Clinical characteristics and follow‐up of children with norovirus‐associated benign convulsions with mild gastroenteritis

Abstract

Objective

Explore the clinical characteristics and prognosis of children with norovirus (NoV)‐associated benign convulsions with mild gastroenteritis (CwG).

Methods

We retrospectively analyzed the Clinical and laboratory data of children with NoV‐associated CwG admitted to the emergency department of Guangzhou Children's Hospital between January 2019 and January 2020. And patients were followed up for 23–36 months.

Results

There are 49 cases met the CwG criteria. Vomiting was the first symptom in 31 (63.3%) patients, and vomiting could be the main or the only gastrointestinal symptom. The mean frequency of seizures was 3.8 ± 2.4 episodes. Most patients (95.9%) experienced seizures that lasted for less than 5 min. Of the 43 (87.8%) cases followed up from 23 to 36 months, only one experienced recurrent convulsions (after rotavirus infection).

Significance

NoV‐associated CwG patients were prone to experiencing more convulsions. However, because most NoV‐associated CwG patients had good prognosis, long‐term use of anticonvulsants are unnecessary.

Key Points.

• The incidence of CwG caused by NoV is relatively higher than other viruses.

• NoV‐associated CwG patients were prone to experiencing more convulsions.

• Most NoV‐associated CwG patients had good prognosis; long‐term use of anticonvulsants are unnecessary.

1. INTRODUCTION

Morooka and colleagues first reported mild gastroenteritis in infants and young children with benign convulsions in 1982 in Japan. ¹ Norovirus (NoV) has replaced rotavirus as the leading cause of acute viral gastroenteritis in humans worldwide after launching a rotavirus vaccine. ² , ³ , ⁴ Infantile convulsions with mild gastroenteritis (CwG) have been documented since 2000, and in addition to rotaviruses, small round‐structured viruses (including NoVs) have similarly been found in the stools of patients with infantile benign convulsions. ⁵ NoV can cause global epidemics, and the incidence of NoV infections and outbreaks has been gradually increasing throughout the year. The characteristics of repeated seizures in NoV‐associated CwG cases have attracted the attention of nurses and caused panic among parents, especially in community hospitals. Furthermore, CwG is often misdiagnosed as complex febrile convulsions, epilepsy, viral encephalitis, or toxic encephalopathy, which can hinder appropriate clinical treatment and lead to overtreatment. However, there are few studies on CwG related to NoV gastroenteritis, ⁶ , ⁷ especially follow‐up study, the clinical data of children with NoV‐associated CwG are limited.

Thus, our research aimed to summarize and analyze the clinical characteristics and prognosis of pediatric patients with NoV‐associated CwG from the south of the Chinese Mainland, to better understand NoV‐associated CwG and guide clinical management.

2. PATIENTS AND METHODS

2.1. Participants

This retrospective study assessed 132 patients with NoV‐positive stool samples who were admitted to the emergency department (ED) of Guangzhou Children's Hospital from January 2019 to January 2020. Finally, 49 children who met the CwG criteria were included, and their general data, clinical features, laboratory tests, and follow‐up outcomes were analyzed.

The inclusion criteria were based on previous studies ⁸ : (a) previously healthy infants aged 6 months to 3 year of age; (b) mild gastroenteritis with convulsions, no or mild dehydration, and no obvious acid–base balance and electrolyte disorder; (c) no or low fever (body temperature <38.0°C) during convulsions; (d) no epileptiform discharge on the interparoxysmal electroencephalogram, no obvious abnormality in the skull on computerized tomography (CT)/magnetic resonance imaging (MRI), and normal blood glucose, blood calcium, blood magnesium, and cerebrospinal fluid levels; and (e) stool samples positive for NoV by real‐time reverse transcription‐polymerase chain reaction (RT‐PCR). In contrast, the exclusion criteria were as follows: (a) intracranial infection, encephalopathy, or cerebral trauma related to the convulsions; (b) mental or neurologic defects; and (c) intestinal bacterial infection (such as a positive stool culture).

Fever during convulsions was defined as a fever occurring within 30 min before and after convulsions; for patients with multiple convulsions during the illness, we chose the longest convulsion time as the duration of a single convulsion. All patients underwent a follow‐up after at least 23 months to assess the recurrence of convulsions and prognosis through telephone inquiries.

2.2. Methods

The clinical data and related laboratory test data of the enrolled children were retrospectively analyzed. Feces samples were tested for NoV by RT‐PCR using Detection Kit for Norovirus RNA (PCR‐fluorescent probe method) (manufacturer: Guangdong Huayin Medicine Science Co., Ltd.). Enzyme immunoassay was used to detect rotavirus and adenovirus. The follow‐up was conducted by telephone, and detailed questions were asked about the presence, form, and duration of recurrence, as well as disease development.

2.3. Statistical analyses

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 21.0 (IBM corp.). Continuous variables (age, duration of seizures, interval from onset of gastrointestinal symptoms to seizures, and the number of seizures) are expressed as mean ± standard deviation (SD), and categorical variables are expressed as n (%).

3. RESULTS

3.1. General information

In total, 132 cases were tested NoV‐positive in the stool RT‐PCR test, and 49 cases met the CwG criteria. There were 27 males (55.1%) and 22 females (44.9%) with a mean age of 20.8 ± 5.8 months. The season of symptom onset was autumn or winter in over 90% of the cases.

3.2. Clinical characteristics

Vomiting was the first symptom in 31 cases (63.3%) and diarrhea in eight cases (16.3%); one patient developed a seizure before the gastrointestinal symptoms. In total, 44 (89.8%) patients experienced vomiting; 10 (20.4%) experienced vomiting as the only gastrointestinal symptom, and 34 (69.4%) experienced vomiting and diarrhea. Patients experienced vomiting 1–6 times per day and diarrhea approximately 3–15 times per day, mainly as watery stools, with different amounts each time. Diarrhea was resolved within 7 days in 45 cases (91.8%). During the disease course, 24 (49.0%) patients experienced fever; among them, 21 patients (87.5%) developed a temperature less than 38°C, and four patients developed a low fever during convulsions. Two cases (4.1%) had a family history of febrile seizure, and none had a family history of epilepsy.

Convulsions occurred after gastrointestinal symptoms in 48 (98.0%) cases. The intervals between gastrointestinal symptoms and convulsions were as follows: three patients experienced convulsions on day 1 of gastrointestinal symptoms, 13 patients on day 2, 26 patients on day 3, six patients on day 4, one patient on day 5, and one patient experienced convulsions before the gastrointestinal symptoms appeared. Overall, 39 (79.6%) patients experienced convulsions between days 2 and 3. The time interval from gastrointestinal symptoms to seizures was 2.77 ± 0.82 days. Cluster convulsions lasted for 1 day in 31 cases (65.3%), 2 days in 15 cases (30.6%), 3 days in one case (2.0%), and 4 days in one case (2.0%). Forty‐six (93.9%) patients experienced convulsions that lasted for 1–2 days, and the average time elapsed between the first and the last seizure was 1.4 ± 0.65 days. Relevant data on seizures in patients with NoV‐associated gastroenteritis are shown in Table 1.

TABLE 1.

Clinical data of children with seizures associated with NoV gastroenteritis.

Cases	n (%)
No. of patients	49
Male/Female	27 (55.1)/22 (44.9)
Age, mo, Mean ± SD	20.8 ± 5.8
Symptoms at onset
Vomiting	31 (63.3)
Diarrhea	8 (16.3)
Vomiting and Diarrhea	9 (18.4)
Convulsions	1 (2.0)
Family history of febrile convulsions	2 (4.1)
Seizure pattern
Generalized tonic–clonic	36 (73.0)
Generalized tonic	12 (25.0)
Focal seizure	1 (2.0)
Time from onset of gastrointestinal tract symptoms to seizure, d, Mean ± SD	2.77 ± 0.82
Average time from the first to the last seizure, days, Mean ± SD	1.4 ± 0.65
No. of patients with ≥2 seizures	42 (85.7)
Seizure frequency, Mean ± SD	3.84 ± 2.42
Duration of convulsions
<5 min	47 (95.9)
5–10 min	1 (2.0)
11–15 min	1 (2.0)

Drug therapy (a/b)	a (%)
Midazolam (2/7)	2 (28.6)
Phenobarbital (3/5)	3 (60)
Midazolam, Phenobarbital successively (3/8)	3 (37.5)
Midazolam, phenobarbital, chloralhydrate successively (1/1)	1 (100.0)
Midazolam, then chloralhydrate (0/1)	1 (0)
Follow‐up
No. of patients who completed the follow‐up	43 (89.6)
Recurrent convulsion	1 (2.3)
No convulsions	42 (97.7)
Normal psychomotor development	43 (100)

Note: a denotes the number of patients that do not recur after using the drug. b denotes the total patients number who were treated by the drug. a (%) denotes number of recured patients and the effective rate (%).

Forty‐two (85.7%) patients experienced two or more convulsive episodes of seizures (30 patients had 2–4 episodes, nine had 5–7 episodes, and three had more than 10 episodes). The mean number of episodes was 3.8 ± 2.4.

Generalized seizures was observed in 48 cases (36 cases with generalized tonic–clonic seizures and 12 cases with generalized tonic seizures), and one patient developed focal non‐motor seizures wherein unusual staring behavior and loss of awareness were demonstrated. The duration of each convulsion was <5 min in 95.9% of the cases (<2 min in 35 cases), 5–10 min in one case, and 11–15 min in one case.

3.3. Laboratory test results

None of the patients showed significant abnormalities in blood gas electrolytes or acid–base balance disorders. Fecal rotavirus and adenovirus examinations were performed in 32 patients (65.3%), and none of them tested positive.

Nineteen patients (38.8%) underwent an electroencephalogram examination, and only one case showed an abnormal result (because of increased slow waves on the background, which became normal in a later reexamination). Thirteen patients underwent a cerebrospinal fluid examination, all of whom showed normal results. Twenty‐eight patients (57.1%) underwent an MRI examination, and five patients (10.2%) underwent CT examination. Notably, all the results were normal.

3.4. Treatment and follow‐up

After admission, 22 patients (44.9%) received one or more antiseizure medications (mainly midazolam, phenobarbital sodium, and chloral hydrate). Seven patients received intramuscular or intravenous injection of midazolam; two patients (28.6%) did not experience a seizure again. Five patients were treated with phenobarbital; seizures were terminated in three (60.0%) of them. Eight patients received midazolam initially, subsequently, they were administered phenobarbital; three patients did not experience seizures again. One patient experienced convulsions after receiving midazolam and phenobarbital; no more convulsions occurred after being administered chloral hydrate. In addition, one patient still experienced seizures after receiving midazolam and chloral hydrate. It should be noted that after the use of antiseizure medication, some patients had seizure again, but many of them did not receive antiseizure drugs again because of the short duration of convulsion, and fortunately they had no seizures again.

The follow‐up period ranged from 23 to 36 months. Of the 43 (87.8%) children who completed the follow‐up, only one (2.3%) experienced recurrent convulsions (due to gastroenteritis following rotavirus infection). The psychomotor development were normal in all 43 of the 49 children, including the patient in whom recurrent convulsions were observed.

4. DISCUSSION

Since the implementation of rotavirus vaccines, there has been an increasing number of patients with NoV‐associated CwG. ⁹ , ¹⁰ , ¹¹ Previous studies have shown that the incidence of NoV‐associated CwG and non‐NoV‐associated CwG was 20.9% and 3.98%, respectively (P < 0.001). ¹² Kang et al. showed that the incidence of rotavirus combined with CwG was 7.8% (59/755 patients). ¹³ Here, consistent with previous studies, we found an incidence of NoV‐associated CwG in the ED of 37.1% (49/132), which is relatively higher than that of those infected with other viruses. It suggests that children infected with NoV might be more prone to convulsions.

Regarding the pathogenesis of CwG, previous studies ¹⁴ have shown that rotavirus can disrupt calcium homeostasis by releasing the viral enterotoxin Nsp4 or directly invade the central nervous system, leading to CwG. In addition, other studies ¹⁵ found that when rotavirus enters the cerebrospinal fluid, these reactions may lead to neurotoxicity and neurotransmitter disorders, which directly cause seizures. However, up to now, there are few researches on the mechanism of NoV‐associated CwG. Some studies ¹⁴ , ¹⁶ have shown that genetic susceptibility plays an important role in the pathogenesis of CwG, and studies have found that some children with CwG have a family history of convulsions, as well as siblings or monozygotic twins with the disease. In this study, only two patients had a family history of febrile convulsions, and none had a family history of epilepsy, which may be due to the small sample size.

The study found that the peak seasons of NoV‐associated CwG were autumn and winter; the age of onset of infection was 20.8 ± 5.8 months, and vomiting was the most prominent symptom, which is similar to the results of previous studies. ¹¹ In this study, 63.3% of cases had vomiting as the first symptom, and vomiting was the only gastrointestinal symptom in 20.4% of cases. This indicates that vomiting is the main gastrointestinal manifestation of NoV‐associated CwG, and diarrhea may not occur in NoV‐infected children. In addition, one of our patients demonstrated that seizures could occur before the onset of gastrointestinal symptoms, and this should be considered during diagnosis.

In our study, 85.7% of patients had ≥2 seizures during the illness and a mean frequency of seizures of 3.84 ± 2.42 episodes, higher than that previously reported in rotavirus‐associated CwG (2.15 ± 1.16). ¹¹ The higher frequency might be caused by the retrospective nature of the studies or differences in treatment protocols. It might also result from the different virus species. Based on these results, prevention after the first convulsion may be needed to reduce the incidence of subsequent convulsions, which requires further investigation. In this study, seven patients received midazolam alone (two patients responded, 28.6%), five patients were administered phenobarbital alone (three patients responded, 60%), and eight patients were treated with midazolam and phenobarbital (seizures terminated in three patients, 37.5%). The results suggest that antiseizure medications (midazolam and phenobarbital) had poor effects in stopping the seizures of NoV‐related CwG. However, our data showed 46 (93.9%) patients experienced convulsions that lasted for only 1–2 days. So the patients may not require more antiseizure medications when 2 days after the first seizure. Seizures caused by NoV‐associated CwG may have the tendency of spontaneous remission.

The telephone follow‐up from 23 to 36 months was completed by 43 out of 49 (87.8%) children, lost contact with six patients. All patients showed good growth and development, and none developed epilepsy. Therefore, this suggests that CwG has a good prognosis, and long‐term anticonvulsants are unnecessary, as Kang Bwere et al put forward. ¹⁷ Only one case (2.3%) reported seizure recurrence due to rotavirus enteritis during the follow‐up. Compared with the recurrence rate of rotavirus‐associated CwG (8.0%) in our previous study, ⁸ the recurrence rate of NoV‐associated CwG is low. The virus type associated with CwG may be a risk factor for CwG recurrence; nevertheless, further research with larger sample size and long‐term follow‐up is needed.

5. CONCLUSIONS

In conclusion, this study reported that NoV‐associated CwG has specific characteristics. Most notably, vomiting may be the main or the only gastrointestinal symptom for many patients. Patients with NoV‐associated CwG had a relatively high seizure frequency. However, the recurrence rate of NoV‐associated CwG was low, and patients' prognoses were good, long‐term use of anticonvulsants are unnecessary.

AUTHOR CONTRIBUTIONS

KS designed this study and wrote the article. DJ and YL collected the clinical data and completed the follow‐up. JY made statistics on the data. WC and PL reviewed the article.

FUNDING INFORMATION

This research received no specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.

CONFLICT OF INTEREST STATEMENT

The authors declare that there is no conflict of interest.

ETHICS STATEMENT

This study complied with the relevant requirements of the Declaration of Helsinki of the World Medical Association. This study was approved by the Ethics Committee of Guangzhou Children's Hospital (Approval Number: [2022] 294A01). We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Shi K, Jiang D, Yang J, Li Y, Chen W, Li P. Clinical characteristics and follow‐up of children with norovirus‐associated benign convulsions with mild gastroenteritis. Epilepsia Open. 2023;8:1049–1053. 10.1002/epi4.12782