Current Literature In Clinical Science
Consequences of Status Epilepticus in the Intensive Care Unit: What We Know and What We Need to Know
Electrographic Status Epilepticus and Long-Term Outcome in Critically Ill Children. Wagenman KL, Blake TP, Sanchez SM, Schultheis MT, Radcliffe J, Berg RA, Dlugos DJ, Topjian AA, Abend NS. Neurology 2014;82:396–404.
OBJECTIVE: Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in children in the pediatric intensive care unit (PICU) with acute neurologic conditions. We aimed to determine whether ES or ESE was associated with worse long-term outcomes. METHODS: Three hundred children with an acute neurologic condition and encephalopathy underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study. We aimed to obtain follow-up data from 137 subjects who were neurodevelopmentally normal before PICU admission. RESULTS: Follow-up data were collected for 60 of 137 subjects (44%) at a median of 2.7 years. Subjects with and without follow-up data were similar in clinical characteristics during the PICU admission. Among subjects with follow-up data, ES occurred in 12 subjects (20%) and ESE occurred in 14 subjects (23%). Multivariable analysis indicated that ESE was associated with an increased risk of unfavorable Glasgow Outcome Scale (Extended Pediatric Version) category (odds ratio 6.36, p = 0.01) and lower Pediatric Quality of Life Inventory scores (23 points lower, p = 0.001). Among subjects without prior epilepsy diagnoses ESE was associated with an increased risk of subsequently diagnosed epilepsy (odds ratio 13.3, p = 0.002). ES were not associated with worse outcomes. SIGNIFICANCE: Among children with acute neurologic disorders who were reported to be neurodevelopmentally normal before PICU admission, ESE but not ES was associated with an increased risk of unfavorable global outcome, lower health-related quality of life scores, and an increased risk of subsequently diagnosed epilepsy even after adjusting for neurologic disorder category, EEG background category, and age.
Commentary By definition, critically ill patients are expected to have a complex clinical picture, with multiple immediate life-threatening concerns ranging from major systemic dysfunctions to devastating acute neurological injuries. So, in the extreme environment of an intensive care unit (ICU), survival is the goal and seizures/status epilepticus represent “yet another problem” to rule out and treat so that acute encephalopathy can resolve and the patient can regain independent control of basic life functions. Eventually, though, as imminent concerns gradually resolve, the bigger picture emerges and the main questions about which parents and family members obsess are: “what next? Is my loved one going to be normal again or does he/ she have to carry consequences of this major traumatic experience with them for the rest of his/her life?” These questions are particularly difficult if the patient was neurodevelopmentally intact prior to the ICU stay. Let’s review some of the answers as provided by the current literature, including the work highlighted here by Wagenman et al. and by others. Epilepsy Currents, Vol. 14, No. 6 (November/December) 2014 pp. 337–338 © American Epilepsy Society
First, status epilepticus (SE) is associated with increased mortality following an ICU stay in both adults (1) and children (2). This increased mortality risk seems to be less relevant for isolated seizures in this setting. Of 49 adult patients with nonconvulsive seizures studied with continuous EEG monitoring, the overall mortality was 33%, with an odds ratio of 1.13 for every additional hour of uncontrolled seizures (1). Of 550 children evaluated with continuous EEG monitoring in an ICU setting, 25% died if they had SE as opposed to 12% in either those who had seizures without SE or those without seizures (2). Second, seizures in the ICU are associated with worse functional outcomes, across various etiologies. In one retrospective cohort study of 42 consecutive patients (of all ages) with primary central nervous system infection who underwent continuous EEG monitoring, electrographic seizures with or without clinical symptoms were associated with a poor outcome at discharge (severe disability, vegetative state, or death): 52% of the patients with a poor outcome at discharge had recorded seizures as opposed to only 16% of those with a favorable outcome (3). In another study of 201 adults admitted to the medical ICU, mostly with sepsis, 89% of patients with electrographic seizures died or had a severe disability upon discharge versus 39% otherwise (4). The study at hand by
337
Status Epilepticus in ICU
Wagenman et al. sheds further light on this issue, particularly in the pediatric population with a normal developmental baseline, as only 13% of encephalopathic children in the pediatric ICU with status epilepticus had a favorable outcome (upper good recovery indicating no impact to activities of daily living to moderate disability) as opposed to 64% of their counterparts with no seizures. In this same study, the difference was not as dramatic in the case of seizures with no SE (23% had a favorable outcome) and did not achieve statistical significance. Overall, this would be consistent with the literature referenced earlier (1, 2) where outcomes were directly related to seizure duration, so are expected to be worse when seizures last longer and evolve into status epilepticus. Third, status epilepticus—but not isolated seizures—is associated with a higher risk of developing epilepsy in both adults (5) and children. In a large cohort study following adults with acute symptomatic seizures, the risk of a subsequent unprovoked seizure at 10 years of follow-up was 41% for those with acute symptomatic seizure with status epilepticus and 13% for those without it, reflecting a 3.3-fold increased risk after controlling for age, sex, and cause. The extent of this increase in risk varied in a direction mirroring that of the expected brain damage in relation to different etiologies, as it was highest for patients with anoxic encephalopathy (18.8-fold), lowest for those with a metabolic cause (3.6-fold) and intermediate for those with a structural cause (7.1-fold) (6). Similar, albeit slightly worse, results seem to apply in the pediatric population, as Wagenman et al. report here that 69% (9/13) of children who developed status epilepticus in the ICU subsequently developed epilepsy after a mean follow-up of 2.7 years, as opposed to 21% (7/33) of those with no seizures, and 38% (3/8) of those with isolated seizures. Major unfavorable outcomes seem then somewhat quantified, including the subsequent risks of death, vegetative state, and long-term epilepsy, as summarized above. The critical question that remains to be answered though is whether any of these “unfavorable associations” can be prevented or even reversed by the treatment of seizures or status epilepticus. In fact, evidence abounds about multiple mechanisms of neuronal injury caused by status epilepticus from programmed cell necrosis (7), to a breakdown of GABA inhibition (8), to altered neuro-inflammation (9), ultimately leading to cell death within and outside the hippocampus (10). Stopping seizures should stop the brain damage they cause. The caveat though is this: it remains unclear how much of our unfavorable outcomes is actually caused by the seizures themselves rather than other nonmodifiable factors. The development of status epilepticus by itself may reflect a more severe underlying neurological insult and, thus, a wider spectrum of expected neurological deficits. That said, the development of status epilepticus in some patients but not others with similar neurological insults may by itself reflect
338
a higher genetic tendency for seizures and, thus, a lower threshold for neurological complications. Either way, the last two possibilities would contribute to mechanisms of poor neurological outcomes that may not necessarily be modifiable by the treatment of acute seizures. The extent to which all these factors contribute to longterm outcomes after status epilepticus needs to be further investigated. Carefully designed prospective studies are key to moving our understanding of this very challenging topic to the next level. by Lara Jehi, MD References 1. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology 1996;47:83–89. 2. Abend NS, Arndt DH, Carpenter JL, Chapman KE, Cornett KM, Gallentine WB, Giza CC, Goldstein JL, Hahn CD, Lerner JT, Loddenkemper T, Matsumoto JH, McBain K, Nash KB, Payne E, Sánchez SM, Fernández IS, Shults J, Williams K, Yang A, Dlugos DJ. Electrographic seizures in pediatric ICU patients: Cohort study of risk factors and mortality. Neurology 2013;81:383–391. 3. Carrera E, Claassen J, Oddo M, Emerson RG, Mayer SA, Hirsch LJ. Continuous electroencephalographic monitoring in critically ill patients with central nervous system infections. Arch Neurol 2008;65:1612–1618. 4. Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit Care Med 2009;37:2051–2056. 5. Leung H, Man CB, Hui AC, Kwan P, Wong KS. Prognosticating acute symptomatic seizures using two different seizure outcomes. Epilepsia 2010;51:1570–1579. 6. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann Neurol 1998;44:908–912. 7. Niquet J, Lopez-Meraz ML, Wasterlain CG. Programmed necrosis after status epilepticus. In: Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds.) Bethesda, MD: Oxford University Press, 2012:1–13XXX–XXX. 8. Reddy DS, Kuruba R. Experimental models of status epilepticus and neuronal injury for evaluation of therapeutic interventions. Int J Mol Sci 2013;14:18284–18318. 9. Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Banderó CR, Löscher W, Vezzani A.. Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 2013;59:183–193. 10. Scholl EA, Dudek FE, Ekstrand JJ. Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience 2013;252:45–59.
Consequences of Status Epilepticus in the Intensive Care Unit: What We Know and What We Need to Know
Electrographic Status Epilepticus and Long-Term Outcome in Critically Ill Children. Wagenman KL, Blake TP, Sanchez SM, Schultheis MT, Radcliffe J, Berg RA, Dlugos DJ, Topjian AA, Abend NS. Neurology 2014;82:396–404.
OBJECTIVE: Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in children in the pediatric intensive care unit (PICU) with acute neurologic conditions. We aimed to determine whether ES or ESE was associated with worse long-term outcomes. METHODS: Three hundred children with an acute neurologic condition and encephalopathy underwent clinically indicated EEG monitoring and were enrolled in a prospective observational study. We aimed to obtain follow-up data from 137 subjects who were neurodevelopmentally normal before PICU admission. RESULTS: Follow-up data were collected for 60 of 137 subjects (44%) at a median of 2.7 years. Subjects with and without follow-up data were similar in clinical characteristics during the PICU admission. Among subjects with follow-up data, ES occurred in 12 subjects (20%) and ESE occurred in 14 subjects (23%). Multivariable analysis indicated that ESE was associated with an increased risk of unfavorable Glasgow Outcome Scale (Extended Pediatric Version) category (odds ratio 6.36, p = 0.01) and lower Pediatric Quality of Life Inventory scores (23 points lower, p = 0.001). Among subjects without prior epilepsy diagnoses ESE was associated with an increased risk of subsequently diagnosed epilepsy (odds ratio 13.3, p = 0.002). ES were not associated with worse outcomes. SIGNIFICANCE: Among children with acute neurologic disorders who were reported to be neurodevelopmentally normal before PICU admission, ESE but not ES was associated with an increased risk of unfavorable global outcome, lower health-related quality of life scores, and an increased risk of subsequently diagnosed epilepsy even after adjusting for neurologic disorder category, EEG background category, and age.
Commentary By definition, critically ill patients are expected to have a complex clinical picture, with multiple immediate life-threatening concerns ranging from major systemic dysfunctions to devastating acute neurological injuries. So, in the extreme environment of an intensive care unit (ICU), survival is the goal and seizures/status epilepticus represent “yet another problem” to rule out and treat so that acute encephalopathy can resolve and the patient can regain independent control of basic life functions. Eventually, though, as imminent concerns gradually resolve, the bigger picture emerges and the main questions about which parents and family members obsess are: “what next? Is my loved one going to be normal again or does he/ she have to carry consequences of this major traumatic experience with them for the rest of his/her life?” These questions are particularly difficult if the patient was neurodevelopmentally intact prior to the ICU stay. Let’s review some of the answers as provided by the current literature, including the work highlighted here by Wagenman et al. and by others. Epilepsy Currents, Vol. 14, No. 6 (November/December) 2014 pp. 337–338 © American Epilepsy Society
First, status epilepticus (SE) is associated with increased mortality following an ICU stay in both adults (1) and children (2). This increased mortality risk seems to be less relevant for isolated seizures in this setting. Of 49 adult patients with nonconvulsive seizures studied with continuous EEG monitoring, the overall mortality was 33%, with an odds ratio of 1.13 for every additional hour of uncontrolled seizures (1). Of 550 children evaluated with continuous EEG monitoring in an ICU setting, 25% died if they had SE as opposed to 12% in either those who had seizures without SE or those without seizures (2). Second, seizures in the ICU are associated with worse functional outcomes, across various etiologies. In one retrospective cohort study of 42 consecutive patients (of all ages) with primary central nervous system infection who underwent continuous EEG monitoring, electrographic seizures with or without clinical symptoms were associated with a poor outcome at discharge (severe disability, vegetative state, or death): 52% of the patients with a poor outcome at discharge had recorded seizures as opposed to only 16% of those with a favorable outcome (3). In another study of 201 adults admitted to the medical ICU, mostly with sepsis, 89% of patients with electrographic seizures died or had a severe disability upon discharge versus 39% otherwise (4). The study at hand by
337
Status Epilepticus in ICU
Wagenman et al. sheds further light on this issue, particularly in the pediatric population with a normal developmental baseline, as only 13% of encephalopathic children in the pediatric ICU with status epilepticus had a favorable outcome (upper good recovery indicating no impact to activities of daily living to moderate disability) as opposed to 64% of their counterparts with no seizures. In this same study, the difference was not as dramatic in the case of seizures with no SE (23% had a favorable outcome) and did not achieve statistical significance. Overall, this would be consistent with the literature referenced earlier (1, 2) where outcomes were directly related to seizure duration, so are expected to be worse when seizures last longer and evolve into status epilepticus. Third, status epilepticus—but not isolated seizures—is associated with a higher risk of developing epilepsy in both adults (5) and children. In a large cohort study following adults with acute symptomatic seizures, the risk of a subsequent unprovoked seizure at 10 years of follow-up was 41% for those with acute symptomatic seizure with status epilepticus and 13% for those without it, reflecting a 3.3-fold increased risk after controlling for age, sex, and cause. The extent of this increase in risk varied in a direction mirroring that of the expected brain damage in relation to different etiologies, as it was highest for patients with anoxic encephalopathy (18.8-fold), lowest for those with a metabolic cause (3.6-fold) and intermediate for those with a structural cause (7.1-fold) (6). Similar, albeit slightly worse, results seem to apply in the pediatric population, as Wagenman et al. report here that 69% (9/13) of children who developed status epilepticus in the ICU subsequently developed epilepsy after a mean follow-up of 2.7 years, as opposed to 21% (7/33) of those with no seizures, and 38% (3/8) of those with isolated seizures. Major unfavorable outcomes seem then somewhat quantified, including the subsequent risks of death, vegetative state, and long-term epilepsy, as summarized above. The critical question that remains to be answered though is whether any of these “unfavorable associations” can be prevented or even reversed by the treatment of seizures or status epilepticus. In fact, evidence abounds about multiple mechanisms of neuronal injury caused by status epilepticus from programmed cell necrosis (7), to a breakdown of GABA inhibition (8), to altered neuro-inflammation (9), ultimately leading to cell death within and outside the hippocampus (10). Stopping seizures should stop the brain damage they cause. The caveat though is this: it remains unclear how much of our unfavorable outcomes is actually caused by the seizures themselves rather than other nonmodifiable factors. The development of status epilepticus by itself may reflect a more severe underlying neurological insult and, thus, a wider spectrum of expected neurological deficits. That said, the development of status epilepticus in some patients but not others with similar neurological insults may by itself reflect
338
a higher genetic tendency for seizures and, thus, a lower threshold for neurological complications. Either way, the last two possibilities would contribute to mechanisms of poor neurological outcomes that may not necessarily be modifiable by the treatment of acute seizures. The extent to which all these factors contribute to longterm outcomes after status epilepticus needs to be further investigated. Carefully designed prospective studies are key to moving our understanding of this very challenging topic to the next level. by Lara Jehi, MD References 1. Young GB, Jordan KG, Doig GS. An assessment of nonconvulsive seizures in the intensive care unit using continuous EEG monitoring: An investigation of variables associated with mortality. Neurology 1996;47:83–89. 2. Abend NS, Arndt DH, Carpenter JL, Chapman KE, Cornett KM, Gallentine WB, Giza CC, Goldstein JL, Hahn CD, Lerner JT, Loddenkemper T, Matsumoto JH, McBain K, Nash KB, Payne E, Sánchez SM, Fernández IS, Shults J, Williams K, Yang A, Dlugos DJ. Electrographic seizures in pediatric ICU patients: Cohort study of risk factors and mortality. Neurology 2013;81:383–391. 3. Carrera E, Claassen J, Oddo M, Emerson RG, Mayer SA, Hirsch LJ. Continuous electroencephalographic monitoring in critically ill patients with central nervous system infections. Arch Neurol 2008;65:1612–1618. 4. Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ. Continuous electroencephalography in the medical intensive care unit. Crit Care Med 2009;37:2051–2056. 5. Leung H, Man CB, Hui AC, Kwan P, Wong KS. Prognosticating acute symptomatic seizures using two different seizure outcomes. Epilepsia 2010;51:1570–1579. 6. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: Effect of status epilepticus. Ann Neurol 1998;44:908–912. 7. Niquet J, Lopez-Meraz ML, Wasterlain CG. Programmed necrosis after status epilepticus. In: Jasper’s Basic Mechanisms of the Epilepsies. 4th ed. (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds.) Bethesda, MD: Oxford University Press, 2012:1–13XXX–XXX. 8. Reddy DS, Kuruba R. Experimental models of status epilepticus and neuronal injury for evaluation of therapeutic interventions. Int J Mol Sci 2013;14:18284–18318. 9. Noe FM, Polascheck N, Frigerio F, Bankstahl M, Ravizza T, Marchini S, Beltrame L, Banderó CR, Löscher W, Vezzani A.. Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol Dis 2013;59:183–193. 10. Scholl EA, Dudek FE, Ekstrand JJ. Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience 2013;252:45–59.
