Risk of seizures after immunization in children with epilepsy: a risk interval analysis

Immunization programs are among the most effective public health interventions ever developed. [1] However, as the incidence of vaccine-preventable infections has decreased, healthcare professionals and the public have become increasingly concerned about the risk of adverse events following immunization (AEFIs). [2] Neurological events are among the most serious AEFIs, frequently resulting in emergency visits or hospitalization. Seizure is both the most frequent neurological AEFI reported and the most common neurological disorder in children. [3] Up to 10% of children will experience a seizure by their 16th birthday, and approximately 0.5% of children have epilepsy, making it one of the more common chronic diseases in children. [4‐6]

Certain vaccines [e.g., measles-mumps-rubella (MMR) vaccine, trivalent inactivated influenza vaccine] have been associated with febrile seizures in young children. [7‐11] The timing of febrile seizures after immunization coincides with the peak inflammatory response. Inactivated vaccines such as inactivated influenza vaccine stimulate an immune response within hours, inducing fever (and febrile seizure) within 1–2 days after immunization. [7, 8] After live vaccines (e.g., MMR), the risk of febrile seizure is delayed until 5–14 days post-immunization, after the attenuated virus has reached sufficient levels in the bloodstream to be detected by the immune system. [9, 10] In contrast, immunizations have not been associated with afebrile seizures in large cohort studies, and several studies and reviews concluded that immunizations do not trigger the onset of epilepsy [9, 12‐15]. However, the risk of seizure after routine immunizations in children with pre-existing epilepsy has not been systematically evaluated. Despite limited direct evidence of vaccine safety in this population, current practice guidelines recommend that children with epilepsy follow the routine immunization schedule. [16]

The study objective was to estimate the relative risk of medically attended seizure after immunization among children less than 7 years of age with a diagnosis of epilepsy. Evidence of the safety of immunization in these children would reassure parents and healthcare providers concerned about the risk of immunization-induced seizures.

In total, 302 children met the inclusion criteria, of whom 38% had partial (focal) epilepsy, 33% had unclassified epilepsy, 18% had idiopathic generalized epilepsy (52% of whom had absence epilepsy), 5% had benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy), and 4% had severe epilepsy. Parents of 166 children consented to release their immunization records (Fig. 1). Immunization information was available on 147 children from either Public Health or the primary care physician. Eighty children had one or more immunization visits between their epilepsy diagnosis and 7th birthday. Demographic and clinical characteristics are shown in Table 1. Children with immunization events were diagnosed at a younger mean age (2.1 years versus 4.0 years versus 3.1 years, p < 0.001) and had more seizure events during the observation period (mean events per subject = 2.5 versus 0.7 versus 0.9, p < 0.001) than either children with no immunization events or children whose records were unavailable.

There were 161 immunization events among the 80 subjects who received immunizations between their epilepsy diagnosis and seventh birthday (Table 2). Thirty-nine of 59 (67%) children with immunization records who were diagnosed with epilepsy before 4 years of age and followed until ≥6 years of age had ≥1 immunization visit. Inactivated vaccines were administered at nearly all immunization visits, either alone or with live vaccines.

Children with immunization visits had a total of 197 healthcare encounters for seizure during the study period. The majority of encounters were telephone calls to the neurologist (131/197; 66%), followed by ED visits (31/197; 16%), hospitalizations (20/197; 10%), and unscheduled outpatient visits (15/197; 8%). The number of seizure events was similar across all four seasons, ranging from 54 events in winter (27%) to 43 events in summer (22%). The mean age at the time of the seizure event was 3.5 years (standard deviation = 1.7).

The results of the risk interval analysis are shown in Table 3. The relative risk of seizure was not increased during the risk period 0–14 days after any vaccine versus the control period 21–83 days post-immunization (RR = 1.14, 95% CI: 0.46, 2.83). Similarly, there was no increase in the relative risk of seizure events 0–2 days versus 21–83 days after inactivated vaccines. No seizure events occurred during the risk periods 7–10 days or 5–14 days after a live vaccine; therefore the RR could not be estimated. In sensitivity analyses, the RR was estimated using a 0–3 day risk interval after inactivated vaccines, and a control period of 7–83 days prior to immunization (see Additional file 1). In all models, the estimate of RR was similar to the primary analysis.

The rate of seizure events during the 0–14 day risk period after any immunization was 0.92 events per person-year versus 0.76 events per person-year during the control period, which corresponds to a rate difference of 0.16 seizure events per person-year (95% CI: -0.67, 0.98). The upper confidence limit corresponds to 1 additional seizure event in the 0–14 day risk period per 25 immunizations. The rate of seizure events was 0.790 per person-year during the 0–2 day risk period versus 0.788 per person-year in the control period, corresponding to a rate difference of 0.002 seizures per person-year (95% CI: -1.611, 1.615). The upper confidence limit corresponds to 1 additional seizure event in the 0–2 day risk period per 75 inactivated immunizations.

In this study, children < 7 years of age who were followed by a neurologist for epilepsy did not appear to be at increased risk of seizure requiring medical attention after any immunization or after inactivated vaccines, compared to their baseline risk. The lack of seizure events during the risk periods after live vaccines suggests that the risk of seizure is not increased after live vaccines, although the relative risk could not be estimated.

The study findings are consistent with a self-controlled case series of adults and children 0–24 years of age with and without epilepsy which found no increased risk of seizure requiring inpatient or outpatient hospital care during the risk periods 0–7 days or 8–30 days after adjuvanted pandemic H1N1 influenza immunization versus the controls periods 31–90 days pre-immunization or 31–90 days post-immunization. [20] However, the risk was not assessed specifically in young children and the 0–7 day risk period may have been too long to detect a transient increase in risk 24–48 h after an inactivated vaccine. [7, 8] In addition, this study captured only seizure events severe enough to require hospital care, while our study also captured non-severe seizure events managed via telephone or in the outpatient clinic.

In contrast, a study of 17 children with severe myoclonic epilepsy of infancy whose parents completed seizure diaries after MMR immunization reported an incidence rate ratio of parent-reported seizure of 2.3 (95% CI: 1.5–3.4) in the 5–12 days after the first MMR dose versus the control periods of 0–4 days and 13–42 days post-immunization. [21] Children with severe myoclonic epilepsy of infancy are particularly susceptible to fever-induced seizure, which may explain the increased risk of seizures after MMR vaccine during the period when MMR-associated febrile seizures are observed. In addition, in 16% to 21% of children with severe myoclonic epilepsy of infancy, their first seizure occurred after immunization. [21, 22] Only 15 children in our study had a severe epilepsy syndrome (severe myoclonic epilepsy of infancy, infantile spasms, or Lennox-Gastaux syndrome); therefore, we are unable to exclude a risk in this subgroup. While we may have expected to see an increased risk of seizures after MMR/MMRV in this study, most participants were diagnosed with epilepsy after 12 months of age when the first dose is recommended. The second MMR dose does not appear to be associated with an increased risk of febrile seizure. [23] Further evaluation of vaccine safety in these high-risk children is needed.

Although not an objective of our study, our results provide some evidence to suggest that children with epilepsy may be underimmunized for their age. Only 17% of children with immunization records had received influenza vaccine which is recommended annually for all children over 6 months of age, especially those with epilepsy who are at increased risk of severe influenza. [24] Twenty of 147 (14%) children whose immunization records were available had no recorded immunization events between ages 4 and 7 years, suggesting that they had not received their preschool booster immunizations. It is not clear whether these children were less likely to be immunized than children without epilepsy as overall vaccine coverage in Nova Scotia is below target levels. [25] However, limited evidence suggests that children with epilepsy are less likely to be fully immunized than children without epilepsy. [26, 27] Whether a diagnosis of epilepsy negatively impacts future vaccine uptake is an important question that merits further study.

This study had limitations. We were unable to obtain immunization records on all patients and records may have been incomplete, underlining the importance of central immunization registries for evaluating vaccine safety. Children with immunization events experienced more seizure events than those without immunization events or whose records were not available, which would be expected to lead to an overestimation of the risk of post-immunization seizure. Ascertainment of healthcare encounters for seizure may have been incomplete if some telephone calls to the neurologist were not documented or if some emergency visits and admissions to hospitals outside of the IWK were not reported to the neurologist. In addition, if parents were warned that seizures could occur after immunization, they may have been less likely to report post-immunization seizures. This could have led to an underestimation of the risk of post-immunization seizure. The precision of the results was limited by the small sample size and there were no healthcare encounters during the risk period after a live vaccine, which precluded determination of the relative risk. Nonetheless, we demonstrated that the upper limit of the attributable risk of seizure during the 0–14 day and 0–2 day risk intervals was only 1 seizure per 25 immunizations and 1 per 75 inactivated immunizations, respectively, with two-thirds of events being mild enough to be managed by telephone. A strength of this study was the ascertainment of both severe and non-severe seizure events after immunization among children with all types of epilepsy.

Parents and vaccine providers can be reassured that children with epilepsy do not appear to be at increased risk of medically attended seizure after immunization. While a small increased risk of seizure after immunization cannot be excluded, when balanced against the risk of seizure associated with a vaccine-preventable infection, the benefits appear to outweigh the risks. Further studies are needed in different populations to confirm these findings.