- Email: [email protected]
“Simple febrile seizures plus (SFS +)”: More than one febrile seizure within 24 hours is usually okay
Epilepsy & Behavior 27 (2013) 472–476
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
“Simple febrile seizures plus (SFS +)”: More than one febrile seizure within 24 hours is usually okay Marie F. Grill a, Yu-Tze Ng b,⁎ a b
Department of Neurology, University of California San Francisco, San Francisco General Hospital, 1001 Potrero Avenue, 4M62 Box 0870, San Francisco, CA 94110, USA Department of Neurology, University of Oklahoma College of Medicine, 711 Stanton L. Young Blvd, Ste 215, Oklahoma City, OK 73104, USA
a r t i c l e
i n f o
Article history: Received 7 January 2013 Revised 1 March 2013 Accepted 11 March 2013 Available online 24 April 2013 Keywords: Multiple febrile seizures EEG Neuroimaging GEFS +
a b s t r a c t This study aimed to investigate whether children with recurrent febrile seizures within a 24-hour period need to be worked up differently from children with simple febrile seizures. Inclusion criteria included the following: (i) children with first seizure cluster between 4 months and 3 years of age, (ii) children who had more than one febrile seizure within 24 hours, and (iii) children who returned to baseline between and after each event. Thirty-two patients met the inclusion criteria over a 3-year period. All patients underwent brain CT and/or MRI and EEG. All head CTs were normal. Two children had abnormal MRI findings — both benign: one is thought to represent postictal changes, and the other one is an incidental arachnoid cyst. Of the 4 abnormal EEGs, one showed epileptiform discharges, while the others showed generalized ictal or postictal features. We propose the term “simple febrile seizures plus (SFS+)” to describe children who have more than one seizure within 24 hours but who are otherwise not different in presentation from children with SFS. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Febrile seizures represent the most common pediatric seizure disorder, affecting an estimated 2–5% of children, and are generally considered a benign entity [1]. They can fall into one of two groups: simple febrile seizures or complex febrile seizures, based on seizure phenotype, duration, and frequency. Simple febrile seizures refer to those febrile seizures that lack any focal features (i.e., are generalized), resolve spontaneously within less than 10 min, and do not occur more than once within a 24-hour period [2]. In contrast, complex febrile seizures are those that have evidence of focality, last longer than 10–15 min, or are recurrent within a 24-hour period [3]. An estimated 70–75% of febrile seizures are simple, while 9–35% meet the criteria for a complex febrile seizure [4,5]. It should be noted that the dichotomization of febrile seizures into simple and complex groups was historic and empiric in origin and not based on scientific evidence, i.e., defined years before the widespread availability and use of neuroimaging [1].
Abbreviations: CT, computerized tomography; MRI, magnetic resonance imaging; EEG, electroencephalogram; LP, lumbar puncture; SFS+, simple febrile seizures plus; GEFS +, generalized epilepsy with febrile seizures plus; ILAE, International League Against Epilepsy; AAP, American Academy of Pediatrics. ⁎ Corresponding author at: Department of Neurology, University of Oklahoma Health Sciences Center, 711 Stanton L. Young Boulevard, #215, Oklahoma City, OK 73104, USA. Fax: +1 405 271 5723. E-mail address: [email protected] (Y.-T. Ng). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.03.006
Thus, while prognostically this may remain a valid paradigm, the two categories may not necessarily define the best approach to diagnostic investigations. Specific American Academy of Pediatrics (AAP) practice parameters have been published, giving recommendations on the evaluation of a child with a first-time febrile seizure [6,7]. These guidelines apply only in the case of a simple febrile seizure if the child falls between the ages of 6 months and 5 years and if the child does not present with another seizure within 24 hours of the initial SFS. Electroencephalogram (EEG) and neuroimaging are not recommended either on initial evaluation or on follow-up for an otherwise healthy child presenting with an initial simple febrile seizure [6,7]. The literature regarding the management of complex febrile seizures is much more sparse; thus, those patients who do not meet the criteria for the definition of simple febrile seizures frequently undergo a comprehensive evaluation including neuroimaging (computerized tomography (CT) and/or magnetic resonance imaging (MRI) of the brain) and EEG, in addition to lumbar puncture, blood chemistries and cultures, and other related evaluations to investigate potential sources of infection. In addition, these patients are frequently admitted to the hospital in order to facilitate a thorough evaluation. Although, in practice, EEGs and CT and/or MRI of the brain are routinely ordered for these patients, there is limited evidence that these studies yield information that influences patient management, i.e., identifying any structural brain abnormalities that would require intervention or informing physicians of the risk of subsequent development of epilepsy.
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
2. Methods 2.1. Study design and patients The study was performed at the Barrow Neurological Institute/ St. Joseph's Hospital and Medical Center in Phoenix, Arizona. We performed a prospective observational cohort study of children with febrile seizures, with seizure onset between the ages of 4 months and 3 years old, who had more than one febrile seizure in a 24-hour period, and who returned to baseline between and after each event. Patients were excluded if there were any focal ictal features, if duration of any of the seizures was prolonged (greater than 10 min), or if abnormalities were identified on neurological examination. The strict age range was selected to try and isolate the patients as much as possible to be very typical children with simple febrile seizures with the exception only that they all had more than one seizure. Fever was defined as >100°F during their seizures or within 24 hours immediately preceding or following the seizures. These patients were made up of a convenience sample of children seen either in consultation as inpatients in our tertiary care hospital or as outpatients in our pediatric neurology clinic for follow-up (evaluated within 3 months of initial recurrent febrile seizure event). A total of 32 subjects meeting inclusion and exclusion criteria were recruited from January 2008 through March 2011. The study included patients with both incident and prevalent seizures. Management of patients was dictated by individual practitioners and not by study or institutional protocol. As this was a pilot study, no sample size calculation was performed. Requirement for informed consent was waived as study was observational and of minimal risk to participants and consisted of anonymous data collection, i.e., no protected health information was stored in a database. 2.2. Outcome assessment History was obtained from the chart and parents and included history of any prior seizures, perinatal medical history, developmental history, and family history of seizures (distinguishing between febrile and afebrile when possible). Neurological examination was performed on all patients. Data were acquired from EEGs as well as neuroimaging, either MRI (the vast majority of patients) or CT of the brain, and, in some cases, from both. Most patients were followed up for at least three months up to two years following the initial event to ascertain whether or not any further seizures had occurred. 2.3. Ethics St. Joseph's Hospital and Medical Center Institutional Review Board approval was obtained for the study and prospective data collection. 2.4. Statistical analysis Analysis was performed using STATA, version 11.0 (STATA, College Station, TX). Mathematical means with corresponding standard deviations were reported, and categorical data were summarized as proportions. Fisher's exact test was also used to obtain 95% confidence intervals. 3. Results Thirty-three patients with recurrent febrile seizures were initially considered; however, one girl was excluded as one of her recurrent febrile seizures was prolonged at 20 min, and we wished to include only those patients with a single complex febrile seizure feature (she also had a normal brain MRI scan and EEG). The analyzed group consisted of 32 children, aged 5–36 months (mean age 17.0 ± 7.3 months) at the time of their initial febrile seizure. There were 15 females and 17
473
Table 1 Clinical features of the patients including details on their febrile seizure clusters. Clinical characteristics (N = 32)
N (%)
Male Age at onset of first seizure (months) More than 2 seizures within 24 hours More than one cluster of recurrent seizures within 24 hours Time between seizures Family history of seizures (any) Family history of febrile seizures Family history of epilepsy
17 (53.1%) 15 (46.9%) 5 (15.6%)
Mean (S.D.)
Range
17.0 (±7.3) 5–36 3–7
1 min–17 hours 21 (65.6%) 13 (40.6%) 7 (21.9%)
N = number of patients; percentages refer to proportions of total sample size; S.D. = standard deviation.
males. The number of seizures within the 24-hour period ranged from 2 to 7, and all patients returned to baseline interictally. Our series included a total of 39 febrile seizure clusters (episodes of more than one seizure in a 24-hour period) amongst the 32 patients. The mean number of seizures in a cluster was 2.8 seizures per cluster (total of 109 seizures divided by 39 seizure clusters) with a range of only 1 min up to 17 hours between seizures (Table 1). Five patients had subsequent episodes of recurrent febrile seizure clusters. Eighteen of the 32 (56%) patients had a history of simple febrile seizures in addition to their episode(s) of recurrent febrile seizures within a 24-hour period. Perinatal and past medical histories were unremarkable in all cases. One boy had mild speech delay, while the remaining subjects had a normal developmental history. Family history was significant for seizures in 21 of the 32 (65.6%) patients; the majority of seizures were childhood febrile seizures. The neurological exams were all normal, and no children had evidence of neurocutaneous stigmata. All the 32 children underwent further diagnostic testing in the form of EEG and neuroimaging (MRI and/or CT of the brain), and many were admitted to the hospital for this workup (Table 2). The EEGs were normal in the majority of cases with a few exceptions. In the first case, the EEG was abnormal as it was an ictal recording of another diffuse onset febrile generalized tonic–clonic seizure. A repeat EEG was obtained for this patient and was normal. In the second case, the EEG obtained emergently in the postictal period showed mild diffuse slowing consistent with a postictal state. In the third case, the EEG was normal with occipital intermittent rhythmic delta activity (OIRDA) only. Finally, one girl had an EEG that demonstrated bifrontal and left central spikes on a normal background (Table 2, patient #25). This child also had a strong family history of febrile seizures; specifically, the patient's mother had a history of febrile seizures, and the patient's older brother (five years her senior) had a history of febrile seizures while aged six months to 36 months; some of which included recurrent seizures within a 24-hour period. Neither the patient nor her brother or her mother had any subsequent afebrile seizures. Neuroimaging was obtained in all 32 cases. Twenty-seven of the 32 (84%) patients underwent MRI of the brain. Two of the 27 (7.4%) patients had abnormal findings on MRI, while the remaining majority of scans were normal. One three-year-old girl had a brain MRI significant for slightly increased size of the right hippocampus that was thought to be a sequela of postictal swelling. Two of her three seizures were of longer duration at 5 min and 10 min than the vast majority of the other patients whose seizures were either 1–2 min or 3–5 min in length. No intervention was, thus, required for this finding. On follow-up two years later, this patient had remained healthy, was doing well academically, and had not had any additional seizures or other neurological complaints. The other MRI abnormality consisted of an arachnoid cyst in the middle cranial fossa that was a presumed incidental finding. The remaining five patients had CT scans that were all normal. Four children underwent both CT and MRI scans of the brain (Table 1). For both EEG and neuroimaging, we found 0
474
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
Table 2 Family history, investigation results, and longer term associated seizure outcomes of the patients. Patient # EEG
MRI brain (unless otherwise stated CT scan)
Simple Afebrile seizures febrile also (within 3 months–2 years) seizures also
1 2
Normal Normal
No No
Yes Yes
Normal + normal CT Normal Normal Normal Normal CT Normal Postictal hippocampal changes Normal Normal Normal Normal + normal CT Normal Normal Normal Normal Normal Normal Normal Normal Normal CT Normal Normal CT Normal
Yes
No
No No Yes No No No
Yes No Yes Yes Yes Yes
No No No No
No Yes Yes Yes
No No Yes No No No No No No No No No
No No No Yes Yes No Yes Yes No Yes Yes No
Normal
No
No
Normal CT Normal CT Normal Normal + normal CT (L middle fossa arachnoid cyst) Normal Normal
No No No No
No No Yes Yes
No No
No Yes
3
Normal Ictala, repeat normal Normal
4 5 6 7 8 9
Normal Normal Normal Normal Normal Normal
10 11 12 13
Normal Normal Normal Normal
14 15 16 17 18 19 20 21 22 23 24 25
27 28 29 30
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Bifrontal and left central epileptiform discharges on normal background Minimal postictal slowing (performed immediately after a seizure) Normal Normal Normal Normal
31 32
Normal Normal (OIRDA)
26
CT = computerized tomography; MRI = magnetic resonance imaging; OIRDA = occipital intermittent rhythmic delta activity. a Diffuse onset and activity seizure for b1 min.
abnormal findings that changed management in these children (95% CI: 0.000–0.115 by Fisher's exact test). Follow-up was available from 3 months up to 2 years in 29 of the 32 patients. Three of these 29 patients (10%; 95% CI: 0.021–0.302 by Fisher's exact test) went on to develop afebrile seizures though testing for the three commonly identified gene mutations for GEFS+ was negative in these cases. 4. Discussion While many physicians routinely obtain neuroimaging and EEG on patients with complex febrile seizures, there is limited evidencebased medicine to support this practice. In our cohort study of the 29 patients, very few abnormalities were found on EEG or neuroimaging, and even in those cases, no significant diagnostic or prognostic information was gained from performing these studies. All CT scans of the brain were normal. In one of the two cases of patients with an abnormal MRI, the findings were ultimately related to a
sequela of the seizure itself rather than representing any neuropathology. She was neurologically normal with no further seizures at 2-year follow-up, though any follow-up after that period was not available. In the other case, the finding of the arachnoid cyst was incidental and benign and, thus, not diagnostically or prognostically informative. In 3 of the 4 abnormal EEGs, the features were again related to the seizures themselves rather than any underlying seizure disorder, and just as with the normal EEGs, no diagnostic or prognostic information was yielded Finally, in the sole case of a patient with epileptiform discharges, no management changes were made. This child also had a strong family history of febrile seizures. Thus, for both EEG and neuroimaging studies, we found no abnormal findings that changed management in these children (95% CI: 0.000–0.115). These additional tests are not without their risks as sedatives are frequently required; in the case of MRIs specifically, use of general anesthesia is typically required for patients less than 5 years of age, i.e., our entire cohort population. Beyond the risks intrinsically related to use of general anesthesia, sedating measures can also obscure postictal neurological assessment. There is a risk of cumulative radiation exposure related to obtaining CT scans. While radiation risks may be relatively small on a case-by-case basis, population-based estimates of lifetime cancer mortality risks support this as a legitimate concern [8,9]. Finally, admitting patients to the hospital in order to perform this workup only adds to the already expensive cost of the previously mentioned studies. Several other studies have looked into the yield of testing in children with complex febrile seizures. Teng et al. performed a retrospective review of 79 children meeting the criteria for complex febrile seizures from whom data had prospectively been collected, though 71 of them were ultimately analyzed. Forty-six of the 71 (65%) patients underwent neuroimaging (either CT scans in the emergency department or MRI within one week), and none had any significant intracranial pathology demanding of emergent intervention. Seventy-two percent had only one complex feature [10]. A previous study conducted by McAbee et al. found only 1 out of 20 (5%) CT scans to be abnormal in children with complex febrile seizures, and again, the one abnormal study finding did not require intervention [11]. Garvey et al. found abnormalities in only 3 of 17 children with complex febrile seizures [12]. Yucel et al. looked retrospectively at neuroimaging findings in children with complex febrile seizures who had focal seizures, postictal deficits, or focal EEG findings and found that 7 of 45 (16%) patients had an abnormal CT or MRI of the brain, though again, there were no findings that required intervention [13]. Of note, patients with recurrent febrile seizures were not included in this study. Our study is the first to look specifically at those patients with recurrent febrile seizures within a 24-hour period but with no other complex features or abnormalities. Evaluation of children with complex febrile seizures may include too much testing as we acquire more data on the presentation and outcome of this condition. A recently conducted retrospective cohort review looked specifically at the yield of lumbar puncture in pediatric patients presenting with their first complex febrile seizure. Of the 526 patients evaluated in the emergency department over a 13-year period, with a median age of 17 months (with a range of 6 to 60 months), 340 (60%) underwent lumbar puncture to rule out acute bacterial meningitis. Only 14 patients demonstrated a pleocytosis within the CSF, and of those, only 3 had acute bacterial meningitis. The two patients who grew Streptococcus pneumoniae in the CSF culture were clinically altered on presentation: one was nonresponsive, while the other one was apneic and had a bulging fontanelle. The third patient appeared generally well and had a lumbar puncture “contaminated with blood” from which the CSF culture was ultimately negative, though blood culture was ultimately positive for S. pneumoniae so the child was empirically treated for bacterial meningitis for 14 days [14]. In our study, 3 of the 29 patients for which follow-up data are available (10%) went on to develop afebrile seizures (95% CI: 0.021–0.302). All of these three patients had normal brain MRI and EEGs. Although a
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
very small subset, interestingly, none of them had any abnormalities on their studies that could have predicted or even suggested this outcome. The mean duration of follow-up on the available patients was 22.8 months, the median was 23 months, and the interquartile range was 8–36 months. An estimated 3% of children with febrile seizures go on to later develop epilepsy; thus, this was higher than expected for the child with simple febrile seizures [15]. A Rochester study found that the risk of subsequent development of epilepsy was 2.4% for children with simple febrile seizures, 6–8% for children with one complex feature, 17–22% for children with 2 complex features, and 49%, which is the highest, for children with all 3 features [16]. Nelson et al. found that 52 (3%) out of 1104 children with febrile seizures studied up to 7 years of age developed at least one subsequent afebrile seizure, while 34 children (2% of total cohort) developed recurrent afebrile seizures. Of the 34, seven were mentally retarded, and seven also had cerebral palsy. Two hundred twenty-six (16.2%) of 1391 patients had more than one seizure in a 24-hour period; epilepsy developed in 4% of those with at least one complex feature [1]. In the British CHES cohort, 13 (3.4%) of 382 children later developed afebrile seizures, while only 1.6% of the total developed an epilepsy syndrome consisting of complex partial seizures. This cohort study paralleled the Rochester study in demonstrating that the subsequent development of epilepsy more often occurred in children fitting diagnostic criteria for a complex febrile seizure (6.3% in this case) compared with those diagnosed with a simple febrile seizure (1.0%). Of those with complex febrile seizures, the children with the highest risk of future epilepsy were specifically those with prolonged seizures (9.4%) and those with focal seizure semiology (29.0%) [15]. The lowest risk was attributed to those with the single complex feature of recurrent febrile seizures in a 24-hour period. Of note, referral bias may certainly be a consideration in studies such as ours given the setting of a tertiary referral center. Thus, it is possible that our rate estimate may be inflated and that the actual frequency of later development of afebrile seizures is in fact lower. Generalized idiopathic epilepsies with tonic–clonic seizures are the most common type of epilepsy developed in those children with febrile seizures, as a whole, who do go on to have epilepsy. Generalized epilepsy with febrile seizures plus (GEFS+) is the prototypic example of a genetic syndrome clinically manifest as a combination of both febrile and afebrile seizures [17,18]. In our cohort, the three children who developed afebrile seizures did not test positive for the three commonly identified gene mutations for GEFS+. Nevertheless, the majority of our patients had a positive family history of seizures (the majority being febrile seizures), and one child also had a sibling with a similar pattern of recurrent febrile seizures within a 24-hour period. These findings suggest that an underlying genetic component likely plays a role in the development of recurrent febrile seizures [18]. However, even in the aforementioned cases, neuroimaging and EEG studies did not ultimately change the management of these patients. There are some important limitations to this study. First, given the small sample size, we cannot say with statistical confidence that there may not be an occasional patient with recurrent seizures within a 24-hour period who does have some underlying intracranial pathology that would be identified with neuroimaging and would subsequently alter the management of the patient, i.e., may lead to decision to start antiepileptic drugs. A larger study would aid in increasing the power of this study. In addition, follow-up of patients ranged from months to two years; thus, it is conceivable that if followed for a longer period of time, more of these patients could go on to develop afebrile seizures (particularly given the already increased frequency identified in our small cohort). Previous studies have identified the first three years after febrile seizures to be the period with the highest risk for subsequent development of afebrile seizures; thus, our follow-up time was not ideal [1,19]. As previously discussed, however, further development of afebrile seizures was not predicted on the basis of either EEG or neuroimaging.
475
In summary, the categorization of recurrent febrile seizures within a 24-hour period into the complex and less benign grouping may be somewhat antiquated as it was made before the routine use of neuroimaging studies, yet workup of this subtype of seizures has not been updated to reflect the information, or lack thereof, learned from neuroimaging. Furthermore, in terms of diagnosing epilepsy, considering prophylactic antiepileptic drugs and predicting outcomes, multiple afebrile seizures within a 24-hour period are counted as a single seizure [20,21]. The ongoing FEBSTAT study (consequences of prolonged febrile seizures in childhood) continues to give us more information on the specific subgroup of patients with complex febrile seizures; those with a febrile seizure lasting 30 min or more, without specifically looking at our subgroup of patients, i.e., those with recurrent febrile seizures. To date, they have shown us that febrile status epilepticus (as defined by prolonged seizures) is usually focal and suggested that the longer a seizure continues, the less likely it is to spontaneously stop [22]. Other important conclusions in this group of patients include risk of acute hippocampal injury, essentially benign cerebrospinal fluid analysis, human herpes virus 6B is much more commonly associated than human herpes virus 7 and 36.2% of 199 of these patients had focal slowing or attenuation on their EEGs preformed within 72 hours [23–26]. Although our study had a relatively small sample size, our results suggest that patients who have more than one seizure within 24 hours but otherwise meet the criteria for simple febrile seizure should not be worked up differently from those patients with simple febrile seizures. Subsequent practice changes would translate to decreased hospital admission rates, decreased neuroimaging (which is not without its risks given the future risks of cumulative exposure to radiation as well as the sedation frequently required for these studies), and decreased EEGs (which may also require sedation of the child). In other words, this ultimately means avoiding unnecessary tests in this population and improving cost effectiveness in health care. Concurrent with the last AAP statement on simple febrile seizures, limited evidence exists that supports the use of diagnostic workup in patients with complex febrile seizures [7]. We, therefore, propose the term “simple febrile seizures plus (SFS+)” to refer to those patients with recurrent febrile seizures within a 24-hour period who may prognostically be at a slightly higher risk of subsequent development of afebrile seizures but should otherwise be diagnostically considered not different from those having simple febrile seizures, i.e., limited role of neuroimaging and EEG.
5. Conclusion This pilot study suggests that patients with more than one seizure within 24 hours but otherwise meeting the criteria for simple febrile seizures, i.e., return to baseline between each seizure or at least after the seizure cluster and lack any focal features, should not be worked up differently from those patients with simple febrile seizures. This suggests that the criterion could be removed from labeling a child as having complex febrile seizures, simply SFS +. Neuroimaging and EEG do not add any significant diagnostic or prognostic information in these patients and are unnecessary as is hospitalization. Prognostically, these children may be more likely to go on to have afebrile seizures; however, larger powered and longer term outcome follow-up studies are necessary for confirmation.
Disclosure Marie Grill, MD: nothing to disclose. Yu-Tze Ng, MD, FRACP is on the Medical Advisory Board for Lundbeck Pharmaceuticals. He is also on the speakers' bureau for Lundbeck Pharmaceuticals, UCB Pharma and Cyberonics Inc.
476
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
Conflict of interest The authors declare no conflicts of interest.
References [1] Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029–33. [2] Baumann RJ. Technical report: treatment of the child with simple febrile seizures. Pediatrics 1999;103:e86. [3] Berg AT, Shinnar S. Complex febrile seizures. Epilepsia 1996;37:126–33. [4] Shinnar S, O'Dell C. Profiles in seizure management. In: Leppik IE, editor. Managing febrile seizures in young children and epilepsy in the elderly. Princeton Media Associates; 2003. p. 3–15. [5] Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child 2004;89:751–6. [6] American Academy of Pediatrics. Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 1996;97:769–72. [7] Subcommittee on Febrile Seizures; American Academy of Pediatrics. Neurodiagnostic evaluation of the child with a simple febrile seizure. Review Pediatrics 2011;127: 389–94. [8] Brenner DJ. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr Radiol 2002;32:228–31 [discussion 242-4]. [9] Frush DP, Donnelly LF, Rosen NS. Computed tomography and radiation risks: what pediatric health care provides should know. Pediatrics 2003;112:951–7. [10] Teng D, Dayan P, Tyler S, et al. Risk of intracranial pathologic conditions requiring emergency intervention after a first complex febrile seizure episode among children. Pediatrics 2006;117:304–8. [11] McAbee GN, Barasch ES, Kurfist LA. Results of completed tomography in “neurologically normal” children after initial onset of seizures. Pediatr Neurol 1989;5: 102–6.
[12] Garvey MA, Guillard WD, Rusin JA, et al. Emergency brain computed tomography in children with seizures: who is most likely to benefit? J Pediatr 1998;133:664–9. [13] Yucel O, Aka S, Yazicioglu L, Ceran O. The role of early EEG and neuroimaging in determination of prognosis in children with complex febrile seizures. Pediatr Int 2004;46:463–7. [14] Kimia A, Ben-Joseph EP, Rudloe T, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics 2010;126:62–9. [15] Verity CM, Golding J. Risk of epilepsy after febrile convulsions: a national cohort study. BMJ 1991;303:1373–6 [Erratum in: BMJ 1992;304:147]. [16] Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:493–8. [17] Nakayama J. Progress in searching for the febrile seizure susceptibility genes. Brain Dev 2009;31:359–65. [18] Grill MF, Losey TE, Ng YT. The Hitchhiker's guide to the child neurologist's genetic evaluation of epilepsy. Semin Pediatr Neurol 2008;15:32–40. [19] Lennox WG. Significance of febrile convulsions. Pediatrics 1953;11:341–57. [20] Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:429–34. [21] Shinnar S, Berg AT, O'Dell C, Newstein D, Moshe SL, Hauser WA. Predictors of multiple seizures in a cohort of children prospectively followed from the time of their first unprovoked seizure. Ann Neurol 2000;48:140–7. [22] Shinnar S, Hesdorffer DC, Nordli Jr DR, et al. Phenomenology of prolonged febrile seizures; results of the FEBSTAT study. Neurology 2008;15:170–6. [23] Shinnar S, Bello JA, Chan S, et al. MRI abnormalities following febrile status epilepticus in children; the FEBSTAT study. Neurology 2012;79:871–7. [24] Frank LM, Shinnar S, Hesdorffer DC, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results and consequences of prolonged febrile seizures (FEBSTAT) study. J Pediatr 2012;161:1169–71. [25] Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 2012;53:1481–8. [26] Nordli Jr DR, Moshe SL, Shinnar S, et al. Acute EEG findings in children with febrile status epilepticus: results of the FEBSTAT study. Neurology 2012;79: 2180–6.
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
“Simple febrile seizures plus (SFS +)”: More than one febrile seizure within 24 hours is usually okay Marie F. Grill a, Yu-Tze Ng b,⁎ a b
Department of Neurology, University of California San Francisco, San Francisco General Hospital, 1001 Potrero Avenue, 4M62 Box 0870, San Francisco, CA 94110, USA Department of Neurology, University of Oklahoma College of Medicine, 711 Stanton L. Young Blvd, Ste 215, Oklahoma City, OK 73104, USA
a r t i c l e
i n f o
Article history: Received 7 January 2013 Revised 1 March 2013 Accepted 11 March 2013 Available online 24 April 2013 Keywords: Multiple febrile seizures EEG Neuroimaging GEFS +
a b s t r a c t This study aimed to investigate whether children with recurrent febrile seizures within a 24-hour period need to be worked up differently from children with simple febrile seizures. Inclusion criteria included the following: (i) children with first seizure cluster between 4 months and 3 years of age, (ii) children who had more than one febrile seizure within 24 hours, and (iii) children who returned to baseline between and after each event. Thirty-two patients met the inclusion criteria over a 3-year period. All patients underwent brain CT and/or MRI and EEG. All head CTs were normal. Two children had abnormal MRI findings — both benign: one is thought to represent postictal changes, and the other one is an incidental arachnoid cyst. Of the 4 abnormal EEGs, one showed epileptiform discharges, while the others showed generalized ictal or postictal features. We propose the term “simple febrile seizures plus (SFS+)” to describe children who have more than one seizure within 24 hours but who are otherwise not different in presentation from children with SFS. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Febrile seizures represent the most common pediatric seizure disorder, affecting an estimated 2–5% of children, and are generally considered a benign entity [1]. They can fall into one of two groups: simple febrile seizures or complex febrile seizures, based on seizure phenotype, duration, and frequency. Simple febrile seizures refer to those febrile seizures that lack any focal features (i.e., are generalized), resolve spontaneously within less than 10 min, and do not occur more than once within a 24-hour period [2]. In contrast, complex febrile seizures are those that have evidence of focality, last longer than 10–15 min, or are recurrent within a 24-hour period [3]. An estimated 70–75% of febrile seizures are simple, while 9–35% meet the criteria for a complex febrile seizure [4,5]. It should be noted that the dichotomization of febrile seizures into simple and complex groups was historic and empiric in origin and not based on scientific evidence, i.e., defined years before the widespread availability and use of neuroimaging [1].
Abbreviations: CT, computerized tomography; MRI, magnetic resonance imaging; EEG, electroencephalogram; LP, lumbar puncture; SFS+, simple febrile seizures plus; GEFS +, generalized epilepsy with febrile seizures plus; ILAE, International League Against Epilepsy; AAP, American Academy of Pediatrics. ⁎ Corresponding author at: Department of Neurology, University of Oklahoma Health Sciences Center, 711 Stanton L. Young Boulevard, #215, Oklahoma City, OK 73104, USA. Fax: +1 405 271 5723. E-mail address: [email protected] (Y.-T. Ng). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.03.006
Thus, while prognostically this may remain a valid paradigm, the two categories may not necessarily define the best approach to diagnostic investigations. Specific American Academy of Pediatrics (AAP) practice parameters have been published, giving recommendations on the evaluation of a child with a first-time febrile seizure [6,7]. These guidelines apply only in the case of a simple febrile seizure if the child falls between the ages of 6 months and 5 years and if the child does not present with another seizure within 24 hours of the initial SFS. Electroencephalogram (EEG) and neuroimaging are not recommended either on initial evaluation or on follow-up for an otherwise healthy child presenting with an initial simple febrile seizure [6,7]. The literature regarding the management of complex febrile seizures is much more sparse; thus, those patients who do not meet the criteria for the definition of simple febrile seizures frequently undergo a comprehensive evaluation including neuroimaging (computerized tomography (CT) and/or magnetic resonance imaging (MRI) of the brain) and EEG, in addition to lumbar puncture, blood chemistries and cultures, and other related evaluations to investigate potential sources of infection. In addition, these patients are frequently admitted to the hospital in order to facilitate a thorough evaluation. Although, in practice, EEGs and CT and/or MRI of the brain are routinely ordered for these patients, there is limited evidence that these studies yield information that influences patient management, i.e., identifying any structural brain abnormalities that would require intervention or informing physicians of the risk of subsequent development of epilepsy.
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
2. Methods 2.1. Study design and patients The study was performed at the Barrow Neurological Institute/ St. Joseph's Hospital and Medical Center in Phoenix, Arizona. We performed a prospective observational cohort study of children with febrile seizures, with seizure onset between the ages of 4 months and 3 years old, who had more than one febrile seizure in a 24-hour period, and who returned to baseline between and after each event. Patients were excluded if there were any focal ictal features, if duration of any of the seizures was prolonged (greater than 10 min), or if abnormalities were identified on neurological examination. The strict age range was selected to try and isolate the patients as much as possible to be very typical children with simple febrile seizures with the exception only that they all had more than one seizure. Fever was defined as >100°F during their seizures or within 24 hours immediately preceding or following the seizures. These patients were made up of a convenience sample of children seen either in consultation as inpatients in our tertiary care hospital or as outpatients in our pediatric neurology clinic for follow-up (evaluated within 3 months of initial recurrent febrile seizure event). A total of 32 subjects meeting inclusion and exclusion criteria were recruited from January 2008 through March 2011. The study included patients with both incident and prevalent seizures. Management of patients was dictated by individual practitioners and not by study or institutional protocol. As this was a pilot study, no sample size calculation was performed. Requirement for informed consent was waived as study was observational and of minimal risk to participants and consisted of anonymous data collection, i.e., no protected health information was stored in a database. 2.2. Outcome assessment History was obtained from the chart and parents and included history of any prior seizures, perinatal medical history, developmental history, and family history of seizures (distinguishing between febrile and afebrile when possible). Neurological examination was performed on all patients. Data were acquired from EEGs as well as neuroimaging, either MRI (the vast majority of patients) or CT of the brain, and, in some cases, from both. Most patients were followed up for at least three months up to two years following the initial event to ascertain whether or not any further seizures had occurred. 2.3. Ethics St. Joseph's Hospital and Medical Center Institutional Review Board approval was obtained for the study and prospective data collection. 2.4. Statistical analysis Analysis was performed using STATA, version 11.0 (STATA, College Station, TX). Mathematical means with corresponding standard deviations were reported, and categorical data were summarized as proportions. Fisher's exact test was also used to obtain 95% confidence intervals. 3. Results Thirty-three patients with recurrent febrile seizures were initially considered; however, one girl was excluded as one of her recurrent febrile seizures was prolonged at 20 min, and we wished to include only those patients with a single complex febrile seizure feature (she also had a normal brain MRI scan and EEG). The analyzed group consisted of 32 children, aged 5–36 months (mean age 17.0 ± 7.3 months) at the time of their initial febrile seizure. There were 15 females and 17
473
Table 1 Clinical features of the patients including details on their febrile seizure clusters. Clinical characteristics (N = 32)
N (%)
Male Age at onset of first seizure (months) More than 2 seizures within 24 hours More than one cluster of recurrent seizures within 24 hours Time between seizures Family history of seizures (any) Family history of febrile seizures Family history of epilepsy
17 (53.1%) 15 (46.9%) 5 (15.6%)
Mean (S.D.)
Range
17.0 (±7.3) 5–36 3–7
1 min–17 hours 21 (65.6%) 13 (40.6%) 7 (21.9%)
N = number of patients; percentages refer to proportions of total sample size; S.D. = standard deviation.
males. The number of seizures within the 24-hour period ranged from 2 to 7, and all patients returned to baseline interictally. Our series included a total of 39 febrile seizure clusters (episodes of more than one seizure in a 24-hour period) amongst the 32 patients. The mean number of seizures in a cluster was 2.8 seizures per cluster (total of 109 seizures divided by 39 seizure clusters) with a range of only 1 min up to 17 hours between seizures (Table 1). Five patients had subsequent episodes of recurrent febrile seizure clusters. Eighteen of the 32 (56%) patients had a history of simple febrile seizures in addition to their episode(s) of recurrent febrile seizures within a 24-hour period. Perinatal and past medical histories were unremarkable in all cases. One boy had mild speech delay, while the remaining subjects had a normal developmental history. Family history was significant for seizures in 21 of the 32 (65.6%) patients; the majority of seizures were childhood febrile seizures. The neurological exams were all normal, and no children had evidence of neurocutaneous stigmata. All the 32 children underwent further diagnostic testing in the form of EEG and neuroimaging (MRI and/or CT of the brain), and many were admitted to the hospital for this workup (Table 2). The EEGs were normal in the majority of cases with a few exceptions. In the first case, the EEG was abnormal as it was an ictal recording of another diffuse onset febrile generalized tonic–clonic seizure. A repeat EEG was obtained for this patient and was normal. In the second case, the EEG obtained emergently in the postictal period showed mild diffuse slowing consistent with a postictal state. In the third case, the EEG was normal with occipital intermittent rhythmic delta activity (OIRDA) only. Finally, one girl had an EEG that demonstrated bifrontal and left central spikes on a normal background (Table 2, patient #25). This child also had a strong family history of febrile seizures; specifically, the patient's mother had a history of febrile seizures, and the patient's older brother (five years her senior) had a history of febrile seizures while aged six months to 36 months; some of which included recurrent seizures within a 24-hour period. Neither the patient nor her brother or her mother had any subsequent afebrile seizures. Neuroimaging was obtained in all 32 cases. Twenty-seven of the 32 (84%) patients underwent MRI of the brain. Two of the 27 (7.4%) patients had abnormal findings on MRI, while the remaining majority of scans were normal. One three-year-old girl had a brain MRI significant for slightly increased size of the right hippocampus that was thought to be a sequela of postictal swelling. Two of her three seizures were of longer duration at 5 min and 10 min than the vast majority of the other patients whose seizures were either 1–2 min or 3–5 min in length. No intervention was, thus, required for this finding. On follow-up two years later, this patient had remained healthy, was doing well academically, and had not had any additional seizures or other neurological complaints. The other MRI abnormality consisted of an arachnoid cyst in the middle cranial fossa that was a presumed incidental finding. The remaining five patients had CT scans that were all normal. Four children underwent both CT and MRI scans of the brain (Table 1). For both EEG and neuroimaging, we found 0
474
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
Table 2 Family history, investigation results, and longer term associated seizure outcomes of the patients. Patient # EEG
MRI brain (unless otherwise stated CT scan)
Simple Afebrile seizures febrile also (within 3 months–2 years) seizures also
1 2
Normal Normal
No No
Yes Yes
Normal + normal CT Normal Normal Normal Normal CT Normal Postictal hippocampal changes Normal Normal Normal Normal + normal CT Normal Normal Normal Normal Normal Normal Normal Normal Normal CT Normal Normal CT Normal
Yes
No
No No Yes No No No
Yes No Yes Yes Yes Yes
No No No No
No Yes Yes Yes
No No Yes No No No No No No No No No
No No No Yes Yes No Yes Yes No Yes Yes No
Normal
No
No
Normal CT Normal CT Normal Normal + normal CT (L middle fossa arachnoid cyst) Normal Normal
No No No No
No No Yes Yes
No No
No Yes
3
Normal Ictala, repeat normal Normal
4 5 6 7 8 9
Normal Normal Normal Normal Normal Normal
10 11 12 13
Normal Normal Normal Normal
14 15 16 17 18 19 20 21 22 23 24 25
27 28 29 30
Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Bifrontal and left central epileptiform discharges on normal background Minimal postictal slowing (performed immediately after a seizure) Normal Normal Normal Normal
31 32
Normal Normal (OIRDA)
26
CT = computerized tomography; MRI = magnetic resonance imaging; OIRDA = occipital intermittent rhythmic delta activity. a Diffuse onset and activity seizure for b1 min.
abnormal findings that changed management in these children (95% CI: 0.000–0.115 by Fisher's exact test). Follow-up was available from 3 months up to 2 years in 29 of the 32 patients. Three of these 29 patients (10%; 95% CI: 0.021–0.302 by Fisher's exact test) went on to develop afebrile seizures though testing for the three commonly identified gene mutations for GEFS+ was negative in these cases. 4. Discussion While many physicians routinely obtain neuroimaging and EEG on patients with complex febrile seizures, there is limited evidencebased medicine to support this practice. In our cohort study of the 29 patients, very few abnormalities were found on EEG or neuroimaging, and even in those cases, no significant diagnostic or prognostic information was gained from performing these studies. All CT scans of the brain were normal. In one of the two cases of patients with an abnormal MRI, the findings were ultimately related to a
sequela of the seizure itself rather than representing any neuropathology. She was neurologically normal with no further seizures at 2-year follow-up, though any follow-up after that period was not available. In the other case, the finding of the arachnoid cyst was incidental and benign and, thus, not diagnostically or prognostically informative. In 3 of the 4 abnormal EEGs, the features were again related to the seizures themselves rather than any underlying seizure disorder, and just as with the normal EEGs, no diagnostic or prognostic information was yielded Finally, in the sole case of a patient with epileptiform discharges, no management changes were made. This child also had a strong family history of febrile seizures. Thus, for both EEG and neuroimaging studies, we found no abnormal findings that changed management in these children (95% CI: 0.000–0.115). These additional tests are not without their risks as sedatives are frequently required; in the case of MRIs specifically, use of general anesthesia is typically required for patients less than 5 years of age, i.e., our entire cohort population. Beyond the risks intrinsically related to use of general anesthesia, sedating measures can also obscure postictal neurological assessment. There is a risk of cumulative radiation exposure related to obtaining CT scans. While radiation risks may be relatively small on a case-by-case basis, population-based estimates of lifetime cancer mortality risks support this as a legitimate concern [8,9]. Finally, admitting patients to the hospital in order to perform this workup only adds to the already expensive cost of the previously mentioned studies. Several other studies have looked into the yield of testing in children with complex febrile seizures. Teng et al. performed a retrospective review of 79 children meeting the criteria for complex febrile seizures from whom data had prospectively been collected, though 71 of them were ultimately analyzed. Forty-six of the 71 (65%) patients underwent neuroimaging (either CT scans in the emergency department or MRI within one week), and none had any significant intracranial pathology demanding of emergent intervention. Seventy-two percent had only one complex feature [10]. A previous study conducted by McAbee et al. found only 1 out of 20 (5%) CT scans to be abnormal in children with complex febrile seizures, and again, the one abnormal study finding did not require intervention [11]. Garvey et al. found abnormalities in only 3 of 17 children with complex febrile seizures [12]. Yucel et al. looked retrospectively at neuroimaging findings in children with complex febrile seizures who had focal seizures, postictal deficits, or focal EEG findings and found that 7 of 45 (16%) patients had an abnormal CT or MRI of the brain, though again, there were no findings that required intervention [13]. Of note, patients with recurrent febrile seizures were not included in this study. Our study is the first to look specifically at those patients with recurrent febrile seizures within a 24-hour period but with no other complex features or abnormalities. Evaluation of children with complex febrile seizures may include too much testing as we acquire more data on the presentation and outcome of this condition. A recently conducted retrospective cohort review looked specifically at the yield of lumbar puncture in pediatric patients presenting with their first complex febrile seizure. Of the 526 patients evaluated in the emergency department over a 13-year period, with a median age of 17 months (with a range of 6 to 60 months), 340 (60%) underwent lumbar puncture to rule out acute bacterial meningitis. Only 14 patients demonstrated a pleocytosis within the CSF, and of those, only 3 had acute bacterial meningitis. The two patients who grew Streptococcus pneumoniae in the CSF culture were clinically altered on presentation: one was nonresponsive, while the other one was apneic and had a bulging fontanelle. The third patient appeared generally well and had a lumbar puncture “contaminated with blood” from which the CSF culture was ultimately negative, though blood culture was ultimately positive for S. pneumoniae so the child was empirically treated for bacterial meningitis for 14 days [14]. In our study, 3 of the 29 patients for which follow-up data are available (10%) went on to develop afebrile seizures (95% CI: 0.021–0.302). All of these three patients had normal brain MRI and EEGs. Although a
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
very small subset, interestingly, none of them had any abnormalities on their studies that could have predicted or even suggested this outcome. The mean duration of follow-up on the available patients was 22.8 months, the median was 23 months, and the interquartile range was 8–36 months. An estimated 3% of children with febrile seizures go on to later develop epilepsy; thus, this was higher than expected for the child with simple febrile seizures [15]. A Rochester study found that the risk of subsequent development of epilepsy was 2.4% for children with simple febrile seizures, 6–8% for children with one complex feature, 17–22% for children with 2 complex features, and 49%, which is the highest, for children with all 3 features [16]. Nelson et al. found that 52 (3%) out of 1104 children with febrile seizures studied up to 7 years of age developed at least one subsequent afebrile seizure, while 34 children (2% of total cohort) developed recurrent afebrile seizures. Of the 34, seven were mentally retarded, and seven also had cerebral palsy. Two hundred twenty-six (16.2%) of 1391 patients had more than one seizure in a 24-hour period; epilepsy developed in 4% of those with at least one complex feature [1]. In the British CHES cohort, 13 (3.4%) of 382 children later developed afebrile seizures, while only 1.6% of the total developed an epilepsy syndrome consisting of complex partial seizures. This cohort study paralleled the Rochester study in demonstrating that the subsequent development of epilepsy more often occurred in children fitting diagnostic criteria for a complex febrile seizure (6.3% in this case) compared with those diagnosed with a simple febrile seizure (1.0%). Of those with complex febrile seizures, the children with the highest risk of future epilepsy were specifically those with prolonged seizures (9.4%) and those with focal seizure semiology (29.0%) [15]. The lowest risk was attributed to those with the single complex feature of recurrent febrile seizures in a 24-hour period. Of note, referral bias may certainly be a consideration in studies such as ours given the setting of a tertiary referral center. Thus, it is possible that our rate estimate may be inflated and that the actual frequency of later development of afebrile seizures is in fact lower. Generalized idiopathic epilepsies with tonic–clonic seizures are the most common type of epilepsy developed in those children with febrile seizures, as a whole, who do go on to have epilepsy. Generalized epilepsy with febrile seizures plus (GEFS+) is the prototypic example of a genetic syndrome clinically manifest as a combination of both febrile and afebrile seizures [17,18]. In our cohort, the three children who developed afebrile seizures did not test positive for the three commonly identified gene mutations for GEFS+. Nevertheless, the majority of our patients had a positive family history of seizures (the majority being febrile seizures), and one child also had a sibling with a similar pattern of recurrent febrile seizures within a 24-hour period. These findings suggest that an underlying genetic component likely plays a role in the development of recurrent febrile seizures [18]. However, even in the aforementioned cases, neuroimaging and EEG studies did not ultimately change the management of these patients. There are some important limitations to this study. First, given the small sample size, we cannot say with statistical confidence that there may not be an occasional patient with recurrent seizures within a 24-hour period who does have some underlying intracranial pathology that would be identified with neuroimaging and would subsequently alter the management of the patient, i.e., may lead to decision to start antiepileptic drugs. A larger study would aid in increasing the power of this study. In addition, follow-up of patients ranged from months to two years; thus, it is conceivable that if followed for a longer period of time, more of these patients could go on to develop afebrile seizures (particularly given the already increased frequency identified in our small cohort). Previous studies have identified the first three years after febrile seizures to be the period with the highest risk for subsequent development of afebrile seizures; thus, our follow-up time was not ideal [1,19]. As previously discussed, however, further development of afebrile seizures was not predicted on the basis of either EEG or neuroimaging.
475
In summary, the categorization of recurrent febrile seizures within a 24-hour period into the complex and less benign grouping may be somewhat antiquated as it was made before the routine use of neuroimaging studies, yet workup of this subtype of seizures has not been updated to reflect the information, or lack thereof, learned from neuroimaging. Furthermore, in terms of diagnosing epilepsy, considering prophylactic antiepileptic drugs and predicting outcomes, multiple afebrile seizures within a 24-hour period are counted as a single seizure [20,21]. The ongoing FEBSTAT study (consequences of prolonged febrile seizures in childhood) continues to give us more information on the specific subgroup of patients with complex febrile seizures; those with a febrile seizure lasting 30 min or more, without specifically looking at our subgroup of patients, i.e., those with recurrent febrile seizures. To date, they have shown us that febrile status epilepticus (as defined by prolonged seizures) is usually focal and suggested that the longer a seizure continues, the less likely it is to spontaneously stop [22]. Other important conclusions in this group of patients include risk of acute hippocampal injury, essentially benign cerebrospinal fluid analysis, human herpes virus 6B is much more commonly associated than human herpes virus 7 and 36.2% of 199 of these patients had focal slowing or attenuation on their EEGs preformed within 72 hours [23–26]. Although our study had a relatively small sample size, our results suggest that patients who have more than one seizure within 24 hours but otherwise meet the criteria for simple febrile seizure should not be worked up differently from those patients with simple febrile seizures. Subsequent practice changes would translate to decreased hospital admission rates, decreased neuroimaging (which is not without its risks given the future risks of cumulative exposure to radiation as well as the sedation frequently required for these studies), and decreased EEGs (which may also require sedation of the child). In other words, this ultimately means avoiding unnecessary tests in this population and improving cost effectiveness in health care. Concurrent with the last AAP statement on simple febrile seizures, limited evidence exists that supports the use of diagnostic workup in patients with complex febrile seizures [7]. We, therefore, propose the term “simple febrile seizures plus (SFS+)” to refer to those patients with recurrent febrile seizures within a 24-hour period who may prognostically be at a slightly higher risk of subsequent development of afebrile seizures but should otherwise be diagnostically considered not different from those having simple febrile seizures, i.e., limited role of neuroimaging and EEG.
5. Conclusion This pilot study suggests that patients with more than one seizure within 24 hours but otherwise meeting the criteria for simple febrile seizures, i.e., return to baseline between each seizure or at least after the seizure cluster and lack any focal features, should not be worked up differently from those patients with simple febrile seizures. This suggests that the criterion could be removed from labeling a child as having complex febrile seizures, simply SFS +. Neuroimaging and EEG do not add any significant diagnostic or prognostic information in these patients and are unnecessary as is hospitalization. Prognostically, these children may be more likely to go on to have afebrile seizures; however, larger powered and longer term outcome follow-up studies are necessary for confirmation.
Disclosure Marie Grill, MD: nothing to disclose. Yu-Tze Ng, MD, FRACP is on the Medical Advisory Board for Lundbeck Pharmaceuticals. He is also on the speakers' bureau for Lundbeck Pharmaceuticals, UCB Pharma and Cyberonics Inc.
476
M.F. Grill, Y.-T. Ng / Epilepsy & Behavior 27 (2013) 472–476
Conflict of interest The authors declare no conflicts of interest.
References [1] Nelson KB, Ellenberg JH. Predictors of epilepsy in children who have experienced febrile seizures. N Engl J Med 1976;295:1029–33. [2] Baumann RJ. Technical report: treatment of the child with simple febrile seizures. Pediatrics 1999;103:e86. [3] Berg AT, Shinnar S. Complex febrile seizures. Epilepsia 1996;37:126–33. [4] Shinnar S, O'Dell C. Profiles in seizure management. In: Leppik IE, editor. Managing febrile seizures in young children and epilepsy in the elderly. Princeton Media Associates; 2003. p. 3–15. [5] Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child 2004;89:751–6. [6] American Academy of Pediatrics. Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. Pediatrics 1996;97:769–72. [7] Subcommittee on Febrile Seizures; American Academy of Pediatrics. Neurodiagnostic evaluation of the child with a simple febrile seizure. Review Pediatrics 2011;127: 389–94. [8] Brenner DJ. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr Radiol 2002;32:228–31 [discussion 242-4]. [9] Frush DP, Donnelly LF, Rosen NS. Computed tomography and radiation risks: what pediatric health care provides should know. Pediatrics 2003;112:951–7. [10] Teng D, Dayan P, Tyler S, et al. Risk of intracranial pathologic conditions requiring emergency intervention after a first complex febrile seizure episode among children. Pediatrics 2006;117:304–8. [11] McAbee GN, Barasch ES, Kurfist LA. Results of completed tomography in “neurologically normal” children after initial onset of seizures. Pediatr Neurol 1989;5: 102–6.
[12] Garvey MA, Guillard WD, Rusin JA, et al. Emergency brain computed tomography in children with seizures: who is most likely to benefit? J Pediatr 1998;133:664–9. [13] Yucel O, Aka S, Yazicioglu L, Ceran O. The role of early EEG and neuroimaging in determination of prognosis in children with complex febrile seizures. Pediatr Int 2004;46:463–7. [14] Kimia A, Ben-Joseph EP, Rudloe T, et al. Yield of lumbar puncture among children who present with their first complex febrile seizure. Pediatrics 2010;126:62–9. [15] Verity CM, Golding J. Risk of epilepsy after febrile convulsions: a national cohort study. BMJ 1991;303:1373–6 [Erratum in: BMJ 1992;304:147]. [16] Annegers JF, Hauser WA, Shirts SB, Kurland LT. Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:493–8. [17] Nakayama J. Progress in searching for the febrile seizure susceptibility genes. Brain Dev 2009;31:359–65. [18] Grill MF, Losey TE, Ng YT. The Hitchhiker's guide to the child neurologist's genetic evaluation of epilepsy. Semin Pediatr Neurol 2008;15:32–40. [19] Lennox WG. Significance of febrile convulsions. Pediatrics 1953;11:341–57. [20] Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:429–34. [21] Shinnar S, Berg AT, O'Dell C, Newstein D, Moshe SL, Hauser WA. Predictors of multiple seizures in a cohort of children prospectively followed from the time of their first unprovoked seizure. Ann Neurol 2000;48:140–7. [22] Shinnar S, Hesdorffer DC, Nordli Jr DR, et al. Phenomenology of prolonged febrile seizures; results of the FEBSTAT study. Neurology 2008;15:170–6. [23] Shinnar S, Bello JA, Chan S, et al. MRI abnormalities following febrile status epilepticus in children; the FEBSTAT study. Neurology 2012;79:871–7. [24] Frank LM, Shinnar S, Hesdorffer DC, et al. Cerebrospinal fluid findings in children with fever-associated status epilepticus: results and consequences of prolonged febrile seizures (FEBSTAT) study. J Pediatr 2012;161:1169–71. [25] Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 2012;53:1481–8. [26] Nordli Jr DR, Moshe SL, Shinnar S, et al. Acute EEG findings in children with febrile status epilepticus: results of the FEBSTAT study. Neurology 2012;79: 2180–6.