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2/352 www.aapgrandrounds.org
Source: Sun Y, Christensen J, Hviid A, et al. Risk o ebrile
seizuresand epilepsy afer vaccination with diphtheria, tetanus,
acellular
pertussis, inactivated poliovirus, and Haemophilus inuenzaetype
b. JAMA. 2012;307(8):823-831; doi:10.1001/jama.2012.165
Investigators from the Uni-
versity of California, LosAngeles, Aarhus University,
and other centers in Denmarkexamined the risk of febrile
sei-
zures and epilepsy aer vaccina-tion with the combined
diph-theria-tetanus toxoids-acellular
pertussis-inactivated poliovirus-Haemophilus inuenza type
b(DaP-IPV-Hib) vaccine given at 3, 5, and 12 months. A cohort
of
378,834 children born in Denmark between 2003 and 2008 were
fol-lowed through 2009. Outcome measures were International
Statisti-
cal Classication o Diseases, Tenth Revision diagnoses of
febrileseizures within 0 to 7 days aer each DaP-IPV-Hib vaccination
andepilepsy during the 7-year follow-up of the cohort. Te
investigatorsestimated the risk of febrile seizures by comparing an
exposed groupof 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
vaccina-tion. Risk of epilepsy aer the rst DaP-IPV-Hib vaccination
was
determined by comparing unvaccinated and vaccinated children
inthe cohort using the date of the rst DaP-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 aer the rst dose, 32
aer
the second dose, and 201 aer the third dose of DaP-IPV-Hib.
Risk
of febrile seizures during the 0 to 7 days aer the 3 doses was
not sig-nicantly higher than that in the reference cohort of
children. A smallbut signicantly higher risk of febrile seizures,
however, did occur on
the day of the rst 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 doseof the vaccine. Te incidence rates of febrile seizures on
the day of
vaccination were 5.5, 5.7, and 13.1 per 100,000 person-days for
therst, second, and third doses, respectively.
During the 7 years of follow-up, 131 unvaccinated children
and2,117 vaccinated children were diagnosed with epilepsy. Of
these,
813 were diagnosed between 3 and 15 months of age and 1,304
werediagnosed at a later age. Compared with unvaccinated children,
thosewho were vaccinated had a signicantly lower risk of epilepsy
be-
tween 3 and 15 months of age (HR 0.63) and a similar risk later
in life.Te authors conclude that DaP-IPV-Hib vaccination was
associ-
ated with a small increased risk of febrile seizures on the day
of therst 2 vaccinations at 3 and 5 months but was not associated
with an
increased risk of epilepsy.
Commentary byJ. Gordon Millichap, MD, FAAP, Neurology, Childrens
Memorial Hospital,
Northwestern University Medical School, Chicago, IL
Dr Millichap has disclosed no nancial relationship relevant to
this commentary. This commentary does not contain a
discussion of an unapproved/investigative use of a commercial
product/device.
Te mechanism of the febrile seizure is dependent on the heightof
the body temperature, a childs threshold convulsive
temperature,1genetic susceptibility, and other factors such as the
neurotropic
properties of certain causal viruses and cytokine immune
responseto infection. Te fever and height of the body temperature
inducedby infection are the essential triggers, not the rapidity of
tempera-
ture rise1 nor the type of viral infection.2 Te evidence for a
specicencephalitis or encephalopathy in febrile seizures is
inconclusive.2
Te relationship between vaccination and febrile seizure is
com-plex, with the seizure resulting from either a nonspecic fever
or pos-
sibly secondary to an encephalitis or encephalopathy.3
Vaccination-induced fever triggers the onset of febrile seizures in
one third ofpatients with Dravet syndrome, an epileptic
encephalopathy present-
ing in the rst year of life and associated with SCN1A gene
mutationsin 60% to 80% cases reported.4 Five alleged cases of
pertussis vaccine
encephalopathy were rediagnosed years later as Dravet syndrome.
5In a European survey of adverse events following immunization
in
children aged 0 to 6 years, febrile seizures were the specic
adverseevent 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 rst documented seizure in
15of 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
acellularpertussis vaccine. Te public may still be skeptical,
however, leadingto inadequate immunization coverage and danger of
pertussis out-breaks. Febrile seizures following vaccination,
however, are not dif-
ferent from febrile seizures in general and are dependent on the
de-gree of vaccine-induced fever. Te practice of prophylactic
antipyretic
administration at the time of immunization, although
sometimeswarranted, is not routinely recommended since antibody
responses
may be reduced (seeAAP 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.pediatrneu-
rol.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. Kor C, et al.J Child Neurol. 2007;22(2):185-194;
doi:10.1177/08830738073002945. 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.1528-
1167.2011.03134.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
NEUROLOGY
Risk of Febrile Seizures and Epilepsy After Vaccination
PICO
Question: Among children vaccinated with
DTaP-IPV-HiB at 3, 5, and 12 months, what
is the risk of febrile seizures and epilepsy?
Question type: Causation
Study design: Population-based cohort
at Indonesia:AAP Sponsored on May 8,
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