Outcome after acute ischemic stroke is linked to sex-specific lesion patterns

So you have described something, but done nothing to help recover from these lesions. Useless. Predicting stroke severity doesn't help any survivor.

Outcome after acute ischemic stroke is linked to sex-specific lesion patterns

• Anna K. Bonkhoff,
• Markus D. Schirmer,
• […]
• Natalia S. Rost 

Nature Communications volume 12, Article number: 3289 (2021) Cite this article

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Abstract

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.

Introduction

Stroke affects >15 million people each year¹. It is known to result in a substantial overall degree of long-term impairment across men and women^2,3. However, numerous epidemiological studies indicate clinically relevant, sex-related differences in the characteristics of ischemic cerebrovascular disease^4,5. For instance, due to a longer life expectancy, more women than men experience a stroke each year⁶. Expected demographical changes, i.e., an aging population, will widen this gap further: in the US, projections suggest that ~200,000 more women will be disabled after stroke than men by 2030⁷.

Further sex differences relate to women more often presenting with non-classic stroke symptoms, such as fatigue or changes in mental status^8,9, and having a higher risk of delays in hospital arrival^10,11. Also, women feature a higher risk of cardioembolic stroke due to atrial fibrillation¹², which may contribute to the often-observed higher acute ischemic stroke (AIS) severity in female patients¹³. This excess in stroke severity in women persists even after adjusting for their greater age at onset, comorbidities, and prestroke level of independence^14,15. Importantly, women seem to experience more severe strokes despite comparable lesion sizes in men and women¹⁶. In fact, a similar observation of sex-specific lesion volume effects was noted in the case of aphasia, where women had a smaller lesion volume threshold to cause aphasia than men¹⁷.

Going beyond lesion volume, lesion-symptom mapping studies have enriched our understanding of anatomically unique lesion locations underlying specific symptoms post-stroke^18,19,20. In the case of stroke severity, these analyses have determined widespread lesions in white matter, basal ganglia, pre- and postcentral gyri, opercular, insular, and inferior frontal regions to be most relevant for a higher stroke severity, especially if affecting the left hemisphere²¹. While these lesion-symptom studies have uncovered eloquent lesion locations with high spatial resolution, they have been systematically blind to any potential sex disparities. If considered at all, sex was treated as a nuisance variable and regressed out prior to the main analysis²¹. Thus, none of the recently employed analytical approaches in clinical neuroimaging allowed for a dedicated, explicit investigation of sex-specific lesion pattern effects in relation to continuous outcome scores.

In this work, we aim to design and conduct a lesion-symptom analysis capable of capturing male- and female-specific lesion patterns, underlying stroke severity in a statistically robust and spatially precise manner to address previous methodological constraints. For this purpose, we leverage neuroimaging data originating from two large, independent hospital-based cohorts gathering data of 555 (derivation) and 503 (validation) AIS patients in total. We tailor and deploy sex-aware hierarchical Bayesian models to simulate predictions of AIS severity and to elucidate the sex-specific effects of lesion patterns affecting similar brain regions in women and men. We seek to map the lesion constellations underpinning female-specific more severe strokes, potentially indicating sex-specific maps of functional deficits on the one hand and encouraging more sex-aware acute stroke treatment decisions on the other. Such a sex-informed acute stroke care has the potential to alleviate the burden of disease on an individual patient level, as well as broader and socioeconomically relevant levels.

Results

We here present a generative analysis of acute stroke severity, putting a particular focus on sex-specific lesion pattern effects. We successively combined (1) the automated low-dimensional embedding of high-dimensional DWI-derived lesion information via non-negative matrix factorization (NMF)²², and (2) probabilistic modeling, based on the latent NMF embedding, to simulate the prediction of acute stroke severity, as measured by the National Institute of Health Stroke Scale (NIHSS)²³. We thus first determined pivotal, general lesion pattern effects across all patients and successively concentrated on similarities and differences between men and women (sex assessed by patients’ medical records). We interpreted explanatory relevances on the level of NMF-derived low-dimensional lesion representations, that we call lesion atoms, as well as the same relevances transformed back to the level of the anatomical gray matter brain regions and white matter tracts.

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