Early rehabilitation and improved outcomes in patients with status epilepticus: Evidence from cases presenting to the emergency department
Abstract
Objective
Status epilepticus (SE) is a common neurological emergency characterized by prolonged or recurrent seizures that can cause permanent brain damage. Although these seizures can be controlled with appropriate treatment, SE is associated with poor outcomes and a high mortality rate. SE can cause physical, cognitive, and psychological complications at every stage of treatment. Understanding the treatment of SE and its outcomes is important both clinically and socially. Intensive care unit-acquired weakness and post-intensive care syndrome are significant issues in survivors of SE. This study aimed to determine if early rehabilitation in the intensive care unit can improve outcomes in patients with SE, given the limited options for intervention after hospitalization.
Methods
This observational study was approved by our ethics committee (B-2023-654) and included 1039 adult patients brought to our center with SE between 2011 and 2023. The patients were divided into a prospectively enrolled rehabilitation intervention group, in which rehabilitation was initiated within 24 h after admission post-2022, and a retrospective non-intervention group from before that time. We examined the current status of these patients to determine the value of ultra-acute rehabilitation and factors associated with favorable outcomes in these patients. The primary outcome was the proportion of patients with a Glasgow Outcome Scale score of 5 at discharge.
Results
The average age was 52.3 years, with 619 cases aged 65 years or older. Mortality was 2.5%, and 519 patients achieved a Glasgow Outcome Scale score of 5. Rehabilitation initiated within 24 h of hospitalization did not significantly affect the length of hospital stay but did increase home discharge rates and functional independence, particularly in older patients.
Significance
This study provides a systematic and insightful observational analysis suggesting that early rehabilitation may be associated with improved outcomes in patients with status epilepticus (SE). Further validation and investigation are required.
Plain Language Summary
When patients experience the severe epileptic condition known as status epilepticus, they are often admitted to the intensive care unit (ICU), where their chances of recovery can be poor. However, this study shows that starting rehabilitation early, even in the ICU, can help improve the recovery of these patients. By beginning rehabilitation soon after admission, patients may have an increased chance of returning home rather than facing long-term care. This research highlights the potential benefits of early rehabilitation for improving outcomes in patients with severe epilepsy who require emergency care.
Key points
- This study aimed to determine if early rehabilitation in the intensive care unit can improve outcomes in patients with SE.
- This study provides a systematic and insightful observational analysis suggesting the potential association of early rehabilitation with improved outcomes in SE patients, requiring further validation.
- These findings underscore the importance of combining seizure control with early rehabilitation for optimal patient recovery.
1 INTRODUCTION
Status epilepticus is a common medical emergency and is characterized by persistence or recurrence of seizures, which may lead to significant neurological impairments that are associated with higher mortality rates and poor prognosis due to permanent brain injury.1, 2 Traditionally, status epilepticus was defined as seizure activity lasting for more than 30 min. However, experimental studies have demonstrated that even shorter durations of seizure activity can result in brain injury. Therefore, to avoid undertreatment, the definition was revised to include sustained seizure activity lasting for more than 5–10 min without a return of consciousness to baseline or two or more seizures.3 As a result, there has been an increase in cases deemed to be severe and requiring transport to the emergency department.
While seizures can be controlled with appropriate treatment, reports indicate a high mortality rate and a considerable incidence of poor outcomes.4 Status epilepticus has the potential to cause complications at every stage of treatment, ranging from epilepsy-related organ dysfunction to physical, cognitive, and psychological disabilities among survivors of an intensive care unit (ICU) admission, necessitating a multifaceted approach.5, 6
Short-term mortality is approximately 25% in patients with status epilepticus and increases to about 40% in patients in whom seizure activity persists despite treatment. Furthermore, it has been reported that 43% of patients who survive for 30 days post-seizure die within 10 years.7 Survivors can also experience cognitive dysfunction, motor impairment, exacerbation of pre-existing epilepsy, and residual seizures following new episodes of status epilepticus. A retrospective cohort study4 that focused on patients with new-onset status epilepticus reported that Glasgow Outcome Scale (GOS) scores at discharge were significantly poorer in those showing refractory seizure activity than in other patients. The GOS is a validated, practical, and reliable tool that is primarily used to assess overall outcomes in patients with neurological disorders and is appropriate for evaluating the physical and functional burden following status epilepticus.8-13
Moreover, despite the short-term mortality rate being as high as 25%, there is a paucity of data regarding ICU admissions for status epilepticus and its treatment. The outcome variable of interest is usually short-term mortality, with limited data available on long-term mortality or functional outcomes. Four retrospective observational studies have investigated ICU mortality rates in patients with status epilepticus.14-17
Even in survivors, status epilepticus can significantly impact physical and mental health, leading to substantial deterioration in the ability to perform activities of daily living (ADL). Understanding the treatment of status epilepticus and its outcomes is essential not only clinically but also socially. In the intensive care setting, issues such as ICU-acquired weakness and post-intensive care syndrome are common, and patients with status epilepticus are no exception.
Status epilepticus can lead to complications at every stage of treatment. As one of the serious conditions associated with epilepsy-related organ dysfunction and severe illness, status epilepticus requires a multifaceted approach to address the physical, cognitive, and psychological impairments experienced by survivors. Numerous factors associated with outcomes have been reported; however, the options for interventions after hospitalization are limited. Therefore, we hypothesized that early rehabilitation intervention in the ICU may help to improve outcomes. In this study, we examined the current status of patients brought to the emergency department with status epilepticus, dividing them into a rehabilitation intervention group, which has actively engaged in rehabilitation since April 2022, and a non-intervention group of patients who presented before that date, in an effort to determine the efficacy of ultra-acute rehabilitation and factors associated with favorable outcomes.
2 MATERIALS AND METHODS
2.1 Patients
We included patients with status epilepticus, excluding pediatric patients with febrile seizures, who were brought to our facility over a 13-year period starting in 2011. Patients aged 18 years or older who were admitted to our emergency department with status epilepticus in 2022 and 2023 were also prospectively enrolled. Cases admitted with status epilepticus between 2011 and 2021 were used as a comparator group.
2.2 Definition
Status epilepticus was defined as seizure activity lasting for at least 5 min or the occurrence of two or more seizures during emergency transport to the hospital without complete recovery of consciousness in between seizures.
2.3 Outcome assessment
The primary endpoint was the GOS score, which reflects both mortality and morbidity following discharge from the ICU. A GOS score of 5 was defined as a good outcome, indicating survival with sufficient recovery to be able to return to previous levels of occupational or educational activity regardless of the presence of mild physical or mental impairments.
2.4 Statistical analysis
Quantitative parameters are reported as the median (interquartile range) and qualitative parameters as the number (percentage). Categorical variables were compared between groups using Fisher's exact test and continuous variables using the Wilcoxon rank-sum test. To identify associations between patient characteristics and a GOS score of 5, univariate analysis was performed with a significance level of p < 0.05. Clinically relevant variables were analyzed further in a multivariate model. All statistical analyses were performed using StatFlex Plus ver. 7 (Artech Co.). All tests were two-sided, and a p value of <0.05 was considered statistically significant.
2.5 Primary endpoint
A GOS score of 5 at discharge was considered a favorable outcome. A GOS score of 4 was regarded as a deterioration from the patient's performance of ADL before admission and was not included as a favorable outcome. The GOS score was determined by the attending medical team at the time of discharge.
3 RESULTS
3.1 Patient characteristics
A total of 1039 patients were included in the study. The average age was 52.3 ± 26.7 years, with 619 cases (40.5%) being aged 65 years or older. There were 661 male patients and 378 female patients. The median Glasgow Coma Scale (GCS) score was 10 (interquartile range 4, 14), and the average length of hospital stay was 8.8 ± 11.0 days.
The most common triggers for status epilepticus were stroke (18.9%) and a history of epilepsy (14.8%), followed by post-traumatic seizures (8.8%), alcohol dependence (4.0%), brain tumors (2.6%), and other causes (50.8% in total). There were 26 deaths, which translated into a mortality rate of 2.5%. The 1039 patients included in the study were divided into two groups: Group A (2011–2021, n = 972) and Group B (2022–2023, n = 67). The average age was 52.1 ± 26.6 years in Group A and 54.8 ± 27.3 years in Group B, with 40.0% and 44.8% of patients aged 65 years or older, respectively. The proportion of male patients was 63.8% in Group A and 61.2% in Group B. The median Glasgow Coma Scale (GCS) score was 10 (IQR 4, 14) in Group A and 11 (IQR 5, 15) in Group B. The average length of hospital stay was 8.7 ± 11.2 days in Group A and 9.3 ± 9.8 days in Group B. Mortality rates were 2.4% (n = 23) in Group A and 4.5% (n = 3) in Group B. The most common triggers for status epilepticus in both groups were stroke and a history of epilepsy. Stroke was identified as a trigger in 18.8% (n = 183) of cases in Group A and 20.9% (n = 14) in Group B. A history of epilepsy was noted in 14.8% (n = 144) of cases in Group A and 14.9% (n = 10) in Group B. Post-traumatic seizures accounted for 8.8% (n = 86) and 9.0% (n = 6) of cases in Group A and Group B, respectively. Other triggers included alcohol dependence (4.0% in Group A, 4.5% in Group B), brain tumors (2.6% in Group A, 3.0% in Group B), and other causes (50.9% in Group A, 47.8% in Group B) (Table 1).
| Parameter | No rehabilitation | Rehabilitation | p-value |
|---|---|---|---|
| Cases, n | 972 | 67 | |
| Age, years | 53.0 | 49.5 | 0.29 |
| Sex | |||
| Male | 622 | 39 | 0.07 |
| Female | 350 | 28 | |
| Cause of SE | |||
| Stroke | 183 | 14 | 0.73 |
| Epilepsy | 142 | 12 | |
| Trauma | 86 | 5 | |
| Alcohol abuse | 39 | 3 | |
| Brain tumor | 24 | 3 | |
| Other | 498 | 30 | |
| GCS score | 10 (6, 14) | 8 (3, 14) | 0.19 |
| APACHE II score | 20.2 | 20.9 | 0.56 |
| Length of stay, days | 8.9 | 6.7 | 0.11 |
| Underwent rehabilitation | 0 | 67 | |
- Note: The data are shown as the mean ± standard deviation, median (interquartile range), or number as appropriate.
- Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; GCS, Glasgow Coma Scale; IQR, interquartile range; SE, status epilepticus.
3.2 Management in the ICU
All cases included in the study were admitted to the ICU, and treatment was initiated according to the most recent guidelines for managing status epilepticus. Immediate interventions, including head computed tomography scans, blood tests, and electrocardiograms, were implemented to control seizures and identify causes, with head magnetic resonance imaging performed as necessary. Patients were intubated and mechanically ventilated as required, with approximately 75% of cases needing ventilatory support. Antiepileptic drugs were administered in accordance with the guidelines for patients without acute symptomatic seizures related to a metabolic disorder or drug intoxication. Initial treatment consisted of intravenous anticonvulsant therapy followed by extensive diagnostic investigations. If necessary, neuroimaging and intermittent electrocardiographic monitoring were performed. The electrocardiograms were interpreted by neurocritical care physicians, who assessed the patients as needed. No identifiable cause was found in 17% of cases.
3.3 Rehabilitation
Rehabilitation was initiated within 24 h of hospitalization in the rehabilitation intervention group (n = 67), regardless of the patient's condition. In some cases, rehabilitation consisted only of range-of-motion exercises. The intervention was implemented by physical therapists under the direction of the attending physician. In contrast, rehabilitation was not initiated in the historical non-rehabilitation intervention group (n = 972). There was no significant difference in the average length of hospital stay between the intervention group and the non-intervention group (8.9 days vs. 7.4 days). Similarly, there were no statistically significant between-group differences in outcomes. In the non-rehabilitation intervention group, the rate of discharge to home for elderly patients aged 65 years or older was very low at 36%, and those who experienced status epilepticus were often required to transfer to convalescent hospitals or other care facilities. The Functional Independence Measure (FIM) showed gains of approximately 16 even within this short period. Cases eligible for rehabilitation transfer increased significantly from 9.9% (n = 96) to 22.4% (n = 15), excluding cases that were discharged to home (Table 2).
| Parameter | No rehabilitation | Rehabilitation | p-value |
|---|---|---|---|
| Cases, n | 972 | 67 | |
| Length of stay, days | 8.9 | 7.2 | 0.30 |
| GOS score | |||
| 5 | 484 | 35 | 0.82 |
| 4 | 334 | 24 | |
| 3 | 78 | 4 | |
| 2 | 52 | 2 | |
| 1 | 24 | 2 | |
| FIM score | |||
| At admission | — | 39.9 ± 7.9 | 0.28 |
| At discharge | 57.2 ± 33.5a | 55.9 ± 24.7 | |
| Transfer to a rehabilitation hospital | 96 | 15 | <0.01 |
| Discharge to home | 553 | 32 | 0.42 |
- Note: Data are shown as the mean ± standard deviation or number as appropriate.
- Abbreviations: FIM, functional independence measure; GOS, Glasgow Outcome Scale.
- a Number of cases transferred to rehabilitation hospitals only.
The effects of rehabilitation intervention were also examined in the context of age, comparing patients aged 65 years and older with those who were younger. The younger group had significantly shorter hospital stays and better outcomes and were more likely to be discharged to home (Table 3).
| Parameter | Age < 65 years | Age ≥ 65 years | p-value |
|---|---|---|---|
| Cases, n | 45 | 22 | |
| Sex | |||
| Male | 30 | 12 | 0.64 |
| Female | 15 | 10 | |
| Length of stay, days | 7.2 | 8.9 | <0.01 |
| GOS score | |||
| 5 | 29 | 6 | <0.01 |
| 4 | 12 | 12 | |
| 3 | 3 | 1 | |
| 2 | 1 | 1 | |
| 1 | 0 | 2 | |
| FIM score | |||
| At admission | 43.8 ± 27.4 | 31.9 ± 19.9 | <0.01 |
| At discharge | 63.0 ± 35.1 | 41.4 ± 29.9 | |
| Transfer to a rehabilitation hospital | 7 | 5 | <0.01 |
| Discharge to home | 35 | 7 | <0.01 |
- Note: Data are shown as the mean ± standard deviation or number as appropriate.
- Abbreviations: FIM, functional independence measure; GOS, Glasgow Outcome Scale; NS, not statistically significant.
There were 519 cases with a GOS score of 5. Univariate analysis revealed that GCS on arrival, early rehabilitation status, Acute Physiology and Chronic Health Evaluation (APACHE) II score, length of stay, and age were independently associated with the outcome. There was no between-group difference in the lactate level, blood CO2 concentration, duration of seizures, or transport time (Table 4).
| Parameter | GOS 1–4 | GOS 5 | p-value |
|---|---|---|---|
| Cases, n | 520 | 519 | |
| Underwent rehabilitation | 18 | 49 | <0.01 |
| Age, years | 62.1 | 45.3 | <0.01 |
| Length of stay, days | 13.0 | 5.8 | <0.01 |
| Median GCS score | 7 | 11 | <0.01 |
| APACHE II | 23.2 | 18.6 | <0.01 |
| ABG on admission | |||
| CO2, torr | 49.4 | 46.6 | 0.17 |
| Lactate, mmol/L | 6.16 | 6.20 | 0.93 |
- Abbreviations: ABG, arterial blood gas analysis; APACHE II, Acute Physiology and Chronic Health Evaluation II; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale.
The parameters that showed significant differences in univariate analysis, namely, GCS on arrival, early rehabilitation status, the APACHE II score, length of stay, and age, were entered into the multivariate model for analysis. Significant differences were found for all variables, except the APACHE II score. The importance of rehabilitation intervention was confirmed (Table 5).
| Parameter | Odds ratio | 95% CI | p-value |
|---|---|---|---|
| Rehabilitation intervention | 30.1 | 5.59–161.9 | <0.01 |
| Age, years | 1.02 | 1.01–1.03 | <0.01 |
| Length of stay, days | 1.59 | 1.40–1.08 | <0.01 |
| GCS score | 1.09 | 1.03–1.14 | <0.01 |
| APACHE II score | 1.00 | 0.98–1.03 | 0.58 |
- Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; GCS, Glasgow Coma Scale; GOS, Glasgow Outcome Scale.
4 DISCUSSION
In this study, 26 (2.5%) of 1039 patients with status epilepticus managed in the ICU died, and 519 had good outcomes as defined by a GOS score of 5. Among the parameters independently associated with a poor outcome (a GOS score < 5), namely, the initial GCS score, early rehabilitation status, APACHE II score, length of stay, and age, only early rehabilitation intervention had the potential to improve outcomes.
The findings of this study highlight the importance of early rehabilitation intervention in the treatment and management of patients with status epilepticus, in particular, those who are older. Notably, 40.5% of patients in our study cohort were aged 65 years or older, and several studies have found that older adults are at higher risk of experiencing seizures.18-21 Furthermore, the average age of patients admitted for status epilepticus at our facility has been increasing over the years. The primary triggers for status epilepticus were found to be post-stroke status and a prior history of epilepsy, suggesting that these patient populations warrant specific attention. While the mortality rate was relatively low at 2.5%, the discharge rate to home was only 36% for older adults, indicating that returning home becomes difficult if they experience status epilepticus. This trend highlights the significant impact that status epilepticus can have on the ability to perform ADL and quality of life in older adults, further underscoring the need for early rehabilitation interventions.
The FIM score is often used to assess the effects of rehabilitation.22, 23 While other metrics such as the ICU Mobility Scale and Medical Research Council Scale have also been used, we used the FIM score in our study because of its frequent use in rehabilitation hospitals for continued assessment post-transfer. Our rehabilitation intervention group achieved FIM scores at discharge that were comparable with those in patients in the non-rehabilitation group who were able to transfer for rehabilitation, suggesting that short-term rehabilitation in an emergency department setting can be very effective. Of note, the group that started rehabilitation within 24 h saw a substantial increase in the number of patients eligible for transfer to rehabilitation hospitals. Furthermore, many patients discharged to home after training in rehabilitation hospitals achieved a GOS score of 5, which highlights the importance of collaboration between facilities. Consequently, this study found that early rehabilitation contributes to improved long-term outcomes in patients with status epilepticus.
While other scoring systems, including STESS (Status Epilepticus Severity Score) and EMSE (Epidemiology-based Mortality Score in Status Epilepticus), have been reported to be useful for predicting outcomes in patients with status epilepticus,24-29 our study identified the initial GCS score, early rehabilitation status, APACHE II score, length of stay, and age to be independent factors related to outcomes in univariate analysis. This finding indicates that these are significant prognostic factors and should be considered when evaluating the timing of rehabilitation and overall management during hospitalization.
Our finding that the lactate level, blood CO2 concentration, duration of seizures, and transport time did not significantly affect the prognosis suggests that while these indicators are important when assessing severity, they may not be predictors of outcomes. The reason for this finding may lie in the specific regional characteristics of our facility, which is a trauma center located in Tokyo with multiple trauma centers nearby, meaning that prompt medical intervention is possible without a long transport time. Future research should focus on broader data analysis and comparisons with other patient populations to accumulate further evidence.
This study has several limitations. First, it had a single-center design, which raises questions about the generalizability of our findings. It is also unclear how representative our findings are in terms of all patients with status epilepticus, considering that some patients may have died before medical intervention while others may have fully recovered without requiring admission to the ICU. Second, this study defined status epilepticus using a recent operational definition, which considers seizure activity lasting more than 5 min rather than the traditional 30-min definition. This definition is now widely used to promote early intensification of anticonvulsant therapy in patients experiencing prolonged seizures before onset of status epilepticus. However, our aim was to include all critically ill patients with status epilepticus requiring ICU management. Third, the GOS is widely used to assess outcomes in patients with neurological disorders. While the structured GOS format has been shown to be valid, practical, and reliable, indirect GOS evaluations based on physician interviews with patients were not investigated. Fourth, a GOS score of 4 could also be considered a favorable outcome. This GOS score indicates “moderate disability” in patients who can live independently but are unable to return to work or school and is associated with functional impairment because “some previous activities in either work or social life are now impossible due to physical or mental deficits.” Therefore, as in other studies of outcomes in patients with serious neurological disorders, we defined a GOS score of <5 as a poor outcome. This assessment provided an opportunity to understand functional impairment. Finally, a hospital stay of approximately 10 days at our facility may have been too short to judge functional outcomes accurately. However, given our mission as an emergency medical center and the infeasibility of longer follow-up, this study provides useful data that can serve as a reference for many emergency-related hospitals.
5 CONCLUSIONS
The findings of this study highlight the importance of early rehabilitation intervention in the treatment of status epilepticus. Patients who started rehabilitation within 24 h were significantly more likely to be transferred to a rehabilitation facility, show improvement in the ability to perform ADL, and be discharged to home. Comprehensive care that includes early rehabilitation intervention is essential for improving outcomes in patients with status epilepticus, especially in older adults. Treatment strategies should not only focus on seizure management but also include a multifaceted approach that combines early rehabilitation interventions.
AUTHOR CONTRIBUTIONS
Hidetaka Onda: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, validation, visualization, writing—original draft preparation, and writing—review and editing. Shoji Yokobori: supervision and writing—review and editing.
ACKNOWLEDGMENTS
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
CONFLICT OF INTEREST STATEMENT
None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ETHICS STATEMENT
This prospective observational study was approved by the Ethics Committee of Nippon Medical School (approval number B-2023-654). Written informed consent was obtained from all patients upon admission. The data supporting the findings of this study are not publicly available because of privacy and ethical restrictions but can be obtained from the corresponding author upon reasonable request.
INFORMED CONSENT
All patients provided written informed consent for inclusion in this study.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
