Analysis of status epilepticus related presumed encephalitis in children

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Official Journal of the European Paediatric Neurology Society

Original article

Analysis of status epilepticus related presumedencephalitis in children

Jainn-Jim Lina,b, Kuang-Lin Lina,�, Huei-Shyong Wanga,Shao-Hsuan Hsiab, Chang-Teng Wub

aDivision 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, TaiwanbDivisions 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

a r t i c l e i n f o

Article history:

Received 5 February 2007

Received in revised form

18 April 2007

Accepted 14 May 2007

Keywords:

Presumed encephalitis

Status epilepticus

nt matter & 2007 Europe07.05.007

hor. Tel.: +886 3 [email protected]

a b s t r a c t

Objective: Encephalitis is an acute infection of brain parenchyma characterized clinically

by fever, headache, and an altered level of consciousness. There may also be focal or

multifocal neurologic deficits, and focal or generalized seizure activity. Here we report an

analysis of status epilepticus (SE) related presumed encephalitis in a series of children.

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

included age, sex, clinical symptoms, seizure type, presence of SE or refractory status

epilepticus (RSE), initial electroencephalogram (EEG) finding, neuroimaging study, cere-

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.

an Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

8200; fax: +886 3 3288957.(K.-L. Lin).

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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 con-

sciousness 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 benzodia-

zepine (BZD), followed by therapeutic dosage of both pheny-

toin (PHT) and phenobarbital (PB).8,10 The goal of treatment

was to achieve complete clinical seizure control or burst-

suppression (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 neurol-

ogist.

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

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 dis-

ability) 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 abil-

ities 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 associa-

tion 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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Table 3 – Positive result of serologic test and/or virusculture in 18 patients

Patient no. Serologic test Virus culture

1 Mycoplasma IgM

2 EV (rectal)

3 HSV IgM HSV-1 (throat)

4 EV (throat, rectal)

5 Mycoplasma IgM

6 Influenza A (throat)

7 VZV IgM

8 HSV IgM HSV-1 (throat)

9 EV (throat, rectal)

10 EV (throat, rectal)

11 EV (throat)

12 Influenza A (throat)

13 Mycoplasma IgM

14 Mycoplasma IgM

15 Mycoplasma IgM

16 Mycoplasma IgM HSV-1 (throat)

17 Adenovirus (throat)

18 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 withpresumed encephalitis

EEG pattern SE(n ¼ 26)

RSE(n ¼ 20)

Negative 4 (15.4%)

Focal/diffuse cortical 9 (34.6%)

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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 under-

went 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 pre-sumed encephalitis

Fever 46/46 (100%)Upper respiratory tract infection 26/46 (56.5%)

Altered level of consciousness 21/46 (45.6%)

Vomiting 20/46 (43.4%)

Headache 13/46 (28.2%)

Behavioral disturbances 2/46 (4.3%)

Table 2 – The initial seizure patterns of 46 children withpresumed encephalitis

SE(n ¼ 26)

RSE(n ¼ 20)

Focal (n ¼ 9, 19.5%) 4 5

Generalized (n ¼ 33, 71.7%) 21 12

Primary focal and secondary

generalized (n ¼ 4, 8.7%)

1 3

SE, status epilepticus; RSE, refractory status epilepticus.

dysfunction

Epileptiform discharge

Focal 8 (30.8%) 1 (5%)

Multifocal 5 (19.2%) 14 (70%)

Generalized 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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Table 6 – Correlation of demographic data and neurolo-gical outcome

Variable Number p-value

Age (n ¼ 46) 0.421

o1 y/o 2

1–5 y/o 15

5–10 y/o 19

410 y/o 10

Seizure pattern (n ¼ 46) 0.77

Focal 9

GTC 33

Focal/GTC 4

Seizure duration (n ¼ 46) 0.027�

SE 26

RSE 20

Cerebrospinal fluid

WBC (n ¼ 29) 0.863

0–10 18

10–100 9

4100 2

Total protein (n ¼ 29) 0.086

0–30 13

30–100 11

E UR O P EA N J O UR NA L O F PA ED I ATR I C N E U RO L O G Y 12 (2008) 32 – 37 35

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 antiepilep-

tic 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.

Neuroimagea NP

CT (n ¼ 30)

No specific finding 30

MRI (n ¼ 8)

No specific finding 8

Initial EEG (n ¼ 46) 0.011�

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 childrenwith presumed encephalitis

Statusepilepticus

(n ¼ 26)

Refractory statusepilepticus

(n ¼ 19)a

Mortality 4 (15.4%) 6 (31.6%)

Epilepsy and/or

neurologic deficits

16 (61.5%) 13 (68.4%)

Seizure at follow-up

Well control by %2

kind AEDs

13 3

Well control by 42

kind AEDs

0 6

Poor control 1 4

Neurological outcome

(GOS score)

1 (Good recovery) 14 4

2 (Moderate disability) 0 2

3 (Severe disability) 2 5

4 (Vegetative status) 0 2

Cognition at follow-up

Normal 12 0

Learning disability 2 4

Mild MR 0 3

Moderate MR 2 6

Return to baseline 6 (23.1%) 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.

Multifocal and generalized discharge 24

Other 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 serocon-

version 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 abnormal-

ities 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 multi-

focal 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 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). Therefore, prolonged

uncontrolled seizure may cause permanent neurologic da-

mage 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 develop-

mental 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% re-

turned 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

dysrhythmia, derangements of metabolic and autonomic

function, neurogenic pulmonary edema, hyperthermia, rhab-

domyolysis, and pulmonary aspiration. Prolonged SE in-

creases risk for these complications. Second, permanent

neurologic damage in encephalitis with prolonged uncon-

trolled 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 devel-

opment 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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