Risk of Febrile Seizures and Epilepsy After Vaccination AAP Grand Rounds 2012;27;52 DOI: 10.1542/gr.

27-5-52

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NEUROLOGY

Risk of Febrile Seizures and Epilepsy After Vaccination

Source: Sun Y, Christensen J, Hviid A, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b. JAMA. 2012;307(8):823-831; doi:10.1001/jama.2012.165 nvestigators from the UniPICO versity of California, Los Question: Among children vaccinated with Angeles, Aarhus University, DTaP-IPV-HiB at 3, 5, and 12 months, what and other centers in Denmark is the risk of febrile seizures and epilepsy? examined the risk of febrile seiQuestion type: Causation zures and epilepsy after vaccinaStudy design: Population-based cohort tion with the combined diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus-Haemophilus influenza type b (DTaP-IPV-Hib) vaccine given at 3, 5, and 12 months. A cohort of 378,834 children born in Denmark between 2003 and 2008 were followed through 2009. Outcome measures were International Statistical Classification of Diseases, Tenth Revision diagnoses of febrile seizures within 0 to 7 days after each DTaP-IPV-Hib vaccination and epilepsy during the 7-year follow-up of the cohort. The investigators estimated the risk of febrile seizures by comparing an exposed group of children in the cohort who were within 0 to 7 days of vaccination with a referent group who were not within 0 to 7 days of vaccination. Risk of epilepsy after the first DTaP-IPV-Hib vaccination was determined by comparing unvaccinated and vaccinated children in the cohort using the date of the first DTaP-IPV-Hib vaccination as a time-varying exposure variable. Of 7,811 children diagnosed with febrile seizures before 18 months of age, 17 were diagnosed within 7 days after the first dose, 32 after the second dose, and 201 after the third dose of DTaP-IPV-Hib. Risk of febrile seizures during the 0 to 7 days after the 3 doses was not significantly higher than that in the reference cohort of children. A small but significantly higher risk of febrile seizures, however, did occur on the day of the first and on the day of the second dose (hazard ratios [HR] 6.02 and 3.94, respectively), but not on the day of the third dose of the vaccine. The incidence rates of febrile seizures on the day of vaccination were 5.5, 5.7, and 13.1 per 100,000 person-days for the first, second, and third doses, respectively. During the 7 years of follow-up, 131 unvaccinated children and 2,117 vaccinated children were diagnosed with epilepsy. Of these, 813 were diagnosed between 3 and 15 months of age and 1,304 were diagnosed at a later age. Compared with unvaccinated children, those who were vaccinated had a significantly lower risk of epilepsy between 3 and 15 months of age (HR 0.63) and a similar risk later in life. The authors conclude that DTaP-IPV-Hib vaccination was associated with a small increased risk of febrile seizures on the day of the first 2 vaccinations at 3 and 5 months but was not associated with an increased risk of epilepsy.

Commentary by

J. Gordon Millichap, MD, FAAP, Neurology, Childrens Memorial Hospital, Northwestern University Medical School, Chicago, IL
Dr Millichap has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

The mechanism of the febrile seizure is dependent on the height of the body temperature, a childs threshold convulsive temperature,1 genetic susceptibility, and other factors such as the neurotropic properties of certain causal viruses and cytokine immune response to infection. The fever and height of the body temperature induced by infection are the essential triggers, not the rapidity of temperature rise1 nor the type of viral infection.2 The evidence for a specific encephalitis or encephalopathy in febrile seizures is inconclusive.2 The relationship between vaccination and febrile seizure is complex, with the seizure resulting from either a nonspecific fever or possibly secondary to an encephalitis or encephalopathy.3 Vaccinationinduced fever triggers the onset of febrile seizures in one third of patients with Dravet syndrome, an epileptic encephalopathy presenting in the first year of life and associated with SCN1A gene mutations in 60% to 80% cases reported.4 Five alleged cases of pertussis vaccine encephalopathy were rediagnosed years later as Dravet syndrome.5 In a European survey of adverse events following immunization in children aged 0 to 6 years, febrile seizures were the specific adverse event in 49% of 247 cases and various epilepsy syndromes in 12.6%. Severe childhood epilepsies were diagnosed in 11.7%, with the vaccination-associated event being the first documented seizure in 15 of 29 patients.6 Early diagnosis of an epilepsy syndrome is important for determination of the correct etiology of a vaccine-related seizure. Current evidence supports the safety of vaccination of children in general, and pertussis vaccination in particular, especially since the replacement of the whole-cell vaccine with a less reactogenic acellular pertussis vaccine. The public may still be skeptical, however, leading to inadequate immunization coverage and danger of pertussis outbreaks. Febrile seizures following vaccination, however, are not different from febrile seizures in general and are dependent on the degree of vaccine-induced fever. The practice of prophylactic antipyretic administration at the time of immunization, although sometimes warranted, is not routinely recommended since antibody responses may be reduced (see AAP Grand Rounds, January 2010;23[1]:27).
References
1. Millichap JG. Pediatrics. 1959;23:76-85 2. Millichap JG, et al. Pediatr Neurol. 2006;35:165-172; doi:10.1016/j.pediatrneurol.2006.06.004 3. Cendes F, et al. Epilepsia. 2011;52(suppl 3):23-25; doi:10.1111/j.1528-1167.2011.03032.x 4. Korff C, et al. J Child Neurol. 2007;22(2):185-194; doi:10.1177/0883073807300294 5. Reyes IS, et al. Pediatrics. 2011;128(3):e699-e702; doi:10.1542/peds.2010-0887 6. von Spiczak S, et al. Epilepsia. 2011;52(8):1506-1512; doi:10.1111/j.15281167.2011.03134.x 7. Prymula R, et al. Lancet. 2009;374(9698):1339-1350; doi:1016/s0140-6736(09)61208-3

Key words: epilepsy, febrile seizure, vaccination

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Risk of Febrile Seizures and Epilepsy After Vaccination AAP Grand Rounds 2012;27;52 DOI: 10.1542/gr.27-5-52

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