Current Literature In Clinical Science
Nonconvulsive Seizures and Periodic Discharges: No Longer Such Innocent Bystanders
Seizure Burden in Subarachnoid Hemorrhage Associated With Functional and Cognitive Outcome. De Marchis GM, Pugin D, Meyers E, Velasquez A, Suwatcharangkoon S, Park S, Falo MC, Agarwal S, Mayer S, Schmidt JM, Connolly ES, Claassen J. Neurology 2016;86:253–260.
OBJECTIVE: To assess the relationship between seizure burden on continuous EEG (cEEG) and functional as well as cognitive outcome 3 months after subarachnoid hemorrhage (SAH). METHODS: The study included all consecutive patients with a spontaneous SAH admitted to the Columbia University Medical Center Neurological Intensive Care Unit and monitored with cEEG between 1996 and 2013. Seizure burden was defined as the duration, in hours, of seizures on cEEG. Cognitive outcomes were measured with the Telephone Interview for Cognitive Status (TICS, ranging from 0 to 51, indicating poor to good global mental status). RESULTS: Overall, 402 patients with SAH were included with a median age of 58 years (interquartile range (IQR) 46-68 years). The median duration of cEEG monitoring was 96 hours (IQR 48-155 hours). Seizures were recorded in 50 patients (12%), in whom the median seizure burden was 6 hours (IQR 1-13 hours). At 3 months, in multivariate analysis, seizure burden was associated with unfavorable functional and cognitive outcome. Every hour of seizure on cEEG was associated with an odds ratio of 1.10 (95% confidence interval [CI] 1.011.21, p = 0.04) to 3-month disability and mortality, and the TICS-score decreased, on average, by 0.16 points (adjusted coefficient -0.19, 95% CI -0.33 to -0.05, p = 0.01). CONCLUSION: In this study, after adjusting for established predictors, seizure burden was associated with functional outcome and cognitive impairment 3 months after SAH. Metabolic Crisis Occurs With Seizures and Periodic Discharges After Brain Trauma. Vespa P, Tubi M, Claassen J, Buitrago-Blanco M, McArthur D, Velazquez AG, Tu B, Prins M, Nuwer M. Ann Neurol 2016;79:579–590.
OBJECTIVE: Traumatic brain injury (TBI) results in persistent disruption of brain metabolism that has yet to be mechanistically defined. Early post-traumatic seizures are one potential mechanism for metabolic crisis and hence could be a therapeutic target. We hypothesized that seizures and pseudoperiodic discharges (PDs) may be mechanistically linked to metabolic crisis as measured by cerebral microdialysis. METHODS: A prospective multicenter study of surface and intracortical depth EEG were performed in conjunction with cerebral microdialysis in a cohort of severe TBI patients with time-locked analysis of the neurochemical response to seizures and pseudoperiodic discharges. RESULTS: Seizures or PDs occurred in 61% of 34 subjects, with 42.9% of these seizures noted only on intracortical depth EEG and in some cases lasted for many hours. Metabolic crisis as measured by elevated cerebral microdialysis lactate/pyruvate ratio occurred during seizures or PDs but not during electrically nonepileptic epochs. INTERPRETATION: In TBI patients, seizures and periodic discharges are one mechanism for metabolic crisis, and hence represent a therapeutic target for future study.
Commentary Nonconvulsive seizures (NCS) and periodic discharges are some of the most common findings on EEG in neurocritically ill patients, and some combination of these patterns is seen every single day in reasonably large institutions. Given the prevalence of these findings as well as its long historical recognition, it is somewhat surprising that we still do not necessarily underEpilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 319–321 © American Epilepsy Society
stand their significance particularly well, in part because of the wide morphologic variability in their presentations across many different etiologies. Studies have shown association with poor outcome with some of these patterns, but definitive studies implicating a direct relationship have been sparse. Specifically, the question as to whether NCS and periodic patterns on EEG are mechanistically involved in causing morbidity or whether they are mere bystanders/markers of acute brain injury has been at the forefront of this line of research since continuous EEG (cEEG) studies had demonstrated a high prevalence of these patterns in critically ill patients. Two recent studies have helped illuminate the significance of these patterns.
319
NCS and Periodic Discharges in Critically Ill Patients
De Marchis et al. tap into a long-running database at Columbia University—collected over a period of 17 years— studying patients with spontaneous subarachnoid hemorrhages to evaluate the effect of seizure burden on clinical outcome. Their cohort consisted of 402 patients who underwent EEG monitoring for a median of 96 hours. Seizures were recorded in 50 patients, with a median 6 hours of seizures. Outcome was assessed at 3 months using a functional (modified Rankin scale) as well as a cognitive measure (telephone interview for cognitive status [TICS]). Functional outcome was assessed in 308 patients; both the presence of seizures and seizure burden were associated with unfavorable functional outcomes. Cognitive outcome was available in 121 patients, though only 11 patients had seizures. Seizure burden was associated with a decrease in TICS; the effect size was small but conceptually important. Curiously, cognitive outcomes were not associated with the mere presence of seizures. This seems counterintuitive, as absence of seizures can be considered the ultimate low seizure burden. One simple answer may be just a question of sample size. The effect size for cognitive decline in the presence of seizures (compared to other significant variables) appears robust, and there was too much variability. Another potential explanation may be that patients with more prolonged NCS were intractable to medications, leading to aggressive inpatient and subsequent outpatient treatment. The study is impressive for the foresight required for implementing the long and extremely consistent follow-up. The authors have carefully adjusted for all known confounders. Nonetheless, one considers that this is an uncontrolled observational study and that the link between seizure burden and outcome is an association rather than a causation. However, within those confines, demonstrating a dose response to seizures is truly suggestive that the linkage may be more than mere association. The mechanism behind such changes had been postulated by the authors; the same group has investigated and implicated a proinflammatory cascade as a potential mechanism linking both NCS and poor outcome (1). Another mechanism is suggested by the study by Vespa et al., a multicenter prospective trial of moderate-severe TBI patients in whom multimodal monitoring was performed with invasive sensors, including intracortical depth electrodes and a microdialysis catheter. A total of 34 patients were studied; of these, 21 (61.8%) had seizures or periodic discharges. Of the 20 patients with both EEG and microdialysis, the authors found that patients with epileptiform activity had elevated lactate-to-pyruvate ratios and decreased glucose, a finding they defined as metabolic crisis. Furthermore, through careful analysis of within-subject changes in electrical activity and microdialysis measurements, they demonstrate time-locked metabolic changes with electrical disturbance. The authors present evidence that the invasive electrodes themselves are not the cause of these electrical and metabolic disturbances. Although, as the authors admit, the cause and effect cannot necessarily be established; nonetheless, they provide convincing evidence that electrical disturbance leads to metabolic changes. The common strength of both studies is the careful evaluation of confounders as well as their focus on homogeneous populations. There is other converging evidence corroborat-
320
ing the validity of the results by other authors: One recent study demonstrated seizure burden to be associated with neurological decline in children (2). Several studies have demonstrated that patterns in the ictal–interictal continuum, including periodic patterns, are associated with a hypermetabolic state (3). However, there are conflicting results, as some studies have not found association of periodic discharges with outcome (4), though outcome measures differed between these studies. Where do these results leave the practitioner in terms of clinical management of these patients? The immediate implications may seem that patients with NCS or even periodic discharges should be treated as though the phenomena themselves are causing ongoing brain injury. In that case, is one justified in aggressively treating patients with lateralized periodic discharges in a patient with a brain injury, or even generalized periodic discharges that are a result of metabolic disarray? One would have to caution against treatment generalizations based on these types of observational result. Treatment, and particularly overtreatment, have potential costly consequences. Use of anesthetic medications in particular has been associated with greater morbidity and mortality across a wide range of outcome measures (5)—though, again, such studies are observational, and the association definitely does not imply causation. As a general rule, the absolute best treatment of such patterns is to treat the underlying etiology wherever possible—whether it is treating a metabolic disarray, infections, removing offending immunomodulatory tumors, or even discontinuing certain provocative medications. It should be emphasized that the epileptiform activity associated with periodic patterns often lie in a continuum in both epileptogenicity as well as the propensity to cause neuronal injury. Several expert opinions are available for heuristic guidance for such patterns (6, 7). Clearly, further work is needed to determine whether intervention can affect outcome. One promising trial is underway in patients who have sustained cardiac arrest with electrographic status epilepticus and who are randomized to aggressive versus no treatment (TELSTAR trial) (8). Although the results from this study will directly pertain only to that particular population, it will likely give insight into potential treatment across a variety of underlying pathologies. Further replicative studies with standardization of both the EEG assessment as well as the outcome measures would provide confidence in the validity of these results. While awaiting definitive assessment, though, NCS and periodic patterns continue to leave their guilty footprints on these observational studies. by Jong Woo Lee, MD, PhD References 1. Claassen J, Albers D, Schmidt JM, De Marchis GM, Pugin D, Falo CM, Mayer SA, Cremers S, Agarwal S, Elkind MS, Connolly ES, Dukic V, Hripcsak G, Badjatia N. Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann Neurol 2014:75:771– 781. 2. Payne ET, Zhao XY, Frndova H, McBain K, Sharma R, Hutchison JS, Hahn CD. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014;137(pt 5):1429–1438.
NCS and Periodic Discharges in Critically Ill Patients
3. Struck AF, Struck AF, Westover MB, Hall LT, Deck GM, Cole AJ, Rosenthal ES. Metabolic correlates of the ictal-interictal continuum: FDGPET during continuous EEG. Neurocrit Care 2016;24:324–331. 4. Crepeau AZ, Kerrigan JF, Gerber P, Parikh G, Jahnke H, Nakaji P, Little A, Chapman KE. Rhythmical and periodic EEG patterns do not predict short-term outcome in critically ill patients with subarachnoid hemorrhage. J Clin Neurophysiol 2013;30:247–254. 5. Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: Risk or rescue? A 6-year cohort study. Neurology 2014;82:656–664.
6. Sivaraju A, Gilmore EJ. Understanding and managing the ictalinterictal continuum in neurocritical care. Curr Treat Options Neurol 2016;18:8. 7. Claassen J. How I treat patients with EEG patterns on the ictal-interictal continuum in the neuro ICU. Neurocrit Care 2009;11:437–444. 8. Ruijter BJ, van Putten MJ, Horn J, Blans MJ, Beishuizen A, van Rootselaar AF, Hofmeijer J; TELSTAR study group. Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): Study protocol for a randomized controlled trial. Trials 2014;15:433.
321
Nonconvulsive Seizures and Periodic Discharges: No Longer Such Innocent Bystanders
Seizure Burden in Subarachnoid Hemorrhage Associated With Functional and Cognitive Outcome. De Marchis GM, Pugin D, Meyers E, Velasquez A, Suwatcharangkoon S, Park S, Falo MC, Agarwal S, Mayer S, Schmidt JM, Connolly ES, Claassen J. Neurology 2016;86:253–260.
OBJECTIVE: To assess the relationship between seizure burden on continuous EEG (cEEG) and functional as well as cognitive outcome 3 months after subarachnoid hemorrhage (SAH). METHODS: The study included all consecutive patients with a spontaneous SAH admitted to the Columbia University Medical Center Neurological Intensive Care Unit and monitored with cEEG between 1996 and 2013. Seizure burden was defined as the duration, in hours, of seizures on cEEG. Cognitive outcomes were measured with the Telephone Interview for Cognitive Status (TICS, ranging from 0 to 51, indicating poor to good global mental status). RESULTS: Overall, 402 patients with SAH were included with a median age of 58 years (interquartile range (IQR) 46-68 years). The median duration of cEEG monitoring was 96 hours (IQR 48-155 hours). Seizures were recorded in 50 patients (12%), in whom the median seizure burden was 6 hours (IQR 1-13 hours). At 3 months, in multivariate analysis, seizure burden was associated with unfavorable functional and cognitive outcome. Every hour of seizure on cEEG was associated with an odds ratio of 1.10 (95% confidence interval [CI] 1.011.21, p = 0.04) to 3-month disability and mortality, and the TICS-score decreased, on average, by 0.16 points (adjusted coefficient -0.19, 95% CI -0.33 to -0.05, p = 0.01). CONCLUSION: In this study, after adjusting for established predictors, seizure burden was associated with functional outcome and cognitive impairment 3 months after SAH. Metabolic Crisis Occurs With Seizures and Periodic Discharges After Brain Trauma. Vespa P, Tubi M, Claassen J, Buitrago-Blanco M, McArthur D, Velazquez AG, Tu B, Prins M, Nuwer M. Ann Neurol 2016;79:579–590.
OBJECTIVE: Traumatic brain injury (TBI) results in persistent disruption of brain metabolism that has yet to be mechanistically defined. Early post-traumatic seizures are one potential mechanism for metabolic crisis and hence could be a therapeutic target. We hypothesized that seizures and pseudoperiodic discharges (PDs) may be mechanistically linked to metabolic crisis as measured by cerebral microdialysis. METHODS: A prospective multicenter study of surface and intracortical depth EEG were performed in conjunction with cerebral microdialysis in a cohort of severe TBI patients with time-locked analysis of the neurochemical response to seizures and pseudoperiodic discharges. RESULTS: Seizures or PDs occurred in 61% of 34 subjects, with 42.9% of these seizures noted only on intracortical depth EEG and in some cases lasted for many hours. Metabolic crisis as measured by elevated cerebral microdialysis lactate/pyruvate ratio occurred during seizures or PDs but not during electrically nonepileptic epochs. INTERPRETATION: In TBI patients, seizures and periodic discharges are one mechanism for metabolic crisis, and hence represent a therapeutic target for future study.
Commentary Nonconvulsive seizures (NCS) and periodic discharges are some of the most common findings on EEG in neurocritically ill patients, and some combination of these patterns is seen every single day in reasonably large institutions. Given the prevalence of these findings as well as its long historical recognition, it is somewhat surprising that we still do not necessarily underEpilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 319–321 © American Epilepsy Society
stand their significance particularly well, in part because of the wide morphologic variability in their presentations across many different etiologies. Studies have shown association with poor outcome with some of these patterns, but definitive studies implicating a direct relationship have been sparse. Specifically, the question as to whether NCS and periodic patterns on EEG are mechanistically involved in causing morbidity or whether they are mere bystanders/markers of acute brain injury has been at the forefront of this line of research since continuous EEG (cEEG) studies had demonstrated a high prevalence of these patterns in critically ill patients. Two recent studies have helped illuminate the significance of these patterns.
319
NCS and Periodic Discharges in Critically Ill Patients
De Marchis et al. tap into a long-running database at Columbia University—collected over a period of 17 years— studying patients with spontaneous subarachnoid hemorrhages to evaluate the effect of seizure burden on clinical outcome. Their cohort consisted of 402 patients who underwent EEG monitoring for a median of 96 hours. Seizures were recorded in 50 patients, with a median 6 hours of seizures. Outcome was assessed at 3 months using a functional (modified Rankin scale) as well as a cognitive measure (telephone interview for cognitive status [TICS]). Functional outcome was assessed in 308 patients; both the presence of seizures and seizure burden were associated with unfavorable functional outcomes. Cognitive outcome was available in 121 patients, though only 11 patients had seizures. Seizure burden was associated with a decrease in TICS; the effect size was small but conceptually important. Curiously, cognitive outcomes were not associated with the mere presence of seizures. This seems counterintuitive, as absence of seizures can be considered the ultimate low seizure burden. One simple answer may be just a question of sample size. The effect size for cognitive decline in the presence of seizures (compared to other significant variables) appears robust, and there was too much variability. Another potential explanation may be that patients with more prolonged NCS were intractable to medications, leading to aggressive inpatient and subsequent outpatient treatment. The study is impressive for the foresight required for implementing the long and extremely consistent follow-up. The authors have carefully adjusted for all known confounders. Nonetheless, one considers that this is an uncontrolled observational study and that the link between seizure burden and outcome is an association rather than a causation. However, within those confines, demonstrating a dose response to seizures is truly suggestive that the linkage may be more than mere association. The mechanism behind such changes had been postulated by the authors; the same group has investigated and implicated a proinflammatory cascade as a potential mechanism linking both NCS and poor outcome (1). Another mechanism is suggested by the study by Vespa et al., a multicenter prospective trial of moderate-severe TBI patients in whom multimodal monitoring was performed with invasive sensors, including intracortical depth electrodes and a microdialysis catheter. A total of 34 patients were studied; of these, 21 (61.8%) had seizures or periodic discharges. Of the 20 patients with both EEG and microdialysis, the authors found that patients with epileptiform activity had elevated lactate-to-pyruvate ratios and decreased glucose, a finding they defined as metabolic crisis. Furthermore, through careful analysis of within-subject changes in electrical activity and microdialysis measurements, they demonstrate time-locked metabolic changes with electrical disturbance. The authors present evidence that the invasive electrodes themselves are not the cause of these electrical and metabolic disturbances. Although, as the authors admit, the cause and effect cannot necessarily be established; nonetheless, they provide convincing evidence that electrical disturbance leads to metabolic changes. The common strength of both studies is the careful evaluation of confounders as well as their focus on homogeneous populations. There is other converging evidence corroborat-
320
ing the validity of the results by other authors: One recent study demonstrated seizure burden to be associated with neurological decline in children (2). Several studies have demonstrated that patterns in the ictal–interictal continuum, including periodic patterns, are associated with a hypermetabolic state (3). However, there are conflicting results, as some studies have not found association of periodic discharges with outcome (4), though outcome measures differed between these studies. Where do these results leave the practitioner in terms of clinical management of these patients? The immediate implications may seem that patients with NCS or even periodic discharges should be treated as though the phenomena themselves are causing ongoing brain injury. In that case, is one justified in aggressively treating patients with lateralized periodic discharges in a patient with a brain injury, or even generalized periodic discharges that are a result of metabolic disarray? One would have to caution against treatment generalizations based on these types of observational result. Treatment, and particularly overtreatment, have potential costly consequences. Use of anesthetic medications in particular has been associated with greater morbidity and mortality across a wide range of outcome measures (5)—though, again, such studies are observational, and the association definitely does not imply causation. As a general rule, the absolute best treatment of such patterns is to treat the underlying etiology wherever possible—whether it is treating a metabolic disarray, infections, removing offending immunomodulatory tumors, or even discontinuing certain provocative medications. It should be emphasized that the epileptiform activity associated with periodic patterns often lie in a continuum in both epileptogenicity as well as the propensity to cause neuronal injury. Several expert opinions are available for heuristic guidance for such patterns (6, 7). Clearly, further work is needed to determine whether intervention can affect outcome. One promising trial is underway in patients who have sustained cardiac arrest with electrographic status epilepticus and who are randomized to aggressive versus no treatment (TELSTAR trial) (8). Although the results from this study will directly pertain only to that particular population, it will likely give insight into potential treatment across a variety of underlying pathologies. Further replicative studies with standardization of both the EEG assessment as well as the outcome measures would provide confidence in the validity of these results. While awaiting definitive assessment, though, NCS and periodic patterns continue to leave their guilty footprints on these observational studies. by Jong Woo Lee, MD, PhD References 1. Claassen J, Albers D, Schmidt JM, De Marchis GM, Pugin D, Falo CM, Mayer SA, Cremers S, Agarwal S, Elkind MS, Connolly ES, Dukic V, Hripcsak G, Badjatia N. Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann Neurol 2014:75:771– 781. 2. Payne ET, Zhao XY, Frndova H, McBain K, Sharma R, Hutchison JS, Hahn CD. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014;137(pt 5):1429–1438.
NCS and Periodic Discharges in Critically Ill Patients
3. Struck AF, Struck AF, Westover MB, Hall LT, Deck GM, Cole AJ, Rosenthal ES. Metabolic correlates of the ictal-interictal continuum: FDGPET during continuous EEG. Neurocrit Care 2016;24:324–331. 4. Crepeau AZ, Kerrigan JF, Gerber P, Parikh G, Jahnke H, Nakaji P, Little A, Chapman KE. Rhythmical and periodic EEG patterns do not predict short-term outcome in critically ill patients with subarachnoid hemorrhage. J Clin Neurophysiol 2013;30:247–254. 5. Sutter R, Marsch S, Fuhr P, Kaplan PW, Rüegg S. Anesthetic drugs in status epilepticus: Risk or rescue? A 6-year cohort study. Neurology 2014;82:656–664.
6. Sivaraju A, Gilmore EJ. Understanding and managing the ictalinterictal continuum in neurocritical care. Curr Treat Options Neurol 2016;18:8. 7. Claassen J. How I treat patients with EEG patterns on the ictal-interictal continuum in the neuro ICU. Neurocrit Care 2009;11:437–444. 8. Ruijter BJ, van Putten MJ, Horn J, Blans MJ, Beishuizen A, van Rootselaar AF, Hofmeijer J; TELSTAR study group. Treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation (TELSTAR): Study protocol for a randomized controlled trial. Trials 2014;15:433.
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