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Pediatrics International (2015) ••, ••–••
doi: 10.1111/ped.12566
Original Article
Non-convulsive seizures in children with infection-related altered mental status Kyoko Fujita,1 Hiroaki Nagase,1 Taku Nakagawa,2 Yohsuke Saji,3 Azusa Maruyama1 and Yoshiyuki Uetani2 Departments of 1Neurology, 2General Medicine and 3Emergency and Critical Care Medicine, Hyogo Prefectural Kobe Children’s Hospital, Hyogo, Japan Abstract
Background: In the intensive care unit, the use of continuous electroencephalography (cEEG) in children with altered mental status often results in the detection of non-convulsive seizures (NCS). Children with influenza can occasionally display altered mental status, but the prevalence of NCS in children with influenza with altered mental status is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. Methods: We retrospectively reviewed admissions to the pediatric intensive care unit between September 2009 and February 2010 and confirmed the presence of NCS on cEEG in children with influenza A(H1N1)pdm09 and with altered mental status. Results: Of the 15 patients (aged 41−159 months old), NCS was identified on cEEG in five children (33%). Conclusions: Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status had NCS. Further research is needed to determine if the detection and management of NCS improve outcome in these children.
Key words confusion, influenza A virus, H1N1 subtype, intensive care, pediatrics, seizure.
The occurrence of non-convulsive seizures (NCS) in patients in intensive care may be associated with poor prognosis1,2 and neuronal injury.3 Furthermore, the risk of mortality may be associated with the etiology of NCS.1,4 In pediatric patients with altered mental status, NCS frequently occur. The prevalence of NCS in children in intensive care who are comatose or have abnormal mental status has been reported at 46%,5 and we reported that NCS occurred in 29% of children with prolonged altered mental status.6 Patients with influenza can occasionally display altered mental status, convulsions, and abnormal behavior, which are the initial symptoms of acute encephalitis associated with influenza. It has been suggested that altered mental status is the most important symptom.7 It is expected that NCS could occur in children with influenza in the intensive care unit (ICU), but the prevalence of NCS in this setting is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. Correspondence: Hiroaki Nagase, MD PhD, Kobe Children’s Hospital, 1-1-1 Takakuradai, Suma, Kobe, Hyogo 654-0081, Japan. Email: [email protected] This article is a secondary publication based on a study first reported in J. Japan Pediatr. Soc. 2013; 117: 986–91 (in Japanese). Received 13 December 2013; revised 2 December 2014; accepted 10 December 2014.
© 2014 Japan Pediatric Society
Methods This study consisted of a retrospective, observational case series of influenza A(H1N1)pdm09-infected pediatric patients with altered mental status who were admitted to the pediatric ICU (PICU) of Kobe Children’s Hospital in Hyogo, Japan, between September 2009 and February 2010 and who underwent continuous electroencephalography (cEEG). Patients with a history of epilepsy were excluded. We retrospectively collected data on age, sex, neurological symptoms, duration of impaired consciousness, level of consciousness, presence of NCS, medical therapy, and neurological outcome. Influenza A(H1N1)pdm09 infection was diagnosed using reverse transcription–polymerase chain reaction of nasal swab samples. Altered mental status was classified as a score 10 s, must be met Primary criteria 1. Repetitive generalized or focal spikes, sharp waves, spike and wave or sharp and slow wave complexes at >3/s 2. Repetitive generalized or focal spikes, sharp waves, spike and wave or sharp and slow wave complexes at 4‡ 4,3,5 >6‡ 1,1,1 >6‡ 2,4,4 >6‡ 1,1,4 54 1,1,1 >6‡ 4,4,5 >6‡ 1,2,4 14 2,5,6 15 3,4,6 4 8 4,5,6† 3,3,4 9 3,2,4 11 2,2,4 4 4,4,5 12
Convulsion
Abnormal behavior
✓ ✓ ✓ ✓
✓ ✓ ✓ ✓ ✓
✓ ✓
✓ ✓
✓ ✓
NCS
✓ ✓ ✓ ✓ ✓
cEEG duration
88 h 86 h 4h 175 h 20 min 11 h 22 min 35 h 28 min 95 h 38 min 3 h 26 min 14 h 37 min 13 h 55 min 8h 3 h 39 min 13 h 45 min 8 h 12 min 24 h 1 min
‡
Level of consciousness difficult to assess due to intubation and continuous i.v. anticonvulsant drug treatment. †Patient 11 had disturbance of orientation. cEEG, continuous electroencephalography; E, eye opening; GCS, Glasgow Coma Scale; M, motor response; NCS, non-convulsive seizure; V, verbal response.
Discussion To our knowledge, this is the first study to report the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection, resulting in a detection of NCS on cEEG in 33% of the children. These results agree with previous studies using cEEG to detect NCS in children in the intensive care setting, in which 29−46% of the children had NCS.5,6,10,11 The patients in these previous reports were admitted to ICU with epilepsy, central nervous system infections, or hypoxic–ischemic encephalopathy, among other conditions. Therefore, the prevalence of NCS associated with each disease could not be determined. The NCS occurred significantly more often in the present patients who did not experience convulsions than in the patients who did. Anticonvulsants, including diazepam, were frequently used in the present patients with convulsions in the early stage of
treatment and before cEEG, and these therapies might have prevented NCS. In this study, we adopted the criteria for seizures suggested by Young et al.,1 which is frequently used in the ICU12,13 and in the diagnosis of non-convulsive status epilepticus.14 The cEEG patterns of patients 3–5 in the current study included highamplitude, rhythmic delta or theta waves, without spikes and sharp waves. It is possible that these cEEG patterns indicated paroxysmal activity owing to their similarity to the rhythmic theta background in children with epilepsy15 and to non-epileptic EEG changes after febrile convulsion.16 Further study is required to refine the criteria for NCS and to reach a consensus regarding epileptology and treatment in the ICU. Despite reports that NCS may be associated with poor prognosis1,2 and risk of neuronal injury,3 an appropriate treatment strategy has not yet been identified.17 Furthermore, the contribution of specific etiologies to mortality risk is unknown.1,4 Only
Table 3 cEEG patterns in NCS patients Patient
Age (months)
Interval from start cEEG to first NCS (min)
1
58
0
2
119
5
3
98
45
4
93
19
5
115
142
cEEG Persistence Continuous seizures for duration of 95 min Intermittent seizures for duration of 148 min Intermittent seizures for duration of 20 min Intermittent seizures within 10 min 90 IU/L within 6 h of onset),19 treatment included normothermia, mechanical ventilation, and/or i.v. barbiturates, but, due to the small sample size, we could not assess the effect of NCS or treatment on neurological prognosis. This study had several limitations. First, we used four-channel cEEG, while most studies use multichannel standard cEEG.1,3,6,7,13 Therefore, because of the reduced number of cEEG channels, the possibility of false positives and false negatives must be considered. Second, we did not use video-EEG, which may have resulted in incorrect NCS determinations. Third, the small sample size did not allow for examination of relationships between NCS and prognosis. Fourth, it is possible that we could have detected NCS in more patients than in only the present five if we had started cEEG earlier. Some patients may have been at risk of NCS but did not undergo or underwent delayed cEEG. Further research is needed to determine if outcome is improved with the detection and management of NCS in children with infection. Conclusion
Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status presented with NCS, supporting the results from previous studies conducted with pediatric patients in the ICU.
Acknowledgments We thank the PICU pediatricians at Kobe Children’s Hospital who participated in this study. There was no financial support or relationship related to this study.
References 1 Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology 1996; 47: 83–9. 2 Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit. Care Med. 2009; 37: 2051–6. 3 Rabinowicz AL, Correale JD, Bracht KA, Smith TD, DeGiorgio CM. Neuron-specific enolase is increased after nonconvulsive status epilepticus. Epilepsia 1995; 36: 475– 9. 4 Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003; 61: 1066–73. 5 Abend NS, Gutierrez-Colina AM, Topjian AA et al. Nonconvulsive seizures are common in critically ill children. Neurology 2011; 76: 1071–7. 6 Maruyama A, Nagase H. [Continuous electroencephalogram monitoring in a pediatric intensive care unit]. No To Hattatsu 2010; 42: 23–8. 7 Acute encephalitis and encephalopathy associated with influenza research division of the Health and Welfare Ministry. The Guideline for Acute Encephalitis Associated with Influenza Infection, revised edn. Health and Welfare Ministry, Tokyo, Japan, 2009. [Cited 12 November 2014.] Available from URL: http:// www.mhlw.go.jp/kinkyu/kenkou/influenza/hourei/2009/09/dl/ info0925-01.pdf 8 Claassen J, Hirsch LJ, Emerson RG, Bates JE, Thompson TB, Mayer SA. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001; 57: 1036–42. 9 Fiser DH. Assessing the outcome of pediatric intensive care. J. Pediatr. 1992; 121: 68–74. 10 Jette N, Claassen J, Emerson RG, Hirsch LJ. Frequency and predictors of nonconvulsive seizures during continuous electroencephalographic monitoring in critically ill children. Arch. Neurol. 2006; 63: 1750–55. 11 McCoy B, Sharma R, Ochi A et al. Predictors of nonconvulsive seizures among critically ill children. Epilepsia 2011; 52: 1973– 8.
© 2014 Japan Pediatric Society
6
K Fujita et al.
12 Mirski M, Varelas P. Status epilepticus. In: Torbey MT (ed). Neurocritical Care. Cambridge University Press, New York, 2009; 185–98. 13 Brenner RP. Is it status? Epilepsia 2002; 43: 103–13. 14 Herman ST. The electroencephalogram of nonconvulsive status epilepticus. In: Kaplan PW, Drislane FW (eds). Nonconvulsive Status Epilepticus. Demos Medical Publishing, New York, 2009; 41–61. 15 Doose H, Baier WK. Theta rhythms in the EEG: A genetic trait in childhood epilepsy. Brain Dev. 1988; 10: 347–54. 16 Yamamoto N. Prolonged nonepileptic twilight state with convulsive manifestations after febrile convulsions: A clinical and electroencephalographic study. Epilepsia 1996; 37: 31–5.
© 2014 Japan Pediatric Society
17 Walker MC. Principles of treatment of nonconvulsive status epilepticus. In: Kaplan PW, Drislane FW (eds). Nonconvulsive Status Epilepticus. Demos Medical Publishing, New York, 2009; 263–70. 18 van Rooij LG, Toet MC, van Huffelen AC et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: Randomized, controlled trial. Pediatrics 2010; 125: e358–66. 19 Nagase H, Nakagawa T, Aoki K et al. Therapeutic indicators of acute encephalopathy in patients with complex febrile seizures. Pediatr. Int. 2013; 55: 310–14.
Pediatrics International (2015) ••, ••–••
doi: 10.1111/ped.12566
Original Article
Non-convulsive seizures in children with infection-related altered mental status Kyoko Fujita,1 Hiroaki Nagase,1 Taku Nakagawa,2 Yohsuke Saji,3 Azusa Maruyama1 and Yoshiyuki Uetani2 Departments of 1Neurology, 2General Medicine and 3Emergency and Critical Care Medicine, Hyogo Prefectural Kobe Children’s Hospital, Hyogo, Japan Abstract
Background: In the intensive care unit, the use of continuous electroencephalography (cEEG) in children with altered mental status often results in the detection of non-convulsive seizures (NCS). Children with influenza can occasionally display altered mental status, but the prevalence of NCS in children with influenza with altered mental status is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. Methods: We retrospectively reviewed admissions to the pediatric intensive care unit between September 2009 and February 2010 and confirmed the presence of NCS on cEEG in children with influenza A(H1N1)pdm09 and with altered mental status. Results: Of the 15 patients (aged 41−159 months old), NCS was identified on cEEG in five children (33%). Conclusions: Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status had NCS. Further research is needed to determine if the detection and management of NCS improve outcome in these children.
Key words confusion, influenza A virus, H1N1 subtype, intensive care, pediatrics, seizure.
The occurrence of non-convulsive seizures (NCS) in patients in intensive care may be associated with poor prognosis1,2 and neuronal injury.3 Furthermore, the risk of mortality may be associated with the etiology of NCS.1,4 In pediatric patients with altered mental status, NCS frequently occur. The prevalence of NCS in children in intensive care who are comatose or have abnormal mental status has been reported at 46%,5 and we reported that NCS occurred in 29% of children with prolonged altered mental status.6 Patients with influenza can occasionally display altered mental status, convulsions, and abnormal behavior, which are the initial symptoms of acute encephalitis associated with influenza. It has been suggested that altered mental status is the most important symptom.7 It is expected that NCS could occur in children with influenza in the intensive care unit (ICU), but the prevalence of NCS in this setting is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. Correspondence: Hiroaki Nagase, MD PhD, Kobe Children’s Hospital, 1-1-1 Takakuradai, Suma, Kobe, Hyogo 654-0081, Japan. Email: [email protected] This article is a secondary publication based on a study first reported in J. Japan Pediatr. Soc. 2013; 117: 986–91 (in Japanese). Received 13 December 2013; revised 2 December 2014; accepted 10 December 2014.
© 2014 Japan Pediatric Society
Methods This study consisted of a retrospective, observational case series of influenza A(H1N1)pdm09-infected pediatric patients with altered mental status who were admitted to the pediatric ICU (PICU) of Kobe Children’s Hospital in Hyogo, Japan, between September 2009 and February 2010 and who underwent continuous electroencephalography (cEEG). Patients with a history of epilepsy were excluded. We retrospectively collected data on age, sex, neurological symptoms, duration of impaired consciousness, level of consciousness, presence of NCS, medical therapy, and neurological outcome. Influenza A(H1N1)pdm09 infection was diagnosed using reverse transcription–polymerase chain reaction of nasal swab samples. Altered mental status was classified as a score 10 s, must be met Primary criteria 1. Repetitive generalized or focal spikes, sharp waves, spike and wave or sharp and slow wave complexes at >3/s 2. Repetitive generalized or focal spikes, sharp waves, spike and wave or sharp and slow wave complexes at 4‡ 4,3,5 >6‡ 1,1,1 >6‡ 2,4,4 >6‡ 1,1,4 54 1,1,1 >6‡ 4,4,5 >6‡ 1,2,4 14 2,5,6 15 3,4,6 4 8 4,5,6† 3,3,4 9 3,2,4 11 2,2,4 4 4,4,5 12
Convulsion
Abnormal behavior
✓ ✓ ✓ ✓
✓ ✓ ✓ ✓ ✓
✓ ✓
✓ ✓
✓ ✓
NCS
✓ ✓ ✓ ✓ ✓
cEEG duration
88 h 86 h 4h 175 h 20 min 11 h 22 min 35 h 28 min 95 h 38 min 3 h 26 min 14 h 37 min 13 h 55 min 8h 3 h 39 min 13 h 45 min 8 h 12 min 24 h 1 min
‡
Level of consciousness difficult to assess due to intubation and continuous i.v. anticonvulsant drug treatment. †Patient 11 had disturbance of orientation. cEEG, continuous electroencephalography; E, eye opening; GCS, Glasgow Coma Scale; M, motor response; NCS, non-convulsive seizure; V, verbal response.
Discussion To our knowledge, this is the first study to report the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection, resulting in a detection of NCS on cEEG in 33% of the children. These results agree with previous studies using cEEG to detect NCS in children in the intensive care setting, in which 29−46% of the children had NCS.5,6,10,11 The patients in these previous reports were admitted to ICU with epilepsy, central nervous system infections, or hypoxic–ischemic encephalopathy, among other conditions. Therefore, the prevalence of NCS associated with each disease could not be determined. The NCS occurred significantly more often in the present patients who did not experience convulsions than in the patients who did. Anticonvulsants, including diazepam, were frequently used in the present patients with convulsions in the early stage of
treatment and before cEEG, and these therapies might have prevented NCS. In this study, we adopted the criteria for seizures suggested by Young et al.,1 which is frequently used in the ICU12,13 and in the diagnosis of non-convulsive status epilepticus.14 The cEEG patterns of patients 3–5 in the current study included highamplitude, rhythmic delta or theta waves, without spikes and sharp waves. It is possible that these cEEG patterns indicated paroxysmal activity owing to their similarity to the rhythmic theta background in children with epilepsy15 and to non-epileptic EEG changes after febrile convulsion.16 Further study is required to refine the criteria for NCS and to reach a consensus regarding epileptology and treatment in the ICU. Despite reports that NCS may be associated with poor prognosis1,2 and risk of neuronal injury,3 an appropriate treatment strategy has not yet been identified.17 Furthermore, the contribution of specific etiologies to mortality risk is unknown.1,4 Only
Table 3 cEEG patterns in NCS patients Patient
Age (months)
Interval from start cEEG to first NCS (min)
1
58
0
2
119
5
3
98
45
4
93
19
5
115
142
cEEG Persistence Continuous seizures for duration of 95 min Intermittent seizures for duration of 148 min Intermittent seizures for duration of 20 min Intermittent seizures within 10 min 90 IU/L within 6 h of onset),19 treatment included normothermia, mechanical ventilation, and/or i.v. barbiturates, but, due to the small sample size, we could not assess the effect of NCS or treatment on neurological prognosis. This study had several limitations. First, we used four-channel cEEG, while most studies use multichannel standard cEEG.1,3,6,7,13 Therefore, because of the reduced number of cEEG channels, the possibility of false positives and false negatives must be considered. Second, we did not use video-EEG, which may have resulted in incorrect NCS determinations. Third, the small sample size did not allow for examination of relationships between NCS and prognosis. Fourth, it is possible that we could have detected NCS in more patients than in only the present five if we had started cEEG earlier. Some patients may have been at risk of NCS but did not undergo or underwent delayed cEEG. Further research is needed to determine if outcome is improved with the detection and management of NCS in children with infection. Conclusion
Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status presented with NCS, supporting the results from previous studies conducted with pediatric patients in the ICU.
Acknowledgments We thank the PICU pediatricians at Kobe Children’s Hospital who participated in this study. There was no financial support or relationship related to this study.
References 1 Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology 1996; 47: 83–9. 2 Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit. Care Med. 2009; 37: 2051–6. 3 Rabinowicz AL, Correale JD, Bracht KA, Smith TD, DeGiorgio CM. Neuron-specific enolase is increased after nonconvulsive status epilepticus. Epilepsia 1995; 36: 475– 9. 4 Shneker BF, Fountain NB. Assessment of acute morbidity and mortality in nonconvulsive status epilepticus. Neurology 2003; 61: 1066–73. 5 Abend NS, Gutierrez-Colina AM, Topjian AA et al. Nonconvulsive seizures are common in critically ill children. Neurology 2011; 76: 1071–7. 6 Maruyama A, Nagase H. [Continuous electroencephalogram monitoring in a pediatric intensive care unit]. No To Hattatsu 2010; 42: 23–8. 7 Acute encephalitis and encephalopathy associated with influenza research division of the Health and Welfare Ministry. The Guideline for Acute Encephalitis Associated with Influenza Infection, revised edn. Health and Welfare Ministry, Tokyo, Japan, 2009. [Cited 12 November 2014.] Available from URL: http:// www.mhlw.go.jp/kinkyu/kenkou/influenza/hourei/2009/09/dl/ info0925-01.pdf 8 Claassen J, Hirsch LJ, Emerson RG, Bates JE, Thompson TB, Mayer SA. Continuous EEG monitoring and midazolam infusion for refractory nonconvulsive status epilepticus. Neurology 2001; 57: 1036–42. 9 Fiser DH. Assessing the outcome of pediatric intensive care. J. Pediatr. 1992; 121: 68–74. 10 Jette N, Claassen J, Emerson RG, Hirsch LJ. Frequency and predictors of nonconvulsive seizures during continuous electroencephalographic monitoring in critically ill children. Arch. Neurol. 2006; 63: 1750–55. 11 McCoy B, Sharma R, Ochi A et al. Predictors of nonconvulsive seizures among critically ill children. Epilepsia 2011; 52: 1973– 8.
© 2014 Japan Pediatric Society
6
K Fujita et al.
12 Mirski M, Varelas P. Status epilepticus. In: Torbey MT (ed). Neurocritical Care. Cambridge University Press, New York, 2009; 185–98. 13 Brenner RP. Is it status? Epilepsia 2002; 43: 103–13. 14 Herman ST. The electroencephalogram of nonconvulsive status epilepticus. In: Kaplan PW, Drislane FW (eds). Nonconvulsive Status Epilepticus. Demos Medical Publishing, New York, 2009; 41–61. 15 Doose H, Baier WK. Theta rhythms in the EEG: A genetic trait in childhood epilepsy. Brain Dev. 1988; 10: 347–54. 16 Yamamoto N. Prolonged nonepileptic twilight state with convulsive manifestations after febrile convulsions: A clinical and electroencephalographic study. Epilepsia 1996; 37: 31–5.
© 2014 Japan Pediatric Society
17 Walker MC. Principles of treatment of nonconvulsive status epilepticus. In: Kaplan PW, Drislane FW (eds). Nonconvulsive Status Epilepticus. Demos Medical Publishing, New York, 2009; 263–70. 18 van Rooij LG, Toet MC, van Huffelen AC et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: Randomized, controlled trial. Pediatrics 2010; 125: e358–66. 19 Nagase H, Nakagawa T, Aoki K et al. Therapeutic indicators of acute encephalopathy in patients with complex febrile seizures. Pediatr. Int. 2013; 55: 310–14.
