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Analysis of status epilepticus related presumed encephalitis in children
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 32 – 37
Official Journal of the European Paediatric Neurology Society
Original article
Analysis of status epilepticus related presumed encephalitis in children Jainn-Jim Lina,b, Kuang-Lin Lina,, Huei-Shyong Wanga, Shao-Hsuan Hsiab, Chang-Teng Wub a Division of Pediatric Neurology, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, #5 Fu-Shin Street, Kwei-Shan, Taoyuan 333, Taiwan b Divisions of Pediatric Critical Care and Emergency Medicine, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
ar t ic l e i n f o
abs tra ct
Article history:
Objective: Encephalitis is an acute infection of brain parenchyma characterized clinically
Received 5 February 2007
by fever, headache, and an altered level of consciousness. There may also be focal or
Received in revised form
multifocal neurologic deficits, and focal or generalized seizure activity. Here we report an
18 April 2007
analysis of status epilepticus (SE) related presumed encephalitis in a series of children.
Accepted 14 May 2007
Methods: We retrospectively reviewed cases of SE related presumed encephalitis treated in the pediatric intensive care unit, between February 2002 and June 2006. Factors evaluated
Keywords:
included age, sex, clinical symptoms, seizure type, presence of SE or refractory status
Presumed encephalitis
epilepticus (RSE), initial electroencephalogram (EEG) finding, neuroimaging study, cere-
Status epilepticus
brospinal fluid (CSF) and outcome.
Results: There were 46 patients (19 girls and 27 boys), aged 8 months to 16 years. Twenty (43.4%) of 46 children developed RSE. The major clinical symptoms included fever (100%), upper respiratory symptoms (56.5%) and altered level of consciousness (45.6%). The initial seizure type was categorized as focal (23.9%), generalized (34.8%), primary focal and secondary generalized (41.3%). Initial EEG revealed a focal (30.8%), or multifocal (19.2%) epileptiform discharge in the SE group and a focal (5%), or multifocal (70%) or generalized (25%) epileptiform discharge in the RSE group. The time of follow-up for this study was 6 months to 51 months. In the SE group, 4 died, 16 developed epilepsy and/or neurologic deficits, and 6 returned to baseline. In the RSE group, 6 died, 13 developed epilepsy and/or neurologic deficits, and none returned to baseline. All survivors were discharged on antiepileptic medications.
Conclusions: Our data indicated that children of SE related presumed encephalitis had a high mortality and morbidity. Outcome was related to multifocal or generalized abnormalities of the initial EEG and presence of RSE. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +886 3 3281200x8200; fax: +886 3 3288957.
E-mail address: [email protected] (K.-L. Lin). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.05.007
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
1.
Introduction
Acute viral encephalitis most commonly affects children and young adults. Most viral infections of the central nervous system (CNS) either involve the meninges, leading to aseptic meningitis, or cause mild meningoencephalitis rather than encephalitis. The prognosis of viral encephalitis in pediatric patients is usually excellent. Although the outcome can range from complete recovery to severe neurologic sequelae and death, most children recover without significant residua and require only brief hospitalization. However viral encephalitis remains a significant source of neurologic morbidity and mortality worldwide. Although some previous studies report predictive factors of neurologic outcome in children with encephalitis,1–5 little information is available in the literature about the outcome of status epilepticus (SE) related presumed encephalitis in children. Here, we report an analysis of SE related presumed encephalitis in a series of children.
2.
Methods
Presumed encephalitis was defined as having symptoms of an acute febrile illness prior to, or at the time of, the onset of SE,6,7 and no positive findings in cerebral spinal fluid (CSF) culture. All children were previous healthy and none had prior seizures including febrile seizure. Any child with a family history of epilepsy or febrile seizure, a prior neurologic insult, progressive neurologic disorder, electrolyte imbalance and hypoglycemia was excluded. SE was defined as continuous seizure activity lasting 30 min or as two or more discrete seizures between which consciousness was not fully regained.8,9 RSE was defined as seizures lasting 42 h, despite treatment with conventional antiepileptic drugs including initial therapy with a benzodiazepine (BZD), followed by therapeutic dosage of both phenytoin (PHT) and phenobarbital (PB).8,10 The goal of treatment was to achieve complete clinical seizure control or burstsuppression (BS) pattern on electroencephalogram (EEG), aiming for an interburst interval of 45 s.11 BS coma was induced by high-dose suppressive therapy consisting of midazolam (MDL), lidocaine, propofol, thiopental, citosol or high-dose PB. Weaning of the high-dose suppressive therapy was guided by EEG monitoring. The weaning process was aborted if there was return of SE or frequent clinical or electrographic seizures. All children were cared for in the pediatric intensive care unit in Chang Gung Children’s Hospital. EEG in SE group was performed within 24 h. However, in the RSE group, 24 h EEG monitor was performed immediately. All EEGs were interpreted by pediatric neurologist. From February 2002 to August 2006, 46 children with presumed encephalitis complicated with SE were enrolled. Information was collected by retrospective chart review regarding: age, sex, etiology, initial seizure type, presence of SE or RSE, initial EEG, neuroimaging, CSF analysis and outcome. The diagnosis of initially seizure types was based upon clinical impression by attending neurologists. The initial EEGs were categorized as having either negative, or a
1 2 (20 08) 32 – 3 7
33
focal/diffuse cortical dysfunction, or a focal, or multifocal or generalized epileptiform discharge. The cortical dysfunction was defined as slow waves in EEG. Patient outcome including mortality, a new neurologic deficit, or return to baseline was determined from last clinic visit, which was a minimum of 6 months after the episode of SE. The neurological deficits were categorized as seizure, neurological outcome and cognition outcome. The neurological outcome was according to the Glasgow outcome scale classification. GOS ¼ 1 (good recovery) was capacity to resume normal occupational and social activities, although there may be minor physical or mental deficits or symptoms. GOS ¼ 2 (moderate disability) was independent and can resume almost all activities of daily living. Disabled to the extent that they cannot participate in a variety of social and work activities. GOS ¼ 3 (severe disability) was no longer capable of engaging in most previous personal, social or work activities. Limited communication skills and have abnormal behavioral or emotional responses. Typically are partially or totally dependent on assistance from others in daily living. GOS ¼ 4 (persistent vegetative state) was not aware of surroundings or purposely responsive to stimuli. The cognition outcomes were classified as normal, learning disability, mild mental retardation (MR) and other MR. Normal indicates that a child had an intelligence quotient of more than 70 without learning disabilities. Learning disability was defined as significant difficulties in the acquisition and use of certain skills such as listening, speaking, reading, writing, reasoning or mathematical abilities in individuals with normal intelligence. Mild MR was defined as intelligence quotient scores of between 55 and 80 and moderate MR was defined as intelligence quotient scores of less than 55. The time of follow-up for the study group was 6 months to 51 months.
3.
Data analysis
Clinical and laboratory factors obtained upon admission were analyzed as possible predictors of neurologic outcome, defined at last clinic visit, which was a minimum of 6 months after the episode of SE. These factors included age, seizure pattern, presence of SE or RSE, EEG finding, Neuroimaging study, CSF leukocyte and protein measurement. The association between each of these variables and neurologic outcome was examined. Statistical analysis was performed using the SPSS (10.0) statistical software. The relationships between parameters were analyzed using Pearson product moment correlation. Statistical significance was set at po0.05.
4.
Results
Forty-six children with presumed encephalitis complicated with SE were enrolled. The age at presentation of the children ranged from 8 months to 16 years. There were 19 (41%) girls and 27 (59%) boys. Twenty (43.4%) of 46 children developed RSE. The clinical symptoms included fever (46/46, 100%), upper respiratory symptoms (26/46, 56.5%), altered level of consciousness (21/46, 45.6%), vomiting (20/46, 43.4%),
ARTICLE IN PRESS 34
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
headache (13/46, 28.2%), behavioral disturbances (2/46, 4.3%). The initial seizure type was categorized as focal (11/46, 23.9%), generalized (16/46, 34.8%), primary focal and secondary generalized (19/46, 41.3%). The clinical characteristics and initial seizure pattern of all 46 children are summarized in Tables 1 and 2. All patients underwent a thorough investigation during their hospitalization, including serologic tests for viruses, polymerase chain reaction (PCR) in CSF for herpes simplex virus (HSV) DNA (n ¼ 14) and virus culture of throat (n ¼ 34), CSF (n ¼ 33), and rectal (n ¼ 28) specimens. Most children underwent serologic tests for HSV (n ¼ 31), epstein-barr virus (EBV) (n ¼ 28), mycoplasma pneumoniae (n ¼ 27), human herpesvirus 6 (HHV-6) (n ¼ 4) and varicella-zoster virus (VZV) (n ¼ 1). Positive result for serologic tests or/and virus culture was noted in 18 patients. In all other cases, no organism was identified. Positive IgM result of serologic tests was VZV 1 (100%), mycoplasma pneumonia 7 (25.9%), and HSV 3 (9.6%). The result of virus culture was throat 10 (29%), rectal 4 (14.2%) and CSF 0 (0%). Positive result for serologic tests or/and virus culture in 18 patients is shown in Table 3. Lumbar puncture was performed in 33 patients. White blood cell (WBC) count in the CSF studies ranged from 0 to 109 cells/uL. There was a predominance of monocytes (60–100%). The glucose level in the CSF ranged from 48 to 128 mg/dL and protein level was 16.6–179.5 mg/dL. Neuroimaging studies of brain computed tomography (CT) or magnetic resonance imaging (MRI) were divided into acute phase (o1 weeks after disease onset), non-acute phase (1 weeks to 3 month after disease onset) and follow-up neuroimages (43 month after disease onset). The first brain CT (n ¼ 30) or MRI (n ¼ 8) performed during acute phase was no specific including increased letomeningeal enhancement or brain swelling, whereas the non-acute MRI (n ¼ 15)
Table 1 – Clinical symptoms of 46 children with presumed encephalitis Fever
46/46 (100%)
Upper respiratory tract infection Altered level of consciousness Vomiting Headache Behavioral disturbances
26/46 21/46 20/46 13/46 2/46
(56.5%) (45.6%) (43.4%) (28.2%) (4.3%)
Table 2 – The initial seizure patterns of 46 children with presumed encephalitis
Focal (n ¼ 9, 19.5%) Generalized (n ¼ 33, 71.7%) Primary focal and secondary generalized (n ¼ 4, 8.7%)
SE (n ¼ 26)
RSE (n ¼ 20)
4 21 1
5 12 3
SE, status epilepticus; RSE, refractory status epilepticus.
12 (2008) 32 – 37
Table 3 – Positive result of serologic test and/or virus culture in 18 patients Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Serologic test
Virus culture
Mycoplasma IgM EV (rectal) HSV-1 (throat) EV (throat, rectal)
HSV IgM Mycoplasma IgM
Influenza A (throat) VZV IgM HSV IgM
Mycoplasma Mycoplasma Mycoplasma Mycoplasma
HSV-1 (throat) EV (throat, rectal) EV (throat, rectal) EV (throat) Influenza A (throat) IgM IgM IgM IgM
HSV-1 (throat) Adenovirus (throat)
Mycoplasma IgM
Mycoplasma, mycoplasma pneumoniae; HSV, herpes simplex virus; EBV, epstein-barr virus; VZV, varicella-zoster virus, EV, enterovirus.
Table 4 – The initial EEG pattern in 46 children with presumed encephalitis EEG pattern
SE (n ¼ 26)
Negative Focal/diffuse cortical dysfunction Epileptiform discharge Focal Multifocal Generalized
4 (15.4%) 9 (34.6%)
8 (30.8%) 5 (19.2%)
RSE (n ¼ 20)
1 (5%) 14 (70%) 5 (25%)
revealed mild atrophy in 1 patients. Three patients had unilateral or bilateral hippocampal hyperintensity in T2 suggestive of focal edema, 5 had multiple focal hyperintensity in T2 suggestive of encephalitis or acute disseminated encephalomyelitis (ADEM), 2 had global hypoxic ischemic encephalopathy and 4 had no specific finding. A follow-up brain CT was performed for seven patients and brain atrophy was found in all seven patients. In the SE group, initial EEG was revealed to be negative in 4 (15.4%), focal/diffuse cortical dysfunction in 9 (34.6%), and a focal epileptiform discharge in 8 (30.8%), or multifocal in 5 (19.2%). In the RSE group, initial EEG revealed a focal in 1 (5%), or multifocal in 14 (70%) or generalized epileptiform discharge in 5 (25%) (Table 4). In RSE group, the duration from seizure onset to complete clinical seizure control or appearance of BS pattern on EEG was ranged from 1 to 20 days (mean7SD ¼ 6.6575.60). If the duration was less than 3 days, there was less cognition delay
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at follow-up (p ¼ 0.041). If the duration was less than 5 days, there was less seizure at follow-up (p ¼ 0.037). However, there was no correlation between GOS and the duration of clinical seizure control or appearance of BS (p ¼ 0.842). Sixteen patients received BS coma. The duration of first cycle BS coma was ranged from 2 to 4 days. However, nine patients continued with seizures following the first cycle of BS. The total duration of BS coma was ranged from 2 to 9 days (mean7SD ¼ 5.172.2 days). The correlation of duration of BS and GOS, cognition and seizure at follow-up were not significant. Outcome of the 46 children, 10 (21.7%) died and 36 was survival (78.2%). All survivors were discharged on antiepileptic medications. Thirty-five children followed-up with the minimum duration of 6 months. In the SE group of 26 children, 4 died, 16 developed epilepsy and/or neurologic deficits, and 6 returned to baseline. Of the 20 children in the RSE group, 1 transferred to another hospital, 6 died, 13 developed epilepsy and/or neurologic deficits, and none returned to baseline. The severities of neurological sequence in RSE group were more severe than SE group. Subsequent neurological outcomes are summarized in Table 5. The correlations of demographic data and subsequent neurologic outcome are summarized in Table 6.
5.
Discussion
The gold standard of diagnosis in encephalitis is virus isolation in cell culture, now to be replaced by the detection Table 5 – Subsequent neurological outcome in 45 children with presumed encephalitis
Mortality Epilepsy and/or neurologic deficits Seizure at follow-up Well control by %2 kind AEDs Well control by 42 kind AEDs Poor control Neurological outcome (GOS score) 1 (Good recovery) 2 (Moderate disability) 3 (Severe disability) 4 (Vegetative status) Cognition at follow-up Normal Learning disability Mild MR Moderate MR Return to baseline
Status epilepticus (n ¼ 26)
Refractory status epilepticus (n ¼ 19)a
4 (15.4%) 16 (61.5%)
6 (31.6%) 13 (68.4%)
13
3
0
6
1
4
14 0 2 0
4 2 5 2
12 2 0 2 6 (23.1%)
0 4 3 6 0
AED: antiepileptic drug; GOS: Glasgow outcome score; MR: mental retardation. a In the refractory status epilepticus group, one patient was transferred to another hospital.
35
1 2 (20 08) 32 – 3 7
Table 6 – Correlation of demographic data and neurological outcome Variable Age (n ¼ 46) o1 y/o 1–5 y/o 5–10 y/o 410 y/o Seizure pattern (n ¼ 46) Focal GTC Focal/GTC Seizure duration (n ¼ 46) SE RSE Cerebrospinal fluid WBC (n ¼ 29) 0–10 10–100 4100 Total protein (n ¼ 29) 0–30 30–100 4100 Neuroimagea CT (n ¼ 30) No specific finding MRI (n ¼ 8) No specific finding Initial EEG (n ¼ 46) Multifocal and generalized discharge Other
Number
p-value 0.421
2 15 19 10 0.77 9 33 4 0.027 26 20 0.863 18 9 2 0.086 13 11 5 NP 30 8 0.011 24 22
GTC: generalized tonic clonic; Focal/GTC: primary focal and secondary generalized; SE: status epilepticus; RSE: refractory status epilepticus: CT: computed tomography; MRI: magnetic resonance imaging; EEG: electroencephalogram. p-value: statistical significance; po 0.05. a Neuroimage in acute stage.
of specific nucleic acid from CSF or brain. Intrathecal antibody production to a specific virus is similarly a strong evidence for etiology. However, virus detection from throat, stool, urine or blood as well as systemic serological responses like seroconversion or a specific IgM provides less strong evidence.12 Therefore, in our study, we defined presumed encephalitis as having symptoms of an acute febrile illness prior to, or at the time of, the onset of SE,6,7 and no positive findings in CSF culture. Although some patients had positive culture and some had brain MRIs that fitted ADEM, but no cases had direct evidence from positive CSF culture or brain biopsy to support pathogen. We were thus categorized these cases as presumed encephalitis. Incidence of encephalitis complicated with SE in children is about 3.8–13.7%.13–15 However, there was frequently no defined viral etiology in a majority of the cases. Presumed encephalitis is a group of patients frequently encountered in a pediatric intensive care unit. They had a history of acute febrile illness, and suddenly developed SE.6,7 The courses were fulminant and catatrophic. Maytal et al. report 15 (7.8%) of the 193 SE children have a history of CNS infection. Seven
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E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
(46.7%) of 15 children present status epilepticus 41 h.13 In our study, 46 children with presumed encephalitis complicated with SE are enrolled. Twenty (43.4%) of 46 children develop RSE. So SE related presumed encephalitis etiology has a higher rate to develop RSE. All of our patients had either continuous EEG monitoring or routine EEG recordings. The neurologic outcome among patients with multifocal or generalized epileptiform discharge on the initial EEG are poorer than others (p ¼ 0.011). The existence of more than one epileptic focus owing to encephalitis is not surprising and probably plays a part in the severity of the epileptic process. Previous studies show multifocal or generalized abnormalities on initial EEG had higher mortality6 and poor neurologic outcome.16 Besides, EEG abnormality at 1 h predicts seizure recurrence within 24-h.17 Our data demonstrates that multifocal or generalized epileptiform discharges on the initial EEG are the factors associated with a worse neurologic outcome. In RSE group, the duration from seizure onset to complete clinical seizure control or appearance of BS pattern on EEG was correlated with morbidity. In our study, if the duration was less than 3 days, there was less cognition delay at followup (p ¼ 0.041). If the duration was less than 5 days, there was less seizure at follow-up (p ¼ 0.037). Therefore, prolonged uncontrolled seizure may cause permanent neurologic damage in encephalitis. However, the duration of BS pattern on EEG was not correlation with morbidity included GOS, cognition and seizure at follow-up. Aggressive treatment to achieve complete clinical seizure control or appearance of BS pattern on EEG was emphasized. It is not unexpected that there is higher morbidity in the survivors of RSE than in SE. In our RSE group, all survivors develop epilepsy and/or neurologic deficits, and none return to baseline. Besides, the severities of neurological sequence were more severe in RSE than SE group (Table 5). In a recent series of children with seizures lasting 430 min, only 23% of the survivors are normal at follow-up; 34% show developmental deterioration, and 36% develop new-onset epilepsy.18 However, in two other small retrospective reviews of severe RSE children with a presumed encephalitic etiology, who were refractory to initial therapy with a BZD, follow therapeutic levels of either PHT or PB, for 460 min; 83.3% of the survivors develop epilepsy and/or neurologic deficits and 16.6% returned to baseline.5,6 Our data demonstrate that the RSE owing to presumed encephalitis carries a high morbidity in the survivors of RSE (p ¼ 0.027). The overall mortality rate in pediatric SE is zero to 10%.13,14,18,19 However, there is high mortality in the RSE group with a presumed encephalitic etiology. Maytal et al. report low morbidity and mortality of SE in children, except in acute or progressive neurologic insults group. The mortality rate in this group was 12.5%.13 In another two studies, the mortality rate in the RSE group owing to presumed encephalitis in children was about 25%.5,8 In our study, the mortality rate also was higher in RSE group than in SE group (31.6% vs. 15.4%). Taken together, these studies suggest that mortality and morbidity associated with pediatric RSE owing to presumed encephalitis may be higher than that previously thought. There are several possible explanations for this situation. First, the complications of SE include cardiac
12 (2008) 32 – 37
dysrhythmia, derangements of metabolic and autonomic function, neurogenic pulmonary edema, hyperthermia, rhabdomyolysis, and pulmonary aspiration. Prolonged SE increases risk for these complications. Second, permanent neurologic damage in encephalitis with prolonged uncontrolled convulsive activity may occur by direct virus invasion, stimulating host dependent immune response or SE-induced neuronal death.20 Long duration of SE is associated with markedly poor neurologic outcome, in particular, the development of post-SE symptomatic epilepsy.21,22 Third, because our patients are treated in a major tertiary care referral center, and several cases had been transferred from other hospitals, they may represent the more severe cases. Factors that are not correlated with adverse outcomes included age, any type of seizure occurrence, initial brain CT/ MRI or abnormal CSF findings. In conclusion, our data demonstrate a high mortality and morbidity in the RSE group of presumed encephalitis in children. Neurologic outcome is related to multifocal or generalized abnormalities on the initial EEG and the presence of RSE.
R E F E R E N C E S
1. Kennedy CR, Duffy SW, Smith R, Robinson RO. Clinical predictors of outcome in encephalitis. Arch Dis Child 1987;62:1156–62. 2. Rantala H, Uhari M, Uhari M, Saukkonen A, Sorri M. Outcome after childhood encephalitis. Dev Med Child Neurol 1991;33:858–67. 3. Klein SK, Hom DL, Anderson MR, Latrizza AT, Toltzis P. Predictive factors of short-term neurologic outcome in children with encephalitis. Pediatr Neurol 1994;11:308–12. 4. Bhutto E, Naim M, Ehtesham M, et al. Prognostic indicators of childhood acute viral encephalitis. J Pak Med Assoc 1999;49:311–6. 5. Kramer U, Shorer Z, Ben-Zeev B, et al. Severe refractory status epilepticus owing to presumed encephalitis. J Child Neurol 2005;20:184–7. 6. Sahin M, Menache CC, Holmes GL, Riviello Jr. JJ. Outcome of severe refractory status epilepticus in children. Epilepsia 2001;42:1461–7. 7. Sahin M, Menache CC, Holmes GL, Riviello Jr. JJ. Prolonged treatment for acute symptomatic refractory status epilepticus: outcome in children. Neurology 2003;61:398–401. 8. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl J Med 1998;338:970–6. 9. Chapman MG, Smith M, Hirsch NP. Status epilepticus. Anaesthesia 2001;56:648–59. 10. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380–6. 11. Sahin M, Riviello JJ. Prolonged treatment of refractory status epilepticus in a child. J Child Neurol 2001;16:147–50. 12. Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, et al. Viral encephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 2005;12:331–43. 13. Maytal J, Shinnar S, Moshe SL, Alvarez LA. Low morbidity and mortality of status epilepticus in children. Pediatrics 1989;83:323–31. 14. Lacroix J, Deal C, Gauthier M, Rousseau E, Farrell A. Admissions to a pediatric intensive care unit for status epilepticus: a 10-year experience. Crit Care Med 1994;22:827–32.
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15. Chin RF, Neville BG, Peckham C, et al. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:222–9. 16. Trinka E, Dubeau F, Andermann F, et al. Clinical findings, imaging characteristics and outcome in catastrophic postencephalitic epilepsy. Epileptic Disord 2000;2:153–62. 17. Kalita J, Misra UK, Patel R. Initial EEG in status epilepticus is helpful in predicting seizure recurrence. Electromyogr Clin Neurophysiol 2006;46:139–44. 18. Barnard C, Wirrell E. Does status epilepticus in children cause developmental deterioration and exacerbation of epilepsy? J Child Neurol 1999;14:787–94.
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19. Eriksson KJ, Koivikko MJ. Status epilepticus in children: aetiology, treatment, and outcome. Dev Med Child Neurol 1997;39:652–8. 20. Fujikawa DG. Prolonged seizures and cellular injury: understanding the connection. Epilepsy Behav 2005;7:S3–S11. 21. Holtkamp M, Othman J, Buchheim K, Meierkord H. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005;76:534–9. 22. Maegaki Y, Kutozawa Y, Hanaki Koch Ohno K. Risk factors for fatality and neurological sequelae after status epilepticus in children. Neuropediatrics 2005;36:186–92.
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Official Journal of the European Paediatric Neurology Society
Original article
Analysis of status epilepticus related presumed encephalitis in children Jainn-Jim Lina,b, Kuang-Lin Lina,, Huei-Shyong Wanga, Shao-Hsuan Hsiab, Chang-Teng Wub a Division of Pediatric Neurology, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, #5 Fu-Shin Street, Kwei-Shan, Taoyuan 333, Taiwan b Divisions of Pediatric Critical Care and Emergency Medicine, Chang Gung Children’s Hospital and Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
ar t ic l e i n f o
abs tra ct
Article history:
Objective: Encephalitis is an acute infection of brain parenchyma characterized clinically
Received 5 February 2007
by fever, headache, and an altered level of consciousness. There may also be focal or
Received in revised form
multifocal neurologic deficits, and focal or generalized seizure activity. Here we report an
18 April 2007
analysis of status epilepticus (SE) related presumed encephalitis in a series of children.
Accepted 14 May 2007
Methods: We retrospectively reviewed cases of SE related presumed encephalitis treated in the pediatric intensive care unit, between February 2002 and June 2006. Factors evaluated
Keywords:
included age, sex, clinical symptoms, seizure type, presence of SE or refractory status
Presumed encephalitis
epilepticus (RSE), initial electroencephalogram (EEG) finding, neuroimaging study, cere-
Status epilepticus
brospinal fluid (CSF) and outcome.
Results: There were 46 patients (19 girls and 27 boys), aged 8 months to 16 years. Twenty (43.4%) of 46 children developed RSE. The major clinical symptoms included fever (100%), upper respiratory symptoms (56.5%) and altered level of consciousness (45.6%). The initial seizure type was categorized as focal (23.9%), generalized (34.8%), primary focal and secondary generalized (41.3%). Initial EEG revealed a focal (30.8%), or multifocal (19.2%) epileptiform discharge in the SE group and a focal (5%), or multifocal (70%) or generalized (25%) epileptiform discharge in the RSE group. The time of follow-up for this study was 6 months to 51 months. In the SE group, 4 died, 16 developed epilepsy and/or neurologic deficits, and 6 returned to baseline. In the RSE group, 6 died, 13 developed epilepsy and/or neurologic deficits, and none returned to baseline. All survivors were discharged on antiepileptic medications.
Conclusions: Our data indicated that children of SE related presumed encephalitis had a high mortality and morbidity. Outcome was related to multifocal or generalized abnormalities of the initial EEG and presence of RSE. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +886 3 3281200x8200; fax: +886 3 3288957.
E-mail address: [email protected] (K.-L. Lin). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.05.007
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
1.
Introduction
Acute viral encephalitis most commonly affects children and young adults. Most viral infections of the central nervous system (CNS) either involve the meninges, leading to aseptic meningitis, or cause mild meningoencephalitis rather than encephalitis. The prognosis of viral encephalitis in pediatric patients is usually excellent. Although the outcome can range from complete recovery to severe neurologic sequelae and death, most children recover without significant residua and require only brief hospitalization. However viral encephalitis remains a significant source of neurologic morbidity and mortality worldwide. Although some previous studies report predictive factors of neurologic outcome in children with encephalitis,1–5 little information is available in the literature about the outcome of status epilepticus (SE) related presumed encephalitis in children. Here, we report an analysis of SE related presumed encephalitis in a series of children.
2.
Methods
Presumed encephalitis was defined as having symptoms of an acute febrile illness prior to, or at the time of, the onset of SE,6,7 and no positive findings in cerebral spinal fluid (CSF) culture. All children were previous healthy and none had prior seizures including febrile seizure. Any child with a family history of epilepsy or febrile seizure, a prior neurologic insult, progressive neurologic disorder, electrolyte imbalance and hypoglycemia was excluded. SE was defined as continuous seizure activity lasting 30 min or as two or more discrete seizures between which consciousness was not fully regained.8,9 RSE was defined as seizures lasting 42 h, despite treatment with conventional antiepileptic drugs including initial therapy with a benzodiazepine (BZD), followed by therapeutic dosage of both phenytoin (PHT) and phenobarbital (PB).8,10 The goal of treatment was to achieve complete clinical seizure control or burstsuppression (BS) pattern on electroencephalogram (EEG), aiming for an interburst interval of 45 s.11 BS coma was induced by high-dose suppressive therapy consisting of midazolam (MDL), lidocaine, propofol, thiopental, citosol or high-dose PB. Weaning of the high-dose suppressive therapy was guided by EEG monitoring. The weaning process was aborted if there was return of SE or frequent clinical or electrographic seizures. All children were cared for in the pediatric intensive care unit in Chang Gung Children’s Hospital. EEG in SE group was performed within 24 h. However, in the RSE group, 24 h EEG monitor was performed immediately. All EEGs were interpreted by pediatric neurologist. From February 2002 to August 2006, 46 children with presumed encephalitis complicated with SE were enrolled. Information was collected by retrospective chart review regarding: age, sex, etiology, initial seizure type, presence of SE or RSE, initial EEG, neuroimaging, CSF analysis and outcome. The diagnosis of initially seizure types was based upon clinical impression by attending neurologists. The initial EEGs were categorized as having either negative, or a
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33
focal/diffuse cortical dysfunction, or a focal, or multifocal or generalized epileptiform discharge. The cortical dysfunction was defined as slow waves in EEG. Patient outcome including mortality, a new neurologic deficit, or return to baseline was determined from last clinic visit, which was a minimum of 6 months after the episode of SE. The neurological deficits were categorized as seizure, neurological outcome and cognition outcome. The neurological outcome was according to the Glasgow outcome scale classification. GOS ¼ 1 (good recovery) was capacity to resume normal occupational and social activities, although there may be minor physical or mental deficits or symptoms. GOS ¼ 2 (moderate disability) was independent and can resume almost all activities of daily living. Disabled to the extent that they cannot participate in a variety of social and work activities. GOS ¼ 3 (severe disability) was no longer capable of engaging in most previous personal, social or work activities. Limited communication skills and have abnormal behavioral or emotional responses. Typically are partially or totally dependent on assistance from others in daily living. GOS ¼ 4 (persistent vegetative state) was not aware of surroundings or purposely responsive to stimuli. The cognition outcomes were classified as normal, learning disability, mild mental retardation (MR) and other MR. Normal indicates that a child had an intelligence quotient of more than 70 without learning disabilities. Learning disability was defined as significant difficulties in the acquisition and use of certain skills such as listening, speaking, reading, writing, reasoning or mathematical abilities in individuals with normal intelligence. Mild MR was defined as intelligence quotient scores of between 55 and 80 and moderate MR was defined as intelligence quotient scores of less than 55. The time of follow-up for the study group was 6 months to 51 months.
3.
Data analysis
Clinical and laboratory factors obtained upon admission were analyzed as possible predictors of neurologic outcome, defined at last clinic visit, which was a minimum of 6 months after the episode of SE. These factors included age, seizure pattern, presence of SE or RSE, EEG finding, Neuroimaging study, CSF leukocyte and protein measurement. The association between each of these variables and neurologic outcome was examined. Statistical analysis was performed using the SPSS (10.0) statistical software. The relationships between parameters were analyzed using Pearson product moment correlation. Statistical significance was set at po0.05.
4.
Results
Forty-six children with presumed encephalitis complicated with SE were enrolled. The age at presentation of the children ranged from 8 months to 16 years. There were 19 (41%) girls and 27 (59%) boys. Twenty (43.4%) of 46 children developed RSE. The clinical symptoms included fever (46/46, 100%), upper respiratory symptoms (26/46, 56.5%), altered level of consciousness (21/46, 45.6%), vomiting (20/46, 43.4%),
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headache (13/46, 28.2%), behavioral disturbances (2/46, 4.3%). The initial seizure type was categorized as focal (11/46, 23.9%), generalized (16/46, 34.8%), primary focal and secondary generalized (19/46, 41.3%). The clinical characteristics and initial seizure pattern of all 46 children are summarized in Tables 1 and 2. All patients underwent a thorough investigation during their hospitalization, including serologic tests for viruses, polymerase chain reaction (PCR) in CSF for herpes simplex virus (HSV) DNA (n ¼ 14) and virus culture of throat (n ¼ 34), CSF (n ¼ 33), and rectal (n ¼ 28) specimens. Most children underwent serologic tests for HSV (n ¼ 31), epstein-barr virus (EBV) (n ¼ 28), mycoplasma pneumoniae (n ¼ 27), human herpesvirus 6 (HHV-6) (n ¼ 4) and varicella-zoster virus (VZV) (n ¼ 1). Positive result for serologic tests or/and virus culture was noted in 18 patients. In all other cases, no organism was identified. Positive IgM result of serologic tests was VZV 1 (100%), mycoplasma pneumonia 7 (25.9%), and HSV 3 (9.6%). The result of virus culture was throat 10 (29%), rectal 4 (14.2%) and CSF 0 (0%). Positive result for serologic tests or/and virus culture in 18 patients is shown in Table 3. Lumbar puncture was performed in 33 patients. White blood cell (WBC) count in the CSF studies ranged from 0 to 109 cells/uL. There was a predominance of monocytes (60–100%). The glucose level in the CSF ranged from 48 to 128 mg/dL and protein level was 16.6–179.5 mg/dL. Neuroimaging studies of brain computed tomography (CT) or magnetic resonance imaging (MRI) were divided into acute phase (o1 weeks after disease onset), non-acute phase (1 weeks to 3 month after disease onset) and follow-up neuroimages (43 month after disease onset). The first brain CT (n ¼ 30) or MRI (n ¼ 8) performed during acute phase was no specific including increased letomeningeal enhancement or brain swelling, whereas the non-acute MRI (n ¼ 15)
Table 1 – Clinical symptoms of 46 children with presumed encephalitis Fever
46/46 (100%)
Upper respiratory tract infection Altered level of consciousness Vomiting Headache Behavioral disturbances
26/46 21/46 20/46 13/46 2/46
(56.5%) (45.6%) (43.4%) (28.2%) (4.3%)
Table 2 – The initial seizure patterns of 46 children with presumed encephalitis
Focal (n ¼ 9, 19.5%) Generalized (n ¼ 33, 71.7%) Primary focal and secondary generalized (n ¼ 4, 8.7%)
SE (n ¼ 26)
RSE (n ¼ 20)
4 21 1
5 12 3
SE, status epilepticus; RSE, refractory status epilepticus.
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Table 3 – Positive result of serologic test and/or virus culture in 18 patients Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Serologic test
Virus culture
Mycoplasma IgM EV (rectal) HSV-1 (throat) EV (throat, rectal)
HSV IgM Mycoplasma IgM
Influenza A (throat) VZV IgM HSV IgM
Mycoplasma Mycoplasma Mycoplasma Mycoplasma
HSV-1 (throat) EV (throat, rectal) EV (throat, rectal) EV (throat) Influenza A (throat) IgM IgM IgM IgM
HSV-1 (throat) Adenovirus (throat)
Mycoplasma IgM
Mycoplasma, mycoplasma pneumoniae; HSV, herpes simplex virus; EBV, epstein-barr virus; VZV, varicella-zoster virus, EV, enterovirus.
Table 4 – The initial EEG pattern in 46 children with presumed encephalitis EEG pattern
SE (n ¼ 26)
Negative Focal/diffuse cortical dysfunction Epileptiform discharge Focal Multifocal Generalized
4 (15.4%) 9 (34.6%)
8 (30.8%) 5 (19.2%)
RSE (n ¼ 20)
1 (5%) 14 (70%) 5 (25%)
revealed mild atrophy in 1 patients. Three patients had unilateral or bilateral hippocampal hyperintensity in T2 suggestive of focal edema, 5 had multiple focal hyperintensity in T2 suggestive of encephalitis or acute disseminated encephalomyelitis (ADEM), 2 had global hypoxic ischemic encephalopathy and 4 had no specific finding. A follow-up brain CT was performed for seven patients and brain atrophy was found in all seven patients. In the SE group, initial EEG was revealed to be negative in 4 (15.4%), focal/diffuse cortical dysfunction in 9 (34.6%), and a focal epileptiform discharge in 8 (30.8%), or multifocal in 5 (19.2%). In the RSE group, initial EEG revealed a focal in 1 (5%), or multifocal in 14 (70%) or generalized epileptiform discharge in 5 (25%) (Table 4). In RSE group, the duration from seizure onset to complete clinical seizure control or appearance of BS pattern on EEG was ranged from 1 to 20 days (mean7SD ¼ 6.6575.60). If the duration was less than 3 days, there was less cognition delay
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at follow-up (p ¼ 0.041). If the duration was less than 5 days, there was less seizure at follow-up (p ¼ 0.037). However, there was no correlation between GOS and the duration of clinical seizure control or appearance of BS (p ¼ 0.842). Sixteen patients received BS coma. The duration of first cycle BS coma was ranged from 2 to 4 days. However, nine patients continued with seizures following the first cycle of BS. The total duration of BS coma was ranged from 2 to 9 days (mean7SD ¼ 5.172.2 days). The correlation of duration of BS and GOS, cognition and seizure at follow-up were not significant. Outcome of the 46 children, 10 (21.7%) died and 36 was survival (78.2%). All survivors were discharged on antiepileptic medications. Thirty-five children followed-up with the minimum duration of 6 months. In the SE group of 26 children, 4 died, 16 developed epilepsy and/or neurologic deficits, and 6 returned to baseline. Of the 20 children in the RSE group, 1 transferred to another hospital, 6 died, 13 developed epilepsy and/or neurologic deficits, and none returned to baseline. The severities of neurological sequence in RSE group were more severe than SE group. Subsequent neurological outcomes are summarized in Table 5. The correlations of demographic data and subsequent neurologic outcome are summarized in Table 6.
5.
Discussion
The gold standard of diagnosis in encephalitis is virus isolation in cell culture, now to be replaced by the detection Table 5 – Subsequent neurological outcome in 45 children with presumed encephalitis
Mortality Epilepsy and/or neurologic deficits Seizure at follow-up Well control by %2 kind AEDs Well control by 42 kind AEDs Poor control Neurological outcome (GOS score) 1 (Good recovery) 2 (Moderate disability) 3 (Severe disability) 4 (Vegetative status) Cognition at follow-up Normal Learning disability Mild MR Moderate MR Return to baseline
Status epilepticus (n ¼ 26)
Refractory status epilepticus (n ¼ 19)a
4 (15.4%) 16 (61.5%)
6 (31.6%) 13 (68.4%)
13
3
0
6
1
4
14 0 2 0
4 2 5 2
12 2 0 2 6 (23.1%)
0 4 3 6 0
AED: antiepileptic drug; GOS: Glasgow outcome score; MR: mental retardation. a In the refractory status epilepticus group, one patient was transferred to another hospital.
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Table 6 – Correlation of demographic data and neurological outcome Variable Age (n ¼ 46) o1 y/o 1–5 y/o 5–10 y/o 410 y/o Seizure pattern (n ¼ 46) Focal GTC Focal/GTC Seizure duration (n ¼ 46) SE RSE Cerebrospinal fluid WBC (n ¼ 29) 0–10 10–100 4100 Total protein (n ¼ 29) 0–30 30–100 4100 Neuroimagea CT (n ¼ 30) No specific finding MRI (n ¼ 8) No specific finding Initial EEG (n ¼ 46) Multifocal and generalized discharge Other
Number
p-value 0.421
2 15 19 10 0.77 9 33 4 0.027 26 20 0.863 18 9 2 0.086 13 11 5 NP 30 8 0.011 24 22
GTC: generalized tonic clonic; Focal/GTC: primary focal and secondary generalized; SE: status epilepticus; RSE: refractory status epilepticus: CT: computed tomography; MRI: magnetic resonance imaging; EEG: electroencephalogram. p-value: statistical significance; po 0.05. a Neuroimage in acute stage.
of specific nucleic acid from CSF or brain. Intrathecal antibody production to a specific virus is similarly a strong evidence for etiology. However, virus detection from throat, stool, urine or blood as well as systemic serological responses like seroconversion or a specific IgM provides less strong evidence.12 Therefore, in our study, we defined presumed encephalitis as having symptoms of an acute febrile illness prior to, or at the time of, the onset of SE,6,7 and no positive findings in CSF culture. Although some patients had positive culture and some had brain MRIs that fitted ADEM, but no cases had direct evidence from positive CSF culture or brain biopsy to support pathogen. We were thus categorized these cases as presumed encephalitis. Incidence of encephalitis complicated with SE in children is about 3.8–13.7%.13–15 However, there was frequently no defined viral etiology in a majority of the cases. Presumed encephalitis is a group of patients frequently encountered in a pediatric intensive care unit. They had a history of acute febrile illness, and suddenly developed SE.6,7 The courses were fulminant and catatrophic. Maytal et al. report 15 (7.8%) of the 193 SE children have a history of CNS infection. Seven
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(46.7%) of 15 children present status epilepticus 41 h.13 In our study, 46 children with presumed encephalitis complicated with SE are enrolled. Twenty (43.4%) of 46 children develop RSE. So SE related presumed encephalitis etiology has a higher rate to develop RSE. All of our patients had either continuous EEG monitoring or routine EEG recordings. The neurologic outcome among patients with multifocal or generalized epileptiform discharge on the initial EEG are poorer than others (p ¼ 0.011). The existence of more than one epileptic focus owing to encephalitis is not surprising and probably plays a part in the severity of the epileptic process. Previous studies show multifocal or generalized abnormalities on initial EEG had higher mortality6 and poor neurologic outcome.16 Besides, EEG abnormality at 1 h predicts seizure recurrence within 24-h.17 Our data demonstrates that multifocal or generalized epileptiform discharges on the initial EEG are the factors associated with a worse neurologic outcome. In RSE group, the duration from seizure onset to complete clinical seizure control or appearance of BS pattern on EEG was correlated with morbidity. In our study, if the duration was less than 3 days, there was less cognition delay at followup (p ¼ 0.041). If the duration was less than 5 days, there was less seizure at follow-up (p ¼ 0.037). Therefore, prolonged uncontrolled seizure may cause permanent neurologic damage in encephalitis. However, the duration of BS pattern on EEG was not correlation with morbidity included GOS, cognition and seizure at follow-up. Aggressive treatment to achieve complete clinical seizure control or appearance of BS pattern on EEG was emphasized. It is not unexpected that there is higher morbidity in the survivors of RSE than in SE. In our RSE group, all survivors develop epilepsy and/or neurologic deficits, and none return to baseline. Besides, the severities of neurological sequence were more severe in RSE than SE group (Table 5). In a recent series of children with seizures lasting 430 min, only 23% of the survivors are normal at follow-up; 34% show developmental deterioration, and 36% develop new-onset epilepsy.18 However, in two other small retrospective reviews of severe RSE children with a presumed encephalitic etiology, who were refractory to initial therapy with a BZD, follow therapeutic levels of either PHT or PB, for 460 min; 83.3% of the survivors develop epilepsy and/or neurologic deficits and 16.6% returned to baseline.5,6 Our data demonstrate that the RSE owing to presumed encephalitis carries a high morbidity in the survivors of RSE (p ¼ 0.027). The overall mortality rate in pediatric SE is zero to 10%.13,14,18,19 However, there is high mortality in the RSE group with a presumed encephalitic etiology. Maytal et al. report low morbidity and mortality of SE in children, except in acute or progressive neurologic insults group. The mortality rate in this group was 12.5%.13 In another two studies, the mortality rate in the RSE group owing to presumed encephalitis in children was about 25%.5,8 In our study, the mortality rate also was higher in RSE group than in SE group (31.6% vs. 15.4%). Taken together, these studies suggest that mortality and morbidity associated with pediatric RSE owing to presumed encephalitis may be higher than that previously thought. There are several possible explanations for this situation. First, the complications of SE include cardiac
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dysrhythmia, derangements of metabolic and autonomic function, neurogenic pulmonary edema, hyperthermia, rhabdomyolysis, and pulmonary aspiration. Prolonged SE increases risk for these complications. Second, permanent neurologic damage in encephalitis with prolonged uncontrolled convulsive activity may occur by direct virus invasion, stimulating host dependent immune response or SE-induced neuronal death.20 Long duration of SE is associated with markedly poor neurologic outcome, in particular, the development of post-SE symptomatic epilepsy.21,22 Third, because our patients are treated in a major tertiary care referral center, and several cases had been transferred from other hospitals, they may represent the more severe cases. Factors that are not correlated with adverse outcomes included age, any type of seizure occurrence, initial brain CT/ MRI or abnormal CSF findings. In conclusion, our data demonstrate a high mortality and morbidity in the RSE group of presumed encephalitis in children. Neurologic outcome is related to multifocal or generalized abnormalities on the initial EEG and the presence of RSE.
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