Status epilepticus (SE) can present with varied
clinical manifestations, and have different etiologies,
which vary with age and geographical areas. It is well known
that the duration of SE positively correlates with the
refractoriness to treatment, and the prognosis is poor in
children who have prolonged uncontrolled seizures [1-3]. Due
to poor access to healthcare facilities in developing
countries, there is higher likelihood of prolongation of
seizures and delay in initiation of treatment. There is
paucity of data regarding the etiology and treatment
outcomes of SE in Indian children [4]. Therefore, the
objective of the present study was to understand the
clinical profile and short term treatment outcome in
children with SE.
Methods
This prospective cohort study was undertaken at a teaching
government hospital in New Delhi, India from January 2017 to
April 2018. Institutional ethics committee approval was
obtained. Consecutive children aged 1 month to 18 years
presenting in convulsive SE were enrolled. SE was defined as
active seizures of
≥5 minutes duration or recurrent episodes
of seizures without gaining consciousness in between [5].
Psychogenic non-epileptic seizures were excluded. Written
informed consent was taken from the caregivers after initial
stabilization of the child.
The enrolled children
were treated as per the hospital SE protocol in accordance
with the current guidelines in India [4]. The anti-epileptic
drug (AED) was considered effective if there was clinical
cessation of seizures within 10 minutes of the initial dose
of medication and if there was no recurrence of seizures for
30 minutes [6]. A patient was classified to have
benzodiazepine - responsive SE if the SE responded with
first or second dose of benzodiazepine (BZD). Established SE
was defined as SE which persisted despite two BZD doses and
required 2nd line AED. Refractory SE was defined as SE
persisting despite the administration of two appropriate
anticonvulsants at acceptable doses and responding only to
3rd line AED or midazolam infusion [7]. Super-refractory SE
was defined as SE that continued 24 hours or more even after
the onset of anesthesia, including those cases in which the
SE recurred on the reduction or withdrawal of anesthesia
[8].
Detailed history, examination and investigations
were documented in a predesigned form. Neuroimaging was done
in all children with SE, except in hypocalcemic seizures,
typical febrile seizures, and known cases of epilepsy
without any new neurological deficits. The etiology of SE
was determined according to the history, examination and the
investigations done. The patients were followed till
discharge or death during the hospital admission. The
patients with pre-morbid developmental delay were evaluated
for return to their baseline functional status.
Neurologically normal patients were classified using the
pediatric overall performance category (POPC) scale at the
time of discharge [9]. POPC scale scores of 1-2 were
considered as a favorable outcome and scores of
≥3 were considered as an unfavorable
outcome.
Statistical analysis: This was performed
using IBM SPSS software version 21. Continuous data was
represented as mean with standard deviation or median with
interquartile range. Qualitative data was represented as
proportions or percentages. Multivariate logistic regression
model was used to predict unfavorable outcome at discharge.
A P-value of <0.05 was considered statistically significant.
Results
A total of 115
children presenting as SE were assessed for eligibility
during the study period and 109 were enrolled (3 declined to
participate, and 3 children had psychogenic non-epileptic
seizures) The median age at presentation was 2 (IQR 1-6)
years. Generalized tonic clonic seizures were seen in 70
(64.2%) children. The clinico-etiological characteristics of
the study population are presented in Table I.
TABLE I Clinico-etiological Characteristics of Children with Status Epilepticus (N=109)
|
Characteristics |
No. (%) | |
#Age , y |
2 (1 - 6) | |
Males |
64 (58.7) | |
‡Pre-existing epilepsy |
32 (29.4) | |
Seizure duration, min |
17.5 (7 – 60) | |
Type of seizures | | |
Generalized tonic-clonic |
70 (64.2) | |
Focal, impaired awareness |
20 (18.3) | |
Focal evolving to bilateral tonic-clonic |
10 (9.2) | |
Generalized tonic |
9 (8.3) | |
Etiology of status epilepticus | | |
Acute symptomatic |
66 (60.6) | |
Acute CNS infections |
27 (24.8) | |
Febrile status epilepticus |
16 (14.7) | |
Neurocysticercosis |
14 (12.8) | |
Hypocalcemic seizures |
7 (6.4) | |
ADEM |
1 (0.9) | |
CSVT |
1 (0.9) | |
Remote symptomatic seizures |
27 (24.8) | |
Perinatal insult |
18 (16.5) | |
Mesial temporal sclerosis |
2 (1.8) | |
Focal cortical dysplasia |
1 (0.9) | |
Congenital intrauterine infections |
1 (0.9) | |
Hippocampal atrophy* |
1 (0.9) | |
Miscellaneous |
4 (3.7) | |
Unknown etiology |
16 (14.7) | |
All values in n (%) except #median (IQR); *One case each of late infantile neuronal ceroid lipofuscinosis type 2, Dravet syndrome, suspected case of IEM, and Wolcott Rallison syndrome; ‡Only 15 of these were receiving antiepileptic drugs; CNS: Central nervous system ADEM: Acute disseminated encephalomyelitis, CSVT: Cerebral sinus venous thrombosis. |
Sixty five (59.6%) children responded to first line AED
(midazolam). Second dose midazolam was given in 29 patients
(15 patients received one pre-hospital dose) but with no
added benefit as seizures persisted in all. Out of the 44
cases who did not respond to midazolam (established SE), 28
responded to 2nd line AEDs. In the remaining 16 patients
(refractory SE), 12 responded to 3rd line AEDs or midazolam
infusion and 4 were classified into super-refractory SE. The
response to medications in the study population is
summarized in Fig. 1. In 44 children who
did not respond to midazolam, 37 were given phenytoin and 7
were given valproate as second line AED. Valproate was used
based on history of compliant maintenance therapy with high
normal dose phenytoin or past history of adverse reaction to
phenytoin. Twenty two (59.5%) responded after phenytoin and
6 (85.7%) responded after valproate. Out of the 15 who did
not respond to phenytoin, valproate was used in 12 children,
out of which 4 (33.3%) responded. In 12 children, where
valproate was either ineffective or was not used as third
line AED, phenobarbitone or levetiracetam was used.
Levetiracetam was effective in 4 out of 10 children (40%),
whereas phenobarbitone was effective in 2 out of 7 children
(28.6%).
 |
| Fig. 1 Response to
anti-epileptic drugs in the study population
presenting with status epilepticus. |
Six children were initiated on midazolam infusion.
The seizures subsided within 24 hours of midazolam infusion
in one child and did not recur on stopping the infusion
(refractory SE). One child died within 24 hours of midazolam
infusion. Four children had super-refractory SE; of these
three received phenobarbitone infusion and one received
thiopentone infusion.
Viral meningoencephalitis was
present in 14 children (12.8%), bacterial meningitis in 9
(8.3%), tubercular meningitis in 3 (2.8%), and encephalitis
(non-specific) in 1 (0.9%) child. Thirty two (29.4%)
children in the study were known cases of epilepsy. They
were already on maintenance AEDs. Only 2 (0.1%) patients had
missed AED doses, leading to precipitation of SE.
All 26 children with pre-morbid disability returned to their
pre-illness state at discharge. The remaining 83 were
classified according to the POPC scale. Favorable outcome
was seen in 67 (80.7%) children whereas 16 (19.3%) had
unfavorable outcome. Eight children (7.3%) died during the
hospital stay. Out of these, 6 were diagnosed with
meningoencephalitis, 1 with tubercular meningitis and 1 with
late infantile neuronal ceroid lipofuscinosis type 2. Out of
the 8 children who died, 3 had super-refractory SE and 3 had
refractory SE.
Multivariate logistic regression
showed that presence of an acute symptomatic etiology
(adjusted OR 4.50, 95% CI 1.5,13.6) and no AED administered
prior to hospitalization (adjusted OR 3.97, 95% CI 1.1,14.8)
predicted unfavorable outcome at discharge. The age, sex,
presence of pre-existing epilepsy, duration of seizures
prior to reaching the hospital, and response to the first
line BZD were not found to be significant.
Discussion
This prospective cohort study
explored the clinical profile and treatment outcomes of
pediatric SE, in the setting of a developing country. Acute
symptomatic etiology was identified in a majority of the
cases. BZD-responsive SE was seen in more than half of the
children. Predictors of unfavorable outcome were found to be
acute symptomatic etiology, and absence of an AED
administered prior to reaching the hospital.
TABLE II Multivariate Logistic Regression Model to Predict Unfavorable Outcome at Discharge
|
Independent variable |
Adjusted Odds ratio (95% CI) |
P value | |
Age |
1.07 (0.94, 1.21) |
0.29 | |
Male sex |
1.19 (0.47, 3.07) |
0.71 | |
Pre-existing epilepsy |
0.39 (0.12, 1.22) |
0.10 | |
Acute symptomatic etiology |
4.50 (1.49, 13.62) |
0.008 | |
Seizures duration |
1.01 (0.99, 1.0) |
0.52 | |
No anti-convulsant drug administered pre-hospital |
3.97 (1.06, 14.81) |
0.04 | |
Response to first anti-line benzodiazepine |
0.72 (0.25, 2.05) |
0.54 | |
Unfavorable outcome: Pediatric overall performance category ≥ 3. |
We used the second dose of midazolam in children who
continued to have seizures after 10 minutes of the first
dose. However, none of these children responded. The reason
for this may be the inherent pharmacokinetics of BZDs; with
higher doses of these drugs, proportionate increase in
clinical effect may not be seen. We could not find any
literature providing data on the use of second dose of
intravenous (IV) midazolam. The response to IV midazolam
noted in more than half of the patients in our study is
similar to another study which observed an efficacy of
around 70% in children given lorazepam or diazepam [6]. In
another study, midazolam was reported to be effective in
90.3% children [10]. The reason for such a high response
rate was that they considered it effective even if it failed
as initial injection, but was effective as infusion. In a
Cochrane review of studies including patients of all age
groups, IV lorazepam was found to be more efficacious than
diazepam; however, no difference was seen between IV
midazolam, diazepam or lorazepam [11]. A few studies done in
the pediatric age group have not shown superiority of any
particular BZD over the others [6,12]. In a retrospective
analysis of patients with SE [13], 31% of the patients
required midazolam infusion [13], as compared to 5% in this
study. This difference could be attributed to possible
delays in reaching the centre/initiation of treatment as the
study center is a busy referral centre in Northern India.
Further, the retrospective collection of data might also
have influenced the results.
The causes for SE
differ greatly in developed and developing countries. In
contrast to developing countries where CNS infections are
the predominant cause of SE in children, febrile SE and
idiopathic (unknown etiology) cause form the majority in
developed countries [10,14]. Due to the wider age range of
children in our study, we probably had a large spectrum of
causes of SE. In the studies from developed countries,
though the acute symptomatic cause is less common, but still
CNS infections constitute the majority in the acute
symptomatic group [10,14,15].
In our study, children
with acute symptomatic etiology and non-administration of
AED prior to the hospital were found to predict unfavorable
outcome. Children with refractory SE and super refractory
SE, had a significantly unfavorable outcome. In previous
studies, younger age group, longer duration of SE, poor
response to initial anticonvulsants, acute symptomatic group
and refractoriness to the overall treatment have been shown
to be associated with higher mortality [1-3,16,17].
In conclusion, CNS infections are the single leading cause
of SE in children in this region. Absence of pre-hospital
AED treatment predicts an unfavorable outcome for the
children. However, more than half of the children have BZD
responsive SE. Increasing the awareness of parents and
primary health care providers about the appropriate use of
BZDs may decrease the morbidity and poor outcome of SE.
Contributors: SS, SA: conceived the study; CC,SS,SBM,SA:
provided clinical care to the patients; CC,SS,PJ: did the
data analysis and interpretation; CC, SBM: wrote the first
draft which was the read, revised and approved by all the
authors. All authors approved the final version of
manuscript, and are accountable for all aspects related to
the study.
Funding: None;
Competing
interests: None stated.
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