Farah Aleisa, MD

Ali M, van Os HJA, van der Weerd N, Schoones JW, Heymans MW, Kruyt ND, Visser MC, Wermer MJH. Sex Differences in Presentation of Stroke: A Systematic Review and Meta-Analysis. Stroke. 2021.

In the literature, women do worse after stroke than men, mortality and severe stroke are higher among women, and atypical clinical presentation of acute stroke could explain the higher rate of misdiagnosis in women. Interestingly, a previous cohort study indicated that women who presented with a transient ischemic attack (TIA) or minor stroke more frequently received a diagnosis of stroke mimic compared with men with similar symptomatology; at the same time, stroke recurrence rate within 90 days of stroke onset were similar in both men and women, raising the possibility of sex biases in diagnosing acute stroke. Here, we will go through a systematic analysis of different acute stroke presentations between men and women.

A search was conducted through PubMed and the Cochrane Library for published articles from their inception until May 2020 to identify studies that reported comparisons between men and women in acute stroke symptomatology. Authors applied the following selection criteria for inclusion of studies: patients age >18 years old with diagnosis of acute stroke including TIA; use of a cohort, cross-sectional, case-control, or randomized controlled trial design; diagnosis of stroke based on neurological examination and neuroimaging (either computed tomography or magnetic resonance imaging). The assessment risk of bias was performed through a customized version of the Newcastle-Ottawa Scale with adjustments for the assessment of stroke and TIA symptoms. Studies were scored low risk, high risk, or possible/unclear on the domains (1) validation of diagnosis, (2) assessment of symptoms, (3) adjustment for confounding, and (4) generalizability. They did statistical analysis by the sex-specific number of symptom occurrences provided in the study, along with the total number of women or men studied to calculate ORs. They also used this information to calculate the corresponding 95% CIs and the degree of overlap in symptom presentation between men and women in percentages.

They included 60 studies with total of 582844 patients (50% women); the median age was 74 years for women (interquartile range, 69–75) and 69 years for men (interquartile range, 64–70).

The overall pooled OR of occurrence of non-focal symptoms in women versus men was 1.24 (95% CI, 1.16–1.33) with a summary incidence of 27% for men versus 31% (95% CI, 30%–33%) for women and considerable heterogeneity (I2=91.9%). Headache including migraine (OR, 1.24 [95% CI, 1.11–1.39]; summary incidence: 16% for men versus 19% [95% CI, 17%–21%] for women; I2=75.2%; 30 studies; 47254 patients), minor change in level of consciousness or mental status change (GCS score, ≤14; OR, 1.38 [95% CI, 1.19–1.61]; summary incidence: 17% for men versus 22% [95% CI, 20%–25%] for women; I2=95.0%; 17 studies; 122465 patients), and coma or stupor (GCS score, ≤8; OR, 1.39 [95% CI, 1.25–1.55]; summary incidence: 6% for men versus 8% [95% CI, 7%–9%] for women; I2=27.0%; 13 studies; 37196 patients) occurred more frequently in women compared with men. Specific neurological or other neurological symptoms occurred less frequently in women (OR, 0.96 [95% CI, 0.94–0.97]; summary incidence: 32% for men versus 31% [95% CI, 31%–31%] for women.

The conclusion of the systematic analysis is mostly that non-focal neurological symptoms occurred in women, like change in level of consciousness, and headache, whereas other focal neurological symptoms like weakness and diplopia were more common in men.

The strengths of this systematic review and meta-analysis include the large number of included studies using all known contemporary data from almost 600,000 patients, the subgroup analysis by stroke type to assess impact on effect estimates and heterogeneity, and the evaluation of a wide variety of non-focal and focal symptoms.

Several hypotheses exist for mechanisms underlying possible sex differences in stroke symptomatology. First, cardioembolic stroke and SAH occur more frequently in women. Second, women tend to be older at stroke onset and have more comorbidities. The increased prevalence of dementia, psychosocial stressors, and depression among women could impact stroke presentation. Third, women are more likely to be diagnosed with a stroke mimic such as migraine, seizure, or other psychiatric disorders, which could point toward caregivers’ biases toward patients’ sex.

Significant differences were found between women’s and men’s non-focal neurological presentation, but this still requires further investigation. Additional research studies are needed with better methodological quality, and more specific approach looking for the effect of other confounding factors like stroke subtype and underlying mechanism.