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Original article

A comparative study of febrile and afebrile seizures associated with mild gastroenteritis
Eun Hye Lee, Sajun Chung
Department of Pediatrics, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Received 9 July 2012; received in revised form 17 September 2012; accepted 26 September 2012

Abstract Purpose: Seizures associated with mild gastroenteritis have been increasingly reported. We analyzed the clinical characteristics of febrile and afebrile seizures associated with mild gastroenteritis, and attempted to determine the inuence of fever in these two groups. Methods: We reviewed the medical records of 59 children presenting with seizures during a mild gastroenteritis episode. They were classied into an afebrile group (n = 27) and a febrile group (n = 32). We compared the age of onset, sex, seizure semiology, frequency, duration, family history, and prior history of seizures between the two groups. Results: The mean age, family history, seizure semiology, and frequency of seizures were not signicantly dierent between the two groups. However, more patients in the afebrile group experienced P2 seizures/day than in the febrile group (63% vs. 38%, p = 0.051). The febrile patients had a tendency of experiencing prolonged seizures lasting P5 min compared with the afebrile group (34% vs. 11%, p = 0.063). Prior febrile seizures were noted in 5 of the 32 patients (15.6%) in the febrile group, while none of the 27 patients in the afebrile group had a history of prior seizures (p = 0.056). Conclusions: It seems that the presence of fever may inuence the clinical characteristics of seizures associated with mild gastroenteritis. We suggest that afebrile seizures associated with gastroenteritis may be regarded as a distinct condition from those associated with fever, and it needs to be claried by a further large sample study. 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Gastroenteritis; Benign convulsions; Fever

1. Introduction Afebrile seizures commonly occur during episodes of mild gastroenteritis in young children. This condition is usually referred to as benign convulsions associated with mild gastroenteritis (CwG). They are characterized as afebrile, brief, and generalized seizures accompanying symptoms of gastroenteritis without clinical signs of

Corresponding author. Address: Department of Pediatrics, College of Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Republic of Korea. Tel.: +82 2 958 8301; fax: +82 2 958 8845. E-mail address: sajchung@khmc.or.kr (S. Chung).

dehydration or electrolyte disturbance [1,2]. Since CwG was rst described in Japan in 1982, several reports followed from other locations around the world, including the United States and Europe [35]. According to the denition of CwG, most published reports excluded patients with fever before and after the seizure. However, in the practical clinical setting, patients often experience febrile seizures as well as afebrile seizures with gastroenteritis. Nevertheless, few previously published articles have reported on the impact of fever in seizures associated with gastroenteritis. In the current study, we evaluated the clinical characteristics of children presenting with afebrile or febrile seizures associated with mild gastroenteritis and attempted to identify dierences in these two conditions.

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Please cite this article in press as: Lee EH, Chung S. A comparative study of febrile and afebrile seizures associated with mild gastroenteritis.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.014

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2. Methods The clinical data of 59 children who presented with seizures associated with mild gastroenteritis at the Department of Pediatrics of Kyung Hee University Hospital between the years 2000 and 2011 were assessed. We retrospectively analyzed age at onset, seizure semiology, duration, clustering of seizures, and family histories (febrile seizures or epilepsy). Findings on general physical examination and neurologic examinations were noted. The presence of fever, the interval between an episode of diarrhea and seizure, serum electrolytes, acidbase status, and the presence of stool rota antigen were also investigated. The febrile group was dened as patients having a body temperature greater than 38.0 C 24 h before or after the seizures. The afebrile group was dened as those having a body temperature less than 38.0 C 24 h before and after the seizures. None of the patients had severe dehydration or electrolyte derangement. Children with neurological decits or patients with meningitis or meningoencephalitis, and children with a previous history of epilepsy were excluded. Electroencephalographies (EEGs) were obtained within a week after the seizures using an international 1020 system in 53 patients; these EEGs were evaluated by a pediatric neurologist. For statistical analyses, chi-square tests and Fishers exact tests were used to compare the characteristics of the febrile and afebrile groups as appropriate. Statistical analyses were performed using SPSS software. A p-value less than 0.05 was considered statistically signicant. 3. Results There were 29 boys and 30 girls in the patient population. The age of onset ranged from 3 to 62 months (mean 20.4 10.7 months). The afebrile group was comprised of 27 patients, and the febrile group was comprised of 32 patients. The age at onset, sex, and variables associated with gastroenteritis were not signicantly different between the two groups (Table 1). However, the interval between the onset of gastroenteritis and seizures demonstrated dierent patterns. Seizures preceded symptoms of gastroenteritis in 1/26

patients (3.8%) in the afebrile group and 5/29 patients (17.2%) in the febrile group. In the febrile group, seven patients experienced seizures on the day of gastroenteritis onset, while no patients did so in the afebrile group (Fig. 1). In four patients of febrile group, fever preceded the seizure and subsequent diarrhea. Table 2 shows data for the comparisons of seizure characteristics between febrile and afebrile patients. Regarding the seizure semiology, afebrile patients had generalized seizures (n = 24), partial seizures (n = 2),

Table 1 Demographic data and clinical variables of gastroenteritis patients. Afebrile (n = 27) Age (months) Range Sex (Male:Female) Vomiting Diarrhea Vomiting and diarrhea 18.6 8.4 342 11:16 2 5 20 Febrile (n = 32) 22.0 12.2 1162 18:14 1 19 12

Fig. 1. The intervals between symptoms of gastroenteritis and seizures in the afebrile group (A) and febrile group (B). The majority of patients in the afebrile group developed seizures 14 days after the onset of gastroenteritis, while febrile patients had comparatively variable intervals. In the febrile group, seven patients had seizures at the same day of gastroenteritis onset and ve patients experienced seizures before the onset of gastroenteritis. Negative numbers indicate that seizures preceded the onset of gastroenteritis. Four patients were excluded due to incomplete data.

Please cite this article in press as: Lee EH, Chung S. A comparative study of febrile and afebrile seizures associated with mild gastroenteritis.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.014

E.H. Lee, S. Chung / Brain & Development xxx (2012) xxxxxx Table 2 Comparison of seizure characteristics between the afebrile and febrile groups Afebrile (n = 27) Semiology Generalized Partial Atonic Clustering Mean P2 times P3 times Duration Mean P5 min Previous febrile seizures Family history of febrile seizure 24 2 1 2.3 1.5 17 (63%) 9 (33%) 2.4 1.6 3 (11%) 0 4 (15%) Febrile (n = 32) 32 0 0 1.7 1.2 12 (38%) 4 (13%) 4.4 6.4 11 (34%) 5 (16%) 10 (33%) 0.081 0.051 0.067 0.081 0.063 0.056 0.132 p value 0.084

and atonic seizure (n = 1), while all of the febrile patients (n = 32) had generalized seizures. Afebrile patients were more likely to experience seizures P2 times/day than febrile patients with marginal statistical signicance (63% vs.38%, p = 0.051). Signicant dierences in the mean duration of seizures were not found between the two groups (p = 0.09), nevertheless, the febrile patients tended to experience prolonged seizures lasting P5 min (34% vs. 11%, p = 0.063). A previous history of febrile seizures was noted in 5 of 32 patients (15.6%) in the febrile group, while none of the 27 patients in the afebrile group had a history of febrile seizures (p = 0.056). A family history of febrile seizures was more common in the febrile group, but statistical signicance was not noted (p = 0.132). Among the 59 patients, no patient had family history of epilepsy, or neuropsychological disorders. Laboratory ndings, including serum electrolytes, acidbase status were not signicantly dierent between groups. Unfortunately, not all patients underwent complete evaluation for stool rota antigen, and bacterial cultures. Rota antigen was positive in one patient of afebrile group (1/22), and two of febrile group (2/20). No patients had enteritis-causing bacteria in afebrile group (0/21), but Salmonella B were identied from two patients of febrile group (2/25). Electroencephalographies were obtained in 25 afebrile patients and 28 febrile patients, and the results are summarized in Table 3. Of the 59 patients, mean time of follow-up duration was 14.5 months. One patient of afebrile group (1/27)
Table 3 Electroencephalographic ndings. Afebrile (n = 26) Normal Focal spike Generalized slow wave bursts Generalized background slowing Background asymmetry 19 4 1 2 0 Febrile (n = 28) 25 2 0 0 1

and two of febrile group (2/32) experienced recurrence of febrile seizures, but none of the patients experienced seizure recurrence during gastroenteritis. One afebrile patient with interictal EEG abnormalities remained focal epileptiform discharges after 17 months, but did not suer from seizure under receiving phenobarbital treatment. Psychomotor development was normal in all patients at last follow-up. 4. Discussion Acute gastroenteritis is a common disease among infants and young children throughout the world. It is well known that seizures can occur during acute gastroenteritis due to severe electrolyte imbalance with dehydration or fever. The afebrile seizures associated with mild gastroenteritis without electrolyte imbalance or severe dehydration have been reported as benign convulsions with mild gastroenteritis (CwG) since 1982 [1]. This condition typically occurs in previously healthy 6 month to 3 year-old infants and young children, with a tendency to occur in a repetitive or clustered manner. Interictal EEGs demonstrate no abnormalities and most patients have a good prognosis without developing subsequent epilepsy [2,6,7]. The early investigators [1] have reported CwG were generalized seizures; nevertheless, following studies [3,5,7] found that partial seizures or partial to generalized seizures are frequently observed in this condition. The patients in the current study who had afebrile seizures associated with gastroenteritis (the afebrile group) can be regarded as having CwG according to the pre-existing descriptions. Their age of onset ranged from 3 to 42 months, with most patients presenting with brief generalized seizures (24/27). The seizures occurred in clusters in 63% of patients without fever, while 38% of febrile patients had clustering of seizures. In addition, the patients of afebrile group presented various seizure types and EEG ndings than patients of febrile group, which suggest a clinical heterogeneity of this condition.

Please cite this article in press as: Lee EH, Chung S. A comparative study of febrile and afebrile seizures associated with mild gastroenteritis.. Brain Dev (2012), http://dx.doi.org/10.1016/j.braindev.2012.09.014

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In the clinical setting, physicians frequently see patients with gastroenteritis suering from fever during the illness, some of whom experience seizures with fever. However there is a lack of data regarding the impact of fever in seizures associated with gastroenteritis. Recently, Zifman et al. [8] studied the impact of fever in gastroenteritis-related seizures in children. They found no signicant dierence in age, serum sodium level, and seizure duration between febrile (n = 26) and afebrile (n = 18) patients with seizures during mild gastroenteritis. In comparison to the current study, they had fewer patients (n = 6) with prolonged seizure (>5 min), and they seem to not have compared clustering of seizures between the two groups. However, it is notable that more patients of febrile group (n = 4) experienced prolonged seizure than patients of afebrile group (n = 2) despite very small number of the cited study. We suggest that this nding may imply similar meaning to the current study. In the current study, we retrospectively evaluated the clinical features of children with febrile or afebrile seizures associated with mild gastroenteritis. We found that the febrile patients had dierent clinical manifestations when compared with afebrile patients (CwG) in several respects. First, seizures preceded the onset of gastroenteritis more often in febrile group than in afebrile group. Second, more patients in the afebrile group tended to experience seizure clustering than patients in the febrile group (63% vs. 38%, p = 0.051). In spite of the marginal signicance, it is noteworthy because seizure clustering is a well known feature of CwG rather than febrile seizures. Furthermore, patients in the febrile group had a tendency to experiencing prolonged seizures lasting P5 min than afebrile patients (34% vs. 11%, p = 0.063). Third, febrile patients were more likely to have a previous history of febrile seizures than afebrile patients (p = 0.056). Although the statistical signicance was not evident, the febrile group in the current study seemed to have some overlapping features with both febrile seizures and CwG in their seizure manifestations and previous histories. These data suggest that seizures during gastroenteritis with fever could be regarded as a dierent clinical entity than afebrile seizures associated with gastroenteritis (CwG). It is believed that CwG and febrile seizures have different pathomechanisms. In febrile seizures, fever inuences cellular processes, such as the electrical activity of neurons, resulting in a hyperexcitable brain in young children [9]. Of children with febrile seizures, 24% had a family history of febrile seizures, which suggests a strong genetic inuence for febrile seizures [10]. The pathogenic mechanism of CwG remains unclear. Some authors have suggested that CwG may be on a continual spectrum of benign infantile convulsions as both syndromes share some clinical features [11,12].

They postulated that underlying genetic factors may confer seizure susceptibility in patients with CwG, resulting in a lower seizure threshold during gastroenteritis than in the general population [11]. Weng et al. [13] hypothesized that a channelopathy may be responsible for the pathogenesis of CwG, and performed mutation analysis of the SCN1A gene in 12 CwG patients, although no mutations were identied. Rotaviral infection also plays a role in the development of CwG. Rotavirus antigen has frequently been detected in the stool of CwG patients [5,6]. The most probable mechanism of seizures associated with rotaviral infection is direct central nervous system invasion or a secondary eect of the virus via nitric oxide toxicity [14]. Interestingly, fever preceded the symptoms of gastroenteritis and caused seizures in four patients of febrile group. In the strict sense, these patients might experience seizures due to fever rather than due to the pathomechanism of gastroenteritis. We think it is dicult to distinctly classify those patients into one or the other, and a more in-depth understanding about pathomechanism of the two conditions is needed. In summary, the afebrile and febrile patients who experienced seizures associated with mild gastroenteritis seemed to have several distinct features. The febrile group may demonstrate pathomechanisms of both CwG and febrile seizures. Further studies will be required to clarify whether febrile patients with seizures associated with gastroenteritis have distinct clinical features from those with febrile seizures in the absence of gastroenteritis. The current study has several limitations, including its retrospective design and lack of long-term followup data. However, our results demonstrate the possibility that seizures during episodes of mild gastroenteritis have clinically distinct manifestations based on the presence or absence of fever. We suggest that the febrile cases may be considered as a distinct clinical condition from afebrile seizures associated with gastroenteritis (CwG), and it should to be determined by a large sample study. Conict of interest statement The authors have no conicts of interest to declare. References
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