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The incidence of seizures following aneurysmal SAH is 5%–27%, with the majority occurring within 24 hours of the time of aneurysm rupture or following

rebleeding.3,9,17,34,38 It is also well established that SAH is a risk factor for epilepsy following discharge from the hos-pital,1 although it remains unclear whether the occurrence

of early seizures is predictive of long-term post-SAH epi-lepsy.3,7 While inpatients with documented seizures fol-lowing aneurysmal SAH should benefit from treatment with AEDs, the use of prophylactic AEDs2 in patients who present with SAH is controversial, and clinical practices are highly discrepant.36

On the one hand, seizures have been associated with early neurological deterioration and poor outcomes in patients following SAH.2,7,22 Furthermore, early-onset sei-zures can cause increased intracranial pressure or rebleed-ing from an unsecured aneurysm. On the other hand, the

Clinical, laboratory, and radiographic predictors of the occurrence of seizures following aneurysmal subarachnoid hemorrhage

Clinical articleGeorGe M. IbrahIM, M.D., arIa Fallah, M.D., anD r. loch MacDonalD, M.D., Ph.D.Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, and Department of Surgery, University of Toronto, Ontario, Canada

Object. At present, the administration of prophylactic antiepileptic medication following aneurysmal subarach-noid hemorrhage (SAH) is controversial, and the practice is heterogeneous. Here, the authors sought to inform clini-cal decision making by identifying factors associated with the occurrence of seizures following aneurysm rupture.

Methods. Exploratory analysis was performed on 413 patients enrolled in CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring after Subarachnoid Hemorrhage), a prospective random-ized trial of clazosentan for the prevention of angiographic vasospasm. The association among clinical, laboratory, and radiographic covariates and the occurrence of seizures following SAH were determined. Covariates with a sig-nificance level of p < 0.20 on univariate analysis were entered into a multivariate logistic regression model. Receiver operating characteristic (ROC) curve analysis was used to define optimal predictive thresholds.

Results. Of the 413 patients enrolled in the study, 57 (13.8%) had at least 1 seizure following SAH. On univariate analysis, a World Federation of Neurosurgical Societies grade of IV–V, a greater subarachnoid clot burden, and the presence of midline shift and subdural hematomas were associated with seizure activity. On multivariate analysis, only a subarachnoid clot burden (OR 2.76, 95% CI 1.39–5.49) and subdural hematoma (OR 5.67, 95% CI 1.56–20.57) were associated with seizures following SAH. Using ROC curve analysis, the optimal predictive cutoff for subarachnoid clot burden was determined to be 21 (of a possible 30) on the Hijdra scale (area under the curve 0.63).

Conclusions. A greater subarachnoid clot burden and subdural hematoma are associated with the occurrence of seizures after aneurysm rupture. These findings may help to identify patients at greatest risk for seizures and guide informed decisions regarding the prescription of prophylactic anticonvulsive therapy. Clinical trial registration no.: NCT00111085 (ClinicalTrials.gov).(http://thejns.org/doi/abs/10.3171/2013.3.JNS122097)

Key WorDs • subarachnoid hemorrhage • seizure • traumatic brain injury

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Abbreviations used in this paper: ACA = anterior cerebral artery; AED = antiepileptic drug; AUC = area under the curve; CONSCIOUS-1 = Clazosentan to Overcome Neurological Isch-emia and Infarction Occurring after Subarachnoid Hemorrhage; ICA = internal carotid artery; MCA = middle cerebral artery; ROC = receiver operating characteristic; SAH = subarachnoid hemor-rhage; WFNS = World Federation of Neurosurgical Societies.

This article contains some figures that are displayed in color on line but in black-and-white in the print edition.

G. M. Ibrahim, A. Fallah, and R. L. Macdonald

348 J Neurosurg / Volume 119 / August 2013

toxicity of AEDs is well noted. The use of prophylactic AEDs following SAH has been associated with increased in-hospital complications and worse patient outcomes.31,36 The 2009 and 2010 consensus guidelines published by the American Heart and American Stroke Foundations sug-gest that the administration of prophylactic anticonvul-sants “may be considered in the immediate posthemor-rhagic period (Class IIb, Level of Evidence B).”4,12 It is, therefore, important to identify patients at greatest risk for early-onset seizures following aneurysm rupture, so that informed decisions can be made regarding the use of pro-phylactic AEDs.

The goal in the current study was to identify clinical, laboratory, and radiographic factors associated with the occurrence of seizures following aneurysm rupture in a large cohort of patients enrolled in the CONSCIOUS-1 trial. The identification of such factors may serve to in-form clinical decisions to initiate AEDs in patients who present with SAH.

MethodsThis post hoc analysis was conducted by the au-

thors. Actelion Pharmaceuticals approved its publica- tion but had no input into its design or analysis. The CONSCIOUS-1 trial was registered with the ClinicalTri-als.gov database (http://clinicaltrials.gov), and its regis-tration no. is NCT00111085.

Study PopulationWe performed a post hoc analysis of 413 patients en-

rolled in the CONSIOUS-1 trial, a prospective, random-ized, double-blind Phase IIb trial evaluating the efficacy of clazosentan in preventing angiographic vasospasm.29 Patients were enrolled between January 2005 and March 2006. The methods and results of the study are published elsewhere.29

Clinical AssessmentPatients with CT-confirmed SAH were admitted to

the respective neurosurgical units. The primary outcome of interest was whether patients had seizure activity fol-lowing SAH. Clinical and demographic information was obtained for all participants. The severity of each pa-tient’s presenting symptoms was classified based on the WFNS scale.40

Laboratory InvestigationsBecause disturbances in serum electrolytes, extended

electrolytes, and glucose levels are known risk factors for seizures, we also collected these variables on admis-sion. Hypokalemia and hyperkalemia were defined as potassium levels < 3.2 and > 5.0 mmol/L, respectively. Hyponatremia and hypernatremia were defined as so-dium concentrations < 130 and > 145 mmol/L, respec-tively. Calcium concentrations were corrected for albumin concentrations, where corrected calcium was defined as measured calcium (in mmol/L) + 0.02 (40 - serum albu-min [in g/L]), where 40 represents the average albumin concentration in g/L. Hypocalcemia and hypercalcemia

were defined as corrected serum calcium concentrations of 1.9 and 2.6 mmol/L, respectively. Hypoglycemia and hyperglycemia were defined as a glucose level < 4 and > 12 mmol/L, respectively. These definitions were based on commonly used definitions of the normal ranges for these serum chemicals. Serum magnesium and phosphate levels were unavailable. The mean time between SAH ictus and laboratory investigations was 23.5 ± 18.2 hours.

Radiological StudiesAll patients underwent CT upon presentation. The

subarachnoid clot burden was quantified using the Hijdra scale, which is applied to evaluate the amount of clot in 10 fissures and cisterns using a scoring system: 0, no blood; 1, small amount of blood; 2, moderately filled with blood; or 3, completely filled with blood. The total amount of blood was calculated by adding the 10 scores, for a range of scores from 0 to 30.20 The extent of intraventricular hemorrhage was quantified using a modification of the Graeb score, whereby a score of 0 (no blood), 1 (sedimen-tation of blood, < 25% filled), 2 (moderately filled with blood), or 3 (completely filled with blood) was given to each ventricle for a maximum possible score of 12.16,27 The frequency of intracerebral hemorrhage as well as hy-drocephalus, midline shift, and subdural hematomas was also documented.

Statistical AnalysisDescriptive statistics are reported as frequencies.

Where indicated, variables were dichotomized by their median value. The Fisher exact test was used to compare proportions where indicated. Univariate analysis was per-formed to determine associations between the occurrence of seizures after SAH and potential covariates. Covari-ates with a p < 0.20 were entered into a binary logistic regression. Variables with fewer than 5 events were ex-cluded from the final models. For all final models, statis-tical significance was set at p < 0.05. Receiver operating characteristic curve analysis was performed to define op-timal cutoff values for significant continuous covariates. Analysis was performed using SAS software, Version 9.3 (SAS Institute, Inc.).

Results

Patient Factors

Four hundred thirteen patients were enrolled in the CONSCIOUS-1 trial. The mean patient age was 51 years, and the majority (76%) had WFNS Grades I–III SAH. Furthermore, most aneurysms (89%) were located in the anterior circulation. A summary of clinical and ra-diographic information is presented in Table 1. Of these individuals, 57 (13.8%) had seizure activity following an-eurysm rupture and prior to the aneurysm-securing proce-dure. During their course in the hospital, 155 individuals (37.5%) were treated with AEDs. Of these, 128 (82.6%) were treated with phenytoin. Patients who presented with seizure activity were more likely to be placed on AEDs (p = 0.018, Fisher exact test).


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Univariate AnalysisOn univariate analysis (Table 2) factors associated

with the occurrence of seizure activity following an-eurysm rupture were WFNS Grades IV–V (p = 0.02), greater subarachnoid clot burden (Hijdra score ≥ 18; p = 0.003), midline shift (p = 0.001), and subdural hema-toma (p = 0.002). When the occurrence of seizures was analyzed by aneurysm location, no significant association was identified (anterior vs posterior: p = 0.86; MCA vs all other locations: p = 0.90; ICA vs all other locations: p = 0.40; ACA vs all other locations: p = 0.56). We also evalu-ated age and preexisting hypertension as continuous and dichotomous variables, and no significant associations were identified. No other associations between seizures and clinical, laboratory, and radiographic covariates were identified.

Multivariate AnalysisIn the binary logistic regression model, we included

variables that were associated with seizures after aneu-rysm rupture at a p < 0.20 on univariate analysis. These included WFNS grade, subarachnoid clot burden, midline shift, and subdural hematoma as well as aneurysm size

and intraventricular clot burden (Table 3). Of these, only a greater subarachnoid clot burden (OR 2.76, 95% CI 1.39–5.49, p = 0.004) and subdural hematoma (OR 5.67, 95% CI 1.56–20.57, p = 0.008) were associated with the occur-rence of seizures following SAH. The confidence interval for the latter is wide because of the low incidence of sub-dural hematomas within this cohort (13 patients [3.1%]).

Receiver Operating Characteristic Curve AnalysisThe only significant continuous variable associated

with the occurrence of seizures was the subarachnoid clot burden, as measured using the Hijdra scale. To establish the optimal cutoff at which a subarachnoid clot may be associated with seizure activity, we applied ROC curve analysis (Fig. 1). A Hijdra score (maximum of 30) of 2 and 30 provided 100% sensitivity and 100% specificity, respectively. The optimal cutoff, as determined via ROC

TABLE 1: Clinical, laboratory, and radiographic characteristics of 413 patients with aneurysmal SAH*

Variable No. (%)

mean age in yrs 51.0 ± 10.8no. of males 121 (29.3)patients w/ hypertension 175 (42.4)WFNS grade Grades I–III 313 (75.8) Grades IV–V 100 (24.2)aneurysm location† ant circulation 360 (88.9) pst circulation 45 (11.1) aneurysm size in mm‡ ≤5 167 (42.2) >5 229 (57.8)subarachnoid clot burden, Hijdra score 18.3 ± 5.9intraventricular clot burden, modified Graeb score

3.9 ± 2.4

patients w/ hydrocephalus 375 (90.8)patients w/ intracerebral hemorrhage 50 (12.1) patients w/ midline shift 16 (3.9) patients w/ subdural hematoma 13 (3.1) potassium level in mmol/L 3.8 ± 0.4sodium level in mmol/L 139.6 ± 4.2glucose level in mmol/L 7.7 ± 2.2corrected calcium level in mmol/L 2.15 ± 0.54

* Values expressed as the mean ± standard deviation. Abbreviations: ant = anterior; pst = posterior.† Aneurysm location recorded in 405 patients.‡ Aneurysm size available for 396 patients.

TABLE 2: Univariate analysis of potential predictors of seizure following aneurysmal SAH

Variable OR (95% CI) p Value

age 0.98 (0.96–1.01) 0.28sex, M vs F 0.78 (0.33–1.87) 0.58WFNS grade, IV–V vs I–III 2.04 (1.13–3.69) 0.02*hypertension 1.37 (0.78–2.39) 0.28aneurysm location ACA vs pst 1.00 (0.32–3.10) 0.74 ICA vs pst 1.31 (0.41–4.17) 0.45 MCA vs pst 1.06 (0.30–3.66) 0.93aneurysm size, ≤5 vs >5 mm 1.58 (0.87–2.89) 0.13*subarachnoid clot burden, Hijdra score ≥18 vs <18†

2.56 (1.37–4.81) 0.003*

intraventricular clot burden, modified Graeb score >4 vs ≤4†

1.59 (0.87–2.90) 0.13*

presence of hydrocephalus 0.76 (0.28–2.08) 0.59presence of intracerebral hemorrhage

1.01 (0.43–2.37) 0.98

presence of midline shift 5.37 (1.91–15.07) 0.001*presence of subdural hematoma 5.83 (1.88–18.05) 0.002*potassium high vs normal 2.00 (0.20–19.59) 0.96 low vs normal too few events too few eventssodium high vs normal 1.23 (0.45–3.36) 0.64 low vs normal 3.21 (0.29–36.0) 0.40corrected calcium high vs normal 3.04 (0.54–17.04) 0.21 low vs normal 0.46 (0.14–1.57) 0.22glucose high vs normal 1.72 (0.46–6.36) 0.98 low vs normal too few events too few events

* Denotes variable meeting threshold for inclusion in multivariate re-gression (p < 0.20).† Dichotomization thresholds based on median values.



analysis, was a Hijdra score of 21, with a resulting AUC of 0.63. Therefore, the probability of seizure occurrence is significantly elevated when two-thirds of the 10 cisterns and fissures evaluated with the Hijdra scale are filled with blood or when all cisterns are filled approximately two-thirds by blood.

DiscussionIn this exploratory analysis we found that a greater

subarachnoid clot burden and a subdural hematoma inde-pendently predicted seizures after intracranial aneurysm rupture. This study is the first to document subdural he-matoma as a risk factor for early-onset seizures and to es-tablish an optimal predictive threshold for a subarachnoid clot burden using ROC curve analysis. Given the lack of adequate evidence for the use of prophylactic AEDs following SAH and the heterogeneity in prescription practices (see Lanzino and colleagues26), it is important to identify patients who are at greatest risk for having a

posthemorrhagic seizure. Data in this study add to previ-ous research in informing such clinical decision making.

Although the pathogenesis of seizures following SAH is unclear, it has been speculated that they result from acutely elevated intracranial pressure13 or from the hemorrhage itself.17 Alternatively, it has been suggested that angiographic vasospasm during the acute phase of bleeding may trigger seizures. Angiographic vasospasm follows a biphasic pattern, with an early arterial spasm within minutes of hemorrhage and a delayed phase, which is often associated with delayed cerebral ischemia.6,15 Early spreading depolarization has also been proposed as a risk factor for posthemorrhagic seizures.14

Reported risk factors for seizures after SAH include a young age,10,28 an MCA location,9,35,41 an intracerebral hemorrhage,25,35 infarcts,10,24 rebleeding,10,19 a poor neuro-logical grade,10,33 hydrocephalus,10 a loss of consciousness at ictus,28 and a history of hypertension.32 Authors of one study also found that early seizures are a risk factor for postdischarge epilepsy.7

Previous studies have described subarachnoid clot bur den as a risk factor for the occurrence of seizures af-ter SAH.7,10,18,19,28,33,34 A noteworthy improvement in our methodology is the ROC curve analysis, whereby we de-termined that a Hijdra score of 21 is the optimal cutoff point. Categorical scales such as the Fisher scale, which is based on measurements that are difficult to apply us-ing current technology, may not be adequately sensitive for basing clinical decisions.23 In a post hoc analysis of 2143 patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT) for instance, a Fisher grade > 1 on CT showed a trend in predicting posthemorrhagic epi-lepsy (HR 1.34, 95% CI 0.62–2.87). Other studies have defined a Fisher grade of 3 or higher as a risk factor for seizures.28 However, these dichotomization points are ar-bitrary and may confound subarachnoid clot burden with intraventricular clot burden (that is, Fisher Grade 4). Our

TABLE 3: Multivariate analysis of potential predictors of seizure activity following SAH

Variable OR (95% CI) p Value

WFNS grade, IV–V vs I–III 1.32 (0.66–2.63) 0.43aneurysm size, ≤5 vs >5 mm 1.28 (0.69–2.40) 0.43subarachnoid clot burden, Hijdra score ≥18 vs <18*

2.76 (1.39–5.49)† 0.004

intraventricular clot burden, modified Graeb score >4 vs ≤4*

1.14 (0.59–2.20) 0.71

presence of midline shift 2.08 (0.59–7.27) 0.25presence of subdural hematoma 5.67 (1.56–20.57)† 0.008

* Dichotomization thresholds based on median values.† Denotes significant associations (p < 0.05).

Fig. 1. Receiver operating characteristic curve analysis of the Hijdra score. Left: An ROC curve analysis demonstrating an AUC of 0.63, significantly better than chance at identifying patients with posthemorrhagic seizures. Right: Optimal sensitivity and specificity of ROC curve analysis for diagnosis of posthemorrhagic seizures in SAH patients is a Hijdra score of 21 (possible maximum of 30).


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finding that approximately two-thirds of the cisterns and fissures would need to be filled with blood to reach the optimal threshold based on ROC curve analysis may be more useful in practical, clinical decision making in iden-tifying patients with early-onset seizures.

To our knowledge, we are the first to report that the presence of subdural hematomas is associated with the occurrence of seizures following aneurysm rupture, al-though it has been reported to be associated with postdis-charge epilepsy.11 This finding has several important im-plications. It has been suggested that the risk of seizures is increased following the microsurgical treatment of aneurysms, as compared with coil embolization.8,30 How-ever, because patients who present with subdural hema-tomas following SAH are more likely to undergo surgi-cal treatment (to simultaneously evacuate the hematoma and treat the aneurysm), studies that have evaluated the risk of seizures following surgical treatment must adjust for whether a subdural hematoma was present. Indeed, a large, multicenter retrospective study of over 10,000 pa-tients admitted with ruptured aneurysms documented no difference in the risk of epilepsy following adjustment for patient-specific factors.21

We did not identify intracerebral hemorrhage as a predictor of seizures. However, in a large series of patients with supratentorial intracerebral hemorrhage, only 17% had seizure activity, and seizures were associated with extension of blood into the cerebral cortex.5 Given that the prevalence of intracerebral hemorrhage in the current study was 12% (50 patients), it is possible that the sample size was too small to detect a significant association. Fur-thermore, in our series, no clinical or laboratory covari-ates were associated with the occurrence of seizures.

With this analysis we aim to inform clinical deci-sion making regarding the prophylactic administration of AEDs to patients following SAH. The identification of patients at greatest risk may mitigate the harm of AED administration to those who have a low-risk of seizures, while providing prophylactic treatment for those who are likely to have seizure activity. Although seizure prophy-laxis is controversial in SAH patients in general, it is note-worthy that the majority of prophylactic regimens used in the CONSCIOUS-1 trial included phenytoin (82.6% in the current study). Other anticonvulsants, including levetiracetam, may be superior to phenytoin as a prophy-lactic agent.37,39,42 In one retrospective series, the burden of phenytoin was independently associated with worse cognitive function at 3 months after hemorrhage.31 Note that a limitation of previous studies is that anticonvulsant levels have not been routinely monitored. Therefore, care-ful monitoring of patients and the selection of less toxic AEDs may also mitigate the risk to patients.

The main limitation of this study was the fact that we did not have data on some factors that may influence the risk of seizures after SAH, such as serum magne-sium and phosphate concentration levels. Additionally, we did not have information on electroencephalography; therefore, the diagnosis of seizures was made clinically. It has been previously suggested that seizure-like events post-SAH may not be true seizures.12,38 Furthermore, we did not stratify seizures based on semiology, duration, or

sequelae. Our strengths include the systematic and con-sistent documentation of the evaluated covariates through the CONSCIOUS-1 database. Furthermore, we present one of the largest studies evaluating the occurrence of seizures following SAH.

ConclusionsNeurological status based on the WFNS grading sys-

tem, subarachnoid clot burden, and the presence of mid-line shift and subdural hematomas was independently as-sociated with the occurrence of seizures after aneurysmal SAH on univariate analysis. Only the subarachnoid clot burden and subdural hematoma remained significant on multivariate analysis. A Hijdra score of 21 provided the optimal sensitivity and specificity cutoff for identification of seizures as per ROC curve analysis.

Disclosure

Actelion Pharmaceuticals, Ltd., was the sponsor of the CON-SCIOUS-1 trial; the company provided the authors with the trial data set but had no role in this exploratory analysis nor in the develop-ment of the article. The data analysis and writing are the work of the authors. R. Loch Macdonald has ownership in and is the chief scien-tific officer for Edge Therapeutics, Inc.; is a consultant for Actelion Pharmaceuticals; and receives support from the Canadian Institutes of Health Research for non–study related clinical or research effort.

Author contributions to the study and manuscript preparation include the following. Conception and design: Macdonald, Ibrahim. Acquisition of data: Macdonald. Analysis and interpretation of data: Ibrahim, Fallah. Drafting the article: Ibrahim, Fallah. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Macdonald. Statistical analysis: all authors. Study supervision: Macdonald.

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Manuscript submitted November 4, 2012.Accepted March 5, 2013.Please include this information when citing this paper: pub-

lished online April 12, 2013; DOI: 10.3171/2013.3.JNS122097.Address correspondence to: R. Loch Macdonald, M.D., Ph.D., St.

Michael’s Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. email: [email protected].

2013.3.jns122097

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