In this large, single health system, retrospective chart review, we found that CVA prevalence was higher in our cohort of UC patients than in Minnesota and the U.S. at large. The prevalence of CVA in all UC patients increased with age and the most common stroke subtype was ischemic (70%). The predominantly ischemic nature of infarction in our dataset agrees with most studies. However, the majority of stroke literature in IBD patients has presented CVAs as an issue of younger, otherwise healthy patients with severe IBD [2, 3]. In contrast, our study found traditional risk factors for CVA to be common in UC. The fact that our study captured a significant degree of community (outside of tertiary center) UC cases may account for this difference.
Patterns of stroke localization are important to understand underlying pathophysiology. A relatively recent review article demonstrated that the majority of strokes identified in IBD patients were in the left or right middle cerebral artery, making anterior circulation events the most commonly affected area, similar to the general population [9, 13]. A small series of patients with CD identified recurrent posterior circulation strokes, but the three cases described were derived from patients with recurrent strokes, which may have led to biases in the selection of patients with a predilection for this area[14]. In future studies, cerebral imaging with vascular reconstruction should be included for all patients with IBD experiencing CVAs, such to better inform this issue.
An important finding in our study is that post-menopausal women with UC had the highest risk for stroke. This finding contrasts with previous work that showed younger women with UC at greatest risk [3, 12]. Specifically, Ha et al. compared women with IBD (pooled UC and CD) under age 40 to age-matched healthy controls, and found young women with IBD to have a greater risk of stroke [3]. Variations in hormone levels and/or varying degrees of other cumulative sex-specific risk factors, such as hormone contraception use, may be important contributing factors to this finding. Other investigators have demonstrated that women with IBD are at increased risk for cardiovascular disease and it is presumed that hormonal variations may impart a degree of this risk [7, 11, 15]. Possible explanations are hormonal disequilibrium, inflammation, and endothelial dysfunction [16]. In this way, estrogen has myriad effects on cardiovascular health as women age and this dynamic may persist and possibly be exacerbated in the setting of IBD [17]. This is evidenced by literature supporting the role of estrogen in TNF-alpha modulation as it relates to inflammation and interactions within the gut microbiome [18]. Further, murine studies have shown that estradiol downregulates TNF-alpha and subsequently is protective against acute colitis [19]. These findings represent an intriguing avenue of investigation to further link post-menopausal women with IBD, variations in hormone levels, and increased cerebrovascular risk.
Limitations of our study include both its retrospective nature and lack of correlative data to indicate degree of disease activity in the IBD patients at the time of CVA. Further, more generally, our data did not capture personal history of thrombophilia, tobacco smoking history, immobilization, recent surgery, use of central venous catheters, VTE prophylactic measures, IBD medications, and overall compliance. Missing data and differential loss to follow up may be products of our retrospective design. Our strict definition of stroke prioritized specificity over sensitivity and could have resulted in a lower stroke detection rate in our UC and female CD cohorts. However, an artificially low stroke detection rate should have favored the hypothesis that thromboembolism would not be increased in both cohorts, which suggests that our findings are not spurious. Further, IBD disease activity as illustrated via serum C-reactive protein (CRP) levels, fecal calprotectin levels or better yet, endoscopic impression would allow inferences to be made concerning degree of inflammation and thrombotic risk. This is important, as while quiescent disease exhibits a measurable degree of risk, active IBD flares generate the highest risk of VTE propagation, atrial fibrillation, and stroke [10, 20]. Further, increased disease activity is also linked to higher risk of myocardial infarction, stroke, and cardiovascular-related death, with elevated CRP levels acting as a surrogate for disease activity [21]. Lastly, while it is important that we incorporated active cancer and atrial fibrillation, a more comprehensive co-variate model including additional known risk factors for CVA may have yielded a more comprehensive analysis.