The goal of this observational study is to learn about leakage from retinal vessels in cerebral small vessel disease. The main questions it aims to answer are:

• Does retinal vessel leakage occur in cerebral small vessel disease?
• If it does, is the severity of retinal vessel leakage similar to the severity of cerebral small vessel disease generally?

Participants will be tested using fluorescein angiography. This involves an intravenous injection of fluorescent dye, and is a very sensitive way to find leakage from retinal blood vessels.

Participants will have already had brain scans and other examinations and tests to measure the severity of their cerebral small vessel disease. Our new retinal images will complement the information from these previous tests.

Cerebral small vessel disease (SVD) is a common cause of stroke and dementia. The molecular causes are unclear, limiting new therapies. Breakdown of the blood-brain barrier (BBB) is characteristic and may damage brain tissue. However, specialist MRI scans to measure BBB breakdown are expensive and time-consuming.

In contrast, measuring leakage from retinal blood vessels is relatively simple. The blood-retina barrier is very similar to the BBB, and SVD is likely to damage retinal and brain blood vessels in the same way. If so, then retinal angiography could be used to study SVD pathogenesis and measure the effect of new treatments with much greater resolution and lower cost than MRI.

We have three aims:

1. Test the feasibility of fluorescein angiography in people with SVD
2. Discover if retinal vessel leakage occurs people with SVD
3. Discover whether the severity of retinal vessel leakage is associated with clinical features of SVD

We will recruit participants from a well-established cohort of people with SVD - the Mild Stroke Study 3 (MSS3).

Inclusion Criteria:

• Membership in the Mild Stroke Study 3 cohort
• Contrast enhanced MRI within 12 months
• Clear optical media in both eyes, as assessed by study investigator
• Best corrected visual acuity (near vision) ≥N36

Exclusion Criteria:

• Any condition known to cause retinal leakage (i.e., worse than background diabetic retinopathy, retinal vein occlusion, active uveitis, wet age-related macular degeneration, malignant hypertension)
• Previous treatment for retinal leakage (retinal laser, intravitreal anti-VEGF)
• Recent eye surgery
• Shallow anterior chambers as assessed by torch test
• Pregnancy, renal failure
• Severe dementia
• Known allergy to fluorescein
• History of allergy such as food or drug induced urticaria or history of bronchial asthma
• Any other severe or acute medical or psychiatric conditions
• Inability to give informed consent

Adults >18 years old with mild ischaemic stroke with a modified Rankin scale (mRS) greater or equal to 2 at recruitment presenting to Edinburgh/Lothian stroke services.

For details see Clancy, et al (2021) Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3. European Stroke Journal 6:81-88. https://doi.org/10.1177/2396987320929617