YEBEH-04356; No of Pages 3 Epilepsy & Behavior xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy E. Santamarina a,⁎, M. Gonzalez a, M. Toledo a, M. Sueiras b, L. Guzman b, N. Rodríguez a, M. Quintana c, G. Mazuela a, X. Salas-Puig a a b c
Epilepsy Unit, Hospital Vall Hebron, Barcelona, Spain Department of Neurophysiology, Hospital Vall Hebron, Barcelona, Spain Department of Neurology, Hospital Vall Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Revised 21 April 2015 Accepted 22 April 2015 Available online xxxx Keywords: Status epilepticus Epileptogenesis Duration
a b s t r a c t In animal models, SE duration is related to epileptogenesis. Data in humans are scarce, mainly in NCSE; therefore, we aimed to study the prognosis of SE de novo and which factors may influence subsequent development of epilepsy. Methods: We evaluated patients with SE without previous epilepsy at our hospital (February 2011–February 2014), including demographics, etiology, number of AEDs, duration of SE, mortality, and occurrence of seizures during follow-up. Results: Eighty-nine patients were evaluated. Median age was 69 (19–95) years old. Among them, 33.7% were convulsive. Regarding etiology, 59 were considered acute symptomatic (41 lesions, 18 toxic–metabolic), 17 remote or progressive symptomatic, and 13 cryptogenic. The median recovery time was 24 h (30 min–360 h). In-hospital mortality was 29% (n = 26). After a median follow-up of 10 months, 58.7% of survivors (n = 37) showed seizures. Subsequently, we analyzed which factors might be related to the development of epilepsy, and we found that epilepsy development was more frequent with longer SE duration (37 vs. 23 h, p = 0.004); furthermore, patients with a toxic–metabolic etiology developed epilepsy less frequently (33% vs. 67%; p = 0.022). Epilepsy was also correlated (tendency) with focal SE (p = 0.073), a lesion in neuroimaging (p = 0.091), and the use of 2 or more AEDs (p = 0.098). Regarding SE duration, a cutoff of above 24 h was clearly related to chronic seizures (p = 0.014); however, combining etiology and duration, the association of longer SE and epilepsy was significant in acute lesional SE (p = 0.034), but not in epilepsy with cryptogenic or remote/progressive etiology. After a logistic regression, only a duration longer than 24 h (OR = 3.800 (1.277–11.312), p = 0.016) was found to be an independent predictor of the development of epilepsy. Conclusion: In patients with SE, the longer duration is associated with an increased risk of subsequent epilepsy at follow-up, mainly in symptomatic SE due to an acute lesion. It is unclear if it might be the result of a more severe injury causing both prolonged seizures and subsequent epilepsy, and therefore whether more aggressive treatment in this group might avoid this possibility. Most of the patients with cryptogenic or remote/progressive SE developed epilepsy regardless of SE duration. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Brain damage is one of the main short-term consequences after a status epilepticus (SE). This is clearly known in situations of convulsive SE [1,2]; but in cases of nonconvulsive SE (NCSE), the possible neuronal damage is variable and remains a subject of debate. In animal models (mature brain), SE induces neuronal damage affecting large areas of the brain, not only in the hippocampus but in
⁎ Corresponding author at: Eìpilepsy Unit. Hospital Vall Hebron. Pg Vall Hebrron 119129. Barcelona, Spain. E-mail address: [email protected] (E. Santamarina).
the extrahippocampal regions as well [3,4]. This, in addition to other changes that occur within the first days or weeks, results in anatomical changes that induce the reorganization of neural networks (mossy fiber sprouting, neurogenesis, etc.) [4–7]. In humans, data are scarce, and several case reports described a permanent damage, i.e., laminar cortical necrosis in situations of prolonged SE [8,9]. However, there is no clear evidence of the presence of a marked reduction in the density of neurons especially in cases of nonconvulsive SE. Several publications describe alterations in surrogate markers of neuronal damage, as enolase in CSF [10] and MR spectroscopy [11]; however, the clinical implication of these findings is controversial. Based on these data and clinical observations, one could hypothesize possible consequences on the cognitive, behavioral, and epileptogenesis
http://dx.doi.org/10.1016/j.yebeh.2015.04.059 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
2
E. Santamarina et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
functions, but probably, these consequences would be different according to the different types of SE. Our study has focused on this last aspect, and we aimed to evaluate the prognosis of SE de novo, i.e., with no history of previous epilepsy, and specifically, to assess which factors can influence the subsequent development of epilepsy. 2. Methods All nonpediatric patients with SE in our hospital (Hospital Vall d'Hebron—a tertiary hospital) were included prospectively in a database since February 2011. For this study, we followed recent recommendations for classification [12,13], and convulsive status epilepticus (CSE) was defined as a continued epileptic activity for at least 5 min with prominent motor symptoms or two generalized tonic–clonic seizures without recovering consciousness. Nonconvulsive status epilepticus was defined as a continued epileptic activity for 30 min or multiple focal seizures within a 60-min period, both registered with electroencephalographic monitoring, with no prominent motor phenomena in either case; this group included patients with and without impairment of consciousness. The etiology was classified as recommended by the ILAE (acute symptomatic, delayed symptomatic, progressive symptomatic, or cryptogenic). The duration of SE was defined as the moment of the diagnosis until the first time in which the epileptiform activity in the EEG record disappeared. Refractory SE was defined as continued SE despite using 2 AEDs at appropriate doses [14]. We retrospectively analyzed all patients of this registry from February 2011 to February 2014, and we selected all patients with no previous history of seizures. We evaluated demographic variables, etiology, the presence of a lesion in the baseline neuroimaging (CT/MRI), number of AEDs, mortality within the acute phase, and duration of SE (recorded in hours). Finally, we evaluated if the patients had developed epilepsy during the follow-up period. 2.1. Statistical analysis Descriptive and frequency statistical analyses were obtained, and comparisons were made by the use of the SPSS statistical package, version 17.0 for Windows. Statistical significance for intergroup differences was assessed by Pearson's chi-square or Fisher's exact test for categorical variables and the Student's t-test or Mann–Whitney U test for continuous variables. A receiver characteristic operator curve (ROC) was configured in order to calculate a cutoff point for the duration of status epilepticus with the best sensitivity and specificity to predict epilepsy at follow-up. Variables associated in the univariate analysis were entered into an adjusted multivariate logistic regression model to identify factors independently associated with epilepsy at follow-up. A p-value b 0.05 was considered statistically significant.
Table 1 Analysis of variables associated with development of epilepsy among survivors after SE.
Gender (female) Age (mean; years) Abuse of alcohol NCSE Type Generalized Focal Etiology Acute symptomatic Delayed symptomatic Progressive symptomatic Cryptogenic Lesion in imaging Toxic–metabolic etiology Sedation Refractory SE (≥2 AEDs) Recurrence Duration (mean; hours) Duration N 24 h Treatment with AEDs at discharge
Epilepsy at follow-up (n = 37)
No epilepsy at follow-up (n = 26)
p
22 (59.5%) 66.8 ± 15.58 4 (10.8%) 24 (64.9%)
14 (43.8%) 63.35 ± 17.80 3 (11.5%) 17 (65.4%)
0.658 0.412 1 0.966 0.073
1 (2.7%) 36 (97.3%)
5 (19.2%) 21 (80.8%)
22 (59.5%) 9 (24.3%) 2 (5.4%) 4 (10.8%) 31 (83.8%) 5 (13.5%) 10 (27.0%) 16 (43.2%) 13 (35.1%) 37.07 21 (58.3%) 37 (100%)
22 (84.6%) 3 (11.5%) 1 (3.8%) 0 17 (65.4%) 10 (38.5%) 12 (46.2%) 6 (23.1%) 0 23.79 7 (26.9%) 21 (81%)
0.156
0.091 0.022 0.117 0.098 0.001 0.004 0.014
NCSE: nonconvulsive status epilepticus; AED: antiepileptic drugs.
(37.27 vs. 23.79 h; p = 0.004). By means of a ROC curve, we observed that patients with a duration over 24 h had significantly more seizure occurrences than in those whose SE was subjugated earlier (p = 0.014) (Table 1). In addition, it should be noted that recurrence of SE occurred only in patients with long-term epilepsy (p = 0.001), and regarding etiology, patients with toxic–metabolic causes developed epilepsy less frequently (p = 0.022). We also found a trend regarding the presence of focal SE (p = 0.073), the presence of a lesion on brain imaging (p = 0.091), and the need of two or more AEDs (refractory) to control seizures (p = 0.098). It is noteworthy that the percentage of patients who were discharged on AEDs was very high in both groups, and even 100% in those who eventually developed seizures. After a logistic regression adjusted for demographics, only the presence of a duration longer than 24 h remained as an independent factor for the development of epilepsy (OR = 3.800 (1.277-11.312), p = 0.016).
3. Results In total, we collected 89 patients with SE without prior history of epilepsy. The median age was 69 (19–95) years old, and 57% of patients were male. Regarding etiology, 59 were considered acute symptomatic (41 lesions, 18 toxic–metabolic), 17 remote or progressive symptomatic and 13 remained as cryptogenic. The median time for recovery was 24 h (30 min–360 h), with most of the patients recovering at a duration of less than 6 h or more than 3 days. In-hospital mortality was 28% because of etiology or other complications related to SE, and among the survivors (n = 64), 37 (58.7%) showed seizures after a median follow-up time of 10 months. Subsequently, we analyzed which factors might be related to the development of epilepsy during follow-up (see Table 1), and we found that the duration was significantly longer in patients with epilepsy
Fig. 1. Relation between epilepsy and duration of SE with regard to etiology.
Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
E. Santamarina et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
However, we analyzed the duration for all etiologic groups, and we found out that the association between duration and the development of epilepsy was significant in the acute symptomatic SE (p = 0.034) (Fig. 1), while in the chronic or progressive symptomatic or cryptogenic SE, seizures developed regardless of the SE duration.
3
5. Conclusion In patients with SE, the longer duration is associated with an increased risk of subsequent epilepsy at follow-up, mainly in symptomatic SE due to an acute lesion. A more aggressive treatment might avoid this possibility in this group. Most of the patients with cryptogenic or remote/progressive SE developed epilepsy regardless of duration.
4. Discussion Conflicts of interest The number of studies to address the risk of epilepsy after SE is limited. Our prevalence coincides with the estimated risk described in some retrospective studies (50%) [15]. Despite the small number of patients, our results show that the duration of epileptic activity might be related to epileptogenesis, at least in acute lesions, and this is consistent with animal model studies which correlate the severity of neuronal damage with seizure duration [16,17]. In acute lesions, the presence of SE is interpreted as the expression of an acute brain damage, and a possibility for this correlation might be the result of a more severe injury causing both prolonged seizures and subsequent epilepsy; nevertheless, its maintenance over time may also enhance the damage resulting in anatomic changes in networks in the long term. Our sample is too small to analyze the influence of duration in each subtype of acute injury (vascular, traumatic, autoimmune, infectious) and its relationship with the severity of the lesion. For this reason, we cannot draw conclusions regarding the long-term treatment after the acute phase; however, it does seem to indicate that, in general, we should be more aggressive to try to reduce effects of seizure activity at medium-term and long-term. The mechanisms seem to be somewhat different in other chronic or progressive etiologies, and in this case, the epileptogenesis is probably more related to other factors than to the duration of SE. We should note that duration seems to affect equally CSE and NCSE. There are still many questions about the best treatment in NCSE; data such as we found in this study suggest that, in this subgroup, a delay when treating the SE may have medium-term and long-term consequences, and a more aggressive treatment should be considered in some cases. This study has several limitations derived mainly from a retrospective analysis; furthermore, the different EEG patterns were not fully analyzed, and this factor may also add useful information to prognosis. Future studies should consider the inclusion of biomarkers for neuronal damage to correlate with duration in all types of SE.
None of the authors has any conflict of interest to disclose. References [1] Foreman B, Hirsch LJ. Epilepsy emergencies: diagnosis and management. Neurol Clin 2012;30(1):11–41. [2] Fountain NB, Lothman EW. Pathophysiology of status epilepticus. J Clin Neurophysiol 1995;12(4):326–42. [3] Bertram EH. Functional anatomy of spontaneous seizures in a rat model of limbic epilepsy. Epilepsia 1997;38:95–105. [4] Nissinen J, Halonen T, Koivisto E, Pitkanen A. A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat. Epilepsy Res 2000; 38:177–205. [5] Stafstrom CE, Chronopoulos A, Thurber S, Thompson JL, Holmes GL. Age-dependent cognitive and behavioral deficits after kainic acid seizures. Epilepsia 1993;34:420–32. [6] Priel MR, dosSantos NF, Cavalheiro EA. Developmental aspects of the pilocarpine model of epilepsy. Epilepsy Res 1996;26:115–21. [7] Pitkänen A1, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 2011;10(2):173–86. [8] Donaire A, Carreno M, Gómez B, Fossas P, Bargalló N, Agudo R, et al. Cortical laminar necrosis related to prolonged focal status epilepticus. J Neurol Neurosurg Psychiatry 2006;77(1):104–6. [9] Arman F, Kaya D, Dincer A, Sav A, Pamir MN. Serial EEG and MRI changes in status epilepticus-induced excitotoxic neuronal necrosis. Epileptic Disord 2011;13(4): 446–51. [10] DeGiorgio CM, Correale JD, Gott PS, Ginsburg DL, Bracht KA, Smith T, et al. Serum neuron-specific enolase in human status epilepticus. Neurology 1995;45(6):1134–7. [11] Lazeyras F1, Blanke O, Zimine I, Delavelle J, Perrig SH, Seeck M. MRI, (1)H-MRS, and functional MRI during and after prolonged nonconvulsive seizure activity. Neurology 2000;55(11):1677–82. [12] Trinka E1, Höfler J, Zerbs A. Causes of status epilepticus. Epilepsia 2012;53(Suppl. 4): 127–38. [13] Sutter R, Kaplan PW. Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey. Epilepsia 2012;53(Suppl. 3):1–51. [14] Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis LJ, Fitzsimmons BF. Refractory status epilepticus: frequency, risk factors, and impact on outcome. Arch Neurol 2002;59(2):205–10. [15] Auvin S, Dupuis N. Outcome of status epilepticus. What do we learn from animal data? Epileptic Disord 2014;16(Suppl. 1):37–43. [16] Benari Y. Limbic seizure and brain-damage produced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience 1985;14:375–403. [17] Covolan L, Mello L. Temporal profile of neuronal injury following pilocarpine or kainic acid-induced status epilepticus. Epilepsy Res 2000;39:133–52.
Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy E. Santamarina a,⁎, M. Gonzalez a, M. Toledo a, M. Sueiras b, L. Guzman b, N. Rodríguez a, M. Quintana c, G. Mazuela a, X. Salas-Puig a a b c
Epilepsy Unit, Hospital Vall Hebron, Barcelona, Spain Department of Neurophysiology, Hospital Vall Hebron, Barcelona, Spain Department of Neurology, Hospital Vall Hebron, Barcelona, Spain
a r t i c l e
i n f o
Article history: Revised 21 April 2015 Accepted 22 April 2015 Available online xxxx Keywords: Status epilepticus Epileptogenesis Duration
a b s t r a c t In animal models, SE duration is related to epileptogenesis. Data in humans are scarce, mainly in NCSE; therefore, we aimed to study the prognosis of SE de novo and which factors may influence subsequent development of epilepsy. Methods: We evaluated patients with SE without previous epilepsy at our hospital (February 2011–February 2014), including demographics, etiology, number of AEDs, duration of SE, mortality, and occurrence of seizures during follow-up. Results: Eighty-nine patients were evaluated. Median age was 69 (19–95) years old. Among them, 33.7% were convulsive. Regarding etiology, 59 were considered acute symptomatic (41 lesions, 18 toxic–metabolic), 17 remote or progressive symptomatic, and 13 cryptogenic. The median recovery time was 24 h (30 min–360 h). In-hospital mortality was 29% (n = 26). After a median follow-up of 10 months, 58.7% of survivors (n = 37) showed seizures. Subsequently, we analyzed which factors might be related to the development of epilepsy, and we found that epilepsy development was more frequent with longer SE duration (37 vs. 23 h, p = 0.004); furthermore, patients with a toxic–metabolic etiology developed epilepsy less frequently (33% vs. 67%; p = 0.022). Epilepsy was also correlated (tendency) with focal SE (p = 0.073), a lesion in neuroimaging (p = 0.091), and the use of 2 or more AEDs (p = 0.098). Regarding SE duration, a cutoff of above 24 h was clearly related to chronic seizures (p = 0.014); however, combining etiology and duration, the association of longer SE and epilepsy was significant in acute lesional SE (p = 0.034), but not in epilepsy with cryptogenic or remote/progressive etiology. After a logistic regression, only a duration longer than 24 h (OR = 3.800 (1.277–11.312), p = 0.016) was found to be an independent predictor of the development of epilepsy. Conclusion: In patients with SE, the longer duration is associated with an increased risk of subsequent epilepsy at follow-up, mainly in symptomatic SE due to an acute lesion. It is unclear if it might be the result of a more severe injury causing both prolonged seizures and subsequent epilepsy, and therefore whether more aggressive treatment in this group might avoid this possibility. Most of the patients with cryptogenic or remote/progressive SE developed epilepsy regardless of SE duration. This article is part of a Special Issue entitled “Status Epilepticus”. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Brain damage is one of the main short-term consequences after a status epilepticus (SE). This is clearly known in situations of convulsive SE [1,2]; but in cases of nonconvulsive SE (NCSE), the possible neuronal damage is variable and remains a subject of debate. In animal models (mature brain), SE induces neuronal damage affecting large areas of the brain, not only in the hippocampus but in
⁎ Corresponding author at: Eìpilepsy Unit. Hospital Vall Hebron. Pg Vall Hebrron 119129. Barcelona, Spain. E-mail address: [email protected] (E. Santamarina).
the extrahippocampal regions as well [3,4]. This, in addition to other changes that occur within the first days or weeks, results in anatomical changes that induce the reorganization of neural networks (mossy fiber sprouting, neurogenesis, etc.) [4–7]. In humans, data are scarce, and several case reports described a permanent damage, i.e., laminar cortical necrosis in situations of prolonged SE [8,9]. However, there is no clear evidence of the presence of a marked reduction in the density of neurons especially in cases of nonconvulsive SE. Several publications describe alterations in surrogate markers of neuronal damage, as enolase in CSF [10] and MR spectroscopy [11]; however, the clinical implication of these findings is controversial. Based on these data and clinical observations, one could hypothesize possible consequences on the cognitive, behavioral, and epileptogenesis
http://dx.doi.org/10.1016/j.yebeh.2015.04.059 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
2
E. Santamarina et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
functions, but probably, these consequences would be different according to the different types of SE. Our study has focused on this last aspect, and we aimed to evaluate the prognosis of SE de novo, i.e., with no history of previous epilepsy, and specifically, to assess which factors can influence the subsequent development of epilepsy. 2. Methods All nonpediatric patients with SE in our hospital (Hospital Vall d'Hebron—a tertiary hospital) were included prospectively in a database since February 2011. For this study, we followed recent recommendations for classification [12,13], and convulsive status epilepticus (CSE) was defined as a continued epileptic activity for at least 5 min with prominent motor symptoms or two generalized tonic–clonic seizures without recovering consciousness. Nonconvulsive status epilepticus was defined as a continued epileptic activity for 30 min or multiple focal seizures within a 60-min period, both registered with electroencephalographic monitoring, with no prominent motor phenomena in either case; this group included patients with and without impairment of consciousness. The etiology was classified as recommended by the ILAE (acute symptomatic, delayed symptomatic, progressive symptomatic, or cryptogenic). The duration of SE was defined as the moment of the diagnosis until the first time in which the epileptiform activity in the EEG record disappeared. Refractory SE was defined as continued SE despite using 2 AEDs at appropriate doses [14]. We retrospectively analyzed all patients of this registry from February 2011 to February 2014, and we selected all patients with no previous history of seizures. We evaluated demographic variables, etiology, the presence of a lesion in the baseline neuroimaging (CT/MRI), number of AEDs, mortality within the acute phase, and duration of SE (recorded in hours). Finally, we evaluated if the patients had developed epilepsy during the follow-up period. 2.1. Statistical analysis Descriptive and frequency statistical analyses were obtained, and comparisons were made by the use of the SPSS statistical package, version 17.0 for Windows. Statistical significance for intergroup differences was assessed by Pearson's chi-square or Fisher's exact test for categorical variables and the Student's t-test or Mann–Whitney U test for continuous variables. A receiver characteristic operator curve (ROC) was configured in order to calculate a cutoff point for the duration of status epilepticus with the best sensitivity and specificity to predict epilepsy at follow-up. Variables associated in the univariate analysis were entered into an adjusted multivariate logistic regression model to identify factors independently associated with epilepsy at follow-up. A p-value b 0.05 was considered statistically significant.
Table 1 Analysis of variables associated with development of epilepsy among survivors after SE.
Gender (female) Age (mean; years) Abuse of alcohol NCSE Type Generalized Focal Etiology Acute symptomatic Delayed symptomatic Progressive symptomatic Cryptogenic Lesion in imaging Toxic–metabolic etiology Sedation Refractory SE (≥2 AEDs) Recurrence Duration (mean; hours) Duration N 24 h Treatment with AEDs at discharge
Epilepsy at follow-up (n = 37)
No epilepsy at follow-up (n = 26)
p
22 (59.5%) 66.8 ± 15.58 4 (10.8%) 24 (64.9%)
14 (43.8%) 63.35 ± 17.80 3 (11.5%) 17 (65.4%)
0.658 0.412 1 0.966 0.073
1 (2.7%) 36 (97.3%)
5 (19.2%) 21 (80.8%)
22 (59.5%) 9 (24.3%) 2 (5.4%) 4 (10.8%) 31 (83.8%) 5 (13.5%) 10 (27.0%) 16 (43.2%) 13 (35.1%) 37.07 21 (58.3%) 37 (100%)
22 (84.6%) 3 (11.5%) 1 (3.8%) 0 17 (65.4%) 10 (38.5%) 12 (46.2%) 6 (23.1%) 0 23.79 7 (26.9%) 21 (81%)
0.156
0.091 0.022 0.117 0.098 0.001 0.004 0.014
NCSE: nonconvulsive status epilepticus; AED: antiepileptic drugs.
(37.27 vs. 23.79 h; p = 0.004). By means of a ROC curve, we observed that patients with a duration over 24 h had significantly more seizure occurrences than in those whose SE was subjugated earlier (p = 0.014) (Table 1). In addition, it should be noted that recurrence of SE occurred only in patients with long-term epilepsy (p = 0.001), and regarding etiology, patients with toxic–metabolic causes developed epilepsy less frequently (p = 0.022). We also found a trend regarding the presence of focal SE (p = 0.073), the presence of a lesion on brain imaging (p = 0.091), and the need of two or more AEDs (refractory) to control seizures (p = 0.098). It is noteworthy that the percentage of patients who were discharged on AEDs was very high in both groups, and even 100% in those who eventually developed seizures. After a logistic regression adjusted for demographics, only the presence of a duration longer than 24 h remained as an independent factor for the development of epilepsy (OR = 3.800 (1.277-11.312), p = 0.016).
3. Results In total, we collected 89 patients with SE without prior history of epilepsy. The median age was 69 (19–95) years old, and 57% of patients were male. Regarding etiology, 59 were considered acute symptomatic (41 lesions, 18 toxic–metabolic), 17 remote or progressive symptomatic and 13 remained as cryptogenic. The median time for recovery was 24 h (30 min–360 h), with most of the patients recovering at a duration of less than 6 h or more than 3 days. In-hospital mortality was 28% because of etiology or other complications related to SE, and among the survivors (n = 64), 37 (58.7%) showed seizures after a median follow-up time of 10 months. Subsequently, we analyzed which factors might be related to the development of epilepsy during follow-up (see Table 1), and we found that the duration was significantly longer in patients with epilepsy
Fig. 1. Relation between epilepsy and duration of SE with regard to etiology.
Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
E. Santamarina et al. / Epilepsy & Behavior xxx (2015) xxx–xxx
However, we analyzed the duration for all etiologic groups, and we found out that the association between duration and the development of epilepsy was significant in the acute symptomatic SE (p = 0.034) (Fig. 1), while in the chronic or progressive symptomatic or cryptogenic SE, seizures developed regardless of the SE duration.
3
5. Conclusion In patients with SE, the longer duration is associated with an increased risk of subsequent epilepsy at follow-up, mainly in symptomatic SE due to an acute lesion. A more aggressive treatment might avoid this possibility in this group. Most of the patients with cryptogenic or remote/progressive SE developed epilepsy regardless of duration.
4. Discussion Conflicts of interest The number of studies to address the risk of epilepsy after SE is limited. Our prevalence coincides with the estimated risk described in some retrospective studies (50%) [15]. Despite the small number of patients, our results show that the duration of epileptic activity might be related to epileptogenesis, at least in acute lesions, and this is consistent with animal model studies which correlate the severity of neuronal damage with seizure duration [16,17]. In acute lesions, the presence of SE is interpreted as the expression of an acute brain damage, and a possibility for this correlation might be the result of a more severe injury causing both prolonged seizures and subsequent epilepsy; nevertheless, its maintenance over time may also enhance the damage resulting in anatomic changes in networks in the long term. Our sample is too small to analyze the influence of duration in each subtype of acute injury (vascular, traumatic, autoimmune, infectious) and its relationship with the severity of the lesion. For this reason, we cannot draw conclusions regarding the long-term treatment after the acute phase; however, it does seem to indicate that, in general, we should be more aggressive to try to reduce effects of seizure activity at medium-term and long-term. The mechanisms seem to be somewhat different in other chronic or progressive etiologies, and in this case, the epileptogenesis is probably more related to other factors than to the duration of SE. We should note that duration seems to affect equally CSE and NCSE. There are still many questions about the best treatment in NCSE; data such as we found in this study suggest that, in this subgroup, a delay when treating the SE may have medium-term and long-term consequences, and a more aggressive treatment should be considered in some cases. This study has several limitations derived mainly from a retrospective analysis; furthermore, the different EEG patterns were not fully analyzed, and this factor may also add useful information to prognosis. Future studies should consider the inclusion of biomarkers for neuronal damage to correlate with duration in all types of SE.
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Please cite this article as: Santamarina E, et al, Prognosis of status epilepticus (SE): Relationship between SE duration and subsequent development of epilepsy, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.04.059
