|Ahead of print
Nonconvulsive status epilepticus in children with acute encephalopathy: A prospective observational study
Sruthi Thiruveedi1, Lokesh Lingappa2, Ramesh Konanki2, Smilu Mohanlal2
1 Department of Pediatrics, Rainbow Children’s Hospital and Birthright, Banjara Hills, Hyderabad, Telangana, India
2 Department of Pediatric Neurology, Rainbow Children’s Hospital and Birthright, Banjara Hills, Hyderabad, Telangana, India
|Date of Submission||09-Mar-2021|
|Date of Decision||06-Jul-2021|
|Date of Acceptance||08-Aug-2021|
|Date of Web Publication||12-Jul-2022|
Rainbow Children’s Hospital and Birthright, Banjara Hills, Hyderabad 500034, Telangana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Nonconvulsive status epilepticus (NCSE) in children is underrecognized. Objectives: Assessing the incidence of NCSE in children with acute encephalopathy (AE), clinical description, electroencephalogram (EEG) patterns, and therapeutic response were the objectives. Materials and Methods: Children aged from 6 months to 16 years with AE, Glasgow Coma Scale < 12 were included. Clinical assessment, neurological evaluation, laboratory investigations, cerebrospinal fluid (CSF) analysis, and neuroimaging studies were done. EEG was done for 1 h within 24 h of presentation, repeat EEG on day 3, and continuous EEG monitoring, where needed. Improvement in GCS and EEG determined therapeutic response. Results: Twenty-five (25.51%) of 98 children had NCSE. Altered sensorium (100%), seizures (76.5%), and fever (64.2%) were the common presentation. CSF analysis (61/98) was abnormal in 30 children. There was a significant increase in background slowing (24 to 42, P = 0.001), decrease in sleep markers (42 to 22, P = 0.009), significant decrease in the number of patients with epileptiform discharges (28 to 14, P = 0.036). On day 1, 22 of 25 children had NCSE, 11 had persistence until day 3, three exhibited new appearance on day 3. Generalized discharges (64%) on EEG were common and febrile infection-related epilepsy syndrome (FIRES) (40%) the most common etiology. Signal changes in cortex (n = 7), deep gray matter changes (n = 8), and subcortical and deep white matter changes (n = 10) were the abnormalities on magnetic resonance imaging (MRI). Absence of sleep waves, ictal rhythms on EEG, generalized seizures on day 1 and number of episodes, symmetry, focal seizures, and hyperglycemia on day 3 were significant risk factors for NCSE. Sepsis/systemic inflammatory response syndrome, metabolic causes, trauma, and autoimmune disorders had lower risk of developing NCSEConclusion: A strong association between clinical seizures and NCSE is demonstrated. The most common etiology for NCSE was FIRES. EEG on day 3 helps in identifying new occurrence of NCSE.
Keywords: Electroencephalogram, levetiracetam and benzodiazepines, neuroimaging, non-convulsive status epilepticus
| Introduction|| |
Nonconvulsive status epilepticus (NCSE), a group of syndromes with a wide range of responses to anticonvulsant therapy, poses a diagnostic challenge. In children, NCSE can be associated with various conditions, including acute neurological injuries, specific childhood epilepsy syndromes, neurobehavioral manifestations, and learning difficulties. NCSE remains unrecognized within the first 24 h of emergency room visit in >50% of patients presenting with only changes in the mental status, indicating a higher incidence than reported.
It is estimated that NCSE occurs in ≈50% of patients with coma or convulsive status epilepticus and it occurs in 8%–37% of the general intensive care unit population. NCSE in children is under-recognized and studies that specifically address the epidemiology of NCSE in childhood, particularly in acute encephalopathy (AE), are scarce.
| Materials and Methods|| |
This prospective cross-sectional study was conducted by the department of neurology of a tertiary care hospital between August 2016 and March 2018, after obtaining the Institutional Ethics Committee’s approval; the study was conducted as per the research guidelines on human participants. Estimating the incidence of NCSE in children with AE was the primary objective and describing the clinical presentation, EEG patterns, and therapeutic response in children with NCSE were the secondary objectives.
We included children aged 6 months to 16 years admitted to the pediatric intensive care unit (PICU) with AE and Glasgow Coma Scale (GCS) < 12.
Clinical assessment, including general and neurological evaluation, was performed. Laboratory investigations as part of standard care were done. Individualized diagnostic laboratory investigations were performed as per the patient need.
CSF analysis (protein, glucose, cell count—total and differential count, analysis for N-methyl-D-aspartate receptor [NMDA], Polymerase chain reaction [PCR], culture, GeneXpert, if applicable), neuroimaging studies (computed tomography [CT] and MRI) were done as a part of standard care.
EEG was done at predefined intervals (for 1 h within 24 h of presentation, repeat EEG on day 3, and continuous EEG monitoring, if needed). Different EEG patterns considered for assessment were background, sleep markers, symmetry of background, generalized epileptiform discharges, focal, multifocal, lateralized periodic discharges (PLEDS), bilateral periodic discharges (BIPLEDS), generalized periodic discharges (GPLEDS), frontal intermittent rhythmic activity (FIRDA, now termed occasional frontally predominant brief 2/s generalized rhythmic delta activity [SI-evolving LRDA]), ictal rhythms, burst suppression, and decremental response. NCSE was diagnosed as per Trinka and Leitinger.
Therapeutic response to treatment intervention was assessed based on improvement in GCS (clinical improvement) and EEG. The protocol for treatment of NCSE included standard anti-seizure medications that included phenobarbitone and levetiractam in children aged less than one-year-old phenobarbitone and levetiractam, more than one year and levetiracetam and sodium valproate in children aged more than one year age included levetiracetam and sodium valproate. Midazolam infusion was used to achieve burst suppression pattern of 5–10 s with bursts. This was further individualized; based on normal or minimally abnormal brain scan, the burst suppression was aggressively pursued. When there was an associated breakthrough generalised tonic-clonic seizures (GTCS) not controlled with standard anti-seizure medication, ketamine and isoflurane anesthesia was administered.
Student ‘t’ test (unpaired t test) was used as a test of significance for continuous data. The inter-relationship EEG variables between day 1 and 3 were compared by using either chi-square or Fisher’s exact test depending on the cell frequencies.
Odds ratios were calculated for each categorical and continuous risk factor; univariate and multivariate logistic regression were constructed with day 1 and day 3 NCSE to identify independent clinical risk factors for NCSE. Differences in odds ratio between NCSE on day 1 and day 3 were tested using z test.
STATA version 15.1 and the statistical package for social sciences (SPSS 21st version) were used for the analysis. A P value <0.05 with two sides was considered statistically significant.
| Results|| |
One hundred and thirty-nine children diagnosed to have AE with GCS ≤ 12 who were hospitalized were included into the study. Data of 41 were excluded. There were 50 (51.0%) males and 48 (49.0%) females.
The mean ± SD age of the patients was 5 years ±4. Majority of the children were in the age group of 1–4 years (toddlers, n = 39, 39.8%) followed by 4–9 years (n = 28, 28.6%), >9 years (n = 17, 17.3%), and 6 months to 1 year (n = 14, 14.3%). Of the 98 children included in the study, 25 (25.5%) developed NCSE.
Age and gender distribution of NCSE
Of the 25 children with NCSE, 10 (40%) and 8 (32%) were in the age group of 1–4 years, and 4–9 years respectively; five were aged >9 years, and two were aged 6 months to 1 year.
There were 15 (60%) males and 10 (40%) females among those who had NCSE on day 1 and day 3.
The common features apart from encephalopathy included seizures (n = 75, 76.5%) and fever (n = 63, 64.2%). [Table 1] lists the clinical presentations and causes for AE with or without seizures among the study population.
|Table 1: Clinical presentation and causes for acute encephalopathy with or without seizures among the study population |
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There were 11 (11.0%) children with past h/o seizures and were on anti-seizure medications.
A GCS score of 9–12 was noted in 69 (70%) 4–8 in 22 (23% , and 3 in seven (7.0%) children.
CSF analysis (done in 61/98 children) was normal in 31 patients; among those with abnormal CSF analysis (n = 30), 24 had CSF cell count > 5 cells/mm3. CSF viral PCR panel was positive in two patients (tested in nine), and CSF NMDA antibodies were positive in one (tested in nine). CSF culture was negative in all.
Neuroimaging was done in 90 (91.8%) patients. CT brain was abnormal in 26 out of 39 (66.6%) patients; edema (n = 21, 80.7%), hemorrhage (n = 7, 26.9%), infarct (n = 5, 19.2%), midline shift (n = 2, 7.6%), and bony defect (n = 7, 26.9%) were noted.
MRI brain was abnormal in 58 out of 66 (87.8%) patients. Signal changes in cortex (n = 25, 43.1%), deep gray matter changes (n = 37, 63.7%), subcortical and deep white matter changes (n = 25, 43.1%), brainstem changes (n = 12, 20.6%), cerebellar changes (n = 12, 20.6%), and herniation (n = 2, 3.4%) were observed.
Three children presented with acute loss of brainstem reflexes, that is, severe brainstem dysfunction and deteriorated. Neuroimaging of these three children was suggestive of acute necrotizing encephalitis (ANE) [Figure 1].
|Figure 1: A: CT images showing hypodense areas in thalamus and midbrain. B: FLAIR axial MRI brain demonstrating hyperintense signals in midbrain and temporal white matter with partial sparing of red nucleus|
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Day 1 EEG was done for all patients, whereas day 3 EEG was done for 89 patients.
The background was normal in 31 and 21 patients on day 1 and 3, respectively [Table 2].
|Table 2: Comparison between day 1 and day 3 EEG with respect to background, sleep markers, and epileptiform discharges|
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There was a significant increase in background slowing from day 1 to day 3 EEG (P = 0.001) and a significant decrease of sleep markers in day 3 EEG when compared with day 1. There was a significant decrease in the number of patients with epileptiform discharges by day 3 (P = 0.036) and a significant reduction in the generalized epileptiform discharges from day 1 to day 3 (P = 0.043) [Figure 2]. [Figure 3] and [Figure 4] show the different EEG patterns noted in our patients.
|Figure 2: Comparison of different types of EEG abnormalities on day 1 and 3 |
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|Figure 3: EEG demonstrating generalized spike wave discharges with burst suppression pattern in a child with new-onset refractory status epilepticus|
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|Figure 4: Spike and slow wave discharges (more on the left side than the right) at rhythmic intervals (generalized periodic epileptiform discharges) with no normal background activity|
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The presence of NCSE in EEG was seen in 25 out of 98 (26%) patients. On day 1, 22 (22.4%) patients had NCSE and its persistence on day 3 was noted in 11 patients; new appearance of NCSE was observed in three patients on day 3, and all three had a final diagnosis of FIRES.
Of the 25 patients with NCSE, 16 (64%), seven (28%), and two (8%) had a GCS score of 9–12, 4–8, and 3, respectively.
Relation between clinical seizures and NCSE
On day 1 EEG, of the 22 cases with NCSE, 19 (86.3%) had a h/o clinical seizures and three (13.7%) had no clinical seizures (P = 0.217). On day 3 EEG, 14 out of 14 patients with NCSE had a h/o clinical seizures (P = 0.028).
Generalized epileptic discharge (n = 16, 64%) was the common feature on EEG, and FIRES (n = 10, 40%) was the most common etiology.
Neuroimaging in NCSE
MRI brain (n = 21) was normal in five patients; signal changes in cortex (n = 7), deep gray matter changes (n = 8), and subcortical and deep white matter changes (n = 10) were the abnormalities noted on MRI.
CT brain (n = 6) was normal in three patients; edema (n = 2) and bony defect (n = 1) were the abnormalities.
Glasgow Outcome Score (GOS) was used to predict the outcome of the subjects [Table 3].
Of the 30 (30.6%) deaths among the study population, sepsis (11) was the most common cause; unknown etiology (7), CNS infections (5), and FIRES (3) were reported as the other major causes. Trauma and metabolic causes were reported in two patients each. Of the five deaths in NCSE, FIRES (2) was the common cause; trauma, sepsis/SIRS, and unknown cause were noted in one patient each. Presence of NCSE had no significant relationship with the mortality of the patients.
Of the five children with NCSE who died, two and three patients had NCSE for <24 h and >24 h, respectively. However, there was no significant relationship (P = 0.763) between NCSE duration and mortality.
Univariate analysis showed that symmetry on EEG (P = 0.000), absence of sleep waves (P = 0.036), ictal rhythms on EEG (P = 0.000), and generalized seizures (P = 0.000) were the statistically significant risk factors on day 1 [Supplementary Table 1].
Univariate analysis revealed the number of episodes (P = 0.012), symmetry (0.001), focal seizures (0.001), and CSF sugar (0.037) on day 3 [Supplementary Table 2] as significant risk factors.
On multivariate analysis, symmetry (P = 0.000) and generalized seizures (P = 0.000) were statistically significant for day 1 and CSF sugar was the significant risk factor for day 3 NCSE [Supplementary Table 3].
On comparison of parameters on day 1 and day 3, none except symmetry (P = 0.000) were statistically significant risk factors [Supplementary Table 4].
|Supplementary Table 4: Comparison between odds ratio for NCSE day 1 and day 3|
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Patients with NCSE were on multiple anti-seizure medication (ASD) (>2). All (100%) patients received levetiracetam as primary ASD after benzodiazepines. Four patients received only levetiracetam with good control of both clinical and nonconvulsive seizures. Three patients had refractory status epilepticus; among them, two responded to midazolam infusion, and one showed a partial response to valproate, lacosamide and a good response to midazolam infusion.
Isoflurane (6), ketamine (6), midazolam (10), lacosamide (14), phenytoin (9), phenobarbitone (16), and sodium valproate (16) were the other medications prescribed.
Seven children had super refractory status epilepticus (SRSE) with an NCSE; among them, six received isoflurane inhalational gas. Burst suppression was achieved satisfactorily in all; partial response (n = 4) to midazolam infusion, to ketamine (n = 3) and a good response to isoflurane gas (n = 6) was noted.
| Discussion|| |
NCSE is underdiagnosed as indicated by the data that ≈20%–23% SE have NCSEs in AE and seizures., It is also seen in a small proportion (8%) of patients in the comatose state without any evidence of seizure. Among those with stabilized/controlled generalized convulsive SE, NCSE is noted in 14% of patients. Recommendations advocate EEG monitoring in those with an altered mental state to rule out NCSE.,, EEG in acute stage may not reveal characteristic features, necessitating a follow-up EEG; hence, we considered a repeat EEG on day 3.
The incidence of NCSE in children with AE varies between 16% and 46%,,,; we report it to be 26%, and clinical seizures were noted in 22 out of 25 patients. In our study, children younger than 5 years (1–4 years, 40%) were the most affected. Altered sensorium (100%), seizures (76%), and fever (65%) were the common presentation. None of our patients displayed changes in behavior, which was however reported as one of the clinical presentations.
In our study, symmetry on EEG, presence of sleep waves, ictal rhythms on EEG, generalized seizures on day 1 and number of episodes, preservation of symmetry, focal seizures, and CSF sugar on day 3 proved to be the significant risk factors. On multivariate analysis, symmetry, generalized seizures on day 1, and CSF sugar on day 3 were the significant risk factors; on comparison of parameters on day 1 and day 3, only symmetry was the significant risk factor.
The most common EEG pattern in our study was diffuse slowing of background (delta activity) with no sleep spindles, suggesting diffuse cerebral dysfunction. A higher proportion (68% from 40%) of children showed diffuse cerebral dysfunction on day 3, which could be attributable to disease progression. There was a decrease in the sleep markers (24% from 43%) on day 3. This is an indication of a significant increase in cerebral dysfunction on follow-up EEG. There are no similar data available in the literature.
There was a decrease in epileptiform discharges from day 1 to day 3 (29% to 15%), probably due to the treatment response as patients were started on AED as part of treatment protocol. The EEG pattern on day 1 showed that generalized discharges (19/28), ictal rhythms (50%), LPDs (6), PDs (4), focal discharges (4), multifocal (3), and BPDs (1). Decremental response in eight and combination of greater than one type of pattern was noted in six children. None of the previous studies in the pediatric population has described the EEG patterns. On day 3, a significant reduction in generalized discharges (P = 0.043) was noted; the decrease in other types of discharges was not significant.
Acute hypoxic–ischemic injury (26%), exacerbation of underlying neuro-metabolic disease (21%) were predominant; however, acute infection (16%), change in antiepileptic drug regimen (16%), refractory epilepsy (11%), and intracranial hemorrhage (11%) were the other causes reported by Tay et al. FIRES (40%) followed by CNS infection (16%) was the common etiology, and the cause remained unknown in 16% of those with NCSE in our study.
There was a significant correlation between clinical seizures and NCSE (P = 0.028). Reports, indicate that the occurrence of clinical seizures is common in NCSE and if it occurs prior to EEG, there is a greater chance of having NCSE on EEG. In our study, a greater number of patients had clinical seizures (n = 75) among whom 25% had electrographic SE. Schreiber et al. report a higher prevalence of electrographic SE (39%).
In our study, 56 out of 75 (75%) children with clinical seizures and AE had a normal 1-h EEG. There was persistence of EEG changes from day 1 to day 3 in 11 patients in whom etiology was FIRES (7), metabolic (2), CNS infection (1), and unknown (1); however, in three patients (FIRES  and unknown etiology ), NCSE was detected on day 3 EEG, suggesting later development of new-onset NCSE. Hence, follow-up EEG is important even in the absence of clinical improvement. We observed a nonsignificant reduction in the frequency of NCSE from day 1 to day 3.
The EEG waveform morphologies in NCSE were variable in our study, which included typical and atypical spike and wave discharges, multiple or polyspike discharges, and ictal based on the clear evolution of frequency and amplitude, in contrast to the reports of Tay et al., who noted focal epileptiform discharges as predominant.
The presence of clinical seizures and acute neuroimaging abnormality was associated with 82% probability of NCSE. Previous studies reported 82% abnormal MRI in NCSE, which was 76% in our study.
The GOS was used to predict the outcome in our study; there was 20% mortality, and 36% had moderate disability. Mortality was due to the underlying illness, and none died directly from NCSE. We found an association between NCSE and prolonged morbidity, but not with mortality. Studies have shown that altered mental status is associated with higher mortality,,, which we could not establish as the majority of our patients were aged <4 years. Our study showed that the presence or duration of NCSE had no significant association with higher mortality. Poor GCS did not predict the presence or absence of NCSE in EEG, and there are no available data for comparison.
Correlating NCSE with radiology, and outcome with GOS are the strengths of the study. Not assessing the therapeutic efficacy of each AED (as the majority of the patients received >2 drugs) and associations between the variables that did not reach a statistical significance due to low incidence of NCSE (26%), are the limitations. Continuous EEG monitoring (24 × 7) was not done in all except for those with FIRES, consequently missing the episodes of NCSE, limiting the sensitivity in the detection of NCSE. The duration of NCSE (<24 vs. >24 h) was assessed for the non-survivors only.
| Conclusions|| |
A strong association between clinical seizures and NCSE is demonstrated. Diffuse cerebral dysfunction was the most common EEG pattern in comatose children. Day 3 EEG was characterized by a significant increase in diffuse cerebral dysfunction and a decrease in epileptiform discharges. A few patients may develop new-onset NCSE by day 3, and we recommend a repeat EEG. Isoflurane provided the best burst suppression for electrographic seizures on NCSE.
Declaration of patient consent
The authors certify that they have obtained all appropriate consent forms. The patients have given their consent for their images and other clinical information to be reported. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity but anonymity cannot be guaranteed. Patient information sheet and informed consent forms were reviewed by the Institutional Ethics Committee.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]