Highlights
- •Outcome in pediatric status epilepticus is highly related to underlying etiology.
- •Mortality in pediatric SE is relatively low, while morbidity poses more challenges.
- •Greater use of objective, valid, and reliable outcome measures should be utilized.
Abstract
Purpose
To summarize different aspects of short and long-term outcomes associated with SE, including mortality, recurrence, subsequent epilepsy, neurocognitive dysfunction, imaging abnormalities, and health-related quality of life.
Methods
We searched MEDLINE for studies that assessed the short-term and long-term outcome of status epilepticus in pediatric population, including mortality, recurrence of seizure and status epilepticus, neurological, cognitive, or behavioral impairment, and health-related quality of life. We excluded studies that exclusively assessed the adult population.
Results
Mortality in pediatric SE is relatively low, while morbidity poses more challenges. The underlying cause of SE has been shown to be a major determinant in the outcome after SE. However, it is difficult to establish the net effect of SE on outcome due to the heterogeneity of the studies. Notably, this review highlights that health-related quality of life, an important aspect of long-term outcome in pediatric SE, is under-addressed and merits further investigation.
Conclusion
There is a need to acquire high-quality long-term data evaluating QoL, neuroimaging, use of continuous infusions, and cognitive and behavioral outcome of children who experience SE.
Keywords
1. Introduction
Status epilepticus (SE) is one of the most common neurologic emergency in pediatrics. The estimated incidence is about 20/100,000 per year [
[1]
]. It is generally believed that SE is associated with poor short- and long- term outcomes, including mortality and morbidities such as recurrence, development of subsequent epilepsy, and neurological or cognitive impairment. However, the extent of the effect of SE on the outcome is not well understood. There are many obstacles to define the net effect of SE on the observed outcome given potential confounding factors, namely the underlying etiology of SE, in addition to differences in study design, study populations, and outcome measures.In this paper, we review the available data on the outcomes of SE in the pediatric population and focus on key aspects of outcome, including morbidity and mortality. Different aspects of the observed outcomes based on available data are discussed.
2. Methods
We searched MEDLINE using the term “status epilepticus”, combined with “outcome”, “mortality”, “morbidity”, “recurrence” and “quality of life”. Search matches were reviewed to select relevant articles. We included studies that assessed the short-term and long-term outcome of status epilepticus in pediatric population, including mortality, recurrence of seizure and status epilepticus, neurological, cognitive, or behavioral impairment, and health-related quality of life. We excluded studies that exclusively assessed the adult population. All the included articles were then reviewed in full text. References of relevant articles were also searched. Only publications in English language were included in this review.
3. Results and discussion
3.1 Mortality
Short-term mortality rate in 30 days or until discharge ranged from 2.1% to 6% in studies conducted after 2000s, and from 2.7% to 11.5% in studies conducted before 2000. The reported short-term mortality rate was higher in some studies conducted in developing countries [
2
, 3
] (7.1%–17.5%) (Table 1). The advent of modern neurocritical care and improvement of out-of-hospital emergency medical care probably contributed to the decreased mortality. In a systematic review conducted in 2007, the short-term mortality rate of SE ranged from 2.7–5.2% considering only the high-quality studies [[4]
]. Long-term mortality ranged from 2.3% to 11% depending on the duration of follow-up (Table 1) [[5]
].Table 1Mortality and associated risk factors in pediatric CSE.
| Author | Year | Design | Number | Age | F/u | Mortality | Risk factors |
|---|---|---|---|---|---|---|---|
| Pujar [22] | 2017 | Prospective | 226 | 1 month-18 years | median 8·9 years (IQR 8·2–9·5) | 10% (3% within 1 month) | |
| Hommady [42] | 2017 | Retrospective | 116 | 1 month- 10 years (median 4.5 years) | NA | 2.6% | Symptomatic SE etiology |
| Santhanam [43] | 2017 | Retrospective | 610 | 1 month-12 years | NA | 4.6% | Respiratory symptoms (grunt, rales, retractions), cardiovascular dysfunction, shock requiring fluid resuscitation, delayed capillary refill, inappropriate prehospital management. |
| Hassan [44] | 2016 | Prospective | 84 | 21.3 ± 19.9 | Discharge-1 year | 14% | Risk factors for mortality and morbidity: Etiology, age, delay in treatment, absence of past history of epilepsy |
| Prins [45] | 2014 | Prospective | 119 | 95% between 2 and 9 years | 3–4 years | 7.6% | |
| Jayalakshmi [46] | 2014 | Retrospective | 177 | 31.6 ± 19.2 years | 6 months | 6.7% | Mortality was higher in refractory SE (40.0%) and super-refractory SE (35.7%) than non-refractory SE (6.7%) |
| Encephalitis had higher mortality than other etiologies. | |||||||
| Bhalla [47] | 2014 | Prospective | 80 | 13–78 | 2 weeks | 5% | |
| Shatirishvili [48] | 2014 | Prospective | 48 | 1 month–18 years | 30 days | 8.3% | Etiology |
| Loddenkemper [11] | 2012 | Retrospective | 12,365 | <20 years (mean 6.2 years) | – | 0.9% | Near drowning, hemorrhagic shock, sepsis, massive aspiration, mechanical ventilation, transfusion, structural brain lesion, hypoglycemia, sepsis with liver failure, and admission in December |
| Pujar [6] | 2011 | Prospective | 206 | 1 months – 16 years (mean 32.3 months) | 8 years | 11% | Presence of clinically significant neurological impairment prior to CSE |
| Lin [2] | 2009 | Prospective | 141 | 2 months –18 years | 1 month | 7.1% | Etiology, age |
| Molinero [49] | 2009 | Prospective | 47 | 1 months –16 years (mean 4.5 years) | 13 weeks | 13% | Infectious cause, cerebrovascular accident, long duration of SE |
| Mpimbaza [50] | 2008 | Randomized clinical trial | 330 | 3 months – 12 years | Discharge | 6% | Malaria, severe malnutrition, immunosuppression, pneumonia |
| Saddarangani [8] | 2008 | Prospective | 138 | 1 month – 13 years | Discharge | 15% | Acute bacterial meningitis, age, hypoglycemia, focal onset seizures |
| 3 years | 21% | ||||||
| Siddiqui [51] | 2008 | Descriptive cross-sectional | 125 | 2 months – 15 years | 12% | Acute intracranial infections, age, prolonged SE | |
| Hayashi [52] | 2007 | Retrospective | 358 | Mean 48.6 (SD 46.5) months | Discharge | 2.1% | Encephalitis, cerebrovascular disease |
| Muchochi [53] | 2007 | Non-Randomized study | 26 (children with severe malaria) | 6 months – 13 years | Discharge | 11.54% | Pre-existing cerebral malaria, convulsions |
| Chin [13] | 2006 | Prospective | 226 | 29 days – 15 years | 2–26 months | 3% (2–7%) | |
| Ahmad [54] | 2006 | Open randomized trial | 160 | 2 months – 12 years | Discharge | 17.5% | Progressive infection, cerebral malaria, febrile convulsions, acute bacterial meningitis, metabolic derangements |
| Morrison [55] | 2006 | Retrospective | 17 (refractory SE) | 0–17 years (median 3.5 years) | Discharge | 18% | Subdural hematoma, birth asphyxia, post cardiac arrest |
| Maegaki [56] | 2005 | Retrospective | 241 | 1 month –18 years | 3.8% | Prolonged SE, moderate to severe asthma | |
| Kang [57] | 2005 | Retrospective | 189 | <15 years | Mean: 17 months | 3% | Higher mortality in acute symptomatic SE vs. remote symptomatic SE |
| Asadi-Pooya [58] | 2005 | Retrospective | 135 | 1 month – 15 years | 10·4% | Prolonged febrile seizure, CNS infection, metabolic, AED withdrawal, symptomatic epilepsy, prolonged stay | |
| Brevoord [59] | 2005 | Retrospective | 122 | 0.5–197.4 months (median: 24.4 months) | 3 months | 5.7% | Near drowning episode, pneumococcal meningitis, cardiac failure, brainstem tumor, hemorrhagic shock, metabolic defect |
| Gualti [60] | 2005 | Retrospective | 30 | 1–120 months (mean: 56.6 ± 46.5 months) | Discharge | 30% | Prolonged SE, septic shock |
| Berg [61] | 2004 | Prospective | 613 | 1 month – 15 years | Median: 8.0 years | 8.9% | Neurodegenerative disorder, epileptic encephalopathy, prolonged SE |
| Kwong [14] | 2004 | Retrospective | 25 | < 15 years | 36 months | 8% | |
| Wu [62] | 2002 | Retrospective | 2885 | All age groups children and adult | Discharge | 1.9% | Female sex, older age |
| Logroscino [10] | 2002 | Retrospective | 184 | children and adult | 10 years | 7.4% (pediatric) | Prolonged SE, acute symptomatic etiology, myoclonic SE |
| Koul [63] | 2002 | Retrospective | 68 | 2 months – 14 years | 1.5% | ||
| Sillanpaa [64] | 2002 | Prospective | 41 | < 16 years | 30y | 17% | |
| Singhi [65] | 2002 | Prospective | 40(refractory SE) | 2–12 years | Discharge | 25% | Early intubation and ventilation, meningoencephalitis, acute hyponatremia, hepatic encephalopathy |
| Shinnar [27] | 2001 | Prospective | 180 | 1 month – 10 years | 1 month | 0% | |
| Tabarki [66] | 2001 | Retrospective | 139 | 1–24 months, (mean 11 months) | 4 years | 15.8% | Acute symptomatic seizure, progressive encephalopathy |
| Kim [67] | 2001 | Retrospective | 23(severe refractory SE) | 0–15 years | 4 years | 43.5% | Acute symptomatic etiology, anoxia |
| Sahin [68] | 2001 | Retrospective | 22(severe refractory SE) | 4.5 months–18 years | 31·2 months | 31.8% | Remote symptomatic and progressive encephalopathy |
| De Lorenzo [69] | 1999 | Prospective | 228 | >1 month (pediatric and adult) | 1 month | Overall 19%, Pediatric 4% | |
| Mah [70] | 1999 | Retrospective | 59 | Mean: 2 years and 10 months | 5 y | 2% | |
| Bernard [71] | 1999 | Retrospective | 52 | 1 month- 15 years | Discharge | 9.6% | Brain tumors, metabolic disorder, multi-organ failure |
| ≥ 3 months | 15.4% | ||||||
| Waterhouse [72] | 1999 | Prospective | 212 | Adults and pediatric | 5.2% in pediatric | CNS infection, hypoxia, drug withdrawal, continuous SE | |
| Eriksson [73] | 1997 | Retrospective | 65 | Under 16 years | 3–6 years | 0% | |
| Scholtes [74] | 1996 | Retrospective | 112 | 6 months – 15 years | Discharge | 11.5% | Anoxia, presence of complication, Insufficient therapy, prolonged duration |
| Lacroix [75] | 1994 | Retrospective | 147 | 3 days – 18 years | Discharge | 6.1% | |
| 1 year | 9% | ||||||
| Verity [7] | 1993 | Prospective | 37 | Cohort followed from birth to 10 years | Discharge | 2.7% | |
| 10 years | 5.4% | ||||||
| Shinnar [76] | 1992 | Prospective | 95 | 1 months – 18 years | 4–60 months | 4.2% | |
| DeLorenzo [77] | 1992 | Retrospective | 546 (171 pediatric) | from birth to >80 years | 2.3% | Tumor, hematological disease, anoxia, metabolic and congenital malformations | |
| Maytal [25] | 1989 | Retrospective with prospective follow-up | 97 | 1 month – 18 years | 13.2 months | 7.2% | Prolonged SE |
| Dunn [78] | 1988 | Prospective | 97 | Children | Discharge | 8.24% | Severe pre-existing brain damage, meningitis and encephalopathy |
| Yager [28] | 1988 | Prospective | 52 | Median 2 years | 18 months | 5.8% | |
| Cavazzuti [79] | 1984 | Prospective | 66 | <5 years | 5–10 years | 3% | |
| Chervie [80] | 1978 | Prospective | 334 | 28 days – 1 year | 1 year | 6.3% | Symptomatic seizures, age |
| Aicardi [81] | 1970 | Retrospective | 239 | < 15 years | Discharge | 4.2% | Prolonged SE, cerebral disease |
| After a few weeks to several years | 11.2% |
Several study design factors could influence the results, including the definition of SE, age groups enrolled, duration of follow-up, population-based versus hospital-based settings, and the quality of the studies (sample size and power, and selection or information biases).
Different factors have been described to be associated with mortality in SE including etiology, age, SE duration, and neurological and other non-neurological co-morbidities (Table 1).
3.1.1 Etiology
Studies evaluating acute symptomatic etiologies (including CNS infection, trauma, metabolic derangements, hypoxia) consistently demonstrated worse outcomes compared to those without a clear underlying etiology or with febrile seizures [
[5]
]. For previously neurologically healthy children, all deaths occurred in patients who had acute symptomatic convulsive status epilepticus (CSE) in a population-based study in London, with febrile SE having an overall very good short and long-term outcome [[6]
]. Likewise, in another national cohort, mortality in unprovoked or febrile CSE was lower compared to acute symptomatic cases [[7]
]. The finding that mortality is related to the presence of a symptomatic etiology is not surprising as there can be more varied injury secondary to the underlying etiology versus febrile status epilepticus, e.g. − a large hemispheric stroke with cerebral edema may be expected to have a worse outcome than a small lacunar stroke. The bigger challenge is determining what effect status epilepticus has on mortiality independent of the etiology.3.1.2 Age
The association of age and mortality due to SE in pediatric patients have been examined in different studies (Table 1). Several studies have shown higher risk of mortality in younger patients, especially in the first year of life [
4
, 8
, 9
, 10
]. Some other studies have shown no association between age and mortality [6
, 11
], or an increased odds ratio for mortality in the second decade of life compared to the first decade [[12]
]. However, the underlying etiology is a major confounder of the effect of age on mortality. The distribution of etiologies is different among age groups. Acute symptomatic etiology, which is associated with higher mortality as discussed in the etiology section above, is more common in patients under one year old [8
, 13
, 14
, 15
, 16
, 17
]. Thus, the higher mortality rate in the infants under one year old could be at least in part due to the higher prevalence of acute symptomatic etiologies, including CNS infection and metabolic derangements, in this age group.3.1.3 Prior neurological abnormality
The presence of a prior neurological abnormality has been associated with a higher mortality in patients with SE. In a large population-based study of children with prior CSE conducted by North London Epilepsy Research Network with a follow-up duration of 8 years, CSE patients experienced a mortality 46 times higher than an age-matched population, with a history of prior neurological abnormality being the only independent factor that significantly predicted the mortality. Seven of 206 (3%) children died within 30 days after CSE, and the mortality rate during the 8-year follow-up was 11%. Overall, children with a prior history of neurological impairments had a seven times higher risk of death within 8 years following CSE compared with previously neurologically healthy patients. Considering only the subgroup of patients who survived beyond 30 days after CSE, the mortality within 8 years was 19 times higher in those who had prior neurological deficits compared with the previously healthy children [
[6]
]. The authors of this study point out that the mortality rate for these patients is similar to mortality in patients with severe cerebral palsy suggesting that the underlying neurologic abnormality may play a larger role than the episode of status epilepticus itself in long term outcome.3.1.4 Duration of SE
Longer duration of SE is associated with increased mortality. In a population based study, SE duration of greater than 24 h more than doubled the risk of mortality compared with a duration of less than 2 h [
[10]
]. It has been shown that for every minute of increase in the duration of SE, the odds ratio of mortality increased by 0.005 [[18]
]. As with mortality, a longer duration of SE may be related to the severity of underlying etiology [[19]
]. In addition, increasingly aggressive therapies with more potential adverse effects are typically used as the duration of SE increases. How these factors interact can be difficult to control for in retrospective studies.3.2 Morbidity
3.2.1 Recurrence and subsequent epilepsy
According to previous studies, the risk of recurrence of SE was variable, ranging from 3.7-56% (Table 2). As with mortality, the rate of recurrence is highly dependent on the study design and characteristics of study population, such as the underlying etiology and previous history of neurological impairment. Table 2 demonstrates the risk of recurrence in the different etiologic groups as reported in different studies. In general, patients with a previous neurological impairment and symptomatic etiology were more likely to experience recurrence of SE than patients with febrile SE or an idiopathic etiology. This was demonstrated in a prospective study of 27 non-febrile CSE and 27 prolonged febrile seizures followed for one year, where one out of 27 children with prolonged febrile seizures (3.7%) experienced a recurrent episode, compared to 11.1% in the non-febrile group [
[20]
]. Furthermore, in a retrospective study of afebrile CSE, the recurrence rate in 10 years was 31.7% [[21]
].Table 2Rate of recurrence and subsequent epilepsy in pediatric CSE.
| Author | Year | Design | Number | Age | F/u | Recurrence | Subsequent Epilepsy | Comparison among etiologic groups |
|---|---|---|---|---|---|---|---|---|
| Pujar [22] | 2017 | Prospective | 226 | 1 month-18 years | median | 18/73 (24.7%, CI: 16.2–35.6%) | Prolonged febrile: 14.3% (CI: 6.3–29.4%) | |
| 8.9 years (IQR 8.2–9.5) | History of epilepsy before CSE was the only significant predictor of active epilepsy at follow-up (OR 8·4, 95% CI 1·8–39·0) | Acute symptomatic: 13.3% (3.7–37.9%) | ||||||
| Remote symptomatic: 45.5% (CI: 21.3–72.0%) | ||||||||
| Unclassified: 50.0)CI: 25.4–74.6) | ||||||||
| Wagenman [29] | 2014 | Prospective | 300 admitted with acute neurologic conditions (with and without seizures), 137 followed up | Median 3.9 years (IQR: 1.1–12.7) | Median 2.6 years (IQR: 1.5–3.2) | ESE (but not ES) associated with new onset epilepsy at follow-up (OR for ESE compared to those without seizure 13.33; 95% CI 2.49, 71.35). 12 of 13 (92%) of patients with ESE developed subsequent epilepsy. | ||
| Prins [45] | 2014 | Prospective | 119 | 95% were 2–9 years | 3–4 years | 14.5% | ||
| Bhalla [47] | 2014 | Prospective | 80 | 13–78 years | 2 weeks | 25% | ||
| Martinos [20] | 2013 | Prospective | 27 non-febrile CSE, | 1–42 months | 1 year | 3.7–11.1% | Non- febrile: 11.1% | |
| 27 prolonged febrile seizures | Febrile: 3.7% | |||||||
| Lin [2] | 2009 | Prospective | 141 | 2 months –18 years | 1 year | 17% | Those with neurological deficit were more likely to show recurrence | |
| Saddarangani [8] | 2008 | Prospective | 138 | 1 month – 13 years | 1 years | 12% | ||
| Hesdorffer [21] | 2007 | Retrospective | 193 | Pediatric and adult | 10 years | 31.7% (only afebrile SE) | 41% | Risk of recurrence: 100% for progressive |
| Symptomatic SE, 23.6% for remote symptomatic | ||||||||
| SE, 26.1% for idiopathic/cryptogenic SE, and 26.3% for acute symptomatic SE (log rank p = 0.09). | ||||||||
| Progressive symptomatic SE 2.4-fold more likely to recur compared with idiopathic/cryptogenic SE (this risk was no longer significant in the multivariate model (95% CI: 0.6–8.9). | ||||||||
| Chin [13] | 2006 | Prospective | 226 | 29 days – 15 years | 2–26 months | 13%, (95% CI 9–19) during the follow up; 1-year recurrence: 16% | Pre-existing neurological abnormality: 2·9 times (95% CI 1·01–8·45) more likely to have a recurrence within 1 year; | |
| 17% (95% CI 7–34) of children with first episode of prolonged febrile seizure had a recurrence within 1 year | ||||||||
| Maegaki [56] | 2005 | Retrospective | 234 | 1 month – 18 years | 64·2 months | 23% | ||
| Kang [57] | 2005 | Retrospective | 189 | <15 years | Mean: 17 months | 16% | Risk ratio for recurrence: | |
| Generalized seizure 6.83 | ||||||||
| Epilepsy 4.51 | ||||||||
| Remote symptomatic 3.21 | ||||||||
| Berg [61] | 2004 | Prospective | 613 | 1 month – 15 years | Median: 8.0 years | 32.1% | Recurrent rate: | |
| Idiopathic: 37.5% | ||||||||
| Cryptogenic: 14.8% | ||||||||
| Symptomatic: 52.4% | ||||||||
| Kwong [14] | 2004 | Retrospective | 25 | <15 years | 36 months | 13% | None of the patients with idiopathic or febrile etiology developed subsequent epilepsy | |
| Sillanpaa [64] | 2002 | Prospective | 41 | <16 years | 30y | 56% | Neither etiology nor neurological abnormality were significant predictors of recurrence in multivariate analysis | |
| Sahin [68] | 2001 | Retrospective | 22(refractory SE) | 4.5 months – 18 years | 31·2 months | 100% | 5/8 of subsequent seizure cases had acute symptomatic etiology, 2/8 remote symptomatic, 1/8 remote symptomatic with Acute precipitant | |
| Tabarki [66] | 2001 | Retrospective | 139 | 1–24 months, (mean: 11 months) | 4 years | 29% | Acute symptomatic: 5/56 developed subsequent epilepsy; | |
| Febrile 2/57; | ||||||||
| Progressive/remote symptomatic/idiopathic: 0. | ||||||||
| Another 27 cases developed mental retardation plus epilepsy | ||||||||
| Mah [70] | 1999 | Retrospective | 43 | Mean: 2 years and 10 months | 5 y | 28% | 72% | |
| Barnard [71] | 1999 | Prospective | 52 | 1 month– 15 years | ≥3 months | 50% | 36% | None of the idiopathic or febrile patients developed epilepsy, but 5/8 of non-idiopathic non-febrile did |
| Eriksson [73] | 1997 | Retrospective | 65 | Under 16 years | 3 − 6 years | 23% | 40% of Idiopathic, 4% of febrile, 8% of acute symptomatic, 50% of remote symptomatic, 67% of progressive developed subsequent epilepsy | |
| Verity [7] | 1993 | Prospective | 37 | Cohort followed from birth to 10 years of age | 10 years | 47% | 82% | Afebrile:47% |
| Febrile: 0% | ||||||||
| Shinnar [76] | 1992 | Prospective | 95 | 1 month – 18 years | 4–60 months (mean: 90 months) | 17% | Remote symptomatic: 44% | |
| Progressive: 667% | ||||||||
| DeLorenzo [77] | 1992 | Retrospective | 546, 171 Pediatric | from birth to >80 years | 2years | 43% | ||
| Maytal [25] | 1989 | Retrospective + prospective | 193 | 1month – 18 years | 40.2 months | 14% | 16–44.6% | Development of subsequent seizure: |
| 32.8 months | 6.6% | Idiopathic 15/29 (51.7%), 4/16 (25%)*; | ||||||
| Remote symptomatic 7/11 (63.6%), 1/1 (100%); | ||||||||
| Febrile 2/46 (4.35%), 1/28 (3.57%); | ||||||||
| Acute symptomatic 7/34 (20.6%), 2/21 (9.52%); | ||||||||
| Progressive encephalopathic 5/5 (100%), 3/3(100%) | ||||||||
| Cavazzuti [79] | 1984 | Prospective | 66 | <5years | 5–10 years | 74% | Recurrent seizures: 43/103 (41.7%) cases were symptomatic, and 60/103 (58.3%) were cryptogenic | |
| Aicardi [81] | 1970 | Retrospective | 239 | <15 years | 10.5% | 36% |
*Respectively for the retrospective and the prospective study.
ES: electrographic seizure; ESE: electrographic status epilepticus.
Patients with SE are at risk for subsequent epilepsy, with rates that vary from 12 to 82% depending on the study. The rate of subsequent epilepsy in various studies are summarized in Table 2. If we limit the studies to those with more than 100 subjects within the past 20 years, the rate of epilepsy ranges from 12 to 41% overall. In the large population-based childhood CSE cohort from North London, of 134 survivors of CSE witout prior epilepsy that were followed for a median duration of 8.9 years, 24.7% (95% CI: 16.2–35.6%) developed epilepsy. The incidence was lower in prolonged febrile seizure (14.3%) and acute symptomatic CSE (13.3%) than remote symptomatic (45.5%) and unclassified etiology (50%); however, in the multivariate analysis, absence of fever at CSE was the only predictor of subsequent epilepsy (OR:7.5, 95% CI 2.25–25.1) [
[22]
].3.2.2 Neurological, cognitive, and behavioral impairments
There is compelling evidence in the literature that SE can result in neurological and cognitive impairment. Previous studies have reported new neurological deficits in 6 to 30% of SE patients (Table 3); however, varying outcome measures have been used to study the neurocognitive outcome, making comparison difficult.
Table 3Association of CSE with neurological, cognitive, and behavioral impairments.
| Author | Year | Design | Number | Age | F/u | Outcome measure | Neuropsychological outcome |
|---|---|---|---|---|---|---|---|
| Power [26] | 2017 | Observational | 39 | ≥16 years | 1 year | Neuropsychological Test Automated Battery (CANTAB) | SE patients performed poorer than the normal control in memory tests, but no difference compared to patients with multiple life time GTCs. |
| Pujar [22] | 2017 | Prospective | 226 | 1 month-18 years | median 8·9 years (IQR 8·2–9·5) | Wechsler Abbreviated Scale of Intelligence | Motor disability: 2.1% (CI: 0.6–7.4) |
| Intellectual disability: 10.2% (CI:4.1–21.1) | |||||||
| Atmaca [82] | 2017 | Prospective | 59 | 17–90 years | 1 month | 1.2% had neurological sequela | |
| Hommady [42] | 2017 | 116 | 1 month–10 years | NA | Glasgow Outcome Scale (GOS) score | Etiology and history of prior epilepsy was associated with lower Glasgow Outcome Scale score and moderate-to-severe developmental delay | |
| Reddy [83] | 2017 | Retrospective | 76 | Median 5 months (IQR 6–37 months) | Median 5 months (IQR 2–15 months) | 58% had persistent seizures or neurologic sequelae, with predictors of poor outcome being use of >3 ASMs, intubation >3 days, abnormal brain MRI. | |
| Hassan [44] | 2016 | Prospective | 108 | 21.3 ± 19.9 | Discharge-1 year | 22% had new neurological deficit | |
| Abend [84] | 2015 | Prospective | 300 with acute neurologic conditions, 137 previously neurodevelopmental normal were enrolled, comprising patients without seizure, with ES, and with ESE | Infants and children excluding neonates(median 3.9 years, IQR: 1.1–12.7) | Median 2.6 years (IQR: 1.5–3.2) | The Adaptive Behavior Assessment System—II (ABAS-II) | The Adaptive Behavior Assessment System—II (ABAS-II): median score of 73 (IQR: 48–102) for subjects with ESE; ESE and EEG background were associated with worse score in multivariate analysis (ESE coefficient: −36, p = 0.003) |
| The Child Behavior Checklist (CBCL) | The Child Behavior Checklist (CBCL): median score of 61 (34, 65) for subjects with ESE; difference between the subjects with no seizure, ES, and ESE were not significant | ||||||
| The Behavior Rating Inventory of Executive Function (BRIEF) | The Behavior Rating Inventory of Executive Function (BRIEF): median score 73 (59, 79) for subjects with ESE; no difference between those with no seizure, ES, and ESE | ||||||
| Wagenman [29] | 2014 | Prospective | 300 patients admitted to PIU with acute neurologic conditions, 137 were followed up | Median 3.9 years (IQR: 1.1–12.7) | Median 2.6 years (IQR: 1.5–3.2) | GOS-E | Unfavorable GOS-E Peds for 35% of subjects; ESE was associated with unfavorable GOS-E Peds compared to patients without seizure After controlling for EEG background, acute neurologic disorder, age, and PICU duration (OR: 6.36; 95% CI: 1.48-27.31) |
| Prins [45] | 2014 | Prospective | 119 | 95% were 2–9 years | 3–4 years | Ten-question questionnaire (TQQ) of neurocognitive impairment | 10.9% had neurological deficits at discharge, 30.9% positive in ten-question questionnaire (TQQ) of neurocognitive impairment, 13.6% of 110 screened with TQQ had neurological deficit |
| Shatirishvili [48] | 2014 | prospective | 48 | 1 month –18 years | 30 days | 17% had new neurological deficits: loss of previously reached milestones, diffuse persistent hypotonia, FND-hemiparesis, cranial nerve palsy, cognitive impairment | |
| Martinos [20] | 2013 | Prospective | 27 non-febrile CSE | 1–42 months | 1 year | No differences in the performance of non-febrile and prolonged febrile seizure at baseline on the cognitive, language, and motor scales. | |
| 27 Prolonged febrile seizures | No difference in performance from baseline to follow-up for the prolonged febrile seizure. | ||||||
| In the non-febrile CSE group, baseline and follow-up cognitive, language, and motor composites were positively correlated | |||||||
| Saz [85] | 2011 | Retrospective | 27 | 2.5 months–11 years | 1 year | 14.8% developed new motor or visual deficit none of the febrile SE patients had neurological sequelae | |
| Roy [23] | 2011 | Retrospective | 18 | Infants (mean age: 13.1 months) | Global Developmental Quotient | Patients with SE who were developmentally normal prior to SE scored lower than the healthy controls in Global Developmental Quotient (GDQ) and the | |
| Performance and Eye–Hand Coordination subscales. The score of patients with febrile SE was lower than the healthy individuals but higher than the SE group. | |||||||
| Lin [2] | 2009 | Prospective | 141 | 2 months –18 years | 1 year | GOS | Outcome based on GOS: |
| 9.2% death | |||||||
| 1.4% Vegetative state | |||||||
| 37.6% Severe disability | |||||||
| 31.2% Moderate disability | |||||||
| 20.6% Good recovery | |||||||
| Molinero [49] | 2009 | Prospective | 47 | 1 months –16 years, (mean: 4.5 years) | 13 weeks | 6% had new disability | |
| Saddarangani [8] | 2008 | Prospective | 138 | 1 month – 13 years | 3 years | 11% had neurological sequelae, motor and speech impairments each in 7% of children | |
| Siddiqui [51] | 2008 | Descriptive | 125 | ≤ 15 years | Discharge | 8% had adverse neurological outcome | |
| Pisani [86] | 2007 | Prospective | 106 | Neonate | 24 months | Abnormal outcome in 25/26 (96.1%) of patients with SE |
ES: electrographic seizure; ESE: electrographic status epilepticus; GOS: Glasgow Outcome Scale; GOS-E Peds: Glasgow Outcome Scale- Extended, Pediatric Revision.
In an early study of cognitive function after SE, 48% of patients were found to have cognitive impairment after the SE episode. Nearly two-thirds of these patients were developmentally normal prior to the insult. After one-year, the rate of neurological sequelae was 45% [
[16]
]. Moreover, a comparison of young infants with and without episodes of SE showed that the group who had experienced even one episode of SE were more impaired compared to the control group in terms of neurocognitive and developmental outcome [[23]
]. In another study, 30% of a cohort of 147 children with SE had a neurological deficit at discharge; in a follow-up after one year, nearly two-thirds of them still demonstrated the neurologic sequelae [[24]
]. In a different study, new-onset encephalopathy and/or neurologic dysfunction were present in 17/193 (8.8%) children who had an episode of SE; however, 6/17 (35.3%) had seizure occurrence during a progressive neurological disease. Of 17 children who sustained new motor or cognitive deficits after SE, 14 (82.3%) had residual motor findings such as hemiparesis and diparesis after the SE episode, and the other three children had cognitive deficits without any motor impairment. Seven children had cognitive deficits in addition to the motor deficit [[25]
].A recent study showed poorer neurocognitive outcome in patients with SE and patients with 10 or more lifetime generalized tonic clonic seizures (GTC) compared with the normal control group. However, the difference between the SE group and the multiple GTCs was not statistically significant, and the authors decided it was not possible to draw a conclusion that SE has more pronounced effect on cognitive outcome than multiple lifetime GTCs [
[26]
].Similar to mortality and recurrence, the underlying cause and baseline neurological status likely play important roles in the neuropsychological outcome. Although the previous studies show the association of SE with neurological and cognitive impairment, the studies are very heterogeneous, and the confounding role of the underlying etiology should not be overlooked while interpreting these results.
3.2.2.1 Etiology
Febrile and unprovoked etiologies tend to be associated with fewer new neurological sequelae than acute or remote symptomatic etiologies [
4
, 19
]. In a prospective study of 180 children one month to 10 years old with febrile SE, no new cognitive or neurological impairments were observed during a one-month follow-up period [[27]
]. Among a cohort of 54 children presenting with CSE to North London hospitals, followed for a duration of 1 year after CSE, children with prolonged febrile seizure had a better developmental outcome than children with non-febrile CSE [[20]
].In a study of 52 children who presented with SE and were followed for a period of 1 to 18 months, patients with idiopathic or febrile etiology had better neurodevelopmental outcome than those with acute encephalopathic (infectious, metabolic, vascular, and toxic etiologies), and chronic encephalopathic etiologies (post-infectious, hypoxic-ischemic, CNS malformation, tumor, and degenerative). Of 13 patients who developed neurodevelopmental sequelae, only one patient had idiopathic/febrile etiology [
[28]
].When counselling families about the risk of neurologic sequelae, etiology appears to be a primary driver of outcome with generally low risk with febrile SE.3.2.2.2 Age
The incidence of significant sequelae depended on the age groups, decreasing from 29% (12/41) among infants less than one-year-old to 11% (6/54) among children between 1 and 3 years of age and 6% (6/98) in those older than three years. However, the distribution of etiology was not homogeneous among different age groups, as the acute symptomatic and progressive encephalopathy groups consisted predominantly of younger patients [
[25]
].3.2.2.3 Duration of SE
Long duration of SE has been reported to be associated with adverse outcome. In an early study, 57% of 239 children with one episode of SE lasting ≥ 1 h had some kind of disability after the episode of SE (neurological, cognitive, or both). Nearly half of the cases that had permanent neurological signs had acquired the neurological impairment either prior to the SE or as a result of the encephalopathy responsible for the convulsions (as opposed to the sequela of the CSE itself). In the other half (19.7% of the total) the child appeared to be previously neurologically healthy with no other cause directly responsible for the impairment, suggesting the SE as the culprit for the acquired neurological impairment [
[16]
].In an evaluation of outcomes in previously developmentally normal patients who presented with SE, electrographic status epilepticus (ESE) was associated with impaired neurologic outcome at a median of 2.6 years after discharge. Shorter electrographic seizures (ES) were not associated with a worse outcome suggesting that duration of seizure activity may play a role in outcome [
[29]
].Although the longer duration of SE is shown to be associated with increased risk of neurocognitive deficits, prolonged episodes are most often seen in more severe etiologies [
[19]
]. In our prospective cohort of 163 pediatric patients with refractory SE who had at least one year of follow-up, a longer duration of SE was identified as the main risk factor for a new neurological deficit on multivariate analysis [[30]
].3.3 Continuous infusion
The use of continuous infusion (CI) agents intravenously to control SE has been identified as a risk factor for worse outcome, possibly due to associated clinical factors, such as higher risk of infections or hypotension. A cohort of 171 patients were evaluated and the use of CI was associated with a 2.9-fold relative risk of death if they received a CI [
[31]
]. In the pediatric age group, it is unclear if the use of CI may play a role in worsening outcome. In our prospective study of 67 patients with pediatric SE who were previously normal prior to their episode of SE, the use of continuous infusions during refractory CSE was associated with worse outcome after adjusting for potential cofounders [[32]
].3.4 Imaging
MRI abnormalities are often seen in children with SE and are likely related to the underlying etiology of SE. However, MRI changes can be seen in patients with idiopathic SE suggesting that changes are related to the SE itself. Prolonged febrile convulsions can be associated with hippocampal edema within the first 48 h after seizures and asymmetry in the hippocampal volume due to hippocampal sclerosis in later follow-up studies [
[33]
]. In the FEBSTAT study [[34]
], 22 of 226 children with febrile SE (9.7%) had abnormal hippocampal signal on their initial MRI. One-hundred thirty patients then had follow-up MRIs at 1 year with only 1 of the initial abnormal hippocampal signal changes persisting suggesting that this is an acute finding. However, 14 of the 22 (71%) with signal abnormality met visual criteria for hippocampal sclerosis on the follow-up MRI. These findings suggest that the initial episode of febrile SE can cause a cascade of events leading to later hippocampal sclerosis. Although more frequently discussed in association with prolonged febrile seizures, the hippocampal volume loss can occur after the CSE of any etiology and is not limited to the febrile etiology. The insult during the CSE episodes is believed to be crucial for the progressive hippocampal injury [[35]
].Patients with non-febrile CSE had a higher rate of abnormal MRI in the acute setting than those with prolonged febrile convulsion [
[20]
]. Abnormal neurological examination, continuous CSE, and non-prolonged febrile SE were shown to be predictive of an abnormal MRI in a study of 80 children with CSE [[36]
]. The preferential white matter involvement on MRI in the aftermath of SE suggests additional glial dysfunction [[37]
]. Increased fluid attenuated inversion recovery (FLAIR) signal associated with CSE has been shown to represent cytotoxic edema caused by the seizure, leading to neuronal damage [[38]
].While the FEBSTAT study followed patients with febrile status epilepticus, there are few long-term outcome studies that serially follow neuroimaging after symptomatic pediatric status epilepticus. In a recent study of 29 patients diagnosed with febrile infection-related epilepsy syndrome (FIRES), 18/29 (62%) of patients had a normal MRI at initial presentation, while only 3/23 (13%) had a normal follow-up MRI performed within 6 months after disease onset [
[39]
]. Imaging findings included brain atrophy and/or signal changes in various brain regions [[39]
]. In addition, there was a suggestion that the extend of periventricular white matter signal change correlated with clinical outcome [[39]
]. In a similar study of seven children with FIRES, most patients had moderate to severe cerebral atrophy after 6–12 months [[40]
]. Most other studies evaluating long-term MRI outcome are case series in adult patients. There is a clear need to perform additional studies to address neuroimaging changes following pediatric status epilepticus.3.5 Quality of life
Quality of life (QoL) is an increasingly important measure that utilizes a variety of spheres in a person's life to determine the quality of their well-being. While QoL is a very important outcome measure, it has rarely been published in pediatric SE. In a study of QoL in children with epilepsy, using the 76-item parent-report “Quality of Life in Children with Epilepsy” (QOLCE) Questionnaire, children who had experienced CSE were compared with those who did not have CSE, with a follow-up period of 24 months. Health-related QoL was poorer in the CSE group compared to controls [
[41]
]. In another study, children with normal neurodevelopment who were admitted to PICU with acute neurologic conditions were assessed after a median follow-up of 2.6 years (IQR: 1.5–3.2 years). The results showed that children who had a history of ESE had lower scores on health-related QoL, as measured by the Pediatric Quality of Life Inventory (PedsQL), compared to patients without seizure, while controlling for the cofactors such as EEG background, neurological disorder, age, and the duration of PICU stay. Of note, patients who had electrographic seizures without proceeding to SE did not score lower on PedsQL compared to patients without seizure [[29]
]. QoL is dependent on many multi-dimensional factors that are hard to quantify individually, but are critically important for determining how health status affects a person’s well-being. Future prospective studies evaluating QoL following SE should be undertaken to address this important outcome measure.4. Future directions
Outcome measures are an important tool to determine effectiveness of therapy, but these are generally only focused on short term outcomes. In additions, there is a significant gap in the literature in terms of long-term outcome assessment in CSE. Research in this area is often hampered due to methodological complexities inherent in these studies, including variations of the instruments and studies, difficulty in obtaining large sample sizes, and the need to collect data in a course of time rather than single time-point measurements. However, there is a need to acquire high-quality long-term data evaluating QoL, neuroimaging, use of continuous infusions, and cognitive and behavioral outcome of children who experience SE. Combining the data on management protocols and long-term outcome could identify treatment strategies that are associated with more favorable outcome. This could permit evidence-based clinical decision-making and could result in an improved quality of care.
For future studies to assess the outcomes of pediatric CSE, prospective multi-centric studies with large sample sizes compared to a control group without SE are required to be able to carefully adjust for the confounding factors, most importantly the underlying etiology. Because there is a complex interplay between different variables and outcome, studies should be designed with carefully selected control groups that match SE patients in every aspect except for SE, to determine the net effect of SE. In addition, objective, valid, and reliable outcome measures should be utilized to obtain high-quality data, and long follow-up periods should be considered to further assess the long-term outcomes. Predictive modeling could be utilized clinically to inform parents and families more accurately about long-term outcome following pediatric status epilepticus.
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Article info
Publication history
Published online: April 26, 2018
Accepted:
April 24,
2018
Received in revised form:
April 21,
2018
Received:
January 26,
2018
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