Differences Between Ischemic Stroke Subtypes in Vascular Outcomes Support a Distinct Lacunar Ischemic Stroke Arteriopathy

Background and Purpose - Whether and how the arterial pathology underlying lacunar ischemic stroke differs from the atherothrombotic processes causing most other ischemic strokes is still debated. Different risks of recurrent stroke and MI after lacunar versus nonlacunar ischemic stroke may support a distinct lacunar arteriopathy.

Methods - We prospectively followed a hospital-based cohort of 809 first-ever ischemic stroke patients for 1 to 4 years. We compared risks of death, recurrent stroke, and MI in patients with lacunar versus nonlacunar stroke, and performed an updated meta-analysis of recurrent stroke subtype patterns.

Results - During 1725 person-years of follow-up, 109 patients had a recurrent stroke and 31 had MI. All patients at baseline, and 93% with recurrent stroke, had brain imaging and more than half with recurrent stroke had diffusion-weighted MRI. Overall, there was no difference in recurrence risk after lacunar vs nonlacunar stroke, although there was a trend toward a lower recurrence risk in the early weeks after lacunar stroke. Lacunar recurrence was more likely after lacunar than nonlacunar stroke (OR, 6.5; 95% CI, 2.4–17.5; updated meta-analysis OR, 6.8; 95% CI, 4.2–11.2). MI risk was nonsignificantly lower after lacunar than nonlacunar stroke (rate ratio, 0.5; 95% CI, 0.2–1.1; rate ratio after excluding patients with previous ischemic heart disease: 0.3; 95% CI, 0.1–0.9).

Conclusions - Our finding of a trend toward a lower MI risk after lacunar vs nonlacunar stroke and confirmation of both a lower early recurrence risk after lacunar stroke and a tendency of recurrent stroke subtypes to “breed true” support the notion of a distinct nonatherothrombotic lacunar arteriopathy.

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Approximately one-quarter of ischemic strokes are lacunar, presumed to result from occlusion, or perhaps leakiness, of one of the perforating arteries supplying the deep, subcortical areas of the brain. The underlying arterial pathology is poorly understood, but in most cases it is thought to be an intrinsic small vessel disease distinct from the atherothromboembolic processes causing most other ischemic strokes. In support of this is evidence that patients with lacunar ischemic stroke have a lower frequency than those with nonlacunar ischemic stroke of potential sources of thromboemboli (carotid stenosis and sources of cardiac emboli) and of previous ischemic heart disease (IHD), ie, coronary atherothrombosis.

If lacunar stroke is mainly caused by a distinct nonatherothrombotic arteriopathy, then we would also expect a lower early recurrent stroke rate compared with nonlacunar ischemic stroke (attributable to a lower frequency of active sources of thromboemboli); a tendency for recurrent stroke subtypes to “breed true” (ie, a further lacunar ischemic stroke would be more likely after a lacunar than a nonlacunar ischemic stroke); and a lower risk of MI among patients with lacunar vs nonlacunar ischemic stroke. We tested these hypotheses in a large, prospective, hospital-based cohort of well-characterized ischemic stroke patients.

Modified TOAST algorithm used to assign etiological ischemic stroke subtypesClick on image to view larger version. Although previous studies have suggested a lower early recurrence rate among patients with lacunar ischemic stroke, and a tendency for recurrent stroke subtypes to breed true, their reliability was limited by small numbers of events, variable and sometimes biased definitions of recurrent stroke, and low rates of brain imaging among recurrent strokes, with no reported use of diffusion-weighted MRI, which is particularly helpful in differentiating new from old lesions, especially if small or in patients who present late. Several cohort studies have assessed MI risk after ischemic stroke, but only 1 reported this for lacunar and nonlacunar ischemic stroke patients separately, recording only 6 MI. We aimed to overcome these limitations.

Subjects and Methods

Between 2002 and 2005 we prospectively recruited consecutive, consenting patients with stroke (defined according to WHO criteria), admitted to or seen as outpatients at our hospital. In this study, we included patients with a first-ever-in-a-lifetime clinically evident stroke, demonstrated by brain imaging (CT or MRI) to be ischemic (ie, primary hemorrhage excluded). We assigned ischemic stroke subtypes according to the presumed site and size of the causative infarct (anterior circulation lacunar or cortical [including striatocapsular] infarction, or posterior circulation infarction) using the clinical features of the stroke, modified if necessary by the findings on brain imaging if an infarct considered relevant to the presenting stroke was present. We excluded cases of posterior circulation infarction, which include lacunar and nonlacunar events that are often difficult to distinguish, patients with an uncertain subtype, and patients with an unusual cause of stroke (eg, arterial dissection).

We defined recurrent stroke as for index stroke, additionally requiring a period of neurological stability of ?24 hours between index and recurrent stroke, and exclusion of other potential causes of neurological deterioration. We defined definite MI as either autopsy evidence or at least 2 of the following; symptoms of myocardial ischemia (eg, chest pain); enzyme changes indicative of MI (generally raised troponin); and ECG changes suggesting new ischemia (new ST-T wave changes, Q waves, or left bundle branch block). We defined probable MI as sudden death without evidence of an alternative cause.

We followed-up patients for between 1 and 4 years using multiple overlapping methods, including regular patient questionnaires, contact with patients’ general practitioners, and linkage to the national death register. We reviewed all relevant records to confirm the cause of death for more than two-thirds of deaths, including all those for which part I or II of the death certificate mentioned either stroke or MI.

Whenever possible, we arranged specialist review for patients with a suspected recurrent stroke, and CT or MR brain imaging with diffusion-weighted imaging, T2, FLAIR, and gradient echo, aiming particularly to perform diffusion-weighted MRI if CT revealed no visible relevant lesion. For patients with a suspected MI, or those unable to attend a clinical assessment for suspected recurrent stroke, we sought confirmation of the event by reviewing all relevant medical records.

Statistical Analyses
We used STATA version 8. We compared baseline characteristics (lacunar vs nonlacunar) using the {chi}2 test for dichotomous variables, Student t test for normally distributed continuous variables, the Mann-Whitney U test for non-normally distributed continuous variables, and the {chi}2 test for trend for ordered categorical variables. We calculated median length of follow-up as median observation time (from study entry to date of death or date censored). We compared cumulative probability plots (lacunar vs nonlacunar) with the log rank test for each of death, recurrent stroke, and MI (definite or probable), censoring patients at time of the event of interest, death, or end of follow-up. We used Cox regression to obtain unadjusted and age- and sex-adjusted hazard ratios for death and for recurrent stroke for the entire follow-up period and for prespecified periods: 0 to 1 and 1 to 4 years; 0 to 1 month and 1 month to 4 years; and (for recurrent stroke only) 0 to 1 week and 1 week to 4 years. We could not adjust hazard ratios for recurrent stroke at 1 month or 1 week because of low numbers of early recurrences. Multivariate survival analysis techniques for MI were precluded by the relatively small number of events and the complexities of analyzing survival curves that cross multiple times. Therefore, we calculated an unadjusted rate ratio, repeating this analysis after excluding patients with previous IHD, because a higher rate of MI at follow-up could be attributable to established IHD.

In prespecified sensitivity analyses we restricted the nonlacunar comparison group to patients with mild cortical ischemic stroke only (associated with a partial, as opposed to total, anterior circulation stroke syndrome11), and compared small vs large vessel disease ischemic stroke using a modified TOAST classification.

We analyzed recurrent stroke subtype patterns by calculating the odds of a lacunar recurrence after lacunar vs nonlacunar index stroke, using logistic regression to adjust for potential confounding by age, sex, and antithrombotic therapy at onset of recurrence. We updated to the end of 2007 our previous meta-analysis of published studies of recurrent stroke subtype patterns, including unadjusted data from the current study.

We estimated extent of misclassification of ischemic stroke subtypes by calculating the proportion of patients with a visible relevant infarct on their brain scan whose final classification placed them in a different comparison group from their clinical syndrome classification. We then applied this proportion to the patients with no visible relevant infarct on brain imaging to estimate the possible extent of residual misclassification among both index and recurrent ischemic stroke subtypes.

A Prospective, Hospital-Based Study
Caroline A. Jackson, PhD; Aidan Hutchison, BSc; Martin S. Dennis, MD, FRCP; Joanna M. Wardlaw, MD, FRCR; Steff C. Lewis, PhD Cathie L.M. Sudlow, DPhil, FRCP

From the Division of Clinical Neurosciences (all authors) and Institute of Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, Western General Hospital, Edinburgh.

Correspondence to Dr Cathie L.M. Sudlow, Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU. E-mail .(JavaScript must be enabled to view this email address)

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