Neurocrit Care (2012) 16:241–245 DOI 10.1007/s12028-011-9657-x
ORIGINAL ARTICLE
Subacute Seizure Incidence in Thrombolysis-treated Ischemic Stroke Patients P. Couillard • M. A. Almekhlafi • A. Irvine • N. Jette´ • J. Pow • C. St.Germaine-Smith • N. Pillay • M. D. Hill
Published online: 13 December 2011 Ó Springer Science+Business Media, LLC 2011
Abstract Background To assess the incidence of seizures in acute ischemic stroke patients treated with chemical (tPA) thrombolysis. Methods Retrospective study including all thrombolysis patients treated in Calgary between January 1, 2001, and October 31, 2006. Descriptive statistics and age/sexadjusted P values were calculated. Results Of 400 eligible patients (median age 74.0 years, range: 24–77), 16 (4%) developed post-stroke seizures: 10 (62.5%) within one week (early) and 6 (37.5%) after 1 week but within the hospital stay (late). Single-vessel anterior circulation involvement (93.8% vs. 87%, P = 0.34) and hemorrhage (37.5% vs. 20%, P = 0.15) were more common in those with compared to without seizures but did not reach statistical significance. Atrial fibrillation was more common in those with (56.3%) than without (36.1%) seizures
P. Couillard (&) M. A. Almekhlafi A. Irvine N. Jette´ J. Pow C. St.Germaine-Smith N. Pillay M. D. Hill Department of Clinical Neurosciences, University of Calgary, Foothills Medical Centre, 1403 29th Street NW, Calgary, AB T2N 2T9, Canada e-mail:
[email protected] M. A. Almekhlafi A. Irvine N. Jette´ J. Pow M. D. Hill Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada M. A. Almekhlafi Department of Internal Medicine, King Abdulaziz University, Jeddah, The Kingdom of Saudi Arabia M. D. Hill Department of Medicine, University of Calgary, Calgary, AB, Canada
(P = 0.04). Death during admission was more likely (P = 0.03) in those who sustained seizures (37.5%) compared to those without seizures (17.6%). Conclusions In this cohort of tPA-treated patients, poststroke seizures were associated with atrial fibrillation and early mortality. Keywords Tissue plasminogen activator tPA Cerebrovascular accident Seizures Outcomes
Introduction Stroke is the most commonly identified etiology of newonset seizures in individuals over the age of 65 [1]. The risk of early and late post-stroke seizures is estimated at 4.5% and 6.4, respectively, although variation exists due to different study populations, and definitions employed [2–4]. Acute seizures, whether clinical or electrographic, have been shown to be associated with neurological worsening on the National Institutes of Health Stroke Scale (NIHSS) and with increase in brain edema and midline shift [5]. Higher mortality rates have been reported among stroke patients with seizures after 30 days and 1 year, along with poorer neurological function at presentation and worse functional outcome measured on the modified Rankin score at follow-up [6]. Greater stroke severity, cortical involvement, and hemorrhagic stroke including intracerebral or subarachnoid hemorrhage are predictors of post-stroke seizures [6–10]. Thrombolytic treatment of stroke can be associated with hemorrhagic transformation (1–7% symptomatic hemorrhage and up to 40% asymptomatic hemorrhage), but may also reduce infarct size. It is of interest to know whether
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Table 1 Baseline demographics, stroke risk factors, and affected arteries
No Seizures n
Seizures %
n
%
Baseline demographics Median age in years (range)
74.0 (24–101)
–
72.5 (29–94)
–
Median NIHSS score at admission (IQR)
14 (11)
–
16.5 (12.5)
–
Male
188/384
49.0
11/16
68.8
Stroke risk factors Hypertension
252/383
65.8
10/16
62.5
Diabetes
64/381
16.8
2/16
12.5
Smoker
74/380
19.5
2/16
12.5
Dyslipidemia
102/381
26.8
3/16
18.8
Previous stroke
78/380
20.5
3/16
18.8
Coronary artery disease Atrial fibrillation
118/383 138/382
30.8 36.1
6/16 9/16
37.5 56.3
Family history
36/345
10.4
1/16
7.1
Congestive heart failure
22/384
5.7
0/16
0
Valvular heart disease
22/384
5.7
1/16
6.3
COPD
17/384
4.4
0/16
0
Chronic renal failure
5/384
1.3
0/16
0
Deep venous thrombosis
3/384
0.8
0/16
0
Cancer
21/384
5.5
0/16
0
Alcohol/drug abuse
13/384
3.4
1/16
6.3
Hypercoagulable state
3/384
0.8
0/16
0
Migraines
4/384
1.0
0/16
0
Obese
19/384
4.9
0/16
0
Peripheral vascular disease
8/384
2.1
0/16
0
Arrhythmia/pacemaker
8/384
2.1
0/16
0
Prior TIA, aneurysm, stenosis endarterectomy or stenting
15/384
3.9
1/16
6.3
Prior angioplasty or CABG
7/384
1.8
0/16
0
Oral contraceptive
4/384
1.0
0/16
0
Affected arteries
CABG Coronary artery bypass graft surgery, COPD chronic obstructive pulmonary disease, NIHSS National Institutes of Health Stroke Scale, SVAC single-vessel anterior circulation (MCA, ACA, ICA), SVPC single-vessel posterior circulation (PCA, BA, VA), MV multiple vessels (any combination)
SVAC
328/377
87.0
15/16
93.8
SVPC
30/377
8.0
0/16
0
MV
19/377
5.0
1/16
6.3
85/372
22.8
6/16
37.5
Home
155/381
40.7
4/16
25.0
Rehabilitation
94/381
24.7
4/16
25.0
Long-term care Deceased
37/381 67/381
9.7 17.6
1/16 6/16
6.3 37.5
Outside hospital transfer
28/381
7.3
1/16
6.3
Hemorrhage Any Discharge location
thrombolytic treatment is associated with a significant risk of early seizures. Looking solely at the population of thrombolysed stroke patients, our objective was to determine the incidence of seizures among this specific population and search for associated factors.
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Methods Chart data were linked to a prospective stroke thrombolysis database. Subjects included all adults who were thrombolysed for acute ischemic stroke (AIS) between January 1,
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Table 2 Seizure patients: type of seizure, type of anti-epileptic drugs used in hospital and onset post-stroke Patient
Seizure type
AED used in hospital
Onset (days)
NIHSS Admission
Stroke location
Hemorrhage
1
Simple partial
None
12
17
SVAC (MCA)
Yes (subcortical)
2
Simple partial
Phenytoin
0
27
SVAC (MCA)
No
3
Simple partial
Benzodiazepine & phenytoin
0
N/A
SVAC (MCA)
Yes (lobar and subcortical)
4
Simple partial
Phenytoin
0
12
SVAC (MCA)
No
5
Complex partial
None
21
N/A
SVAC (MCA)
No
6
Complex partial
Phenytoin
12
16
SVAC (ICA)
Yes (lobar and subcortical)
7
Complex partial
Phenytoin
5
23
SVAC (MCA)
No
8
Complex partial
Phenytoin
3
32
SVAC (MCA)
No
9
Partial with 20 generalization
Phenytoin
0
15
SVAC (MCA) (MCA)
Yes (lobar)
10
Generalized tonic-clonic
Phenytoin
11
23
SVAC (MCA)
Yes (lobar and subcortical)
11
Generalized tonic-clonic
Phenytoin
8
10
SVAC (MCA)
No
12
Generalized tonic-clonic
Benzodiazepine & phenytoin
1
24
SVAC (MCA)
No
13
Generalized tonic-clonic
Phenytoin
0
13
SVAC (MCA)
No
14
Not specified
Phenytoin
66
2
SVPC (BA)
Yes (cerebellar)
15
Not specified
Phenytoin
4
10
SVAC (MCA)
No
16
Not specified
Phenytoin
1
24
SVAC (MCA)
No
2001, and October 31, 2006, in Calgary, Canada. All patients received intravenous thrombolysis with tissue plasminogen activator (tPA) at standard doses of 0.9 mg/kg infused over 1 h according to national guidelines for tPA use. All patients were treated within 3 h of stroke onset. The study was approved by the local ethics board. Exclusion criteria included prior stroke, history of epilepsy or seizures, use of antiepileptic drugs (AED) prior to hospitalization, thrombolysis received for a final diagnosis of central retinal artery occlusion, venous sinus thrombosis or a stroke mimic, and use of mechanical clot-retrieving devices. The primary endpoint was the incidence of clinical seizures after thrombolysis in AIS. Baseline patient demographics, past medical history, epilepsy risk factors, stroke etiology, use of AEDs in hospital, neurological examination at admission and post-thrombolysis, blood glucose on arrival in hospital, and neuroimaging findings were collected retrospectively. Other parameters examined included the presence of post-thrombolysis intracerebral hemorrhage and discharge location (home, rehabilitation, long-term care, deceased or transferred to outside hospital). Early seizure was defined as seizure occurring within 7 days from stroke onset, according to the International League against Epilepsy guidelines [11]. Unprovoked seizures that developed beyond 1 week after stroke, but
within the length of hospital stay, were termed late seizures. No distinction was made between acute symptomatic seizure and early post-stroke seizure. Seizures were identified by reviewing the inpatient charts from the time of initial admission. Any EEGs done on study subjects while admitted in hospital were also reviewed in addition to the hospital chart data. Data were analyzed using the commercially available statistical software SPSS 15.0 (Chicago, Illinois). For each study variable, descriptive statistics were obtained. Estimates were expressed as proportions or means in patients who had a seizure and those who did not. Age- and sexadjusted P values were obtained for all descriptive variables. All tests were two-sided, and a P value of B0.05 was considered statistically significant.
Results In this cohort, 400 patients met all study eligibility criteria, with a median age of 74.0 years, (range: 24–101) (Table 1). Men represented 49.7% of patients. A total of 312 patients were treated with IV tPA alone, 23 with IA tPA alone, and 65 with both IV and IA tPA. Time to treatment did not differ between the two groups. Most frequent stroke risk factors in seizure versus nonseizure patients included hypertension (62.5% vs. 65.8%),
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dyslipidemia (18.8% vs. 26.8%), coronary artery disease (37.5% vs. 30.8%), and atrial fibrillation (56.3% vs. 36.1%). The age- and sex-adjusted risk of seizure for atrial fibrillation was 3.0 (1.1–8.3). Stroke location was classified as single-vessel anterior or posterior circulation and multiple vessels, which included any combination (Table 1). Single-vessel anterior circulation occlusions were the most prevalent location in seizure subjects (93.8% vs. 87%). Post-stroke seizures occurred in 16 (4%) of the patients: 11 men and five women with 62.5% occurring within 7 days (early seizures), and half of those within the same day as the stroke (Table 2). In this cohort, the median NIHSS in those with versus those without seizures was 16.5 and 14, respectively. Their distribution was not statistically different. Any hemorrhage on follow-up imaging occurred in 37.5% of seizure patients versus 22.8% in the non-seizure group. Death during admission was more likely RR = 2.1 (CI95 1.1–4.2) among those who sustained seizures (37.5%) compared to those without seizures (17.6%).
Conclusion Previous studies examining seizures following stroke have often included strokes of all etiologies and treatments. The current study specifically assessed for potential predictors and associated risk factors of post-stroke seizures in tPAtreated AIS patients. In a second step, it assessed the impact of seizures onto in-hospital death. In this cohort, tPA-treated patients have comparable incidence of seizures (4%) with previously published series [2–4, 10]. These results suggest that tPA in itself does not increase the risk of early or late seizures. The majority of patients with seizures post-tPA have no hemorrhage, but there is a trend toward more hemorrhage in seizing versus non-seizing patients. Atrial fibrillation was associated with an increased seizure risk in this cohort. Cardioembolic strokes have been linked to a higher incidence of seizures than other stroke mechanisms [4]. This is not surprising considering that atrial fibrillation is predominantly associated with cortical strokes, which have been shown to increase the likelihood of seizures [6, 10]. Perhaps, the most important observation in the current study is the increase in likelihood of death in patients who developed seizures. This is consistent with a recent study reporting higher stroke mortality, disability at discharge, and prolonged length of stay when seizures developed after stroke, although treatment allocation was not specified [12]. Using tPA should theoretically result in smaller infarct size and disability. The benefit may be reduced or
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lost if seizures occur. Possibly, seizures in that setting represent a broader marker of cerebral dysfunction as opposed to simply cortical irritability. There are several limitations to this study. The retrospective design, relying on chart review, can sometimes be associated with missing data. Seizure diagnosis relies heavily on history and semiology. Various paroxysmal spells including seizures may have been missed or misdiagnosed. We did have access to EEG records and reports. However, continuous video-EEG, the gold standard to capture seizures, was not used. Whether primary hemorrhagic strokes and post-tPA bleeding confer the same risk of seizures cannot be ascertained by this cohort. Finally, long-term follow-up beyond hospitalization was not available. Despite these limitations, this is the largest study examining the incidence and predictors of seizures and outcome in tPA-treated AIS patients. It reinforces the notion that seizures may be a marker of negative prognosis whether a patient receives targeted stroke treatment or not. It remains to be determined whether treating these patients early or prophylactically with an AED may change their outcomes. One wonders whether continuous video-EEG monitoring is warranted in high-risk patients treated with tPA, such as those with atrial fibrillation. More research is needed to answer these questions and shed light on the intricate relationship between cerebrovascular diseases and seizures. Acknowledgements N. Jette´ holds research salary awards from Alberta Innovates Health Solutions (AI-HS) and from the Canadian Institutes of Health Research (CIHR). This study was in part funded by AI-HS and by the Beulah Dora Olsen Research Endowment fund from Alberta Health Services to N. Jette´. M. Hill holds a research salary award from AI-HS and holds the Heart & Stroke Alberta Professorship in Stroke Research.
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