Received: 16 March 2023

| Revised: 15 July 2023

| Accepted: 17 July 2023

DOI: 10.1111/epi.17720

CRITICAL REVIEW

Are brief febrile seizures benign? A systematic review and

narrative synthesis

Laura Gould1,2 | Victoria Delavale1,2 | Caitlin Plovnick3 | Thomas Wisniewski2,4,5,6 |

Orrin Devinsky1,2,6

1
Comprehensive Epilepsy Center, NYU
Langone Health, New York, New York, Abstract
USA Febrile seizures affect 2%–­5% of U.S. children and are considered benign al-
2
Department of Neurology, NYU though associated with an increased risk of epilepsy and, rarely, with sudden un-
Langone Health and NYU Grossman
School of Medicine, New York, New
explained death. We compared rates of mortality, neurodevelopmental disorders,
York, USA and neuropathology in young children with simple and complex febrile seizures
3
Health Sciences Library, NYU to healthy controls. We systematically reviewed studies of 3-­to 72-­month-­old chil-
Grossman School of Medicine, New
dren with simple or complex febrile seizures ≤30 min. We searched studies with
York, New York, USA
4 outcome measures on mortality, neurodevelopment, or neuropathology through
Department of Pathology, NYU
Langone Health and NYU Grossman July 18, 2022. Bias risk was assessed per study design. Each outcome measure
School of Medicine, New York, New was stratified by study design. PROSPERO registration is CRD42022361645.
York, USA
5
Twenty-­six studies met criteria reporting mortality (11), neurodevelopment (11),
Center for Cognitive Neurology, NYU
Langone Health and NYU Grossman and neuropathology (13), including 2665 children with febrile seizures and 1206
School of Medicine, New York, New seizure-­free controls. Study designs varied: 15 cohort, 2 cross-­sectional, 3 case–­
York, USA
control, 5 series, and 1 case report. Mortality outcomes showed stark contrasts.
6
Department of Psychiatry, NYU
Six cohort studies following children after febrile seizure (n = 1348) reported
Langone Health and NYU Grossman
School of Medicine, New York, New no deaths, whereas four child death series and 1 case report identified 24.1%
York, USA (108/449) deaths associated with simple (n = 104) and complex (n = 3) febrile sei-
Correspondence
zures ≤30 min. Minor hippocampal histopathological anomalies were common
Laura Gould, Comprehensive Epilepsy in sudden deaths with or without febrile seizure history. Most electroencepha-
Center, NYU Langone Health, New lography (EEG) studies were normal. Neuroimaging studies suggested increased
York, NY, USA.
Email: laura.gould@nyulangone.org right hippocampal volumes. When present, neurodevelopmental problems usu-
ally preexisted febrile-­seizure onset. Risk bias was medium or high in 95% (18/19)
Funding information
of cohort and case–­control studies vs medium to low across remaining study de-
Finding A Cure for Epilepsy and
Seizures; National Center for signs. Research on outcomes after simple or brief complex febrile seizures is lim-
Advancing Translational Sciences, NIH, ited. Cohort studies suffered from inadequate sample size, bias risk, and limited
Grant/Award Number: UL1TR001445;
follow-­up durations to make valid conclusions on mortality, neurodevelopment,
SUDC Foundation; SUDC-­UK; U.S.
National Institute of Health, Grant/ and neuropathology. Sudden death registries, focused on a very small percent-
Award Number: P30AG066512 and age of all cases, strongly suggest that simple febrile seizures are associated with
P01AG060882
increased mortality. Although most children with febrile seizures have favorable
outcomes, longer-­term prospective studies are needed.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Epilepsia. 2023;64:2539–2549.  wileyonlinelibrary.com/journal/epi | 2539

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2540    GOULD et al.

KEYWORDS
febrile seizures, mortality, neurodevelopment, neuropathology, SUDC

1 | I N T RO DU CT ION
Febrile seizures are the most common childhood seizure
type, affecting 2%–­5% of children.1 Most are brief, with recur-
rence rates from 15% to 70%.2,3 Much research has focused
on prolonged (>30 min) febrile seizures, which are associ-
ated with a higher risk of subsequent epilepsy, hippocam-
pal abnormalities on imaging, and neurodevelopmental
disorders.4 Parents are assured that brief febrile seizures are
“almost always benign” and outgrown, although case series
from death registries suggest significantly higher rates of
sudden unexplained death in childhood (SUDC).5-­7 Among
SUDC cases 1–­6 years of age, 28% had a febrile seizure his-
tory vs <3% of healthy children at age 1.6 years (median age
of SUDC).6 SUDC affects children after age 12 months for
whom no cause of death is found despite thorough autopsy
and investigation.5 It is the fifth leading category of death
among children aged 1–­4 years, the peak age for febrile sei-
zures.8 SUDC is more frequent in boys,during sleep and
many had a mild illness near death.5,6,9
Febrile seizures are provoked events generally affect-
ing children 6 months to 5 years, resulting from fever or ill-
ness without an underlying central nervous system (CNS)
infection.3,10,11 Simple febrile seizures are generalized,
last <15 min, and do not recur in 24 h; they account for
65%–­90% of febrile seizures.10 Complex febrile seizure last
>15 min or have ictal or postictal focal features.10 Febrile
status epilepticus lasts >30 min as a continuous event or
cluster without full neurological function regained be-
tween seizures.10 More than 25% of cases have a family
history of febrile seizures or epilepsy.12
Morbidity and mortality outcome studies on febrile
seizures focused on complex febrile seizures and febrile
status epilepticus.4
A nested case–­control study of 8172 child deaths and
40 860 matched controls included 232 child deaths with any
febrile seizure history.13 Apart from an increase in mortal-
ity rate ratios of seizure-­related deaths (37–­91 [13.71–­ .31]),
there was also a significant increased mortality rate for “ill-­
defined” (4.27 [1.66–­8.94]) and “unexpected” (4.94 [1.74–­
11]) deaths (International Classification of Diseases, Tenth
Revision [ICD-­10] codes R96 and R99) in the first 2 years
after febrile seizures.13 Such certifications are common in
SUDC, and may result from simple febrile seizures.6
Prospective long-­term outcomes studies after simple
and complex febrile seizures have neither been systematic
nor comprehensive. This deficit limits our recommenda-
tions on monitoring children, educating parents, interven-
tions, and targeted research.
Key points
• Sudden death registries focused on a tiny mi-
nority of febrile seizure cases but support that
simple febrile seizures can rarely increase mor-
tality risk.
• Hippocampal histopathological anomalies are
common in children who die suddenly, with or
without febrile seizures.
• When present, neurodevelopmental issues usu-
ally precede febrile seizure onset.
• Long-­term population-­based prospective stud-
ies are needed to better define outcomes in chil-
dren with febrile seizures.
2 | METHODS
We conducted a systematic review by Preferred Reporting
Items for Systematic Reviews and Meta-­ Analyses
(PRISMA) guidelines and mapped using the PRISMA
2020 flow diagram for new systematic reviews.14 The re-
view is registered in PROSPERO CRD42022361645.
2.1 | Search process
We searched electronic databases with search terms in-
cluding “febrile seizure(s),” “mortality,” “death,” “neu-
ropathology,” and “neurodevelopment” across Medline,
Embase, the Cochrane Library, CINAHL, PubMed, and
Web of Science all databases (formerly Web of Knowledge)
through July 18, 2022, without language restrictions.
Study identification included electronic databases search-
ing strategies and screening citations of relevant reviews.
We included observational studies (case series, prospec-
tive and retrospective cohorts, case cohorts, case controls,
cross-­sectional studies, and case reports) and randomized
controlled trials. Detailed search criteria and terms are de-
scribed in Appendix S1.
2.2 | Inclusion criteria
We included studies examining children 3–­72 months of
age with a diagnosis of simple (ICD: R56.0) or complex
febrile seizures (ICD-­10: R56.01) lasting 30 min or less. We

GOULD et al.
included seizure-­free control subjects where applicable by
study design. We included studies that evaluated the as-
sociation of febrile seizures with mortality (i.e., those that
explicitly referenced an association or lack of association
between mortality and febrile seizures), neuropathology
(i.e., those related to neuroimaging, electroencephalogra-
phy [EEG], histology, and proteomics), and neurodevel-
opmental outcomes.
2.3 | Exclusion criteria
We excluded studies and cases related to prolonged febrile
seizures, febrile seizure epilepticus (ICD-­ 10: G40.901),
afebrile seizures or epilepsy (ICD-­10: G40.9). We excluded
cases younger than 3 months or older than 72 months at
time of febrile seizure onset. We excluded studies con-
ducted on animals, abstracts/conference proceedings,
cost-­effectiveness studies, letters to the editor, systematic
reviews, and meta-­analyses.
2.4 | Screening process
The two reviewers (L.G. and V.D.) used Covidence, a web-­
based service for systematic reviews, to independently
screen titles and abstracts of all studies identified by the
selection criteria (Appendix S1) and review full texts from
studies that met inclusion criteria. If information needed
to classify the study was missing, we attempted to contact
study authors for clarification. L.G. and V.D. discussed
each study; if disagreement persisted, a third reviewer ad-
judicated (T.W.).
The same reviewers independently rated the quality
of cohort and case–­controlled studies using Newcastle-­
Ottawa Quality Assessment Scales and the Joanna Briggs
Institute's (JBI) critical appraisal tools, which do not pro-
vide a final score.15,16 Any differences in bias assessment
scoring defaulted to a third reviewer to adjudicate (T.W.).
To compare and rate studies using JBI's tools, we assessed
affirmative answer rates for each study to the 8–­10 stan-
dardized questions per study design and calculated a per-
centage score from the possible total (i.e., 8/10 affirmative
questions = 80% score). Scores could range from 0%–­33%
(high risk of bias), 34%–­67% medium, and 68%–­100% (low
risk of bias).17
2.5 | Extraction
The two reviewers independently extracted data on
country of origin, study objective(s), population, subject
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   2541
number, number with simple or ≤30-­min complex febrile
seizures, number of seizure-­free controls, and outcomes
measures.
2.6 | Data analysis
We described study results by outcome and study design.
For publications from the same data sets where we could
not identify duplicate cases, we prioritized the publication
reporting the largest sample size. Discrepancies between
published versions were highlighted. We described a nar-
rative synthesis for each outcome. When permissible, we
compared cases with febrile seizures satisfying inclusion
criteria to controls (i.e., seizure-­free subjects).
3 | RESULTS
3.1 | Study selection and screening
Figure 1 is the flow diagram for PRISMA-­guided study se-
lection. Our search criteria and review articles' reference
lists identified 2788 citations. After removing 879 dupli-
cates, the title and abstracts of 1909 were reviewed for
relevance; 510 underwent full-­text review. We excluded
484 studies due to the: wrong patient population (n = 225),
wrong outcomes (n = 91), febrile seizure type not specified
(n = 30), wrong study design (n = 114), redundant data
from another included publication (n = 5), or unable to lo-
cate or obtain English translation (n = 19). There were no
disagreements in screening between the two reviewers to
necessitate a third reviewer.
3.2 | Included studies
The systematic review included 26 studies (Table S1)
between 1978 and 2022.5,6,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,
33,34,35,36,37,38,39,40
All reported ≥1 cases within inclusion cri-
teria and data related to our primary mortality outcome
(11), or secondary outcomes of neurodevelopment (11) or
neuropathology (13). Two studies (Krous et al.5 and Kinney
et al.39) reported mortality data from the same case registry
with undefined case redundancy that could not be clarified
after contact with the author. We only reported one.39 Three
studies (Leitner et al.35,41 and McGuone et al.37) reported
unique outcomes from the same case series with some
known overlap. We included these studies by our group,
relative to their unique methodology and outcome results,
but ensured the accuracy of mortality incidence by measur-
ing each unique case once.
 |
2542   
FIGURE 1 PRISMA flow diagram. Source from Page et al.14
3.3 | Study design and sample
characteristics
Across 26 studies, 2665 subjects (69% of total) had simple or
complex febrile seizures ≤30 min and 1206 seizure-­free con-
trols. Fifteen (57.7%) of the 26 studies used a cohort design,
5 prospective and 10 retrospectives, with variable duration
follow-­up of hospital admission to 12 years from febrile sei-
zure occurrence. The remaining study designs included two
cross-­sectional, three case–­controlled, five case series, and
one case report. No randomized control trials were identi-
fied. (See Table S1 for detailed characteristics.)
3.4 | Quality appraisal
Quality and risk of bias ratings are included in Tables 1–­3,
with detailing scoring in Tables S2–­S4. There were no
disagreements among the reviewers (L.G. and V.D.) on
bias assessments. Study assessments revealed 6 high, 15
medium, and 5 with low risk of bias.
3.5 | Mortality
Eleven studies reported mortality outcomes across 1455
cases and 345 controls (Table 1).
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GOULD et al.
Six (55%) were cohort studies of children after fe-
brile seizure (n = 1348) onset and identified no deaths,
with follow-­ up durations ranging from hospital ad-
mission (n = 31, median 3 days), about 2 years (n = 32
with mean 22.8 months, and n = 482, mean 28 months),
12 years (n = 197), and two studies with unknown dura-
tions.19,21,22,25,27,29 Fifty-­three percent (711/1348) of cohort
study cases had follow-­up ≈2 years or more but lacked con-
trols. One cohort study29 had a low bias risk, whereas the
remaining had medium to high bias risk.
Case mortality was reported in four case series and
one case report. All but one had low risk of bias. The San
Diego SUDC registry reported 20% (12/60) child deaths, 1–­
5.9 years, related to simple febrile seizures.39 A case series
of family interviews of 391 sudden child deaths, 1–­6 years,
included 79 cases associated with simple febrile seizures:
62 unexplained and 17 explained deaths.6 An additional
24 deaths were associated with complex febrile seizures
NOS (not otherwise specified) and not included in re-
view.6 Across the 79 cases with simple febrile seizures only
and 280 seizure-­free sudden child deaths, 90% were unwit-
nessed and sleep-­related deaths.6 Approximately half ex-
perienced recent fever. The prone face-­down position was
reported in 38% of seizure-­free cases and 50% of febrile
seizure cases.6
The SUDC Registry and Research Collaborative re-
ported 5 of its first 10 consecutively enrolled sudden
 TABLE 1 Summary of subjects and risk of bias for 11 studies reporting mortality outcomes.

Cases: SFS Cases: CFS ≤30 min Cases with mortality Seizure-­free controls Controls with Risk of
References (location) Study design (n = 1020) (n = 435) (n = 107) (n = 345) mortality (n = 341) biasa
GOULD et al.

Elshana et al.19 (Turkey) Cohort 443 159 0 0 NA Medium

21
Grill et al. (USA) Cohort 0 32 0 0 NA High
22
Sfaihi et al. (Tunisia) Cohort 266 216 0 0 NA Medium
Landau et al.25 (Israel) Cohort 4 0 0 4 NA Medium
27
Newland et al. (USA) Cohort 27 4 0 0 0 Medium
MacDonald et al.29 (UK) Cohort 177 20 0 0 NA Low
37
McGuone et al. (USA) Case series 9 2 11 8 8 Low
6
Crandall et al. (USA) Case series 78 0 78 280 280 Low
Halvorsen et al.38 (USA) Case series 4 1 5 5 5 Medium
Kinney et al.39 (USA) Case series 12 0 12 48 48 Low
Dlouhy et al.40 (USA) Case report 0 1 1 0 0 Low
Abbreviations: CFS, complex febrile seizures; NA, not applicable; SFS, simple febrile seizures.
a
Risk of bias assessments were completed either according to the Newcastle-­Ottawa Scale or with JBI Critical Appraisal tools with respect to the study design.

TABLE 2 Summary of subjects and risk of bias for 11 studies reporting neurodevelopment outcomes.

Seizure-­free controls Length of Risk of

References (location) Study design SFS (n = 920) CFS (n = 481) (n = 947) % males cases % males controls follow-­up biasa
Adachi et al.18 (Japan) Cohort 185 61 0 UNK NA ƞ=3y High
Leaffer et al.20 (USA) Cohort 104 26 141 70 (87/130) 56.7 (80/141) 1 year Medium
Grill et al.21 (USA) Cohort 0 32 0 53.1 (17/32) NA x̄=22.8 m High
Sfaihi et al.22 (Tunisia) Cohort 266 216 0 UNK NA x̄=28 m Medium
23
Frobert et al. (France) Cohort 2 0 167 100 (2/2) UNK LOS High
24
Ozkan et al. (Turkey) Cohort 5 5 200 30 (3/10) UNK LOS Medium
Newland et al.27 (USA) Cohort 27 4 UNK UNK LOS Medium
Ellenberg et al.31 (USA) Cohort 286 118 431 UNK UNK 7 years Medium
33
Nilsson et al. (Sweden) Cross-­sectional 36 16 0 UNK NA NA Medium
McGuone et al.37 (USA) Case series 9 2 8 36.4 (4/11) 37.5 (3/8) NA Low
40
Dlouhy et al. (USA) Case report 0 1 0 0 NA NA Low
|   

Abbreviations: CFS, complex febrile seizures; LOS, length of stay; m, months; NA, not applicable; SFS, simple febrile seizures; UNK, unknown; y, years.
a
2543

Risk of bias assessments were completed either according to the Newcastle-­Ottawa Scale or with JBI Critical Appraisal tools with respect to the study design.

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 | 2544
  

TABLE 3 Summary of subjects and risk of bias for 13 studies reporting neuropathology outcomes.

CFS ≤30 min Seizure-­free controls % males Risk of

References (location) Study design SFS (n = 568) (n = 341) (n = 184) % males cases controls biasa
Neuroimaging
Hesdorffer et al.26 (USA) Cohort 105 26 0 54.7 (87/159) NA Medium
Grill et al.21 (USA) Cohort 0 32 0 17 NA High
30
Van Landingham et al. (USA) Cohort 0 7 UNK 4 NA High
Szabó et al.34 (USA) Cross-­sectional 0 5 11 2 4 High
Fernández et al.36 (1998) (Germany) Case–­Control 8 1 23 UNK 17 High
40
Dlouhy et al. (USA) Case report 0 1 NA 0 NA Low
EEG
Sfaihi et al.22 (Tunisia) Cohort 266 216 0 UNK NA Medium
28
Maytal et al. (USA) Cohort 0 17 0 UNK NA Medium
Kajitini et al.32 (Japan) Cohort 154 0 0 UNK NA Medium
Grill et al.21 (USA) Cohort 0 32 0 17 NA High
Neuropathology/Histology
Kinney et al.39 (USA) Case series 12 0 48 7 24 Low
37 b
McGuone et al. (USA) Case series 14 2 39 4 3 Low
Leitner et al.41 (USA)b Case–­Control 36 5 26 Medium
Dlouhy et al.40 (USA) Case report 0 1 NA 0 NA Low
Proteomics
Leitner et al.35 (USA) Case–­Control 9 1 27 3 20 Medium
Abbreviations: CFS, complex febrile seizures; NA, not applicable; SFS, simple febrile seizures; UNK, unknown.
a
Risk of bias assessments were completed either according to the Newcastle-­Ottawa Scale or with JBI Critical Appraisal tools with respect to the study design.
b
Reporting each unique case once across overlapping data sets.
GOULD et al.

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GOULD et al.
unexpected child deaths associated with febrile seizures.38
One had complex febrile seizures and Dravet syndrome
due to SCN1A mutation.38 Four cases had only simple
febrile seizures.38 All 10 cases were sleep related and un-
witnessed, and 60% had a recent fever. Cases and controls
had similar ages.38 An additional 11 of 19 decedents from
the same registry experienced febrile seizures before sud-
den death, of which 82% were simple febrile seizures.37 All
case and control deaths were unwitnessed; 18 of 19 were
sleep related.37 The majority of cases (63.6%, 7/11) had re-
cent fever compared to controls (25%, 2/8).37
A case report of a 33-­month-­old female with recent
fever died during sleep. She had a history of brief complex
febrile seizures; one seizure was associated with apnea
and there was a family history of febrile seizures.40
Overall, children with febrile seizures studied during
life (917 cases and 4 controls) did not identify any deaths
across six cohort studies. However, three sudden child
death registries and one case report identified febrile
seizure–­associated child deaths among simple and ≤30-­
min duration complex febrile seizures in 24.1% (108/449)
of unique cases.6,37,38,39 Not included in our review were
24 (5.1%, 24/473) complex febrile seizure–­ associated
deaths of unknown duration and one with confirmed du-
ration >30 min.6 Inclusive of all febrile seizure associated
deaths in these studies, 78% (104/133) were simple febrile
seizures only.
3.6 | Neurodevelopment
Neurodevelopmental outcomes were reported in 11 stud-
ies: 1401 (920 simple and 481 complex febrile seizures
≤30 min) cases and 947 controls reported (Table 2).
Eight cohort studies had variable follow-­up dura-
tions with bias risk medium to high inclusive of 95.5%
(1346/1410) cases and 1% (8/947) controls. Acute neu-
rological outcomes after febrile seizure due to influenza
infections across three studies reported normal neuro-
developmental outcomes (n = 14/14).23,24,27 Studies with
2-­to 3-­year duration follow-­ups identified pre-­existing
neurological abnormalities associated with some cases.
Among 482 febrile seizure cases followed for ≈2 years,
no new neurological deficits were identified.22 Among
32 cases of recurrent febrile seizures within 24 h fol-
lowed for a mean of 28 months, 3% (1/32) had speech
delay.21 Among 263 cases followed for 3 years since fe-
brile seizure onset, cases with neurodevelopmental sup-
port services at school were associated with focal febrile
seizures and pre-­ existing neurodevelopmental abnor-
malities.18 Studies evaluating cognitive outcomes also
identified pre-­existing neurological deficits associated
with febrile seizures. Among 431 sibling pairs in which
|
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   2545
one had ≥1 febrile seizure and IQs were normal prior
to febrile seizure onset, IQs were similar at 7 years of
age.31 Among 130 cases and 141 seizure-­free controls,
cognitive outcomes were similar at 1-­year follow-­up.
Cognitive decline was associated with preexisting neu-
rological abnormalities (p = .05).20
One cross-­sectional, case series, and case report each
reported neurodevelopmental outcomes with critical ap-
praisal scores of medium, low, and low risk of bias, re-
spectively.33,37,40 In a cross-­sectional study of 52 simple
febrile seizure cases, 38% had developmental issues at
age 4 years.33 They were not limited to intellectual dis-
ability, attention-­deficit/hyperactivity disorder, or autism
spectrum disorder.33 However, a case series of sudden
unexpected child deaths identified similar frequencies of
developmental delay among cases and controls (27.2%,
3/11 vs 25%, 2/8) and the case report of sudden death with
complex febrile seizures had normal development.37,40
3.7 | Neuropathology
Thirteen studies reported neuropathology-­ related out-
comes: six neuroimaging, four EEG, four histology, and
one proteomics (Table 3).
Six neuroimaging studies with 176 cases (105 simple
and 71 complex febrile seizures) and 24 controls, had bias
assessed as high (4), medium (1), and low (1). Three co-
hort studies using magnetic resonance imaging (MRI)
identified incidence of abnormalities among cases ranging
from 28.5% (2/7) to 15% (20/131) and 7.4% (2/27).21,26,30
One cross-­sectional and one case–­control study reported
increased right hippocampal volumes. The first studied
five cases with complex febrile seizures; all had right > left
hippocampal volumes vs controls with 7/11 right > left
hippocampal volumes.34 The second case–­control study
of 9 cases and 23 controls across 2 families with familial
convulsions also identified increased right hippocampal
volumes among all cases (mean 1.168, range 1.099–­1.233)
and 6 family member controls (mean 1.16, range 1.081–­
1.324).36 Authors suggested an inherited left hemispheric
hippocampal malformation, which facilitated febrile sei-
zures in these families.36 A final case report of the child
who died suddenly with a previous history of complex
febrile seizures had diffuse edema by computerized to-
mography (CT) upon admission after she was found unre-
sponsive and resuscitated.40
Four cohort studies reported EEG results on 420 sim-
ple and 264 complex febrile seizures without controls.
The bias risk was assessed as medium (3) or high (1). One
study analyzed 44 EEG studies on complex febrile seizures
cases (36 were infants as authors considered any febrile sei-
zure <12 months as complex, 5 focal, and 3 simple febrile
 |
2546   
seizures) considered unremarkable.22 Postictal sleep EEG
recordings on 17 cases of complex febrile seizures were also
considered normal.28 Among 154 cases with simple febrile
seizures only, 3% (5/154) had abnormal EEG findings with
small focal spikes (n = 3) and bilateral small spikes (n = 2).32
Among 32 cases with recurrent febrile seizures within a
24 h timeframe and evaluated with EEG within 3 months of
event, 12.5% (4/32) had abnormal EEG findings related to
diffuse onset tonic–­clonic seizure, diffuse slowing, occipital
rhythmic delta activity, or bifrontal and left central spikes.21
Four studies reported postmortem histopathological
neuropathology across two case series, one case report,
and one case control study of 29 unique sudden death
cases (26 simple and 3 complex febrile seizures) vs 87 con-
trols. Critical appraisals of bias risk were medium (1) and
low (3). One case series reported 12 cases and 48 controls
with variable brain sections available but identified more
frequent hippocampal findings vs controls; 88% (7/8) vs
17% (3/18), most often implicating the dentate gyrus, 63%
(5/8) vs 11% (2/18).39 The SUDC Registry and Research
Collaborative examined comprehensive standardized
brain samplings of 11 cases and 8 controls and also re-
ported the highest incidence of histological findings in
the hippocampus (95%, 18/19); however, they were not
related to febrile seizure history.37 The one case without
hippocampal findings had a history of both simple and
complex febrile seizures.37 An additional experiment from
the same registry included a case–­control study of 9 cases
and 36 controls (explained deaths and unexplained with-
out history of febrile seizures) evaluating hippocampal
morphology across 9 blinded pathologist reviewers.41 The
study found no significant difference in the incidence of
hippocampal findings among cases and controls (p = .90)
as well as a low level of concordance (p = .47) by review-
ers.41 The case report of sudden child death with a history
of complex febrile seizure revealed global cerebral edema
and marked softening of the brain with herniation at au-
topsy but no clear evidence of cause of death.40
One case-­control study of sudden unexplained child
deaths with 10 cases and 27 controls examined frontal and
temporal lobe brain proteomics.35 The highest frequency of
altered protein were expressed in the frontal cortex, with
some altered proteins correlating with fever before death
and febrile seizure history.35 The risk of bias was medium.
4 | DI S C USSION
Our review revealed stark contrasts of simple and ≤30 min
duration complex febrile seizure mortality outcomes
among cohort studies of living children with febrile sei-
zures (0%, 0/1348) compared to sudden child death se-
ries (24%, 108/449). Overall, studies assessing mortality,
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GOULD et al.
neurodevelopment, and neuropathology after simple
or ≤30-­min complex febrile seizures were of relatively low
quality. Most were cohort studies with medium to high risk
of bias, thereby limiting the weight of evidence for conclu-
sions. Only three cohort studies including 711 children
had follow-­ups ≥2 years after onset of febrile seizures.21,22,29
With 2%–­4% of the U.S. population aged 6 months to 5 years
affected by febrile seizures, 711 cases is <.1% of the annual
febrile seizure(s) incidence in the U.S. population.42
Sudden death registries strongly associate febrile sei-
zures and mortality. Although selection bias may have af-
fected case ascertainment, 78% (104/133) of deaths with a
history of any febrile seizure type had only simple febrile
seizures. These observations suggest that current guide-
lines for the care of children with simple febrile seizures
limited to identifying the source of fever should be mod-
ified.10,43 Although the risks are very low, parents should
be warned of the potential risks of prolonged febrile sei-
zures and the low risks of morbidity and mortality. For ex-
ample, because most deaths occur during apparent sleep
periods, the potential for monitoring can be considered.
Assessments of secondary outcomes for neurodevel-
opment and neuropathology were limited by the het-
erogeneity of study data, methodology, bias risk, sample
size, and limited follow-­up durations to assess outcomes.
Neurodevelopmental issues were usually identified before
febrile-­seizure onset, except for Nilsson's population-­based
study in which 20 of 52 cases (38%) with simple febrile
seizure had attention-­deficit/hyperactivity disorder, au-
tism spectrum disorder, developmental coordination, and
other disorders. Diagnosing mild neurodevelopmental is-
sues before peak age of febrile seizure onset, 18 months, is
difficult and may confuse temporal relationships.
EEG studies were mostly normal, while brain structure
studies identified potential abnormalities. Neuroimaging
studies suggested increased right hippocampal volumes
but require replication in larger studies. Some histopathol-
ogy studies suggest more hippocampal findings in sudden
child death, but two recent studies by our group found
minor anomalies in explained and unexplained deaths,
regardless of seizure history. Proteomic studies identified
significant differences among cases and controls, suggest-
ing new pathways to investigate mechanisms of death.
Most SUDCs are unwitnessed sleep-­ related deaths.
Because a terminal febrile seizure is unlikely to provide
physical evidence at autopsy that a seizure occurred,
unwitnessed sleep-­ related child deaths with a remote
history of febrile seizures are commonly certified as “ill-­
defined” or “unexpected” (ICD-­10 R96 or R99). Death
investigations vary greatly, with some pathologists at-
tributing minor pathology to an explained cause of death
(e.g., minor upper respiratory infection) and ignoring the
potential role of febrile seizure history or circumstantial

GOULD et al.
evidence (e.g., recent fever, found prone faced down). We
found a 40% discordance between the original certifier's
cause of death and blinded forensic pathology reviews.44
The National Association of Medical Examiners recom-
mends changes to death certification processes when cer-
tifying a pediatric death as ill-­defined or unexpected by
including a synoptic report documenting intrinsic and
extrinsic factors. Intrinsic factors include past and recent
medical history (e.g., simple febrile seizure, recent fever)
and minor pathology findings.45 Extrinsic findings include
environmental risks (e.g., found prone faced down) that
may contribute to death. Implementation of these recom-
mendations will improve surveillance and tracking of risk
factors associated with sudden child deaths.45
Our presumption of relative safety toward simple and
brief complex febrile seizures is expected given the rarity of
severe outcomes. With more than 33 000 U.S. pediatricians,
most will treat scores of children with febrile seizures but
never experience a patient with a definite adverse outcome
as severe as sudden death.46 In 2021, the United States re-
ported 249 children, ages 1–­4 years, with unexplained sud-
den deaths (1.6/100 000 crude death rate).47 These cases
comprise sudden child death registries in which 25%–­35%
of deaths occur in children with febrile seizure histories.
Public health should balance two extremes. First, avoid
alarming millions of parents about extremely low risks,
which could lead to adverse outcomes for parents, includ-
ing stress, sleep deprivation, unnecessary expenses, and
overprotection of children. Alternatively, counseling with
reassurance but education about very low frequency out-
comes would allow parents to pursue low-­cost monitoring
strategies.47-­50 Among children ages 1–­4 years, SUDC is
more than 2 times as common as deaths due to house fires
(~100 case/year), and about half as common as drown-
ings (~475 deaths/year), yet public education for both fire
prevention and water accidents is commonplace, whereas
SUDC education is not.8,47,51
Febrile seizures are not considered epilepsy but may
be the first presentation of an epilepsy syndrome. Sudden
unexpected death in epilepsy (SUDEP) risk factors are not
contingent on duration of seizures but related to general-
ized tonic–­clonic seizures, unsupervised sleep, and noctur-
nal seizures; all are common in febrile seizure-­associated
SUDC deaths.52 Surveillance barriers from a diverse U.S.
death investigation system compound recognition and
surveillance of febrile seizure-­related deaths, further lim-
iting their potential impact on clinical care guidelines.
4.1 | Strengths/weaknesses
In addition to the risk of bias among studies and inad-
equate follow-­up durations to fully assess outcomes, our
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   2547
review was limited by the exclusion of 30 febrile seizure
studies due to the febrile seizure type not being clarified.
Three of our authors were involved with eight included
studies, which may create a bias. Although the assessment
of bias was reviewed by two study authors, L.G. and V.D.,
with L.G. being a co-­author of eight studies included,
there was 100% agreement on bias appraisals between
them. Risk of publication bias due to small sample size
and study designs such as cases series and case reports
are possible. Finally, although we attempted to calculate
standardized mortality ratios for children with a history
of febrile seizures and calculate odd ratios and risk ratios
where applicable based on study design, the heterogene-
ity of study designs, methodology, and data provided were
not relevant to this goal.
5 | CONC LUSION
Although most febrile seizures appear benign, they
may be a relatively frequent cause of death among tod-
dlers and are likely far more dangerous than fire-­related
deaths in number. Available data are insufficient to cal-
culate the mortality risk of simple and brief complex fe-
brile seizures. However, it appears very low for the febrile
seizure population. Extrapolating from the frequency of
febrile seizures in sudden unexplained death to the pop-
ulation, we estimate that 150 of 1 000 000 sudden deaths
in children ages 1–­4 years may be associated with febrile
seizures. Population-­based studies that assess this ques-
tion are needed. The health system should better identify
children at risk for rare febrile seizure-­related deaths and
other adverse outcomes. We should consider develop-
ing low-­cost monitoring/alarming systems to reduce the
frequency of these deaths, similar to efforts in SUDEP
prevention.48,49,50,52 Understanding genetic, biologic, and
environmental factors that predispose a child's brain to fe-
brile seizures may help distinguish adverse outcomes from
pathogenesis. Genetic factors identified in genome-­wide
association studies related to fever response and neuronal
excitability may represent biomarkers, as well as collabo-
rative studies of SUDEP and SUDC.53 Future prospective
studies with large cohorts of diverse febrile seizure types
followed throughout childhood will inform our under-
standing of the epidemiology, pathogenesis, risk factors,
and outcomes, as well as clinical recommendations.
AUTHOR CONTRIBUTIONS
L.G. conceived the design of this project; drafted and final-
ized the study protocol, performed the screening process,
bias assessments, and data analysis; as well as drafted the
original manuscript and its final revisions and approval.
V.D. assisted with design of protocol and performed the
 |
2548   
screening process and data analysis as well as critical re-
visions of the article. C.P. assisted in drafting the study
protocol as well as search criteria and performing data col-
lection. T.W. conceived of the design of this project as well
as critical revisions of manuscript. O.D. conceived the de-
sign of this project as well as drafting the manuscript and
final revisions. All authors reviewed and approved of the
final version to be published.
ACKNOWLEDGMENTS
This project was supported by Finding A Cure for
Epilepsy and Seizures (FACES), the SUDC Foundation,
SUDC-UK, P30AG066512 and P01AG060882. The pro-
ject described was also supported by the National Center
for Advancing Translational Sciences (NCATS), National
Institutes of Health (NIH), through Grant Award Number
UL1TR001445. The content is solely the responsibility of
the authors and does not necessarily represent the official
views of the NIH.
DISCLOSURES
L.G. reports her current volunteer role at the SUDC
Foundation as an advisor as well as past board member
until January 2023. V.D., C.P., T.W., and O.D. report no
disclosures relevant to this manuscript.
ORCID
Laura Gould https://orcid.org/0000-0001-6789-7770
Thomas Wisniewski https://orcid.
org/0000-0002-3379-8966
Orrin Devinsky https://orcid.org/0000-0003-0044-4632
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SUPPORTING INFORMATION
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Gould L, Delavale V,
Plovnick C, Wisniewski T, Devinsky O. Are brief
febrile seizures benign? A systematic review and
narrative synthesis. Epilepsia. 2023;64:2539–2549.
https://doi.org/10.1111/epi.17720