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Introduction

The term cerebral small vessel disease (CSVD) refers to a syndrome of clinical and imaging findings which are considered to result from pathologies arising from perforating cerebral arterioles, capillaries and venules [1]. CSVD includes white matter lesions (WML) and lacunar infarcts, and is a commonly encountered finding on computed tomography (CT) and magnetic resonance imaging (MRI) scans especially in case of elderly patients [2]. The disease is also found to be associated with vascular risk factors like systemic hypertension, diabetes mellitus, atherosclerosis of vessels and atrial fibrillation [3, 4]. In CSVD the symptoms are mainly due to infarction of subcortical structures. There is increasing evidence that the clinical and pathogenetic pattern, and risk factor profile, of stroke varies among different ethnic groups [5]. Asians, for example, have a high prevalence of intracranial large artery disease and cerebral small vessel disease and a stronger relationship between blood pressure and stroke risk [6, 7]. The retinal blood vessels, measuring 100 to 300 µm in size, offer a unique and easily accessible window to study correlates and consequences of cerebral microvascular disease, because the retina and brain share similar anatomic features and physiological properties [8]. In the last decade, there have been several population-based and clinical studies in white populations which have consistently shown that retinal microvascular signs (eg., retinopathy and retinal venular widening), assessed from retinal photographs, are predictors of clinical stroke events, stroke death and are associated with subclinical measures of cerebral small vessel disease [9]. In a study by Magdalena et al retinal nerve fibre layer thickness assesses by OCT was correlated with the extent of cerebral small vessel disease [10].

In the present study, we aimed to study retinal vasculature by fundus examination in persons identified to have cerebral small vessel disease on MRI brain and an attempt to correlate the retinal vascular changes with the degree of MRI brain changes.

Materials and methods

This case control study was conducted at the department of Neurology, Jubilee Mission Medical College & Research Institute, Thrissur, following approval from institutional ethical committee, The study was conducted for a period of 18 months from July 2020 to January 2022.

One hundred and eighty patients reporting to the neurology department were included in the study. All patients who have evidence of cerebral small vessel disease on MRI brain were taken as cases (90 cases). Age and gender matched controls with no evidence of cerebral small vessel disease on MRI were taken as controls (90 controls). Cerebral small vessel disease was identified and classified as per the modified Fazeka Scale [11]. Ophthalmoscopic examination was done using fundus camera with the help of ophthalmologist. Retinal vascular findings were correlated with cerebral small vessel disease.

Statistical analysis

Collected data was coded and entered in MS excel. Results were expressed in percentages and the data obtained were analysed using standard analytical techniques using SPSS software at the end of the study. Mean and proportions was calculated for continuous and categorial variables respectively. Difference in means was tested for statistically significant using Chi square test. A p value of < 0.05 was considered to be statistically significant.

Results

It can be observed that there was almost equal distribution of cases and controls with respect to their age. Majority of cases and controls were in the age group of 61-70 years (Figure 1).

Figure 1: Distribution of cases and controls with respect to their age.

Comparison of arteriolar narrowing between cases and controls

From the table 1 it can be observed that, 57 (63.3%) cases and 37 (41.1%) controls were found to have arteriolar narrowing. This association was found to be statistically significant.

Table 1: Arteriolar narrowing among cases and controls.  

Comparison of AV crossing changes between cases and controls

From the table 2 it can be observed that, 43 (47.8%) cases and 17 (18.9%) controls were found to have AV crossing changes. This association was found to be statistically significant.

Table 2: AV crossing changes between the groups.  

Comparison of Vessel tortuosity between cases and controls

12 (13.3%) cases and 7 (7.8%) controls were found to have vessel tortuosity (Table 3) and this association was not statistically significant.

Table 3: Vessel tortuosity data. 

Comparison of sheathing of vessels

From the table 4 it can be observed that, none of the cases and 4(4.4) controls were found to have sheathing of arteriole/ venule and this association was not significant.

Table 4: Sheathing of vessels among the groups.  

Comparison of occlusion of vessels

From the table 5 it can be observed that, 6 (6.7%) cases and 4 (4.4%) controls were found to have occlusion of arteriole/venule. P value for the association is 0.515 and the association is not significant.

Table 5: Data on occlusion of arterioles and venules.  

Comparison of microaneurysm between cases and controls

From the table 6 it can be seen that, 2 (2.2%) cases and 13 (14.4%) controls were found to have microaneurysm. This association was found to be statistically significant.

Table 6: Comparison of microaneurysms between the groups.  

Comparison of optic disc edema between cases and controls

From the table 7 it can be concluded that, 12 (13.3%) cases and 3 (3.3%) controls were found to have optic disc edema. This association was found to be statistically significant.

Table 7: Optic disc edema between cases and controls.  

Discussion

Presently, the pathogenesis of cerebral small vessel disease (CSVD) in humans is not completely understood, in part due to the difficulty in imaging in vivo the cerebral microvasculature. There is strong evidence that retinal vascular features are associated with stroke, CSVD and stroke subtype [12-15]. Retinal vascular features are also associated with presence and progression of features of SVD [16, 17].

This case control study was carried out with an aim to study the retinal vasculature by fundus examination in persons identified to have cerebral small vessel disease on MRI brain and attempt has been made to correlate the retinal vascular changes with cerebral small vessel disease.

Retinal arteriolar narrowing is a recognized consequence of chronic hypertension and independently predicts cardiovascular morbidity and mortality. Recent studies in adult populations have shown that retinal arteriolar narrowing is strongly associated with past, current, and future blood pressure levels [18-22] and independently predicts incident stroke, coronary heart disease, and cardiovascular mortality [22].

In the present study we found that 57 (63.3%) cases and 37 (41.1%) controls were found to have arteriolar narrowing. In this study 43 (47.8%) cases and 17 (18.9%) controls were found to have AV crossing changes. In the study of Kwa et al, 154 (86%) patients, were found a retinal arterial abnormality, most frequently narrowing (81%), sclerosis (45%), and crossings (44%). Buckling stimulates wall remodeling and the interaction between artery dynamics, buckling and wall remodeling leads to further development of vessel tortuosity [23].

Vessel tortuosity may be caused by multiple factors: genetic factors, degenerative vascular diseases and an alteration in blood flow and pressure. Cerebral CSVD is characterized by thickening of the walls and elongation and tortuosity of the small perforating arteries in the brain, resulting in lacunar infarcts and cerebral WML [24-26]. In the present study, 12 (13.3%) cases and 7 (7.8%) controls were found to have vessel tortuosity.

In a cross sectional study of 179 patients with known cerebrovascular, cardiovascular or peripheral arterial disease, 108 (60%) had cerebral small vessel disease as assessed by white matter changes on MRI and 154 (86%) had retinal artery abnormalities with one or more of focal arteriolar narrowing, altered AV crossings, arteriolar sclerosis, or vessel tortuosity on retinal photographs as evaluated by expert clinicians [27]. Retinal vessel abnormalities were more frequent in those with MRI changes (92%) than those without (77%), Similar observations were made in a substudy of the atherosclerosis risk in communities (ARIC) cohort study [28]. CSVD in diabetic retinopathy is also studied and found that patients with diabetic retinopathy are more likely to have changes of small vessel disease in brain imaging [29].

Limitations of the study: The study was conducted in a tertiary referral centre which may not reflect the general population. This is a single centre study with limited number of patients, multicentric study with a greater number of patients would have given more robust data.

Conclusion

The study found significant retinal vascular changes in CSVD. Differences between participants with CSVD and healthy controls were pronounced. Cases with CSVD had a statistically significant association with arteriolar narrowing, AV crossing changes and optic disc edema when compared to controls. These associations persist after accounting for confounding variables known to be disease causing in both circulations. It is not known whether the relationships identified reflect other confounding variables such as an individual’s susceptibility to vascular disease. Future research is needed to deepen our understanding of these associations on a pathophysiological level and to identify interventions beyond traditional vascular risk factor modification, that, when prompted by identification of retinal vascular disease, may reduce cerebral vascular morbidity and mortality.

Conflicts of interest

Authors declare no conflicts of interest.