Influence of seizures on stroke outcomes A large multicenter study

Chin-Wei Huang, MD, PhD Gustavo Saposnik, MD Jimming Fang, PhD David A. Steven, MD, MPH Jorge G. Burneo, MD, MSPH

Correspondence to Dr. Burneo: [email protected]

ABSTRACT

Objective: We compared clinical characteristics of seizures at ischemic stroke presentation (SSP) to seizures during hospitalization post ischemic stroke (SDH), and their impacts on stroke outcome, using the Registry of the Canadian Stroke Network (RCSN) database.

Methods: This cohort study included consecutive patients from the RCSN who had an acute ischemic stroke between July 2003 and March 2008. Outcome measures included morbidity, mortality, length of hospital stay, and discharge disposition. Clinical variables for either SSP or SDH were investigated and the stroke outcome was stratified by stroke severity. Results: The study included 10,261 patients with ischemic strokes: 157 patients (1.53%) had SSP and 208 patients (2.03%) had SDH. Compared to stroke patients without seizures, patients with SSP and SDH were younger, had more severe strokes (p , 0.001), a higher admission rate to the intensive care unit (p , 0.001), higher morbidity, and higher mortality (p , 0.05). SSP was associated with female sex and less limb weakness, while SDH was associated with pneumonia and the presence of hemineglect. Importantly, patients with less severe strokes had higher morbidity and mortality (p , 0.005) if SDH occurred. Variables predicting overall mortality were SDH, older age, higher Charlson-Deyo index, more severe strokes, and nonalert status on arrival (all p , 0.001). Conclusions: SSP and SDH have different characteristics. SDH indicates a poorer prognosis in patients. Increased awareness of SSP and efforts to prevent SDH may be important in improving outcomes following clinical stroke care. Neurology® 2014;82:768–776 GLOSSARY ICU 5 intensive care unit; MRA 5 magnetic resonance angiography; mRS 5 modified Rankin Scale; NIHSS 5 NIH Stroke Scale; OR 5 odds ratio; RCSN 5 Registry of the Canadian Stroke Network; SDH 5 seizures occurring after stroke but during hospitalization; SSP 5 seizures occurring at stroke presentation; UTI 5 urinary tract infection.

Seizures during the acute phase of stroke, including ischemia and hemorrhage, are commonly seen in clinical practice and require special attention as significant damage is possible if not treated. Although seizures during stroke are recognized as a clinical phenomenon, questions remain regarding their effect on outcome. Our previous study from the health system perspective demonstrated that the presence of acute seizures after stroke was associated with increased resource utilization, increased length of hospital stay, and decreased survival.1 Based on probable different pathophysiologies for various types of ischemic stroke phases,2–7 development of ischemia, and other potential complications during the hospitalization,8 we undertook investigation of clinical features and outcomes in patients with seizures occurring at stroke presentation (SSP) and seizures occurring after stroke but during hospitalization (SDH). METHODS Using the Registry of the Canadian Stroke Network (RCSN, warehoused at the Institute of Clinical Evaluative Sciences and managed by the Canadian Stroke Network), we prospectively identified all patients with ischemic strokes admitted to Regional Stroke Centers in Ontario, Canada, between July 2003 and March 2008. The RCSN, a large clinical database, includes characterization of demographics, stroke types, severity, care processes, hospital treatments, complications, and outcomes of patients with acute strokes seen at 11 acute care hospitals. Editorial, page 740 From the Epilepsy Program, Department of Clinical Neurological Sciences (C.-W.H., D.A.S., J.G.B.), Western University, London, Canada; Department of Neurology (C.-W.H.), National Cheng Kung University Hospital, School of Medicine, National Cheng Kung University, Tainan, Taiwan; University of Toronto (G.S.), St Michael’s Hospital; and Institute for Clinical Evaluative Sciences (G.S., J.F.), Toronto, Canada. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 768

© 2014 American Academy of Neurology

We systematically collected data during hospitalization and at the time of discharge using standard case report forms and collected information about seizures reported at stroke presentation and during hospitalization. A stroke neurologist served as project leader and trained neurology research nurses conducted patient recruitment and data entry. Exclusion criteria were any of the following: incomplete clinical data, nonstroke diagnosis, diagnosis of hemorrhagic stroke, and TIAs.

Standard protocol approvals, registrations, and patient consent. The appropriate institutional ethics committee approved all study protocols. Since the RCSN was conceived as a quality improvement strategy, consent was waived. Each patient in the RCSN was assigned a unique encrypted identifier. Further details of RCSN were published previously.1,9212 The Publications Committee of the RCSN reviewed and approved the study.

Clinical variables and indicators. We based ischemic stroke subtype assignments on the Oxfordshire Community Stroke Project classification13 and used Charlson-Deyo index to characterize and record patients’ comorbidities. A score of zero indicated that no comorbidities were present, and higher scores indicated a greater burden of comorbidity. The possible scores for this index are 0, 1, 2, or more than 3 comorbidities.1,14 We assessed stroke severity using the Canadian Neurological Scale.15 For the Canadian Neurological Scale, a lower score indicates increasing severity of the acute neurologic status after stroke. The severity of stroke in the Canadian Neurological Scale score is as follows: 0–4 (severe stroke), 5–7 (moderate stroke), .7 (mild stroke). We included pneumonia (radiologically confirmed) as a medical complication if it occurred within the first 30 days of the hospital stay and defined seizures according to the International League Against Epilepsy as a paroxysmal disorder of the CNS with or without loss of consciousness or awareness, and possible motor involvement. We diagnosed seizures at ischemic stroke presentation (SSP) when the paroxysmal disorder occurred within 24 hours of stroke onset and SDH when the paroxysmal disorder occurred more than 24 hours after stroke onset but during hospitalization for stroke. Decerebrate posturing and limb-shaking TIAs were not included as seizures in the present study. Outcome measures. We confirmed stroke fatality and captured out-of-hospital deaths up to 1 year after discharge using the Ontario Registered Person database, developed and maintained by the Ontario Ministry of Health and Long-Term Care. We also analyzed disability at discharge and hospital length of stay. Disability at discharge was measured using the modified Rankin Scale (mRS) score.16 We recorded interventions during hospitalization such as magnetic resonance angiography (MRA), cerebral angiography, carotid duplex ultrasonography, intravenous thrombolysis, physiotherapy, occupational therapy, and speech therapy. Recorded complications during hospitalization included pneumonia, urinary tract infection (UTI), and decubitus ulcer. We compared outcome measures for patients with and without SSP or SDH and also according to ischemic stroke severity in patients with or without SDH. Statistical analysis. We used x2 tests to compare categorical variables, Student t tests, and median 2-sample tests to analyze continuous variables. For mRS analysis, in addition to t tests, we also dichotomized this outcome variable by 2 common cutoff points: 01 (mRS_01) and 012 (mRS_012).17,18 We used logistic regression with backward selection models to determine the relationship of seizures to stroke fatality. When other variables considered for inclusion in the multivariable model were significant, we included them at the p , 0.20 level in univariate analysis to evaluate if findings were related to a possible confounder

effect. We performed statistical analysis using SAS statistical software (version 9.1.3, SAS Institute Inc., Cary, NC) with 2 tails for all tests and significance set at p , 0.05.

RESULTS Demographics, intervention measures, and outcome of patients with or without SSP. Among

10,261 consecutive patients with an acute ischemic stroke, 157 (1.53%) had SSP. Their mean age was 68.9 6 1.4 years, which was younger than those without seizures (72.2 6 0.1 years) (p , 0.01). For stroke patients younger than 60 years, 40 (25.5% of the 157 without seizures) had seizures vs 1,848 (18.3% of the 10,104 without seizures) who did not have seizures (p , 0.05). Ninety patients (57.3%) with seizures were female, compared to 4,851 (48.0%) female patients without seizures (p , 0.05). We did not find differences in Charlson-Deyo scores, concurrent diabetes, or depression when comparing patients with seizures to those without seizures. In addition, SSP patients had lower mean Canadian Neurological Scale scores (5.4 6 0.3 vs 7.7 6 0.0, p , 0.001). Of note, we observed less limb weakness in SSP patients compared to those without SSP (103 [65.6%] vs 8,322 [82.4%], p , 0.001). Patients with lacunar strokes were less likely to have SSP (p , 0.001) (table 1). As to intervention measures and outcomes (table 1), patients with SSP had a higher intensive care unit (ICU) admission rate (34 [21.7%] vs 810 [8.0%], p , 0.001) and SDH rate (34 [21.7%] vs 174 [1.7%], p , 0.001) than patients without SSP. Additionally, SSP patients required fewer interventions during their hospitalization, including MRA (12 [7.6%] vs 1,364 [13.5%], p , 0.05), cerebral angiography (10 [6.4%] vs 1,300 [12.9%], p , 0.05), carotid duplex ultrasonography (62 [39.5%] vs 5,921 [58.6%], p , 0.001), thrombolysis (10 [6.4%] vs 1,630 [16.1%], p , 0.001), physiotherapy (110 [70.1%] vs 8,573 [84.8%], p , 0.001), occupational therapy (105 [66.9%] vs 8,166 [80.8%], p , 0.001), and speech therapy (80 [51.0%] vs 6,457 [63.9%], p , 0.001). SSP patients had higher mean mRS (3.5 6 0.2 vs 3.1 6 0.0, p 5 0.001), fewer mRS_012 (45 [28.8%] vs 3,691 [36.7%], p 5 0.044), and increased mortality rates within 30 days (42 [26.8%] vs 1,354 [13.4%], p , 0.001) or within 1 year (65 [41.4%] vs 2,454 [24.3%], p , 0.001). SSP patients were discharged to acute care facilities at a higher rate than those without SSP (10 [8.2%] vs 657 [7.4%], p , 0.005) (table 1). Demographics, intervention measures, and outcome of patients with or without SDH. Among 10,261 patients,

208 (2.0%) had SDH. We did not find differences between those with SDH and without SDH in terms of age, sex, and the presence of diabetes. We observed Neurology 82

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Table 1

Demographics, intervention measures, and outcomes for patients with ischemic strokes with or without SSP Occurrence of seizures

Variables

Overall

Yes

No

Patients, n

10,261

157

10,104

Age, y

72.2 6 0.1

68.9 6 1.4

72.2 6 0.1

80

3,644 (35.5)

58 (36.9)

3,585 (35.5)

4,941 (48.2)

90 (57.3)

4,851 (48.0)

Age group, y

Female sex

p

0.003 0.031

Charlson-Deyo index

0.021 0.808

0

3,718 (36.2)

52 (33.1)

3,666 (36.3)

1

2,928 (28.5)

50 (31.8)

2,878 (28.5)

2

1,563 (15.2)

22 (14)

1,541 (15.3)

3

684 (6.7)

33 (21.1)

673 (6.7)

Diabetes

2,590 (25.2)

36 (22.9)

2,554 (25.3)

0.502

Depression

598 (5.8)

11 (7.0)

587 (5.8)

0.525

Canadian Neurological Scalea

7.7 6 0.0

5.4 6 0.3

7.7 6 0.0

,0.001

Weakness

8,425 (82.1)

103 (65.6)

8,322 (82.4)

,0.001

Hemineglect

1,942 (18.9)

30 (19.1)

1,912 (18.9)

0.953

PACS

3,989 (38.9)

62 (39.5)

3,927 (38.9)

POCS

2,320 (22.6)

37 (23.6)

2,283 (22.6)

LACS

1,759 (17.1)

13 (8.3)

1,746 (17.3)

TACS

Location of stroke

,0.001

1,240 (12.1)

14 (8.9)

1,226 (12.1)

Admitted to ICU

844 (8.2)

34 (21.7)

810 (8.0)

Admitted to SU

5,585 (54.4)

74 (47.1)

5,511(54.5)

SDH

208 (2)

34 (21.7)

174 (1.7)

MRA

1,376 (13.4)

12 (7.6)

1,364 (13.5)

0.033

Carotid duplex

5,983 (58.3)

62 (39.5)

5,921 (58.6)

,0.001

Thrombolysis

1,640 (16)

10 (6.4)

1,630 (16.1)

0.001

PT

8,683 (84.6)

110 (70.1)

8,573 (84.8)

,0.001

mRS score

3.01 6 0.0

3.5 6 0.1

3.01 6 0.0

Mortality

1,288 (12.6)

35 (22.3)

1,253 (12.4)

,0.001

Within 30 days

1,396 (13.6)

42 (26.8)

1,354 (13.4)

,0.001

Within 1 year

2,519 (24.5)

65 (41.4)

2,454 (24.3)

,0.001

667 (7.4)

10 (8.2)

657 (7.4)

,0.001 0.064 ,0.001

Intervention

Disposition to ACF

0.001

0.002

Abbreviations: ACF 5 acute care facility; ICU 5 intensive care unit; LACS 5 lacunar stroke; MRA 5 magnetic resonance angiography; mRS 5 modified Rankin Scale; PACS 5 partial anterior cerebral stroke; POCS 5 posterior circulation stroke; PT 5 physiotherapy; SDH 5 seizures during hospitalization; SSP 5 seizures at ischemic stroke presentation; SU 5 stroke unit; TACS 5 total anterior cerebral stroke. Values are mean 6 SE or n (%). a Canadian Neurological Scale: score 0–4 (severe stroke), 5–7 (moderate stroke), .7 (mild stroke).

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higher rates of depression during hospitalization (20 [9.6%] vs 578 [5.7%], p 5 0.019) for those with SDH compared to those without SDH, and SDH patients had lower mean Canadian Neurological Scale scores (5.8 6 0.2 vs 7.7 6 0.0, p , 0.001) than those without SDH. SDH patients had similar rates of limb weakness that non-SDH patients (176 [84.6%] vs 8,245 [82.1%], p 5 0.340); nevertheless, those with SDH had a higher percentage of presence of hemineglect (78 3[7.5%] vs 1,864 [18.5%], p , 0.001). Similar to SSP, patients with lacunar strokes were less likely to have SDH (p , 0.001) (table 2). SDH patients had a higher rate of ICU admission (43 [20.7%] vs 801 [8.0%], p , 0.001), but a lower rate of stroke unit admission (93 [44.7%] vs 5,492 [54.6%], p 5 0.005) compared to patients without SDH. SDH patients underwent fewer carotid duplex ultrasonography procedures compared to those without SDH (94 [45.2%] vs 5,889 [58.6%], p , 0.001). There were no differences between patients with SDH and without SDH in the number of patients who underwent MRA and thrombolysis. Importantly, SDH patients had more complications during hospitalization, including pneumonia (36 [17.3%] vs 667 [6.6%], p , 0.001), UTI (47 [22.6%] vs 1,304 [13.0%], p , 0.001), and decubitus ulcer (8 [3.8%] vs 95 [0.9%], p , 0.001) than those without SDH. SDH patients had a higher mean mRS (4.2 6 0.1 vs 3.0 6 0.0, p , 0.001), fewer mRS_01 (12 5.8%] vs 2,101 [21.0%], p , 0.001), fewer mRS_012 (34 [16.3%] vs 3,702 [37.0%], p , 0.001), and higher mortality within 30 days (63 [30.3%] vs 1,333 [13.3%], p , 0.001) and 1 year (99 [47.6%] vs 2,420 [24.1%], p , 0.001) than those without SDH. Finally, those with SDH had longer hospitalizations (25.8 6 2.5 vs 14.8 6 0.2 days, p , 0.001) and more frequent discharges to an acute care facility (21 [14.5%] vs 646 [7.3%], p , 0.001) than those without SDH (table 2). Multivariable analysis of variables associated with SSP and SDH. Multivariable analysis demonstrated that

the following variables were associated with SSP: younger age (age 60–79 vs age ,60, odds ratio [OR] 5 0.551, p 5 0.015), female sex (OR 5 1.485, p 5 0.039), absence of motor weakness (OR 5 0.346, p , 0.001), and more severe stroke (low Canadian Neurological Scale score) (OR 5 0.796, p , 0.001) (figure). Younger age (age 60–79 vs age ,60, OR 5 0.663, p 5 0.025), SSP (OR 5 15.10, p , 0.001), the presence of hemineglect (OR 5 2.176, p , 0.001), low Canadian Neurological Scale score (OR 5 0.902, p , 0.001), ICU admission (OR 5 1.764, p 5 0.014), and pneumonia as complication (OR 5 1.928, p 5 0.003) were associated with SDH (figure).

Table 2

Demographics, intervention measures, and outcome of patients with ischemic strokes with or without SDH Occurrence of seizures

Variables

Overall

Yes

No

Patients, n

10,261

208

10,053

Age, y

72.2 6 0.1

70.9 6 1.1

72.2 6 0.1

80

Age group, y

p

0.172 0.305

3,644 (35.5)

77 (37.0)

3,567 (35.5)

Female sex

4,941 (48.2)

100 (48.1)

4,841 (48.2)

0.982

Diabetes

2,590 (25.2)

52 (25.0)

2,538 (25.2)

0.936

Depression

598 (5.8)

20 (9.6)

578 (5.7)

0.019

0

3,718 (36.2)

72 (34.6)

3,646 (36.3)

1

2,928 (28.5)

49 (23.6)

2,879 (28.6)

2

1,563 (15.2)

41 (19.7)

1,522 (15.1)

3

684 (6.7)

21 (10.1)

663 (6.6)

Canadian Neurological Scalea

7.7 6 0.03

5.8 6 0.2

7.7 6 0.0

Weakness

8,425 (82.1)

176 (84.6)

8,249 (82.1)

0.340

Hemineglect

1,942 (18.9)

78 (37.5)

1,864 (18.5)

,0.001

PACS

3,989 (38.9)

90 (43.3)

3,899 (38.8)

POCS

2,320 (22.6)

36 (17.3)

2,284 (22.7)

LACS

1,759 (17.1)

17 (8.2)

1,742 (17.3)

TACS

Charlson-Deyo index

0.349

,0.001

Location of stroke

,0.001

1,240 (12.1)

50 (24.0)

1,190 (11.8)

Admitted to ICU

844 (8.2)

43 (20.7)

801 (8.0)

Admitted to SU

5,585 (54.4)

93 (44.7)

5,492(54.6)

0.005

MRA

1,376 (13.4)

33 (15.9)

1,343 (13.4)

0.294

Carotid duplex

5,983 (58.3)

94 (45.2)

5,889 (58.6)

,0.001

Thrombolysis

1,640 (16)

37 (17.8)

1,603 (15.9)

0.473

Pneumonia

703 (6.9)

36 (17.3)

667 (6.6)

,0.001

UTI

1,351 (13.2)

47 (22.6)

1,304 (13.0)

,0.001

Decubitus ulcer

103 (1)

8 (3.8)

95 (0.9)

,0.001

mRS score

3.07 6 0.02

4.2 6 0.1

3.0 6 0.0

,0.001

Mortality

,0.001

Intervention

Complications

1,288 (12.6)

63 (30.3)

1,225 (12.2)

,0.001

Within 30 days

1,396 (13.6)

63 (30.3)

1,333 (13.3)

,0.001

Within 1 year

2,519 (24.5)

99 (47.6)

2,420 (24.1)

,0.001

Length of stay, d

15.01 6 0.21

25.8 6 2.5

14.8 6 0.2

,0.001

Disposition to ACF

667 (7.4)

21 (14.5)

646 (7.3)

,0.001

Abbreviations: ACF 5 acute care facility; ICU 5 intensive care unit; LACS 5 lacunar stroke; MRA 5 magnetic resonance angiography; mRS 5 modified Rankin Scale; PACS 5 partial anterior cerebral stroke; POCS 5 posterior circulation stroke; SDH 5 seizures during hospitalization; SU 5 stroke unit; TACS 5 total anterior cerebral stroke; UTI 5 urinary tract infection. Values are mean 6 SE or n (%). a Canadian Neurological Scale: score 0–4 (severe stroke), 5–7 (moderate stroke), .7 (mild stroke).

Outcome comparison by ischemic stroke severity in patients with SDH. SDH patients had higher mortality

at 30 days (30.3% vs 13.3%, p , 0.001) and at 1 year (47.6% vs 24.1%, p , 0.001), and more commonly had a mRS of greater than 3 (mRS . 3; 68.8% vs 40.2%, p , 0.001). For patients with a Canadian Neurological Scale score between 0 and 4, the presence of SDH had no effect on 30-day and 1-year mortality or the likelihood of mRS .3. For patients with a Canadian Neurological Scale score between 5 and 7, those with SDH had higher mortality at 30 days (27.5% vs 14.9%, p 5 0.004) and 1 year (47.8% vs 28.8%, p , 0.001), and were more likely to have a mRS .3 (73.9% vs 56.9%, p 5 0.005). For patients with a Canadian Neurological Scale score greater than 7, those with SDH showed higher mortality at 30 days (21.2% vs 3.8%, p , 0.001) and 1 year (34.8% vs 12.0%, p , 0.001) and were more likely to have mRS .3 (45.5% vs 20.0%, p , 0.001). For patients who were alert on arrival and with SDH, mortality at 30 days (26.1% vs 8.2%, p , 0.001) and at 1 year (43.0% vs 18.4%, p , 0.001) as well as the presence of mRS .3 (61.3% vs 34.0%, p , 0.001) were higher than those without SDH (table 3). Multivariable analysis on stroke outcome measures. Mul-

tivariable analysis of outcome measures showed that SDH (OR 2.398–2.842, p , 0.001), age (OR 1.052–1.056, p , 0.001), Charlson-Deyo index .2 (OR 1.46–2.22, p , 0.001), mRS .3, and moderate to severe stroke (Canadian Neurological Scale ,7) (OR 4.165–6.637, p , 0.001) were associated with death within 30 days and within 1 year (table 4). DISCUSSION Complementary to the NIH Stroke Scale (NIHSS), the Canadian Neurological Scale is a standardized neurologic assessment of cognitive and motor function in stroke patients, especially alertness levels, which are important in the setting of seizures in stroke patients. The Canadian Neurological Scale is simpler to administer and requires less neurologic training (e.g., nurses).19 Previous studies show excellent interrater and intrarater reliability and validity compared to neurologic examination, as well as good correlation with the NIHSS.15,20 Note that for the RCSN, the NIHSS was not available in all cases. We found that SSP and SDH tend to occur in younger patients and those with a lower Canadian Neurological Scale score, but are less common in patients with lacunar syndromes. SSP or SDH patients have higher ICU admission rates, higher morbidity and mortality, and a higher rate of discharge to acute care facilities. In contrast to these similarities, we also found distinct features in SSP patients. For instance, we observed that SSP was more common in female patients, less associated with motor weakness, and Neurology 82

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771

Figure

Multivariable analysis of variables associated with seizures occurring at stroke presentation or seizures occurring after stroke but during hospitalization

(A) The following variables were associated with seizures occurring at stroke presentation (SSP): younger age, female sex, absence of motor weakness, and low Canadian Neurological Scale (CNS) score. (B) The variables associated with seizures occurring after stroke but during hospitalization were the following: younger age, SSP, the presence of hemineglect, low CNS score, intensive care unit admission, and pneumonia.

associated with a reduced requirement for interventions during hospitalization compared to those without SSP. We also found that more SDH patients (compared to SSP patients) had depression, hemineglect, pneumonia, UTI, and decubitus ulcers. These patients were also more likely to have longer hospitalizations. Previous studies showed that women with ischemic stroke may experience longer delays in diagnostic workup after arriving at the emergency department compared to men,21 and that women are less likely to receive tissue plasminogen activator than men.22 Delays in treatment for thrombolysis may aggravate cerebral ischemia and reduce the threshold for seizures, increasing risk for higher morbidity. These findings make sense in light of our results showing that more women had SSP than men (although there were no such differences for patients with SDH). As expected, SSP is associated with SDH, suggesting a potential common underlying basis, such as an 772

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endogenous factor that lowers seizure threshold, either at initial stroke presentation or during hospitalization. The fact that pneumonia is associated with SDH suggests that infection is an important precipitating factor. In addition, SDH patients frequently have other provocative factors, including metabolic disturbances (mainly glucose and electrolytes). Although we have information on relevant metabolic markers, a limitation of the present study was our inability to document a relationship of these markers to seizures sufficient to establish causality. Furthermore, a randomized prospective cohort study would be helpful to determine efficacy for use of an antiepileptic drug after SSP. According to the new definition of epilepsy, in the setting of a cortical lesion, 1 seizure is sufficient for diagnosis of epilepsy.23 SSP patients are less likely to exhibit motor weakness compared to those without. Since our patients had SSP, the level of consciousness (e.g., postictal confusion) during the initial neurologic examination

Table 3

Outcome comparison by ischemic stroke severity Seizures during hospitalization

Variable

Overall

Yes

No

p

All patients Death within 30 days

1,396 (13.6)

63 (30.3)

1,333 (13.3)

,0.001

Death within 1 year

2,519 (24.5)

99 (47.6)

2,420 (24.1)

,0.001

mRS > 3

4,171 (40.8)

143 (68.8)

4,028 (40.2)

,0.001

Death within 30 days

711 (42.8)

30 (43.5)

681 (42.7)

0.901

Death within 1 year

952 (57.2)

41 (59.4)

911 (57.2)

0.709

1,394 (83.9)

59 (85.5)

1,335 (83.9)

0.715

405 (15.3)

19 (27.5)

386 (14.9)

0.004

Severe stroke (Canadian Neurological Scale score 0–4)

mRS > 3 Moderate stroke (Canadian Neurological Scale score 5–7) Death within 30 days Death within 1 year mRS > 3

777 (29.3)

33 (47.8)

744 (28.8)

,0.001

1,514 (57.4)

51 (73.9)

1,463 (56.9)

0.005

Mild stroke (Canadian Neurological Scale score > 7) Death within 30 days

231 (4)

14 (21.2)

217 (3.8)

,0.001

Death within 1 year

705 (12.2)

23 (34.8)

682 (12.0)

,0.001

1,163 (20.3)

30 (45.5)

1,133 (20.0)

,0.001

748 (8.5)

37 (26.1)

711 (8.2)

,0.001

Death within 1 year

1,653 (18.8)

61 (43.0)

1,592 (18.4)

,0.001

mRS > 3

3,009 (34.4)

87 (61.3)

2,922 (34.0)

,0.001

648 (43.5)

26 (39.4)

622 (43.7)

0.486

866 (58.2)

38 (57.6)

828 (58.2)

0.916

1,162 (78.4)

56 (84.8)

1,106 (78.1)

0.190

mRS > 3 Alert on arrival Death within 30 days

Nonalert on arrival Death within 30 days Death within 1 year mRS > 3

Values are n (%). mRS 5 modified Rankin Scale.

could have affected evaluation of motor performance. Given the fact that SSP patients had more severe strokes, we would expect to see altered consciousness. Interestingly, we did not observe decreased frequency of severe limb weakness in SDH patients; this may be due to the fact that seizures that affect consciousness may be attenuated by administration of antiepileptic drugs following hospital admission, rendering motor evaluation more achievable in SDH patients compared to those with SSP. In addition, some SDH patients had more complications during hospitalization, meaning that they may have been even weaker at the time of examination. The presence of hemineglect was associated with SDH but not SSP, again possibly due to the difficulty in detecting hemineglect at presentation in SSP patients. Stroke patients with hemineglect typically have extensive lesions spanning several cortical and subcortical regions.24 Cortical infarcts associated with cardioembolic events are more

likely to be associated with seizures.25 Regions within the vascular territory of the middle cerebral artery are consistently damaged in patients with hemineglect. Thus, specific functional deficits, including seizures in stroke patients, could be lesion location–specific. SSP patients underwent fewer procedures or interventions during hospitalization compared to those without SSP. This may be because SSP patients had more severe strokes, meaning that thrombolytic therapy, MRA, and angiogram were perhaps not indicated. In the emergency setting, it is also difficult to make a differential diagnosis between SSP and a seizure with Todd phenomenon, which may explain partially the lower rate of thrombolysis in SSP patients. Further, due to the more severe nature of their strokes, many SSP patients were likely unsuitable for active rehabilitation. It is not surprising that SDH patients had more depression than those without, as depression is a Neurology 82

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Table 4

Multivariable analysis of outcome measures

Dependent variable

Effect

Odds ratio

p

Death within 30 days

Seizure during hospitalization (yes vs no)

2.842 (2.103–3.842)

,0.001

Age

1.052 (1.046–1.058)

,0.001

Charlson-Deyo index (.2) (yes vs no)

1.63 (1.45–1.833)

,0.001

Canadian Neurological Scale severity (,7 vs .7)

6.481 (5.66–7.422)

,0.001

Arrival alertness (nonalert vs alert)

7.645 (6.698–8.726)

,0.001

Seizure during hospitalization (yes vs no)

2.641 (1.919–3.634)

,0.001

Age

1.056 (1.051–1.061)

,0.001

2.216 (2.002–2.453)

,0.001

a

Death within 1 year

Charlson-Deyo index (.2) (yes vs no) a

>mRS 3

Canadian Neurological Scale severity (,7 vs .7)

4.165 (3.764–4.609)

,0.001

Arrival alertness (nonalert vs alert)

5.879 (5.178–6.675)

,0.001

Seizure during hospitalization (yes vs no)

2.398 (1.602–3.587)

,0.001

Age

1.025 (1.022–1.029)

,0.001

Male

0.9 (0.822–0.985)

Charlson-Deyo index (.2) (yes vs no) a

1.464 (1.329–1.612)

0.023 ,0.001

Canadian Neurological Scale severity (,7 vs .7)

6.637 (5.958–7.393)

,0.001

Arrival alertness (nonalert vs alert)

5.929 (4.958–7.091)

,0.001

Abbreviation: mRS 5 modified Rankin Scale. a Canadian Neurological Scale 5 score 0–4 (severe stroke), 5–7 (moderate stroke), .7 (mild stroke).

recognized comorbidity in the stroke population. Prescription of antidepressants, including selective serotonin reuptake inhibitors, may increase the risk of seizures.26 We did not have detailed information about types of antidepressants prescribed. A recent study showed that early seizures (within 14 days after stroke onset) in stroke patients were not associated with unfavorable outcomes or a higher risk of mortality at 1 month and 1 year.27 Although the nature of ischemic and hemorrhagic strokes is different, this study included both ischemic and hemorrhagic strokes, showing early seizures were at least twice as frequent in patients with hemorrhagic stroke. Multivariable analysis did not show higher morbidity and mortality in stroke patients with early seizures. Unadjusted mortality rates at 1 month and 1 year and an unfavorable outcome were higher in patients with ischemic stroke with early seizures compared to patients with hemorrhagic strokes. A limiting factor when considering these results is that this study included analysis of patients with seizures occurring only within the first 14 days after stroke onset. Animal studies showed that neuron excitability after ischemia may exacerbate neuronal cell loss.28 There is a correlation between the number and the duration of depolarizing events and infarct volume, probably due to more profound ischemia in penumbral tissues.29 For patients with severe strokes (Canadian Neurological Scale score 0–4), we found no difference for SDH patients in death and morbidity compared to those without, as these patients all exhibited “ceiling” mortality and morbidity effects. Importantly, although in 774

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those with milder strokes without SDH mortality and morbidity decreased accordingly, those with milder strokes and SDH showed only modestly decreased mortality and morbidity. In animal experiments, seizures as a consequence of hypoxic-ischemic brain injury contribute to worsened outcome following hypoxic ischemia, but mortality can be reduced with the use of anticonvulsants.30 Such acute postischemic seizures seem to result in worse outcomes than the ischemic stroke itself. Thus, we should pay more attention to SDH, especially in patients with mild strokes. Antiepileptic drug prophylaxis for SDH might be warranted, although this should be assessed more thoroughly in a randomized study. Although there are conflicting data between animal models and humans about the potential of thrombolysis to increase the risk of seizures,31–35 we found no outcome differences following thrombolysis in patients with or without SDH. Even though both SSP and SDH in ischemic stroke are associated with younger age, low Canadian Neurological Scale score, decreased occurrence of lacunar syndrome, higher morbidity and mortality, and more discharges to acute care facilities, they present with different characteristics. Increased awareness of SSP and early prevention of SDH may be important in improving care of stroke patients. AUTHOR CONTRIBUTIONS Dr. Huang interpreted all data, contributed to analysis, and drafted the manuscript. Dr. Saposnik contributed to analysis and revised the

manuscript. Dr. Fang contributed to data collection and conducted statistical analyses. Dr. Steven revised the manuscript. Dr. Burneo conceptualized and designed the study, interpreted study data, and revised the manuscript. Dr. Saposnik and Dr. Burneo both contributed to qualify as the senior authors.

10.

11.

ACKNOWLEDGMENT The authors thank Dr. Frank Silver and Registry of the Canadian Stroke Network (RCSN) Site Investigators for facilitating the data.

STUDY FUNDING Supported by a grant from the Heart and Stroke Foundation of Ontario (HSFO). The RCSN is funded by the Canadian Stroke Network and the Ontario Ministry of Health and Long-Term Care (MOHLTC). The Institute for Clinical Evaluative Sciences (ICES) is funded by the Ontario MOHLTC. The investigators acted as the sponsors of the study. None of the supporting agencies had input on the design, access to the data, execution, analyses, interpretation, or publication of the study. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred.

12.

13.

14.

15. DISCLOSURE C. Huang reports no disclosures. G. Saposnik is supported by the Distinguished Clinician Scientist Award from the Heart and Stroke Foundation of Canada (HSFC). J. Fang reports no disclosures. D. Steven has given talks about epilepsy surgery, sponsored by UCB Canada. He has received financial support for research from UCB Canada. J. Burneo has served on the advisory board and speaker’s bureau for UCB Canada. He has received educational grants from UCB Canada and Eisai. He has received research grants from the Ontario Brain Institute. Go to Neurology.org for full disclosures.

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Influence of seizures on stroke outcomes: A large multicenter study Chin-Wei Huang, Gustavo Saposnik, Jimming Fang, et al. Neurology 2014;82;768-776 Published Online before print January 31, 2014 DOI 10.1212/WNL.0000000000000166 This information is current as of January 31, 2014

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.