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Title: Risk factors for in-hospital seizures and new onset epilepsy in coil embolization of aneurysmal subarachnoid hemorrhage
Key Words: Seizures, Epilepsy, Subarachnoid Hemorrhage, Coil embolization, Risk factors, EEG
Running Title: Risk factors for seizures in subarachnoid hemorrhage
Object: The goal of the study was to determine risk factors for inpatient seizures and long-term epilepsy in patients who had received coil embolization for aneurysm associated subarachnoid hemorrhage.
Methods: A retrospective chart review was conducted for patients admitted at University of Pittsburgh Medical Center from 2010 – 2014 for subarachnoid hemorrhage. The inclusion criterion was having coil embolization. Patients who underwent aneurysm clipping were excluded from the analysis. Variables of interest such as subdural hematoma, hydrocephalus, cerebral infarction, post-operative vasospasm, cerebral edema, and mass effect were collected from the chart review. Seizures were defined as either subclinical electrographic seizures or clinically apparent seizures. After discharge, patients were followed up to determine if they had developed epilepsy. Their degree of functional independence was also assessed through the Modified Rankin scale. The Chi squared test was used to assess univariate associations. Variables which were significant in the univariate model were considered for inclusion into a binary logistic regression model.
Results: 175 patients met the inclusion criteria for the study. 16 (9.1%) of the patients had seizures while in-patient. 5 out of 73 patients successfully interviewed in the follow-up analysis met criteria for epilepsy. None of the patients with epilepsy after discharge had electrographic seizures while in the hospital for subarachnoid hemorrhage. Vasospasm (OR 6.88, 95% CI 1.81 – 26.25) and grade 5 Hunt & Hess score (OR 26.16, 95% CI 3.95 – 173.49) were significantly associated with in-hospital seizures in a multivariable analysis. Epileptiform discharges on EEG were significantly associated with electrographic seizures in the hospital (OR 1.158, CI 1.030 – 1.302). Epileptiform discharges on EEG were significantly associated with mass effect findings on brain imaging (OR 3.5, CI 1.05 – 11.69).
Conclusion: Our results indicate that a Hunt and Hess grade of 5 and vasospasm are independent significant risk factors for seizures in the hospital. In addition, our results show that mass effect is an independent significant risk factor for epileptiform discharges on EEG. Based on our findings, patients with a Hunt and Hess score of 5, vasospasm, and mass effect may benefit from continuous EEG for detection of epileptiform discharges and seizures. Our results may indicate that there is no association between in-hospital seizure and development of epilepsy. This may guide the clinical decision making underlying prescription of antiepileptic drugs in these patients following discharge.
Subarachnoid hemorrhage affects 30,000 Americans every year with a mortality rate of up to 45%.16 Coil embolization is a procedure that is frequently used for treating cerebral aneurysm as it is noninvasive compared to other options such as craniotomy and clipping.11
There are significant complications of subarachnoid hemorrhage such as seizures, epilepsy, and hemiparesis. Coiling of unruptured and ruptured cerebral aneurysms were found to have a 6.2% and 11.1% incidence of seizures or epilepsy, respectively.11 Seizures have been found to be associated with longer hospitalizations and hospital charges.11A study by Claassen et. al. found that in patients with no history of epilepsy, those with in-hospital seizures had a 65% mortality at 12 months while those without in-hospital seizures had a 23% mortality.6 Non-convulsive status epilepticus (NCSE), defined as an event of electrographic seizures that lasts more than 60 minutes, was associated with a 100% mortality rate (8/8) in another study.7 Furthermore, it was found that patients who had developed epilepsy after subarachnoid hemorrhage had a poorer mental and physical quality of life, increased anxiety levels, and reduced functional independence after hospital discharge.6
Early detection and intervention for seizures is important for successfully treating and preventing status epilepticus, especially in patients with severe pathology.7 Seizures can occur without any clinical manifestation such as in comatose patients. Continuous electroencephalogram (cEEG) has been suggested as a potential option to detect epileptogenic activity that would otherwise not be detected.4 However, cEEG requires a significant amount of resources and labor. After detection of epileptogenic activity, patients can receive an antiepileptic drug (AED). Despite the ability to find epileptogenic activity before initiation of antiepileptic treatment, a study conducted in 2015 found that more than half of institutions in the study routinely used seizure prophylaxis without risk stratification for all patients with aneurysmal subarachnoid hemorrhage.8 A 2013 Cochrane review study has determined that there is insufficient evidence to support or reject the use of AEDs for primary and secondary seizure prevention in subarachnoid hemorrhage.14 Prophylactic AED usage has been associated with worsened cognitive function and higher rates of complications such as vasospasm and cerebral infarction.15,19
There is a lack of research that identifies the patients in aneurysmal subarachnoid hemorrhage who would most benefit from AEDs. Determining risk factors for seizures would help with stratifying these patients for diagnostic studies and treatment regimens. Some of the implicated risk factors for epilepsy include cerebral infarction, subdural hematoma, postoperative vasospasm, Hunt and Hess grade of IV or V, high cisternal blood score, large intracerebral hemorrhage, and shunt-dependent hydrocephalus.6 Further investigation of the risk factors for seizures and epilepsy is warranted to help select patients for EEG monitoring and prophylactic AED treatment.
This goal of this study is to evaluate the risk factors for seizures and epilepsy in patients who underwent coil embolization for a ruptured aneurysm causing subarachnoid hemorrhage. This information would help determine who would be better candidates for continuous EEG monitoring. We hypothesized that subdural hematoma and cerebral infarction, previously shown to be significant independent predictors of epilepsy in patients who underwent clipping and coil embolization for aneurysmal subarachnoid hemorrhage6, would be significant risk factors for in-hospital seizures and epilepsy.
A retrospective chart review was conducted. Data was extracted from electronic medical records of patients who underwent coil embolization for subarachnoid hemorrhage at the University of Pittsburgh Medical Center from 2010 – 2014. Patients who had accompanying clipping of an aneurysm were excluded since it involves an invasive approach, thus making these patients at higher risk than those patients who only received coiling. Coiling of arteriovenous malformations and mycotic aneurysms associated with subarachnoid hemorrhage were also excluded as these patients had significantly different pathologies than those patients who received coil embolization only for a conventional aneurysm. QI approval (QI number 002078) was obtained from the University of Pittsburgh.
Data was gathered from history and physical documentation, progress notes, operative reports, radiologic reports, electroencephalogram reports, and discharge summaries. All the patients received CT imaging upon imaging. A portion of the patients in the study had undergone routine and continuous EEG study based on physician discretion in the perioperative or postoperative period of the hospitalization. Continuous EEGs were defined as lasting more than an hour while routine EEGs were defined as less than an hour.
The outcomes of interest in the hospital analysis are seizures. Seizures were also subdivided into clinical seizure and electrographic seizure. Clinical seizure was defined as any observed event representing seizure activity any time from initial presentation from transport to hospital to discharge. These included focal seizures and generalized convulsive seizures reported by caregivers or hospital staff. Classification as a clinical seizure did not require an EEG correlate. An electrographic seizure was defined as a seizure reported on EEG documentation that occurred without any overt clinical accompaniment. Patients may have had a clinical seizure on one occasion and an electrographic seizure on another. It was also noted if a patient had epileptiform discharges if an EEG showed epileptiform discharges without evolution into electrographic seizures. Patients may have had epileptiform discharges on one EEG and an electrographic seizure on a repeat EEG. The presence of epileptiform discharges was included in the statistical analysis. In addition, the presence of an abnormal EEG was noted, defined as any presence of generalized slowing or epileptiform activity. Furthermore, status epilepticus (SE) or non-convulsive status epilepticus (NCSE) were included in the outcome variables. SE was defined as clinically apparent epileptic activity lasting more than five minutes. NCSE was defined as epileptic activity seen on EEG without clinical correlate lasting more than five minutes.
Independent radiographic variables used in the analysis were intraparenchymal hemorrhage, presence of a cisternal clot, mass effect, midline shift, hydrocephalus, intraventricular hemorrhage, sylvian fissure hemorrhage, subdural hematoma, interval increase in subarachnoid hemorrhage, cerebral infarction, and cerebral edema which were obtained from CT scan or MRI report. Postoperative vasospasm and severity was determined from postoperative angiogram reports. Information about the presence of multiple aneurysms, treatment of multiple aneurysms, repeat coiling of same aneurysm, and aneurysm size were also obtained. Aneurysm size was defined as the length of greatest dimension if it was described in multiple dimensions. If there were multiple aneurysms, aneurysm size was designated to be the aneurysm with the biggest dimension. Hunt-Hess grade was obtained from history and physical documentation.
In the follow-up analysis, patients or close family members were interviewed on the phone. If a seizure had occurred, they were asked about the description and length of the seizure, provocations prior to the seizure, and antiepileptic usage. Epilepsy was determined from the history provided by the patient and was defined as having two separate seizures without acute provocations after discharge. Modified Rankin and Depression score were also obtained to evaluate the functional independence of the patients. The Center for Epidemiologic Studies Depression Scale (CES-D) screen was used to evaluate depression on a 0 to 60-point scale. The conventional cut-off value of more than 16 was used to indicate depressive symptoms. Questions regarding depression were not asked if the patient was not the one conducting the interview. The follow-up interval ranged from 6 months to 6 years after discharge.
The data were analyzed with IBM Corporation SPSS Statistics for Windows Version 24.0 (Released 2016, Armonk, NY). The alpha value was set to 0.05. The Chi squared and Fisher exact test, when appropriate, were used to assess the significance of the categorical independent variables. The independent sample two-tailed t-test was used to assess the significance of continuous variables. Variables that were significant in the preliminary univariate analysis and variables which have previously been shown to be of significance were included in multivariable binary logistic regression analyses.
In the hospital analysis, 175 patients were included in the study. There were 120 females (68.6%) and 55 males (31.4%) in the study. The mean age was 58.5 ± 12.67 years, with a range of 29 – 86 years. Fifteen (8.6%) of the patients were African American, 135 (77.1%) of the patients were Caucasian, one patient (0.6%) was Native American, one (0.6%) patient was Asian, and 43 (24.6%) could not be determined. Hunt and Hess grade distributions were as follows: Grade 1 – 5 (2.9%); Grade 2 – 72 (41.1%), Grade 3 – 57 (32.6%), Grade 4 – (17.1%), Grade 5 – 9 (5.1%).
Of the 175 patients, 16 (9.1%) patients had any type of seizure. In a univariate analysis, seizures were significantly associated with intraparenchymal bleed, cerebral infarction, Hunt & Hess Grade, vasospasm, cerebral edema, and epileptiform discharges as shown in table 1. In a multivariable analysis, only vasospasm (OR 6.88, 95% CI 1.81 – 26.25) and grade 5 Hunt & Hess (OR 26.16, 95% CI 3.95 – 173.49) were significantly associated with seizures.
Of the 175 patients, 90 (51.4%) had EEGs. 31 of the patients who had routine EEGs were put on continuous EEG monitoring. Of the patients who had EEGs, 77 (85.6%) had abnormal EEG findings, 38 (42.2%) patients had epileptiform discharges during EEG.
Of the 16 total patients with seizures, 15 underwent EEG. Six patients had electrographic seizures while 14 patients had clinical seizures. Four patients (28.6%) had both clinical seizures and electrographic seizures. Out of the 6 patients with electrographic seizures, two of the patients did not have any clinically apparent seizures at another point during the hospitalization. Four patients had non-convulsive status epilepticus. No patients had convulsive status epilepticus. Three out of the four patients with nonconvulsive status epilepticus also had separate clinically apparent seizures at another point during hospitalization. Figure 1 shows the classifications of seizures that the patients had while hospitalized.
11 (68.75%) out of the 16 patients with seizures had vasospasm. 11/62 (17.7%) of patients with vasospasm had seizure.
In a subgroup analysis for patients who had EEGs, epileptiform discharge was analyzed as an outcome variable. In a univariate analysis, only mass effect and midline shift were significantly associated with epileptiform discharges as shown in table 2. In a multivariable analysis, only mass effect was significantly associated with epileptiform discharges (OR 3.5, CI 1.05 – 11.69). Epileptiform discharges were significantly associated with electrographic seizures in a univariate analysis (p = 0.011, OR 1.158, CI 1.030 – 1.302). Our results also show that having clinical seizures is significantly associated with having an EEG that shows electrographic seizures in a univariate analysis (p = 0.004, OR 16.67, CI 2.67 – 104.19).
Total in-house mortality was 21/175 (12%). 7 (43.8%) out of the 16 patients with seizures died in the hospital. Out of the four patients who had non-convulsive status epilepticus, three (75%) died in the hospital. Among the patients who died, 20 (91%) obtained EEGs with 10 (45%) receiving continuous EEGs. Seizures were significantly associated with hospital death in a univariate analysis (p < .001, OR 7.47, CI 2.43 – 22.93).
Out of the patients who were discharged, 74 patients were lost to follow-up and 6 patients died after discharge. In the 73 patients who were successfully interviewed, Modified Rankin score was obtained for 67 patients and obtained a CES-D score for 62 patients. The interviewed patients’ average age when they were admitted was 57.47 with a standard deviation of 12.08. 5 (6.8%) were African American, 61 (83.6%) were Caucasian, and the rest could not be determined. 48 (65.8%) were female. 5/73 (6.8%) of patients met criteria for epilepsy following discharge. 12 (18.8%) patients were taking an AED. Five of the 12 patients on an AED had at least one seizure following discharge, with four meeting criteria for epilepsy. Two patients had focal seizures, two patients could not characterize their seizure. One patient had only one convulsive seizure following discharge but this was after finishing a tapered course of an AED. This patient was put back on the AED by the patient’s outpatient neurologist after the seizure and did not have any more seizures. Though this patient did not have two separate seizures after discharge, we classified this patient as having epilepsy, albeit controlled with an AED. 4/5 patients with epilepsy were taking antiepileptic medication at the time of interview. Of the patients with epilepsy after discharge, only one had a clinical seizure during their hospital course. None had electrographic seizures or NCSE in the hospital.
For patients who were followed up, male sex, aneurysm size, intraparenchymal bleed, and cerebral edema were significantly associated with epilepsy in a univariate analysis. Table 3 includes the full list of variables analyzed in these patients.
Four (80%) of the patients with epilepsy who answered the depression screen were not found to have depressive symptoms. 18 (29%) out of the total 62 patients who answered the depression screen were found to have depressive symptoms. Depressive symptoms were not found to be significantly associated with having in-hospital seizures (p = 0.31) or epilepsy (p = 0.31). Table 4 includes the Modified Rankin score of the patients.
Our results show that Hunt and Hess score of 5 is significantly associated with seizures during hospitalization after coiling for Aneurysmal subarachnoid hemorrhage. Since a Hunt and Hess score of 5 indicates a comatose state, our findings are in accordance with previous findings that show an association between electrographic seizures and coma in intensive care unit patients undergoing continuous EEG.5
In addition, our results show that vasospasm is significantly associated with seizures. Seizures have been thought to be due to focal pathology, such as cerebral infarction and subdural hematoma.6 The significant association between seizures and vasospasm, a phenomenon resulting in reduced perfusion in a localized area fed by a cerebral artery, supports this paradigm. Reduced perfusion from vasospasm may increase the excitability of the neurons due to impaired function of ion pumps, thus predisposing to epileptic activity. Our results do not specify the directionality of the association, so there is also the possibility that seizures may be increasing the chance of vasospasm. Vasospasm, by presenting with altered mental status, has the potential to present similarly to a seizure. This, in addition to our results showing the association between vasospasm and seizure, should make a clinician suspect the existence of concurrent vasospasm whenever a patient presents with seizure. Interestingly, vasospasm has been shown to be associated with specific EEG findings two days prior to the documentation of vasospasm.21 These specific EEG findings which were found to be associated with vasospasm may be related to the association we have seen between seizures and vasospasm. Seizures may produce an effect that causes vasospasm in a similar manner as cortical spreading depolarization (CSD), a phenomenon thought to be associated with metabolic derangements and localized electrolyte imbalance. CSD has been shown to be associated with delayed cerebral ischemia after the onset of SAH9,10, possibly due to a vascular response mediated by the CSD associated metabolic and electrolyte abnormalities.
A study by Ibrahim et. al. showed a significant association between seizures and subdural hematoma and cerebral edema in the subarachnoid hemorrhage population, which was not seen in our study.12 Another study by Vespa et. al. in patients with hemorrhagic and ischemic stroke showed an association between seizures and midline shift.22 Though there was no significance in a multivariable analysis, we see that midline shift was associated with epileptiform discharges in a univariate analysis. A previous study by Panczykowski et. al. has shown that in patients who receive clipping or coiling for SAH, seizures are significantly associated with intraventricular hemorrhage, cisternal clot burden, and poor neurological grade on admission.18 Intraventricular hemorrhage and presence of cisternal clot were not significantly associated in our results.
In our study, the electrographic seizure rate is 2.9%, a smaller amount from that seen in other studies.3,5 Since only 17.7% of the patients in our study were monitored on cEEG, the small number we obtained may be a reduced capture. Out of those patients who had a cEEG, 16% had an electrographic seizure. This percentage is closer to the incidence found in previous studies. A study by Vespa et. al. found that in a cohort of patients who underwent continuous EEG monitoring, 28% of patients with intracerebral hemorrhage had seizures.22 They found that continuous EEG detected 4 times the amount of electrographic seizures than seen clinically22. Seizures have been detected in 19% of patients in subarachnoid hemorrhage in a study by Claassen et. al., with more than 95% being nonconvulsive.4 Another study by Claassen et. al. in patients with intracerebral hemorrhage who underwent continuous EEG monitoring in the ICU found that 31% had a seizure during the hospital course.3 The aforementioned studies looked at patients who had continuous EEGs, whereas only 17% of our patients had continuous EEGs. 12 (55%) of the patients who died in our study did not receive continuous EEG. Potentially, an unsuspected nonconvulsive status epilepticus contributed to their deaths. This is a potential indication for more liberal use of continuous EEG. With increased use of continuous EEG, there may be higher detection of electrographic seizures and NCSE and therefore treatment and better outcomes.
Our study showed a significant association between epileptiform discharges and electrographic seizure in a univariate analysis. Our study also showed a significant association of epileptiform discharges with mass effect in a multivariable analysis. In a study of patients with mostly poor grade SAH, epileptiform discharges were seen in 23% of patients.4 In our data, 48.9% of the patients with EEGs had epileptiform discharges. There may have been additional patients who did not receive an EEG who would have had epileptiform discharges seen on EEG. Epileptiform discharges have been shown to be associated with worse outcome.2 Based on our results, patients who have had mass effect seen on imaging would benefit from extensive EEG monitoring as it would provide important prognostic information that would affect management.
Seizures have been shown to be a be a independent predictor of poor outcome.1 Our findings corroborate the findings of other studies that show that seizures during subarachnoid hemorrhage significantly increase mortality.20
Our incidence of epilepsy (6.8%) is comparable to other studies.6,13,17 Our study did not show an association between in-hospital seizures and epilepsy, which is in accordance with previous findings by Lin et. al.13 This may indicate that the pathologic process which eventually causes epilepsy has no relation to the process that causes seizures during hospitalization. A study in patients with aneurysmal SAH treated with clipping found that younger age was more likely to be associated with epilepsy.17 In our study, the mean age of patients with epilepsy was 7 years younger than patients without epilepsy, but this difference was not significant. Our study showed that male sex, aneurysm size, intraparenchymal bleed, and cerebral edema were significantly associated with epilepsy in a univariate analysis. However, these findings are limited by a small sample size. In our population, the in-hospital mortality rate was 43.8% in the patients with seizures. This may be a significant source of survivorship bias that diminishes the ability to find the potential associations of epilepsy with various pathologies that can occur with subarachnoid hemorrhage. Thus, there is a need for much larger population follow-up studies for aneurysmal SAH.
Our patient population is limited to the University of Pittsburgh Medical Center patient population and its institutional clinical practices. Thus, it may not have the level of generalizability provided by multi-institutional studies. In addition, our study’s findings are limited by the small sample sizes. Another limitation lies in the follow-up period. Interview data were gathered in a span of a months and patients were admitted to the hospital at different points in a four-year period. Hence, the follow-up interval was different for each patient. The implication is that the study does not account for the change in mortality, rate of epilepsy, and functional independence over time after the onset of subarachnoid hemorrhage.
Our study in patients who have received coil embolization for aneurysmal subarachnoid hemorrhage has shown that vasospasm and a Hunt and Hess score of 5 is significantly associated with seizures. Mass effect was shown to be significantly associated with epileptiform discharges. Patients with mass effect seen on brain imaging would benefit from continuous EEG since these patients are at higher risk for epileptiform discharges, which is associated with electrographic seizures. Our patients with epilepsy did not have electrographic seizures in the hospital. This may serve as an indication that in-hospital seizures, specifically electrographic seizures, have a different pathologic process than the process which causes epilepsy after discharge. This may guide clinical decision making about prescribing antiepileptic medications in these patients following discharge from the hospital. Further studies involving the subarachnoid hemorrhage population can evaluate the incidence of seizures in those who have vasospasm and Hunt and Hess grade of 5 by placing all these patients on continuous EEG monitoring. The low incidence of epilepsy post-discharge and the large in-hospital mortality in patients who have seizures is a significant obstacle in obtaining an adequate sample size when studying these patients. Thus, there is a need for a large, multi-center follow-up study looking for an association between in-hospital seizures and development of epilepsy.
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
The authors would like to express their gratitude to the patients, especially those who participated in the interviews, that have provided data to make this study possible.
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Figure 1 – This is a flowchart showing a breakdown of patients with seizures in the hospital into seizure types and EEG detection methods. The second row shows patients split into groups of having only electrographic seizures, having only clinical seizures, and having both. Arrows with numbers depict how many of the patients from the previous box join the next box.