Retinal Vessel Leakage in Cerebral Small Vessel Disease

Retinal Vessel Leakage in Cerebral Small Vessel Disease: a Sub-study of the Mild Stroke Study 3

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cerebral Small Vessel Diseases; Vascular Dementia; Lacunar Stroke
• Intervention / Treatment: Diagnostic test: Fundus fluorescein angiography, with ultrawide field retinal imaging

Detailed Description

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).

• Study Type: Observational
• Enrollment (Estimated): 40

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Retinal vessel leakage by automated segmentation	The presence and severity of retinal vessel leakage will be measured for each eye in terms of change in pixel brightness over the duration of the angiogram.	within one angiogram
Retinal vessel leakage by manual grading	The presence and severity of retinal vessel leakage will be measured using an manual ordinal grading scale	within one angiogram

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline blood-brain barrier breakdown	BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium	Within one MRI scan
White matter hyperintensity (WMH) volume adjusted for brain volume	This is measured from the most recent structural MRI scan	Within one MRI scan
Change in white matter hyperintensity (WMH) volume adjusted for brain volume	This is measured by comparing the most recent structural MRI scan with the baseline structural MRI scan	Difference in MRI scans up to 5 years prior
Fazekas score	This is measured from the most recent structural MRI scan	Within one MRI scan
Change in Fazekas score	This is measured by comparing the most recent structural MRI scan with the baseline structural MRI scan	Difference in MRI scans up to 5 years prior
Baseline average leakage in white matter hyperintensities	BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium	Within one MRI scan
Baseline average leakage in deep grey matter	BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium	Within one MRI scan
Baseline number of leakage hotspots	BBB breakdown is measured by MRI in terms of image enhancement after intravenous gadolinium	Within one MRI scan

Collaborators and Investigators

• Sponsor: University of Edinburgh

Publications and helpful links

General Publications

• Clancy U, Garcia DJ, Stringer MS, Thrippleton MJ, Valdes-Hernandez MC, Wiseman S, Hamilton OK, Chappell FM, Brown R, Blair GW, Hewins W, Sleight E, Ballerini L, Bastin ME, Maniega SM, MacGillivray T, Hetherington K, Hamid C, Arteaga C, Morgan AG, Manning C, Backhouse E, Hamilton I, Job D, Marshall I, Doubal FN, Wardlaw JM. 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. Eur Stroke J. 2021 Mar;6(1):81-88. doi: 10.1177/2396987320929617. Epub 2020 Jun 5.
• MacCormick IJ, Maude RJ, Beare NA, Borooah S, Glover S, Parry D, Leach S, Molyneux ME, Dhillon B, Lewallen S, Harding SP. Grading fluorescein angiograms in malarial retinopathy. Malar J. 2015 Sep 24;14:367. doi: 10.1186/s12936-015-0897-7.

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: January 15, 2024
• First Submitted That Met QC Criteria: May 14, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Dementia; Infarction; Stroke; Brain Infarction; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Thrombotic Stroke; Ischemic Stroke; Dementia, Vascular; Cerebral Small Vessel Diseases; Stroke, Lacunar
• Other Study ID Numbers: AC24000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No