Infantile convulsions with mild gastroenteritis

Brain & Development 22 (2000) 301±306

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Review article

Infantile convulsions with mild gastroenteritis Toshiaki Abe a,*, Masaaki Kobayashi a, Kazuko Araki a, Hiroko Kodama a, Yasuko Fujita a, Tatsuhiko Shinozaki a, Hiroshi Ushijima b a

Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan b Department of Developmental Medicine, Postgraduate University of Tokyo, Tokyo, Japan Received 26 April 1999; revised 12 July 1999; accepted 15 July 1999

Abstract The development of sensitive new molecular genetic techniques has led to the detection of rotavirus in cerebrospinal ¯uid, stools and throat swabs from patients with gastroenteritis with accompanying clinical symptoms similar to infantile benign convulsions. Small round structured virus (SRSV) has also been found in stools of patients with similar clinical symptoms by a new procedure. However, the mechanism by which these viral infections induce benign convulsions remains to be elucidated. The present paper reviews recent virological and clinical studies of seizures probably caused by gastroenteritis viruses including rotavirus, SRSV and other viruses. q 2000 Published by Elsevier Science B.V. All rights reserved. Keywords: Convulsion; Mild gastroenteritis; Rotavirus; Small round structured virus; Encephalitis; Virus toxin

1. Introduction Fukuyama ®rst described benign infantile convulsions in 1965 [1]. The disease was characterized by: (1) occurrence in infants less than 2 years old, with no family history of epilepsy, no past history of neurological diseases and with normal psychomotor development, (2) an unknown etiology, (3) a seizure type of mostly generalized tonic clonic convulsions, (4) a normal pattern on electroencephalogram, and (5) a benign prognosis. The differences between this disease and diseases such as infantile convulsions with mild gastroenteritis, benign infantile partial epilepsy, and autosomal dominant hereditary benign infantile convulsions have been discussed, but have not been fully elucidated. Recent molecular genetic procedures have facilitated the detection of viral genomes in brain tissue or CSF from patients with viral encephalitis. These methods can detect extremely small amounts of virus in infected tissues and help in the determination of the etiology of some infectious diseases [2]. The many viruses which are known to cause gastroenteritis are shown in Table 1. These viruses include human herpes viruses (HHV)-6 and -7 which cause exanthema subitum in infants [3] and enteroviruses. Recently we found infants infected with a small round struc* Corresponding author. Fax: 181-353-750124. E-mail address: [email protected] (T. Abe).

tured virus (SRSV) called Norwalk-like virus (NW), who also had clustered convulsions, similar to infants infected by rotavirus. Infants less than 2 years of age frequently have gastroenteritis that may be caused by a variety of viruses or bacteria. Rotavirus accounts for the vast majority (83%) of viral gastroenteritis, but adenovirus (8.2%) and SRSV (5.8%) are also common. Astrovirus, classical calicivirus [4], HHV-6, which causes exanthema subitum, and enteroviruses may also be causative agents in a small number of patients. Neurological symptoms such as seizures, unconsciousness and paresis in diarrheic children may be due to several mechanisms. Viruses or fragments of virus may breach the blood-brain barrier to cause encephalitis-encephalopathy or meningitis [5±7]. Alternatively, abnormal electrolyte balance and dehydration due to severe loss of electrolytes and water in stools or vomitus during the clinical course of the disease may induce symptoms [8]. Thirdly, febrile seizure may occur because diarrheic infants frequently show high fever and infants less than 2 years old have a high susceptibility to febrile seizures [9]. In addition, since the development and growth of the central nervous system is so rapid at this age, infants may be more susceptible to seizure from relatively mild stimuli [10]. In the case of seizures probably caused by diarrheic viruses, patients usually have no severe abnormal electrolyte balance and some cases have insuf®cient fever to cause febrile seizure

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T. Abe et al. / Brain & Development 22 (2000) 301±306

Table 1 Viruses which cause gastroenteritis

Table 3 Number of cases with neurological involvement in rotavirus gastroenteritis a

Reoviridae Rotavirus Adenoviridae Caliciviridae Small round structured virus Classical calicivirus Astroviridae Astrovirus Breda virus Enterovirus Poliovirus Coxsackie A, B virus Echo virus Herpes viridae Cytomegalovirus Human herpes virus type 6,7 In¯uenza virus Respiratory syncytial virus Hepatitis A

Clinical diagnosis Benign infantile convulsion Reye syndrome Flaccid paralysis Muscle weakness Meningeal sign Neurotic sequel Total number of neurological patients Rotavirus-positive cases Incidence (%) a

[11], which suggests the third mechanism may be the most likely. The present article describes in detail the characteristics of benign infantile convulsions with mild gastroenteritis caused by rotavirus and SRSV infection.

2. Rotavirus infection Human rotaviruses are the most common agents of sporadic episodes of gastroenteritis in infants and young children in both Japan and the rest of the world. The peak incidence occurs at 6±24 months of age and rotavirus infections account for 35±50% of hospitalizations for infantile gastroenteritis [12]. The incidence of rotavirus gastroenteritis in infants and children under 3 years of age in Japan was recently estimated to be over 600,000 cases per year (in 1988, based on recalculated data from the National Epidemiological Surveillance of Infections and Diseases in Japan [11]).

Tokyo

Taichung

31 1 3

2 1

New Delhi 6

35

3 3

3 2 1 12

1200 2.6

57 5.3

226 5.3

Total 39 2 3 3 2 1 50

Adapted from Ref. [11].

The major clinical symptoms of rotavirus infection differ between outpatients and inpatients (Table 2) [13,14]. The frequencies of dehydration, irritability and vomiting observed are higher in inpatients than in outpatients, implying that the clinical symptoms of inpatients are more severe than those of outpatients. Patients with associated neurological symptoms tend to show more severe systemic symptoms, and practically all such cases will be admitted to the pediatric ward. Patients with rotavirus infection show more frequent vomiting, rash and dehydration than those with non-rotavirus gastroenteritis. Effective replacement of ¯uids and electrolytes limits these clinical symptoms and gastroenteritis is not a prominent cause of mortality in infants and young children in Japan and Western countries. However, the disease is responsible for many deaths in developing countries, even when oral replacement solutions (ORS) are used [12]. This is usually because ORS supplies are not suf®cient for the number of dehydrated infants or because health care workers do not know how to use the ORS correctly. Data from several reports between 1981 and 1989 suggest that seizures occur in 2.6% of Japanese patients with rotavirus infection (Table 3), which is lower than the incidence in China or India. About 18,000 infants suffer from rotavirus gastroenteritis with neurological involvement every year in Japan.

Table 2 Clinical characteristics of patients with acute diarrhea Outpatients

Number of patients Vomiting (%) a Fever (%) Upper respiratory infection (%) Rash (%) Dehydration (%) Irritability (%) a

Inpatients

Rotavirus infection-positive

Rotavirus infection-negative

Rotavirus infection-positive

Rotavirus infection-negative

89 85 57 48 41 n.d. n.d.

283 59 52 57 11 n.d. n.d.

72 96 77 49 n.d. 83 47

78 58 61 32 n.d. 40 40

Percentage of patients with each clinical ®nding, recalculated from data in Refs. [13,14]. n.d., not determined.

T. Abe et al. / Brain & Development 22 (2000) 301±306

These patients showed seizure, unconsciousness and paresis together with the symptoms described above, and were variously diagnosed as encephalitis, encephalopathy, Reye or Reye-like syndrome, acute necrotizing encephalitis, ¯accid paralysis, meningitis, and febrile or afebrile seizure [15±19]. Among these diseases, cases with clinical features similar to benign infantile convulsions are most frequently seen in the pediatric clinic [20±22]. Patients show no family or past history of neurological disease, are 1 year 6 months old on average and the incidence is equivalent between boys and girls. Clinical signs at the ®rst visit to the outpatient clinic are mild to moderate dehydration, vomiting, yellow to white diarrhea and seizure. The seizure is symmetrical, generalized, tonic and clonic, and patients may sometimes have staring and unconsciousness. Seizures may occur in clusters, each lasting for several minutes. The blood chemistry ®ndings show slightly decreased sodium and chloride concentrations, normal levels of transaminases, lactic dehydrogenase, creatine phosphokinase activities and urea nitrogen. Patients show no increase of cells or protein in CSF, no epileptic discharge in interictal EEG records, and no abnormal imaging ®ndings, such as brain abscess, intracranial bleeding or severe brain edema. Various tissues from patients were assayed for the presence of viral genomes by a modi®ed reverse transcription±polymerase chain reaction (RT±PCR) method of Nishimura et al. [23] (Table 4). Serotype 1 was found in CSF, stool, urine and throat swab from all cases except one using RT±PCR or enzyme linked immunosorbent assay (EIA). RNA sequencing revealed that the viruses isolated from both stool and CSF had the same amino acid sequence in the VP7, structural protein region [24]. This result suggests that the same virus species simultaneously infected intestine and CNS, or that the viruses infecting the intestine moved from the original infectious focus to the CNS. In either case, rotaviral-induced encephalitis or meningitis may be the major cause of the seizures.

Table 4 Detection of rotavirus by RT±PCR in CSF from patients with gastroenteritis and convulsions a Case

Age (years)

Sex

CSF

Serum

Stool

EIA of stool

1 2 3 4 5 6 7 8 9 10 11 12

1 3 1 1 1 1 10 months 1 1 2 1 1

F M F F M M M M F F M F

1 1 ± 1 1 1 1 1 1 4 1 1

1 1 n.d. ± ± ± n.d. ± n.d. n.d. n.d. n.d.

n.d. n.d. n.d. 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1

a

1, Serotype 1; n.d., not determined.

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3. Small round structured virus SRSV are a major cause of nonbacterial acute gastroenteritis [25±27]. Recently we found ®ve patients with SRSV gastroenteritis accompanied by similar clinical symptoms to infantile benign convulsions[28]. We analyzed stool samples stored at 2808C from patients with acute gastroenteritis accompanied by seizure in the Tokyo area from October 1995 to March 1998 for diarrheic viruses such as rotavirus, SRSV, astrovirus and adenovirus using EIA, electron microscopy observation and RT±PCR. Seventeen specimens from 14 patients were free of adenovirus, astrovirus and rotavirus. These specimens were examined for SRSV by RT±PCR as described previously [29]. Two primer pairs, CAL1/CAL4 and CAL2b/CAL3, were used for the outer PCR and the nested PCR, respectively. Eleven specimens from eight patients were positive for SRSV, while the specimens from the other six patients were negative. The SRSV-positive fecal specimens from six patients were analyzed directly by electron microscopy and ®ve were also con®rmed to contain SRSV. The clinical manifestations of these cases were as follows. The ®ve SRSV-positive patients were previously healthy without any history of convulsions. Their history was of uneventful pregnancy and delivery, and they had not experienced any seizures until the present event. The clinical features of the ®ve cases are summarized in Table 5. The initial sign in most patients was abrupt vomiting, which continued for a few days. One patient had a seizure 1 day before vomiting, but others had seizures during or after vomiting. All cases had no family or past history of neurological diseases. Their seizures were generalized tonic and clonic with or without unconsciousness and continued for 1±10 min in a cluster of 2±14 events. The blood cell counts and serum chemistry including serum electrolytes were normal in all patients. Two patients showed mild dehydration that was not suf®ciently severe to cause convulsions. The other three patients were not dehydrated. Two patients had a transient high fever during their illness. One patient had convulsions with high fever. The average number of clustered convulsions was four in each case (range: 1±12). The convulsions were generalized tonic clonic or tonic convulsions, and were mostly of short duration (less than 3 min). In cases 2 and 5, convulsions frequently occurred even after administration of anticonvulsants, including diazepam and phenobarbital, and convulsions ceased within 4 and 10 min in case 2 and within 5 min in case 5. The cell count, glucose and protein levels in the CSF were normal. EEG ®ndings showed high-voltage slow activities in ictal records, but no epileptic discharges were seen in post-ictal EEG records. No abnormal imagings such as intracranial bleeding or malformation were observed on CT or MRI. The brain CT scan suggested slight edema in one case. All patients were admitted to the pediatric ward and treated with rest, ¯uids, anticonvulsants such as phenobarbital and diazepam which were ineffective, and antibiotics if neces-

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Table 5 Clinical features of patients with SRSV infection a

Sex Age (months) Fever at onset of seizure (8C) Vomiting Gastroenteritis Unconsciousness Seizures Type Duration (min) Frequency EEG ®ndings Imaging CSF Sequels Virus genomes in stool a

Case 1

Case 2

Case 3

Case 4

Case 5

F 14 37.1 11 1 1

F 21 38.2 11 11 1

F 16 36.8 2 11 1

F 26 36.8 11 1 1

F 24 36.8 11 1 1

gtcc 2±3 2 n n n 2 1

gtcc, gtc 1±10 14 Slow n n 2 1

gtcc 2±3 3 n n n 2 1

gtc 1±2 5 Slow n n 2 1

gtcc 2±5 5 n n n 2 1

n, Normal; gtcc, generalized tonic clonic convulsion; gtc, generalized tonic convulsion. Modi®ed from Ref. [28].

sary. All recovered completely without neurological sequelae in the following few years. 4. Discussion Encephalitis, a common severe disease in children, which may result in permanent neurological dysfunction, was generally thought to be caused by neurotrophic viruses, such as togaviruses, herpes viruses and conventional viruses. However, new molecular genetic methods have identi®ed non-neurotrophic viruses as the etiologic agent in some cases of encephalitis [2]. These viruses include rotavirus, human herpes virus types 6 and 7, and enteroviruses, which cause infantile gastroenteritis, exanthema subitum and gastroenteritis, respectively. Recently, the gastroenterotrophic SRSV has been added to the group of non-neurotrophic encephalitic viruses by our group. SRSV may cause neurological involvement such as clustered seizures in the clinical course of infantile gastroenteritis in some Japanese infants [28], but this generally occurs at a low frequency. Rotavirus infection which does not lead to severe gastroenteritis may still show neurological involvement such as benign convulsions, Reye syndrome and acute necrotizing encephalitis in Japanese, Chinese and Indian children. Severe gastroenteritis causes an abnormal concentration of electrolytes in body ¯uid and dehydration probably induces seizures in these cases. However, viral gastroenteritis usually only causes mild symptoms, very different from severe bacterial gastroenteritis such as dysentery [30]. We detected rotaviral genomic RNA in stools of patients infected by rotavirus with and without neurological involvement, but rotavirus was only detected in CSF in patients with neurological symptoms, consistent with other reports [31,32]. The sequence of the VP7 structural gene was the same in isolates from the CSF and stools [24].

If rotavirus can invade neural tissue, it must have some neurotrophism. Several studies have shown that rotavirus has some af®nity for brain cells. Virus particles or the VP7 virus protein were detected in experimental animals inoculated with rotavirus. However, it has been dif®cult to induce experimental encephalitis or meningitis in animals, which reproduces the high fever, seizures and unconsciousness seen in patients [33±35]. Bacteria are frequently transmitted in food, and patients show clinical signs such as nausea and vomiting within a few hours of eating. The time lag between ingestion and onset of clinical signs in taking bacteria is usually too short for bacteria to multiply and injure tissues. Small amounts of toxin may be produced in the early stage of bacterial infection, which can cause these clinical signs [36]. If the same applies for SRSV infection, the time lag may be enough to cause clinical signs; however, the idea remains to be elucidated. The clinical manifestations of exanthema subitum include fever, rash, upper respiratory infection, gastroenteritis and febrile seizures. Recently Ishiguro et al. reported that HHV-6 and HHV-7 genomes and antigens were frequently detected in patients with exanthema subitum who showed a convulsive seizure, bulging fontanel, encephalitis or encephalopathy [37]. Furthermore, at autopsy of a patient infected with concomitant exanthema subitum and varicella zoster virus infection, HHV-6 was detected in vessels of the frontal area of the brain [38]. Drobyski et al. also found HHV-6 virus in the brain tissue taken from a necropsy case of fatal HHV-6 encephalitis [39]. These results suggest that HHV-6 may be able to invade the CNS of infected infants to cause neurological involvement. Exanthema subitum or roseola infantum is a common benign disease caused by infection with HHV-6 or HHV7, and is characterized by high fever, rash, upper respiratory symptoms and a bulging fontanel, with accompanying convulsions and gastroenteritis. As the patients show

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moderately high fever, it is dif®cult to differentiate the seizures due to HHV-6 or HHV-7 infection of the CNS from febrile convulsions, which is a common benign disease in children. Symptoms of mild gastroenteritis such as loose stools or constipation due to malfunction of gut can be found in almost all HHV-6 and HHV-7 infected patients under careful examination. More than 95% of cases occur in infants between 6 months and 3 years of age and approximately 30% of all children develop the apparent disease, but in the majority of infants it occurs as either an inapparent infection or an afebrile illness without rash. The disease occurs all the year round, with a concentration of cases in the spring and autumn months. Infantile benign convulsions with mild gastroenteritis occurring in the spring and autumn seasons when rotavirus and SRSV infection are seldom seen may therefore be caused by HHV-6 infection. Enteroviruses, such as adenoviruses, Coxsackie and echo viruses, are well known to induce infections of the bowel and CNS, which may lead to meningitis and encephalitis [40,41]. Coxsackie B, echo 30 and entero 71 virus in particular may be neurotrophic and are etiologic agents of encephalitis and meningitis in children. Infections with these viruses are epidemic in the summer season in Japan. The virus can be isolated from either stool or both stool and CSF from patients with CNS involvement. As already discussed, those viruses infect and proliferate in upper respiratory tissues leading to viremia, seeding in brain tissue, and encephalitis. Some cases show clinical symptoms similar to benign infantile convulsions in the summer season. These diseases are treated by high titer immunoglobulin, since only a few antiviral drugs are currently available. Patients are mainly given medication for the relief of symptoms such as seizures, unconsciousness and fever. The restriction of ¯uids for patients with CNS infection is controversial [42]. The administration of steroids, which regulate the immune and chemokine system of the CNS [43], is effective in some of these patients, but may worsen the symptoms of other cases. The better approach is prophylaxis, and we await an effective vaccine for agents such as rotavirus, SRSV, HHV-6 or HHV-7. Acknowledgements We would like to express our thanks to Dr Fukuyama, Professor emeritus of Tokyo Women's Medical College, for suggesting and encouraging us to write the article. This study was supported in part by Health Sciences Research Grants from the Ministry of Health and Welfare, and Education, Science and Culture, Japan. References [1] Fukuyama Y. Borderland of childhood epilepsy-special reference to febrile convulsions and so-called infantile convulsions. Seishin Igaku 1963;5:211±223 [in Japanese].

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