures this was not the case (1.08, 0.71 to 1.64) (table 2). Most importantly, however, the relative incidence for any of the risk periods did not change when we included the buffer period in the model, neither for those with or without epilepsy, indicating robust main results.
In a second sensitivity analysis we used only the first control period for comparison with risk periods after vaccination, but took all episodes and doses into account. For those with epilepsy and seizures, the results remained stable compared with the main analysis (table 3), while for people without epilepsy the risk in the first risk period was equal to unity (relative incidence 0.99, 95% confidence interval 0.39 to 2.53), and for the second risk period showed an increased relative incidence of 1.64, close to significance (95% confidence interval 0.99 to 2.71) (table 3). To further check the robustness of these results we introduced the second control period as a separate parameter into the model, along with the buffer period. The risk estimates in both risk periods remained stable for both subcohorts (table 3), while the risk estimate for the second control period was non-significantly decreased for those with epilepsy and seizures (0.89, 0.76 to 1.05), and significantly increased for those without epilepsy but with seizures (1.88, 1.26 to 2.80). Consequently, a (non-significant) risk increase was also indicated for the buffer period (1.56, 0.95 to 2.56) for those without epilepsy but with seizures.
Table 3 Relative incidence of seizures in risk periods compared with first control period (day 90-31 before vaccination) for people with epilepsy and with seizures (n=738) and for people without epilepsy but with seizures (n=121) for all episodes, all (more ...)
We conducted further sensitivity analyses to assess only the first episode of epileptic seizures and the first dose of vaccine. The results from these analyses did not alter the main result of the study, with one exception—namely, in people without epilepsy who received one dose, there was a non-significantly increased risk in the second risk period (relative incidence 1.41, 95% confidence interval 0.86 to 2.31), while the estimate in the first risk period was close to unity (0.93, 0.34 to 2.53) (data not shown).
Additional analyses with the composite outcome of epileptic and febrile seizures confirmed the results shown in tables 2 and 3.