This study showed two major findings in AIS patients with a single RSSI: (1) Clinical risk factors of PSD with a single RSSI were identified: older age, higher stroke severity (NIHSS), elevated CRP and fibrinogen levels. (2) Dysphagia in single RSSI patients resulted from severe small vascular disease, which was associated with systemic inflammation.
PSD was common in hospitalized patients and associated with increased mortality and comorbidities, including post-stroke pneumonia, malnutrition, dehydration and mortality[29]. Among AIS patients, 50–80% had trouble with swallowing, especially during the first week after their stroke[30]. The importance for screening of PSD had been emphasized at both international symposiums and in clinical audit reports. In the American Heart Association/American Stroke Association 2019 guidelines for the Early Management of AIS, dysphagia screening was effective in identifying patients at increased risk for aspiration, and these guidelines had strength/class of recommendation I (strong benefit to risk ratio) but C-LD level of evidence (limited data)[31]. The prevalence of PSD (17.53%) among AIS patients with RSSI in our study was consistent with other investigators given that 20% suffered from PSD. We also confirmed previous findings demonstrating that patients with PSD carried a high risk of post-stroke pneumonia (44.44%).
Prior studies using different methods demonstrated that bilateral activation of the sensorimotor cortex[32] and a bilateral redistribution of swallowing networks after stroke[33]. In fact, many structures associated with swallowing were located in subcortical regions, such as corticonuclear tracts, periventricular connections of cortical regions and extrapyramidal pathways[8]. Damage to subcortical lesions on one hemisphere might be completely compensated by the contralateral side. However, studies identified that almost one-quarter of patients with RSSI had dysphagia. We hypothesized that PSD may not only be disrupted by a single RSSI but also by concomitant cerebrovascular lesions. Widely distributed morphological changes from SVD may have a strong effect[34]. Studies investigating RSSI patients in the context of SVD were largely unknown[35].
SVD was a common condition that affected small cerebral arterioles, capillaries, and venules. This condition had long been implicated with clinical manifestations ranging from clinically silent to focal neurological dysfunction, such as stroke, and even to global neurological symptoms and dementia[36]. Features of SVD on MRI included RSSI, WMH, lacunes, ePVS, CMBs and atrophy[37]. Terminology for these lesions have highly varied between studies[38, 39]. Neuroimaging consensus standards for classification of SVD were first proposed by the US National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network[40]. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) consensus defined clear, rigorous, evidence-based, and easy-to-apply terminology for SVD, which provided a consistent approach to neuroimaging[41].
Our study identified demographic and clinical factors that were associated with PSD to identify those RSSI patients at an early stage with a greater risk of PSD. Previous research[30, 42, 43] had proposed various risk factors of PSD. Age, stroke severity and larger infarctions were consistently considered to be independent predictors for PSD[31, 44]. In addition to the brain stem, both cortical and subcortical regions played an important role in swallowing[3]. To date, there was no clear conclusion about the relationship between brain lesions locations and the occurrence of PSD. However, almost none of these studies particularly focused on dysphagia in patients with RSSI.
Dysphagia in subcortical stroke may be caused by damage to swallowing pathways, including corticonuclear tracts, extrapyramidal pathways and periventricular connections of cortical regions. Prior studies investigating larger subcortical strokes reported an impact of acute lesion locations on the occurrence and severity of PSD but rarely explored combined effects of acute and pre-existing cerebrovascular lesions on dysphagia[45]. A retrospective study revealed that PSD was closely linked to bilateral pyramidal tract damage by both acute RSSI and pre-existing contralateral cerebrovascular lesions (lacunes and severe WMH)[1]. Therefore, widely distributed morphological changes caused by SVD may additionally contribute to PSD especially for RSSI patients.
Little information was known about the pathogenesis of SVD and how this process resulted in neurological disease. However, the process had been attributed to proximal perforating arteriolar atheroma, lipohyalinosis, or fibrinoid necrosis[46], which were thought largely to result as a consequence of hypertension or vasospasm or recently to result from inflammation. Proximal perforating arteriolar atheroma was associated with a larger infarct of the basal ganglia and more likely to be progressive stroke[47]. Lipohyalinosis was thought to be accompanied with additional features of SVD, such as WMH and lacunes[48]. Only a few acute lacunar infarcts, especially basal ganglia lesions, were caused by emboli.
At present, there were no consistent conclusions about the relationship between systemic inflammation and SVD. Nevertheless, longitudinal investigations demonstrated that systemic inflammation, especially if the inflammation was sustained in the long term, promoted and predicted SVD progression[11]. The Atherosclerosis Risk in Communities study identified that a sustainable elevated level of CRP during midlife highly increased the risk of SVD after 20 years[49]. The existing literature revealed strong associations between SVD and markers of vascular inflammation rather than systemic inflammation in AIS patients, suggesting that the vascular inflammation/endothelial dysfunction and alterations to blood-brain barrier may be the driving force behind SVD[50]. A small number of patients with Lp-PlA2 data may account for the failure to demonstrate the association with dysphagia.
An important difference between our study and those of others was that we focused on RSSI patients and explored relationship between pre-existing SVD and PSD. In addition, the total MRI burden score of SVD we used provided a more complete overall view of the pre-existing SVD than the individual features separately. Several limitations needed to be further addressed. First, both WST and V-VST were assessed using bedside screening tests. Although V-VST had been shown to be a well-validated clinical instrument with high sensitivity and specificity, instrumental testing, such as videofluoroscopic or flexible endoscopic evaluation of swallowing, might have aided in detection with higher precision and yielded higher rates of PSD. Second, further analysis of the various factors influencing the associations between inflammation and SVD (e.g., gender, ethnicity, APOE genotype, duration of inflammation) should be further assessed.