e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e8
Official Journal of the European Paediatric Neurology Society
Original article
Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection Kyung Yeon Lee a, Ki Won Oh a, Young Cheol Weon b,*, Seong Hoon Choi b a
Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea b Department of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
article info
abstract
Article history:
Background and aims: Some full-term neonates presenting seizures show diffusion-
Received 3 September 2013
restricted lesions in the cerebral white matter on brain diffusion-weighted imaging
Received in revised form
(DWI). The purpose of this study was to describe the clinical characteristics and DWI
17 February 2014
findings in a group of neonates with seizures, white matter lesions on DWI, and a high
Accepted 6 April 2014
incidence of rotavirus infection. Methods: Total 30 full-term neonates with seizures were admitted between 2008 and 2010.
Keywords:
Of these, 13 (group A) had the following characteristics on brain DWI: (1) diffusion-
Neonate
restricted lesions in the diffuse symmetric cerebral white matter, including the corpus
Seizure
callosum, and (2) no cerebral cortical lesions. The remaining 17 patients (group B) did not
Diffusion magnetic resonance im-
exhibit the DWI findings. The clinical characteristics were compared between the 2 groups.
aging
Results: The 1-min and 5-min Apgar scores ranged between 7 and 10 in all group A patients,
Rotavirus
whereas the scores were more diverse in the group B patients. Patients’ age at seizure onset was 4.6 0.6 days (range, 4e6 days) in group A and 8.3 7.4 days (range, 1e27 days) in group B. Twelve of 13 patients (92.3%) in group A tested positive for stool rotavirus antigen, while only 2 of 12 (16.7%) in group B tested positive (p < 0.001). Six of 10 group A patients showed normal neurodevelopment, but 4 had delayed development between 6 and 30 months. Conclusions: Rotavirus infection should be considered in neonates with seizures accompanied by diffuse cerebral white matter lesions on DWI, particularly around 5 days of life. ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Radiology, Ulsan University Hospital, 290-3 Jeonha-Dong, Dong-Gu, Ulsan 682-714, Republic of Korea. Tel.: þ82 52 250 8235; fax: þ82 52 252 5160. E-mail address: [email protected] (Y.C. Weon). http://dx.doi.org/10.1016/j.ejpn.2014.04.005 1090-3798/ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee KY, et al., Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection, European Journal of Paediatric Neurology (2014), http:// dx.doi.org/10.1016/j.ejpn.2014.04.005
2
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e8
Introduction
Seizures are one of the most frequent and distinctive clinical manifestations of central nervous system (CNS) dysfunction in neonates. The causes of neonatal seizures are diverse; they include hypoxic-ischaemic encephalopathy, intracranial haemorrhage, intracranial infection, metabolic disorders, and developmental defects.1,2 Although it is not common, some viral infections, such as herpes simplex virus, cytomegalovirus, varicella-zoster virus, enterovirus, human parechovirus, and rotavirus can cause neonatal seizures.1,3e6 Rotavirus is a major causative agent of acute gastroenteritis in infants and young children worldwide. Previously, rotavirus infection was thought to be confined to the small intestine. However, recent studies have demonstrated that rotavirus also causes diverse CNS complications such as benign convulsions with gastroenteritis, encephalopathy/encephalitis and cerebellitis.7e9 Furthermore, it has been reported that the rotavirus RNA and antigen are detected in the cerebrospinal fluid (CSF), as well as in the serum of children presenting with CNS manifestations accompanied by rotavirus gastroenteritis.10e17 Recently, among the neonates who were admitted to our hospital, full-term neonates who presented with seizures around 4e6 days of age and showed diffuse, symmetric diffusion-restricted lesions in the white matter of the bilateral cerebral hemispheres, including the corpus callosum on diffusion-weighted imaging (DWI) revealed a high incidence of rotavirus infection than what the others did. Here, we describe the clinical characteristics, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) findings, including DWI, and short-term neurodevelopmental outcome in this particular group of neonates.
2.
Materials and methods
2.1.
Patients
We retrospectively reviewed the records, EEG and brain MRI findings of 33 consecutive full-term neonates who were admitted to the neonatal intensive care unit and paediatrics department at Ulsan University Hospital because of seizures between January 2008 and October 2010. The patients included in our study were defined as full-term neonates who showed apparent focal clonic or multi-focal clonic limb movements at least 3 times that sustained for more than 30 s and were witnessed by physicians or nurses in our hospital and managed with anti-convulsive medications, such as phenobarbital and phenytoin. Three full-term neonates whose seizures were not obvious and who did not need anticonvulsive treatment were excluded from this study. In all 30 full-term neonates included in this study, MRI, including DWI, was performed. Among them, the 13 patients who showed the following characteristic DWI features on brain MRI were categorised into group A: (1) diffuse, symmetric diffusion-restricted lesions in the white matter of the bilateral cerebral hemispheres, including the corpus callosum and (2) no demonstrable cerebral cortical lesions or haemorrhages in
the brain parenchyma or CSF spaces. The remaining 17 patients were categorised into group B. Clinical and laboratory characteristics were compared between the 2 groups. This study was approved by the institutional review board of our hospital.
2.2.
MRI techniques
MRI was performed on either a 3.0eT system (Intera Achieva; Philips, Best, the Netherlands) or a 1.5eT system (Achieva; Philips) using an 8-channel sensitivity-encoding head coil or a 16-channel SENSE neurovascular head coil. The protocol included T1-weighted images, T2-weighted images, fluidattenuated inversion recovery images, and diffusionweighted images with apparent diffusion coefficient maps.
2.3.
Follow-up brain MRI
All patients who had abnormalities on the initial brain MRI were recommended to undergo a follow-up brain MRI, including DWI, at 1e3 months of age. If the follow-up brain MRI was not obtained at that time, then a follow-up MRI was recommended at 6 months of age.
2.4.
Laboratory studies
CSF was obtained from all 13 patients in group A and 10 of the 17 patients in group B, and white and red blood cell counts, protein and glucose levels, and bacterial cultures were analysed. A stool rotavirus antigen test was performed in all 13 patients from group A and in 12 of the 17 patients from group B on the day of admission. A chromatographic immunoassay kit (Bioland Co., Ltd., Cheungwon-Gun, Korea) was used for the rapid qualitative detection of group A rotavirus antigen. According to the clinical report of its evaluation by the Korean Food and Drug Administration, the Bioland NanoSign Rota assay resulted in 96.0% sensitivity in 204 rotavirus-positive samples and 98.0% specificity in 200 rotavirus-negative samples, and the results exhibited 98.5% correlation with the results determined by reverse transcription-polymerase chain reaction.
2.5.
Electroencephalography
All patients were examined using digital EEG. Nine electrodes were placed on the frontal, central, temporal, occipital, and vertex regions according to the international 10-20 system modified for neonates. When a follow-up EEG was conducted approximately 1 month after the seizures, the electrodes were used in the same location. In cases in which a follow-up EEG was conducted beyond 2 months after the seizures, it was recorded according to the international 10e20 system of electrode placement. The duration of the EEG recordings was approximately 30 min in each patient.
2.6.
Evaluation of short-term outcome
A paediatric neurologist interviewed the parents of the patients over telephone and confirmed the presence of seizure
Please cite this article in press as: Lee KY, et al., Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection, European Journal of Paediatric Neurology (2014), http:// dx.doi.org/10.1016/j.ejpn.2014.04.005
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e8
recurrence, visual and hearing problems, motor delay, speech delay, cognitive problems, or other health problems.
2.7.
Statistical analysis
The Statistical Package for Social Science, version 19.0, software package (IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. A Fisher’s exact test was used to compare the sex and the results of the rotavirus antigen test between the 2 groups. A ManneWhitney U test was used to compare gestational age, birth weight, and seizure onset age. P-values less than 0.05 were considered significant.
3.
Results
3.1.
Clinical and laboratory characteristics
Table 1 shows the differences in the clinical characteristics between groups A and B. Male dominance (M:F ¼ 10:3) was observed in group A. In addition, all 13 group A patients had developed seizures between 4 and 6 days of life (4.6 0.6 days), whereas 17 group B patients had developed seizures between 1 and 27 days (7.9 7.5 days) and 6 group B patients had developed seizures between 4 and 6 days of life (p < 0.001). A stool rotavirus antigen test was performed in all 13 group A patients and in 12 of the 17 group B patients. Twelve of the 13 patients (92.3%) in group A and 2 of the 12 (16.7%) in group B tested positive for the stool rotavirus antigen (p < 0.001). In group A, 4 neonates had hypocalcaemia (total calcium < 7.0 mg/dL and ionised calcium < 1.0 mmol/L) and 1 had hypernatraemia (156 mEq/ L). In group B, hypoxic-ischaemic encephalopathy was present in 4 patients, bacterial meningitis in 2, hypocalcaemia in 2, hypoglycaemia in 1, and benign familial neonatal seizures were present in 1 patient. In 8 neonates from group A and 7 from group B, no other critical abnormalities related to seizures were observed. Table 2 presents the characteristics of the group A patients in more detail. The annual incidence was 4e5 neonates per year with a seasonal distribution of 5 in the spring, 2 in the summer, 2 in the autumn, and 4 in the winter. The 1-min and 5-min Apgar scores ranged between 7 and 10 in
Table 1 e Comparison of the clinical characteristics between the 2 groups of neonates according to brain diffusion-weighted MRI findings. Group A (n ¼ 13) Gestational age (weeks) Birth weight (kg) Sex (male:female) Age at seizure onset (days) Seizure onset between 4 and 6 days of life Positive stool rotavirus antigen test
Group B (n ¼ 17)
p-Value
38.2 0.7 3.0 0.3 10:3 4.6 0.6 (4e6) 13 (100%)
38.7 1.1 3.3 0.4 8:9 7.9 7.5 (1e27) 6 (35.3%)
0.169 0.059 0.141 0.481
12/13 (92.3%)
2/12 (16.7%)
Official Journal of the European Paediatric Neurology Society
Original article
Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection Kyung Yeon Lee a, Ki Won Oh a, Young Cheol Weon b,*, Seong Hoon Choi b a
Department of Pediatrics, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea b Department of Radiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
article info
abstract
Article history:
Background and aims: Some full-term neonates presenting seizures show diffusion-
Received 3 September 2013
restricted lesions in the cerebral white matter on brain diffusion-weighted imaging
Received in revised form
(DWI). The purpose of this study was to describe the clinical characteristics and DWI
17 February 2014
findings in a group of neonates with seizures, white matter lesions on DWI, and a high
Accepted 6 April 2014
incidence of rotavirus infection. Methods: Total 30 full-term neonates with seizures were admitted between 2008 and 2010.
Keywords:
Of these, 13 (group A) had the following characteristics on brain DWI: (1) diffusion-
Neonate
restricted lesions in the diffuse symmetric cerebral white matter, including the corpus
Seizure
callosum, and (2) no cerebral cortical lesions. The remaining 17 patients (group B) did not
Diffusion magnetic resonance im-
exhibit the DWI findings. The clinical characteristics were compared between the 2 groups.
aging
Results: The 1-min and 5-min Apgar scores ranged between 7 and 10 in all group A patients,
Rotavirus
whereas the scores were more diverse in the group B patients. Patients’ age at seizure onset was 4.6 0.6 days (range, 4e6 days) in group A and 8.3 7.4 days (range, 1e27 days) in group B. Twelve of 13 patients (92.3%) in group A tested positive for stool rotavirus antigen, while only 2 of 12 (16.7%) in group B tested positive (p < 0.001). Six of 10 group A patients showed normal neurodevelopment, but 4 had delayed development between 6 and 30 months. Conclusions: Rotavirus infection should be considered in neonates with seizures accompanied by diffuse cerebral white matter lesions on DWI, particularly around 5 days of life. ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Radiology, Ulsan University Hospital, 290-3 Jeonha-Dong, Dong-Gu, Ulsan 682-714, Republic of Korea. Tel.: þ82 52 250 8235; fax: þ82 52 252 5160. E-mail address: [email protected] (Y.C. Weon). http://dx.doi.org/10.1016/j.ejpn.2014.04.005 1090-3798/ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee KY, et al., Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection, European Journal of Paediatric Neurology (2014), http:// dx.doi.org/10.1016/j.ejpn.2014.04.005
2
1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e8
Introduction
Seizures are one of the most frequent and distinctive clinical manifestations of central nervous system (CNS) dysfunction in neonates. The causes of neonatal seizures are diverse; they include hypoxic-ischaemic encephalopathy, intracranial haemorrhage, intracranial infection, metabolic disorders, and developmental defects.1,2 Although it is not common, some viral infections, such as herpes simplex virus, cytomegalovirus, varicella-zoster virus, enterovirus, human parechovirus, and rotavirus can cause neonatal seizures.1,3e6 Rotavirus is a major causative agent of acute gastroenteritis in infants and young children worldwide. Previously, rotavirus infection was thought to be confined to the small intestine. However, recent studies have demonstrated that rotavirus also causes diverse CNS complications such as benign convulsions with gastroenteritis, encephalopathy/encephalitis and cerebellitis.7e9 Furthermore, it has been reported that the rotavirus RNA and antigen are detected in the cerebrospinal fluid (CSF), as well as in the serum of children presenting with CNS manifestations accompanied by rotavirus gastroenteritis.10e17 Recently, among the neonates who were admitted to our hospital, full-term neonates who presented with seizures around 4e6 days of age and showed diffuse, symmetric diffusion-restricted lesions in the white matter of the bilateral cerebral hemispheres, including the corpus callosum on diffusion-weighted imaging (DWI) revealed a high incidence of rotavirus infection than what the others did. Here, we describe the clinical characteristics, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) findings, including DWI, and short-term neurodevelopmental outcome in this particular group of neonates.
2.
Materials and methods
2.1.
Patients
We retrospectively reviewed the records, EEG and brain MRI findings of 33 consecutive full-term neonates who were admitted to the neonatal intensive care unit and paediatrics department at Ulsan University Hospital because of seizures between January 2008 and October 2010. The patients included in our study were defined as full-term neonates who showed apparent focal clonic or multi-focal clonic limb movements at least 3 times that sustained for more than 30 s and were witnessed by physicians or nurses in our hospital and managed with anti-convulsive medications, such as phenobarbital and phenytoin. Three full-term neonates whose seizures were not obvious and who did not need anticonvulsive treatment were excluded from this study. In all 30 full-term neonates included in this study, MRI, including DWI, was performed. Among them, the 13 patients who showed the following characteristic DWI features on brain MRI were categorised into group A: (1) diffuse, symmetric diffusion-restricted lesions in the white matter of the bilateral cerebral hemispheres, including the corpus callosum and (2) no demonstrable cerebral cortical lesions or haemorrhages in
the brain parenchyma or CSF spaces. The remaining 17 patients were categorised into group B. Clinical and laboratory characteristics were compared between the 2 groups. This study was approved by the institutional review board of our hospital.
2.2.
MRI techniques
MRI was performed on either a 3.0eT system (Intera Achieva; Philips, Best, the Netherlands) or a 1.5eT system (Achieva; Philips) using an 8-channel sensitivity-encoding head coil or a 16-channel SENSE neurovascular head coil. The protocol included T1-weighted images, T2-weighted images, fluidattenuated inversion recovery images, and diffusionweighted images with apparent diffusion coefficient maps.
2.3.
Follow-up brain MRI
All patients who had abnormalities on the initial brain MRI were recommended to undergo a follow-up brain MRI, including DWI, at 1e3 months of age. If the follow-up brain MRI was not obtained at that time, then a follow-up MRI was recommended at 6 months of age.
2.4.
Laboratory studies
CSF was obtained from all 13 patients in group A and 10 of the 17 patients in group B, and white and red blood cell counts, protein and glucose levels, and bacterial cultures were analysed. A stool rotavirus antigen test was performed in all 13 patients from group A and in 12 of the 17 patients from group B on the day of admission. A chromatographic immunoassay kit (Bioland Co., Ltd., Cheungwon-Gun, Korea) was used for the rapid qualitative detection of group A rotavirus antigen. According to the clinical report of its evaluation by the Korean Food and Drug Administration, the Bioland NanoSign Rota assay resulted in 96.0% sensitivity in 204 rotavirus-positive samples and 98.0% specificity in 200 rotavirus-negative samples, and the results exhibited 98.5% correlation with the results determined by reverse transcription-polymerase chain reaction.
2.5.
Electroencephalography
All patients were examined using digital EEG. Nine electrodes were placed on the frontal, central, temporal, occipital, and vertex regions according to the international 10-20 system modified for neonates. When a follow-up EEG was conducted approximately 1 month after the seizures, the electrodes were used in the same location. In cases in which a follow-up EEG was conducted beyond 2 months after the seizures, it was recorded according to the international 10e20 system of electrode placement. The duration of the EEG recordings was approximately 30 min in each patient.
2.6.
Evaluation of short-term outcome
A paediatric neurologist interviewed the parents of the patients over telephone and confirmed the presence of seizure
Please cite this article in press as: Lee KY, et al., Neonatal seizures accompanied by diffuse cerebral white matter lesions on diffusion-weighted imaging are associated with rotavirus infection, European Journal of Paediatric Neurology (2014), http:// dx.doi.org/10.1016/j.ejpn.2014.04.005
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y x x x ( 2 0 1 4 ) 1 e8
recurrence, visual and hearing problems, motor delay, speech delay, cognitive problems, or other health problems.
2.7.
Statistical analysis
The Statistical Package for Social Science, version 19.0, software package (IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. A Fisher’s exact test was used to compare the sex and the results of the rotavirus antigen test between the 2 groups. A ManneWhitney U test was used to compare gestational age, birth weight, and seizure onset age. P-values less than 0.05 were considered significant.
3.
Results
3.1.
Clinical and laboratory characteristics
Table 1 shows the differences in the clinical characteristics between groups A and B. Male dominance (M:F ¼ 10:3) was observed in group A. In addition, all 13 group A patients had developed seizures between 4 and 6 days of life (4.6 0.6 days), whereas 17 group B patients had developed seizures between 1 and 27 days (7.9 7.5 days) and 6 group B patients had developed seizures between 4 and 6 days of life (p < 0.001). A stool rotavirus antigen test was performed in all 13 group A patients and in 12 of the 17 group B patients. Twelve of the 13 patients (92.3%) in group A and 2 of the 12 (16.7%) in group B tested positive for the stool rotavirus antigen (p < 0.001). In group A, 4 neonates had hypocalcaemia (total calcium < 7.0 mg/dL and ionised calcium < 1.0 mmol/L) and 1 had hypernatraemia (156 mEq/ L). In group B, hypoxic-ischaemic encephalopathy was present in 4 patients, bacterial meningitis in 2, hypocalcaemia in 2, hypoglycaemia in 1, and benign familial neonatal seizures were present in 1 patient. In 8 neonates from group A and 7 from group B, no other critical abnormalities related to seizures were observed. Table 2 presents the characteristics of the group A patients in more detail. The annual incidence was 4e5 neonates per year with a seasonal distribution of 5 in the spring, 2 in the summer, 2 in the autumn, and 4 in the winter. The 1-min and 5-min Apgar scores ranged between 7 and 10 in
Table 1 e Comparison of the clinical characteristics between the 2 groups of neonates according to brain diffusion-weighted MRI findings. Group A (n ¼ 13) Gestational age (weeks) Birth weight (kg) Sex (male:female) Age at seizure onset (days) Seizure onset between 4 and 6 days of life Positive stool rotavirus antigen test
Group B (n ¼ 17)
p-Value
38.2 0.7 3.0 0.3 10:3 4.6 0.6 (4e6) 13 (100%)
38.7 1.1 3.3 0.4 8:9 7.9 7.5 (1e27) 6 (35.3%)
0.169 0.059 0.141 0.481
12/13 (92.3%)
2/12 (16.7%)
