To the best of our knowledge, this is the first prospective study comparing early and late recurrent ischemic stroke in Egypt. We found that large artery atherosclerosis and cardioembolism are associated with early recurrent ischemic stroke while small vessel disease is associated with late recurrent ischemic stroke. We also found that systolic blood pressure was significantly higher among patients with late recurrence.
Our 1-year selection as a separation point for patients with early and late recurrent ischemic stroke corresponds to the recent trend in the design of stroke studies [9]. Amarenco and colleagues reported that the risk of recurrent stroke within and after the first week and after 1 month, 3 months, and 1 year was less than half that expected from historical cohorts. The 1-year risk still poses a short-term risk for the prevention of strokes for a lifetime [9]. The early and late categorization of our subjects combined with the etiologic classification (TOAST criteria) has enabled us to know which subtype of stroke is associated with early or late recurrence and to unmask the previous controversy as regards the causes of recurrent stroke.
The ranking of the etiologic groups demonstrates different data in the studies that were conducted by different authors [8]. In a previous study that evaluated 889 patients with recurrent ischemic stroke, small vessel disease was the most common causative factor [13]. In another study, cardioembolic strokes were the most common etiological factor followed by strokes with an undetermined etiology [14]. The strokes due to undetermined etiologies and cardioembolic strokes were the most common causes in the study that Murat Sumer and Erturk [15] conducted in 2002. In the study conducted by Kolominsky-Rabas and colleagues [3] in Europe, cardioembolic strokes positioned first and strokes due to large vessel atherosclerosis positioned second in the disease group.
We found that large artery atherosclerosis was statistically higher among patients with early recurrence. This is in accord with a study by Lovett and colleagues who reported that patients with large artery atherosclerotic disease have a high early risk of recurrent ischemic stroke compared with other etiologic subtypes, whereas patients with ischemic strokes due to small vessel disease have the lowest risk of early recurrence [11].
Also, in agreement with our study, Kocaman and colleagues reported that large artery atherosclerosis is the most common etiology for recurrent ischemic stroke [8].
Atherosclerosis in major intracranial arteries prompts changes running from minor thickening of the arterial wall to a significant hemodynamic stenosis of the arterial lumen and is a standout among the most common causes of stroke worldwide [16].
A prior investigation revealed that patients with minor stroke who have more than 70% stenosis of the internal carotid artery (ICA) had a higher rate of recurrent ischemic stroke, which indicates that severe symptomatic extra- or intracranial arterial disease was independently associated with 7-day and 90-day stroke recurrence in minor stroke patients [17].
In their hypothesis, Hankey and colleagues reported that atheroma (the common cause of stroke) is an acute on top of chronic disease, causing recurrent attacks of thromboembolism before settling down as the endothelium of the ulcerated plaque heals [18]. Moreover, animal experimental studies demonstrated that a prior thromboembolic event enhanced the vulnerability of the brain to a subsequent ischemic insult [19, 20]. In line with these data, diffuse atherosclerotic changes in the form of increased intima-media thickness were significantly higher among our patients with early recurrence.
In our study, patients with early recurrent stroke were more likely to have cardioembolic stroke; this was in line with Petty and colleagues, who reported that cardioembolic strokes were the most common cause of recurrent ischemic stroke followed by strokes with an undetermined etiology [14].
Also in line with our findings, the strokes due to undetermined etiologies and cardioembolic strokes were the most common causes with similar frequencies in the study of Murat Sumer and Erturk [15].
Moreover, in the study conducted by Kolominsky-Rabas and colleagues in Europe, cardioembolic strokes ranked first and strokes due to large vessel atherosclerosis ranked second in the disease group [3].
Among our population, the prevalence of small vessel disease among patients with late recurrent ischemic stroke was significantly higher than those with early recurrent ischemic stroke. In agreement with our findings, Leoo and colleagues reported that, according to the TOAST subtypes of the ischemic stroke group, “small vessel disease” was the most common cause of RIS; they also reported that the majority of the patients (75%) had their previous stroke > 12 months before the admission [13].
In agreement with Leoo and colleagues [13], hypertension was the most frequent vascular risk factor among our population (65%).
It was stated in the literature that stroke recurrence increases fourfold in the presence of hypertension, and approximately 60–75% of strokes occur in the presence of hypertension [21]. As shown in a meta-analysis of 7 randomized controlled studies, antihypertensive drugs reduce stroke recurrence after stroke or TIA [22].
Various meta-analyses showed that efficient antihypertensive treatment reduces the rate of recurrence of strokes by 30–40% [22,23,24]. It was also reported in another study that an adequate antihypertensive treatment reduces the rate of stroke recurrence by 50% [25].
The researchers stated in another study that hypertension is a significant modifiable risk factor in their patient population to prevent stroke recurrence [8].
Although we did not find a significant difference between patients with early and late recurrence as regards the prevalence of hypertension, systolic blood pressure was significantly higher among patients with late recurrent ischemic stroke. This may mean that uncontrolled hypertension played a key role as a risk factor for small vessel disease. In line with our findings, in the study, Laloux and colleagues found that the proportion of patients with recurrent stroke who received inadequate antihypertensive medication was 39% [26].
As regards the clinical presentation, we have found that aphasia was significantly more common in patients with early recurrent stroke. In line with our results, researchers in the Oxfordshire Community Stroke Project found that patients with higher cortical dysfunction (e.g., aphasia, visuospatial disorder) were significantly more likely to have an early recurrent stroke due to a partial anterior circulation infarction [27].
A limitation of our study is that the index stroke was not restricted to the first-ever ischemic stroke; however, with reference to a previous study, recurrent stroke subtypes were the same as the index stroke in a large proportion of patients [28]. Dependence on the TOAST classification, in addition to the small size of the sample, made us deal with small vessel disease as a single category. Indeed, small vessel disease is a broad term covering lacunar brain infarcts, white matter hyperintensities, cerebral microbleeds, and atrophy attributed to the vascular origin.
Based on our findings, patients with LAA and CE are at increased risk of early recurrence and warrant special efforts for secondary prevention. Future research should aim at establishing clinical, serological, and imaging biomarkers that can identify high-risk patients. In addition, there is an urgent need to develop novel therapies to lower the risk of stroke in these high-risk patients.
