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Comparison between febrile and afebrile seizures associated with mild rotavirus gastroenteritis

Open ArchivePublished:May 03, 2013DOI:https://doi.org/10.1016/j.seizure.2013.04.007

      Abstract

      Purpose

      We aimed on identifying the differences of febrile and afebrile seizures associated with mild rotavirus gastroenteritis (RVGE) in the pediatric population.

      Method

      Medical charts of pediatric patients who had been admitted between July 1999 and June 2011 due to RVGE were retrospectively reviewed. Subjects were ultimately divided into three groups; ‘no seizure’ (NS: patients without seizure), ‘febrile seizure’ (FS: patients with fever during seizure), ‘afebrile seizure’ (AFS: patients without fever during seizure). Comparisons between groups were carried out on demographic and clinical characteristics, laboratory test results, electroencephalogram findings, brain magnetic resonance imaging findings, antiepileptic treatment, and prognosis.

      Results

      Among the 755 subjects who had been admitted due to mild rotavirus enteritis, 696 (90.3%) did not have any seizures, 17 (2.2%) had febrile seizures, 42 (5.5%) had afebrile seizures. The duration of gastrointestinal symptoms before the onset of seizures were significantly shorter in the FS group compared to the AFS group (1.3 ± 0.8 vs. 2.8 ± 1.0 days; p < 0.0001). A single seizure attack was significantly higher in the AFS group (3.0 ± 1.6 vs. 1.7 ± 1.0 episodes; p = 0.0003), and the frequency of seizures that were of focal type with or without secondary generalization were significantly higher in the AFS group (33.3% vs. 6.0%; p = 0.0139). All patients among the FS and AFS group had not received further antiepileptic treatment after discharge, and none developed epilepsy during follow up period.

      Conclusion

      Despite some differences in seizure characteristics, both febrile and afebrile seizures associated with mild RVGE were mostly benign with a favorable prognosis.

      Abbreviations:

      NS (‘no seizure’ group), FS (‘febrile seizure’ group), AFS (‘afebrile seizure’ group)

      Abbreviations:

      FS (‘febrile seizure’ group), AFS (‘afebrile seizure’ group)

      Abbreviations:

      NS (‘no seizure’ group), FS (‘febrile seizure’ group), AFS (‘afebrile seizure’ group), WBC (white blood cell), CRP (c-reactive protein), BUN (blood urea nitrogen), AST (aspartate aminotransferase), ALT (alanine aminotransferase)

      Keywords

      1. Introduction

      Rotavirus is the most common cause of gastroenteritis and the leading cause of severe diarrhea due to dehydration in infants and young children worldwide. It is responsible for over 2 million hospitalizations and up to 600,000 deaths per year,
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      • Hummelman E.G.
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      Global illness and deaths caused by rotavirus disease in children.
      and its proportion among diarrhea hospitalizations is increasing worldwide.
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      Although, rotavirus replicates mainly in epithelial cells that line the small intestine causing gastroenteritis, mild forms of rotavirus gastroenteritis (RVGE) are known to be capable of inducing benign afebrile convulsions in infants and young children.
      The clinical condition in which mild viral gastroenteritis without severe dehydration, electrolyte imbalance, or hypoglycemia could trigger afebrile convulsions was first reported in Japan.
      • Morooka K.
      Convulsions and mild diarrhea.
      Thereafter, several reports and studies have described the association of benign afebrile seizures with mild gastroenteritis mainly from East Asian countries, such as Japan, Korea, and Taiwan,
      • Komori H.
      • Wada M.
      • Eto M.
      • Oki H.
      • Aida K.
      • Fujimoto T.
      Benign convulsions with mild gastroenteritis: a report of 10 recent cases detailing clinical varieties.
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      Afebrile convulsion associated with rotaviral gastroenteritis in childhood.
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      Acute symptomatic seizure disorders in young children – a population study in southern Taiwan.
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      • Watanabe K.
      Clinical features of benign convulsions with mild gastroenteritis.
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      • et al.
      Rotavirus gastroenteritis associated with afebrile convulsion in children: clinical analysis of 40 cases.
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      Clinical study of benign convulsion with acute gastroenteritis.
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      • et al.
      Benign infantile convulsions associated with mild gastroenteritis: a retrospective study of 39 cases including virological tests and efficacy of anticonvulsants.
      and some from Europe,
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      Benign afebrile cluster convulsions with gastroenteritis: an observational study.
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      Convulsions associated with gastroenteritis in the spectrum of benign focal epilepsies in infancy: 30 cases including four cases with ictal EEG recording.
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      Infantile convulsions with mildgastroenteritis: a retrospective study of 25 patients.
      the United States,
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      Rotaviral gastrointestinal infection causing afebrile seizures in infancy and childhood.
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      Benign afebrile seizures in acute gastroenteritis: is rotavirus the culprit?.
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      • Patrick Hickey P.
      Rotavirus-induced seizures in childhood.
      and South America,
      • Caraballo R.H.
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      • Santos Cde L.
      • Espeche A.
      • Cersósimo R.
      • Fejerman N.
      Benign infantile seizures with mild gastroenteritis: study of 22 patients.
      indicating the possibility of predominant occurrence in East Asian ethnicity. This distinct clinical entity is now widely recognized as ‘benign convulsion with mild gastroenteritis (CwG)’.
      • Komori H.
      • Wada M.
      • Eto M.
      • Oki H.
      • Aida K.
      • Fujimoto T.
      Benign convulsions with mild gastroenteritis: a report of 10 recent cases detailing clinical varieties.
      CwG is defined as convulsions accompanying symptoms of mild diarrhea without moderate to severe dehydration, electrolyte imbalance, and fever (defined as a body temperature ≥ 38 °C) before and after the seizures in previously healthy infants and children without meningitis, encephalitis or encephalopathy.
      • Komori H.
      • Wada M.
      • Eto M.
      • Oki H.
      • Aida K.
      • Fujimoto T.
      Benign convulsions with mild gastroenteritis: a report of 10 recent cases detailing clinical varieties.
      • Verrotti A.
      • Tocco A.M.
      • Coppola G.G.
      • Altobelli E.
      • Chiarelli F.
      Afebrile benign convulsions with mild gastroenteritis: a new entity?.
      Until now studies on seizures associated with rotavirus have mainly focused on determining the characteristics of CwG. Data on the comparison of characteristics between patients with seizures and without seizures among mild RVGE is scarce.
      • Hung J.J.
      • Wen H.Y.
      • Yen M.H.
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      • Yan D.C.
      • Lin K.L.
      • et al.
      Rotavirus gastroenteritis associated with afebrile convulsion in children: clinical analysis of 40 cases.
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      • Furukawa S.
      Clinical characteristics of benign convulsions with rotavirus gastroenteritis.
      Moreover, despite the fact that RVGE is known to be associated with fever and that febrile seizures are known to occur during the illness, data on the comparison of characteristics of febrile and afebrile seizures associated with RVGE is insufficient. Therefore our aim in this study was to identify the characteristics of both febrile and afebrile seizures in infants and children with mild RVGE, and to clarify the clinical differences of febrile and afebrile seizures associated with mild RVGE and reveal the differences between the two distinct clinical entities of seizure in a common infection by rotavirus, which is distinguished until now mainly by the presence of fever during seizure.

      2. Material and methods

      Electronic databases were queried to identify patients who had been admitted to the pediatric department of Inha University Hospital and diagnosed as RVGE between July 1999 and June 2011. Laboratory tests of these patients were additionally checked in order to confirm positive stool rotavirus antigen test results during admission. Electronic medical records and laboratory tests were initially reviewed in order to exclude patients who had been initially admitted due to other diseases and later obtained nosocomial rotavirus infections or had co-infections identified by other positive antimicrobial tests or stool culture during admission.
      We limited ‘mild gastroenteritis’ to the extent of a medical condition of gastroenteritis without moderate to severe dehydration, electrolyte derangement or hypoglycemia during the illness. Therefore, children that were under such condition were excluded from the study. As other abnormal medical conditions are capable of inducing seizures, we also excluded patients who had abnormal neurological development, previous histories of meningitis, encephalitis, encephalopathy, cerebral trauma, brain tumor, hypoxia or epilepsy, and other underlying diseases of the central nervous system.
      Electronic medical records of the subjects were reviewed to obtain data regarding demographic characteristics, clinical symptoms, and laboratory test results at the time of admission. Additional investigation was done in seizure patients on clinical features regarding seizure, electrocencephalogram (EEG) findings, brain magnetic resonance imaging (MRI) findings, anticonvulsant therapy received during admission, and prognosis. According to the presence or absence of seizure, patients were initially divided into two groups; the ‘seizure’ group and the ‘no seizure’ (NS) group. Thereafter, the ‘seizure’ group was additionally divided into the ‘febrile seizure’ (FS) group and the ‘afebrile seizure’ (AFS) group, according to the presence or absence of fever, defined as a body temperature ≥38 °C, at the time of their seizures. As fever is a common symptom of RVGE, and as fever is capable of occurring during interictal periods of seizures during the natural course of the disease, febrile seizures were limited to seizures that were associated with fever at the time of seizures. Consequently, patients that had fever only at the time of seizures were included in the FS group. Patients who had fever during interictal periods but who were afebrile at the time of seizures were included in the AFS group, even though fever may have occurred within 24 h before or after the seizures in these cases. Patients that had both febrile and afebrile seizures were also included in the FS group.
      Rotavirus antigen detection tests in stool samples had been conducted by an immunochromatography assay kit (SD BIOLINE® Rotavirus, Standard Diagnostics, Inc., Yongin, Korea) until December 2010, and by enzyme immunoassay (RIDASCREEN® Rotavirus, R-Biopharm Aktiengesellschaft, Darmstadt, Germany) starting from January 2011.
      Antiepileptic treatment had been initiated with single doses of intravenous benzodiazepines, such as midazolam, diazepam, or lorazepam as the primary drug for patients who had additional seizures after admission. In Korea, it is usual to perform intravenous catheterization in patients who visit a tertiary hospital due to seizures, and therefore antiepileptics are usually administrated intravenously in order to rapidly control seizures, rather than per oral or transrectal administration. A secondary drug of phenobarbital or phenytoin had been administrated intravenously to patients that showed no response to maximum three doses of intravenous benzodiazepines.
      Statistical analysis was carried out on the SAS 9.1.3 service pack 4 program (SAS Institute Inc., Cary, North Carolina, USA.). Chi-square test was used for the comparison of categorical data between groups. For the comparison of dimensional variables, Student t test was used for analysis between two groups, and one-way analysis of variance (ANOVA) test was carried out for analysis between three groups. The p value for statistical significance was defined as p < 0.05. Post hoc analyses with Bonferroni t test was carried out when the p value for the ANOVA test reached less than p < 0.05.
      This study was approved by the Institutional Review Board of Inha University Hospital.

      3. Results

      During the study period between July 1999 and June 2011, 1185 pediatric inpatients had been diagnosed as RVGE with positive rotavirus antigen in stool samples. Among these patients, 430 patients were excluded from the study leaving 755 patients for inclusion into the study.
      Among the 755 subjects who were included in the study, 696 (92.2%) did not have seizures, while 59 (7.8%) had seizures. Among the seizure patients, that were ultimately included for comparison, 17 patients had (2.2%) febrile seizures and 42 patients (5.6%) had afebrile seizures. Among the 17 patients in the FS group, six patients had both febrile and afebrile seizures. In these six patients, all cases of febrile seizures preceded afebrile seizures, and afebrile seizures occurred within 24 h of the development of febrile seizures. Seasonal distribution of incidences showed that there were 527 among 696 patients (75.7%) of the NS group, 13 among 17 patients (76.5%) of the FS group, and 37 among 42 patients (88.1%) of the AFS group that had been admitted between December and April. Comparisons of demographic characteristics and clinical symptoms between the three groups are summarized in Table 1.
      Table 1Clinicodemographic characteristics of patients with febrile and afebrile seizures associated with mild rotavirus gastroenteritis.
      NSFSAFSp Value
      Number of subjectsn = 696n = 17n = 42
      Mean age, months21.0 ± 15.118.8 ± 12.621.1 ± 7.10.8196
      Analysis of variance test, results expressed in mean±standard deviation.
      Sex
       Male406 (58)9 (53)15 (36)0.0151
       Female290 (42)8 (47)27 (64)
      Family history of epilepsy/seizure3 (18)5 (12)0.5596
      Fever during illness573 (82)17 (100)18 (43)<0.0001
      Vomiting647 (93)16 (94)41 (98)0.5000
      Diarrhea688 (99)17 (100)42 (100)0.7098
      Respiratory symptoms251 (36)11 (65)10 (24)0.0124
      Statistical analysis done by chi-square test and results expressed in number of patients (%), except mean age.
      a Analysis of variance test, results expressed in mean ± standard deviation.
      Comparison of seizure characteristics among the FS group and the AFS group revealed significant differences in past history, family history, frequency, types of seizure attacks, the duration between GI symptoms and seizures, and the presence of diarrhea before seizures (Table 2). There were five patients (29.4%) in the FS group, and two patients (4.8%) in the AFS group who had a past history of febrile seizures, showing statistical significance between the two groups (p = 0.0080). There were three patients (17.6%) in the FS group, and five patients (11.9%) in the AFS group who had a family history of febrile seizure or epilepsy, showing no statistical significance between the two groups (p = 0.5596). All three patients in the FS group had a first degree family history of febrile seizures. Among the AFS group, one patient had a first degree family history of epilepsy, three patients had a first degree family history of febrile seizures, and one patient had a second degree family history of febrile seizure. There were 37 patients (88.1%) in the AFS group who had two or more seizures, ranging from one to eight episodes. Meanwhile, there were six patients (35.3%) in the FS group who had multiple seizures ranging from one to four episodes. The duration of the seizure attack (duration from the first to last seizure) ranged from 1 to 21 h in the six patients of the FS group and 1–32 h in the 37 patients of the AFS group. Seizure ceased within 24 h in all six patients in the FS group, while there were two patients among the AFS group whose seizures persisted for more than 24 h. The duration from the first to last seizure in these patients were 27 h and 32 h, respectively. The duration of each seizure mostly ranged from 30 s to less than 5 min in patients among the FS group (28/29 episodes) and in patients among the AFS group (125/128 episodes), showing no significant difference between the two groups (p = 0.7332). The four seizures that exceeded 5 min occurred in four different patients. The duration of seizures that exceeded 5 min were 14 min for the patient in the FS group and 10 min, 30 min, and 45 min, respectively for the three patients in the AFS group.
      Table 2Seizure characteristics of patients with febrile and afebrile seizures associated with mild rotavirus gastroenteritis.
      FSAFSp Value
      Number of subjectsn = 17n = 42
      Seizure type
       Generalized16 (94)28 (67)0.0283
      Chi-square test, results expressed in number of patients (%).
       Focal features
      Focal features include focal seizures with or without secondary generalization.
      1 (6)14 (33)
      Frequency of seizures, episodes1.7 ± 1.03.0 ± 1.60.0003
      Student t test, results expressed in mean±standard deviation.
      Duration of the seizure attack in patients with multiple seizures, h10.0 ± 6.7 (n = 6)7.7 ± 7.7 (n = 37)0.4597
      Student t test, results expressed in mean±standard deviation.
      Duration of gastrointestinal symptoms before seizure onset, days1.3 ± 0.82.8 ± 1.0<0.0001
      Student t test, results expressed in mean±standard deviation.
      Presence of diarrhea before first seizure13 (76)41 (98)0.0083
      Chi-square test, results expressed in number of patients (%).
      a Focal features include focal seizures with or without secondary generalization.
      b Chi-square test, results expressed in number of patients (%).
      c Student t test, results expressed in mean ± standard deviation.
      The duration of GI symptoms before the onset of seizure ranged from 0 to 4 days for the FS group and 1–5 days for the AFS group. The average duration of GI symptoms before the onset of seizure was 1.3 ± 0.8 days for the FS group and 2.8 ± 1.0 days for the AFS group, showing statistical significance between the two groups (p < 0.0001). Although diarrhea was observed in all seizure patients during the illness, the presence of diarrhea before the initiation of seizures were observed in 13 patients (76.5%) in the FS group and 41 patients (97.6%) in the AFS group, showing statistical significance between the two groups (p = 0.012).
      Comparison of laboratory results showed that white blood cell (WBC) counts were significantly lower in the AFS group compared with the NS group (7622 ± 2118 vs. 9829 ± 4194 cells/μL, p = 0.0035). Serum total carbon dioxide (TCO2) level was significantly higher in the AFS group compared to the NS group (17.98 ± 2.92 vs. 16.23 ± 3.59 mEq/L, p = 0.0096). Serum aspartate aminotransferase (AST) was significantly higher in the AFS group compared to the NS group and the FS group (59.31 ± 16.09 vs. 51.66 ± 20.06 vs. 43.76 ± 12.50 IU/L, p = 0.0119). Other laboratory tests showed no significant differences between groups (Table 3).
      Table 3Laboratory test results of patients with febrile and afebrile seizures associated with mild rotavirus gastroenteritis.
      NSFSAFSp Value
      WBC count (cells/μL)9829 ± 419410,012 ± 50977622 ± 21180.0035
      Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value<0.05 between groups.
      ,
      There was statistical significance between groups only in WBC count, AST, and total CO2.
      CRP (mg/dL)1.04 ± 1.901.88 ± 2.500.98 ± 1.720.2093
      Serum glucose (mg/dL)79 ± 2387 ± 2186 ± 240.0611
      BUN (mg/dL)13.3 ± 6.915.0 ± 2.010.6 ± 3.30.045
      Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value<0.05 between groups.
      Creatinine (mg/dL)0.43 ± 0.110.42 ± 0.150.40 ± 0.110.2278
      AST (IU/L)52 ± 2044 ± 1359 ± 160.0119
      Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value<0.05 between groups.
      ,
      There was statistical significance between groups only in WBC count, AST, and total CO2.
      ALT (IU/L)39 ± 3531 ± 1135 ± 160.5206
      Na+ (mEq/L)137.8 ± 3.7136.5 ± 2.3136.6 ± 2.70.0286
      Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value<0.05 between groups.
      K+ (mEq/L)4.2 ± 0.54.2 ± 0.44.1 ± 0.40.1414
      Cl (mEq/L)104.0 ± 5.0103.1 ± 3.5102.8 ± 3.80.1825
      Total CO2 (mEq/L)16.2 ± 3.617.3 ± 4.018.0 ± 2.90.0096
      Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value<0.05 between groups.
      ,
      There was statistical significance between groups only in WBC count, AST, and total CO2.
      Statistical analysis was conducted by analysis of variance test. Results are expressed in means ± standard deviation.
      a Post hoc Bonferroni t test was conducted in laboratory tests that showed a p value < 0.05 between groups.
      b There was statistical significance between groups only in WBC count, AST, and total CO2.
      Interictal EEGs had been taken in five patients among the FS group and 34 patients among the AFS group. There were two patients in the AFS group with abnormal findings on interictal EEG that were compatible of partial seizures. Follow up EEGs taken two months later in both patients were shown to be normal. Brain MRI had been conducted in two patients among the FS group and 12 patients among the AFS group. All findings were normal among the patients except a transient splenic lesion of the corpus callosum in one patient among the AFS group. Cerebrospinal fluid exams had been conducted in seven patient among the FS group and four patients among the AFS group. All 11 patients showed normal results.
      Among the 17 patients in the FS group, only five patients had additional seizures after admission and were treated with intravenous benzodiazepines, while 12 patients required no treatment. All five patients responded well to the primary drug. Among the 42 patients in the AFS group, 36 patients had additional seizures after admission. Benzodiazepines were administered intravenously, and 31 patients responded well, while five patients were refractory to a maximum three doses. Four patients were intravenously administered with phenobarbital and one patient with phenytoin for the secondary antiepileptic drug, which were effective in all five patients. However, there was no significant difference in the types of antiepileptic drugs administered between the two groups (p = 0.3738).
      All patients in both groups had not received any further antiepileptic treatment after discharge, and none developed epilepsy during the follow up period, which ranged from 1 to 5 years. During the follow up period, there were three patients in each group that had new attacks of seizure in the future. Among the patients in the FS group, all three patients had new attacks of febrile seizure associated with other infections. Among the patients in the AFS group, two patients had new attacks of febrile seizure and one patient had a new attack of afebrile seizure, in which all three were associated with other infections. Among these patients, two were associated with gastroenteritis, however showed negative results for rotavirus antigen in stool samples. None of the patients had epilepsy during follow up at the outpatient clinic. There was no statistical significance between the two groups on the recurrence of seizure attacks in the future (17.6% vs. 7.1%, p = 0.2473).

      4. Discussion

      RVGE is well known to occur in cold winter months in most temperate countries. It occurs most commonly among children between 6 and 24 months of age, with virtually all children infected at least once during their first 3–5 years.
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      Results of the total patients in our study were compatible with these results, while respiratory symptoms were significantly prevalent in the FS group than the AFS group, indicating the possibility of more frequent concomitant respiratory infections in patients with febrile seizures than afebrile seizures. Concomitant respiratory infection in the FS group may have some effect in the pathogenesis of febrile seizure by rising the body temperature.
      There is scarce data on the clinical features regarding seizures that occur with fever during RVGE. According to a recent retrospective study which compared the clinicodemographic characteristics of children in rotavirus-associated seizures,
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      there were no differences in the duration and type of seizures between afebrile and febrile seizures. The duration of seizures ranged from 30 s or less to more than 5 min in that study. The duration of seizures in CwG is known to be brief, with seizures usually ranging from 30 s to less than 5 min.
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      Results of our study were compatible with these findings. Although the majority of seizure types associated with CwG are known to be generalized seizures, focal features such as lateral eye deviation and hemiconvulsion or complex partial seizures with symptoms such as loss of responsiveness without convulsive movements have also been reported.
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      Komori et al. reported focal seizures with secondary generalization or vice versa in 4 patients among 10 patients (40%), and Uemura et al. reported complex partial seizures in 11 patients among 105 patients (13%). Caraballo et al. reported focal seizures with secondary generalization in 15 patients (65%), and focal seizures in two patients (9%) among 22 patients. We were able to observe such focal features in both the AFS and FS group, with a significantly higher prevalence in the AFS group, implying a unique characteristic of CwG.
      Another unique characteristic of CwG is that seizures occur in clusters ranging from one to eight episodes within a 24-h period. According to previous reports, two or more seizures developed in 67.5–87% of patients with benign seizures associated with mild RVGE.
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      Results of our study were compatible with these results, with a significantly higher frequency of seizures in the AFS group. This finding of our study is unique in the aspect that there has been no report until now that has revealed the difference in the frequency of seizure between patients with febrile and afebrile seizures associated with mild RVGE.
      Afebrile seizures associated with mild RVGE usually tend to occur within the first 5 days of the onset of symptoms of gastroenteritis, especially on the third day.
      • Hung J.J.
      • Wen H.Y.
      • Yen M.H.
      • Chen H.W.
      • Yan D.C.
      • Lin K.L.
      • et al.
      Rotavirus gastroenteritis associated with afebrile convulsion in children: clinical analysis of 40 cases.
      • Kawano G.
      • Oshige K.
      • Syutou S.
      • Koteda Y.
      • Yokoyama T.
      • Kim B.G.
      • et al.
      Benign infantile convulsions associated with mild gastroenteritis: a retrospective study of 39 cases including virological tests and efficacy of anticonvulsants.
      • Motoyama M.
      • Ichiyama T.
      • Matsushige T.
      • Kajimoto M.
      • Shiraishi M.
      • Furukawa S.
      Clinical characteristics of benign convulsions with rotavirus gastroenteritis.
      According to the study of Kawano et al., the median interval between the onset of gastroenteritis symptoms and the onset of the first seizure in CwG patients with rotavirus etiology was 2.8 ± 1.0 days, which was precisely equal to the data from our study. There has been no data regarding the duration of gastroenteritis symptoms to the first seizure in febrile seizures associated with mild RVGE. Our study was the first to investigate in febrile seizures, with subsequent analysis with the data from patients with afebrile seizures. Our study showed that patients with febrile seizures were more likely to develop seizures earlier than patients with afebrile seizures after the onset of gastroenteritis symptoms, namely vomiting and diarrhea. Data of our study also showed that although diarrhea was present in all the patients that had seizures during the entire illness, diarrhea was less prevalent in patients with febrile seizures than patients with afebrile seizures at the timing of the first seizure. This result also supports our finding that during RVGE, seizures in patients with febrile seizures occur earlier than seizures in patients with afebrile seizures. These findings are unique in the point that it is the first to report clinical differences in the onset of seizure during the course of the illness. These finding may also provide clinical evidence in discriminating two different clinical entities of seizure in a common rotavirus infection; ‘febrile seizures’ and ‘benign afebrile seizures’ that are associated with mild rotavirus gastroenteritis.
      There are only few studies that have investigated laboratory results among patients with seizures associated RVGE.
      • Hung J.J.
      • Wen H.Y.
      • Yen M.H.
      • Chen H.W.
      • Yan D.C.
      • Lin K.L.
      • et al.
      Rotavirus gastroenteritis associated with afebrile convulsion in children: clinical analysis of 40 cases.
      • Kawano G.
      • Oshige K.
      • Syutou S.
      • Koteda Y.
      • Yokoyama T.
      • Kim B.G.
      • et al.
      Benign infantile convulsions associated with mild gastroenteritis: a retrospective study of 39 cases including virological tests and efficacy of anticonvulsants.
      • Motoyama M.
      • Ichiyama T.
      • Matsushige T.
      • Kajimoto M.
      • Shiraishi M.
      • Furukawa S.
      Clinical characteristics of benign convulsions with rotavirus gastroenteritis.
      Hung et al. simply investigated the laboratory data among 40 subjects with rotavirus-associated CwG. Kawano et al. compared laboratory data between 30 subjects with rotavirus-associated CwG and nine subjects with norovirus-associated CwG. Motoyama et al., compared laboratory data between 13 subjects with rotavirus-associated CwG and 83 RVGE subjects who were seizure-free. Our study was the first study to compare laboratory data between seizure-free subjects, febrile seizure subjects and afebrile seizure subjects among patients with mild RVGE. According to the study of Motoyama et al., serum Na+ and Cl levels were significantly lower in rotavirus-associated CwG patients compared to seizure-free RVGE subjects. Although our study also showed that both serum Na+ and Cl levels were lower in the FS and AFS group compared to the NS group, there was no statistical significance between groups, which differs from the results of Motoyama et al. Our study also showed that serum AST levels were significantly higher in the AFS group compared to the NS group and the FS group, while there was no statistical significance between ALT levels among groups. It is known that RVGE may be complicated by elevated transmaminase levels,
      • Teitelbaum J.E.
      • Daghistani R.
      Rotavirus causes hepatic transaminase elevation.
      an extra-intestinal spread of rotavirus. Our finding of higher AST level in the AFS group may indicate the prevalence of more complicated cases of rotavirus infections in afebrile seizures. Serum total CO2 is useful in evaluating serum bicarbonate (HCO3) concentration, as serum bicarbonate comprises about 95% of the total CO2 content.
      • Centor R.M.
      Serum total carbon dioxide.
      The finding of our study that serum TCO2 levels were significantly higher in the AFS group compared to the NS group suggests that patients with afebrile seizures may have a higher pH than seizure-free patients among mild RVGE. Although there was no significant difference, TCO2 levels were also higher in the FS group compared to the NS group. A recent prospective case-controlled study has shown that febrile seizures are associated with a systemic respiratory alkalosis, irrespective of the cause of fever or severity of the underlying infection.
      • Schuchmann S.
      • Hauck S.
      • Henning S.
      • Grüters-Kieslich A.
      • Vanhatalo S.
      • Schmitz D.
      • et al.
      Respiratory alkalosis in children with febrile seizures.
      Systemic respiratory alkalosis may have a common mechanism in the generation of seizures in both febrile and afebrile seizures. However, further prospective comparison studies in the futures are needed in the future to reveal this hypothesis.
      Immunization for rotavirus has been first introduced in 2007 in Korea. However, unfortunately our electronic charts lacked data on the patients’ vaccination for rotavirus. We were therefore unable to investigate the rotavirus vaccination status of our subjects. Further prospective studies may be required in order to investigate this issue.

      5. Conclusion

      According to the presence or absence of fever at the time of seizures, seizures associated with mild rotavirus gastroenteritis were shown to not only differ in the characteristics of seizures but also the onset of seizure during the clinical course of illness. Febrile seizures associated with mild RVGE develop earlier during the course of the illness compared to afebrile seizures. Seizures were more frequent in afebrile seizures, and focal seizures with or without secondary generalization were more frequently observed in afebrile seizures. However, despite these differences both febrile and afebrile seizures associated with mild RVGE were mostly benign with a favorable prognosis.

      Acknowledgment

      This study was supported by INHA UNIVERSITY Research Grant .

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