Dr. Marco Pasi and Prof. Charlotte Cordonnier
Dr. Marco Pasi and Prof. Charlotte Cordonnier

An interview with Dr. Marco Pasi, MD, Stroke Clinical Fellow at Université de Lille, CHU Lille, Inserm U1172, France, on his article “Clinical Relevance of Cerebral Small Vessel Diseases.” The article, co-authored by Prof. Charlotte Cordonnier, was published in the January 2020 issue of Stroke as part of a Focused Updates in Cerebrovascular Disease series of articles on topics related to cerebral small vessel diseases.

Interviewed by Dr. Parneet Grewal, MD, Vascular Neurology Fellow at Rush University Medical Center, Chicago, Illinois.

Dr. Grewal: First, I would like to thank Dr. Pasi and Pr. Cordonnier for agreeing to do this interview. This is an interesting paper which discusses in detail the main manifestations of cerebral small vessel disease (SVD) along with their impact. Can you please summarize the key findings of your paper and their application to clinical practice?

Dr. Pasi: Cerebral small vessel diseases (SVD) have gained increased interest in the last decades as they play a crucial role in a large variety of conditions, such as aging, stroke, cognitive impairment, and other age-related disabilities. The term SVDis used with various meanings according to the context, but from a neuropathological perspective, SVD describes a group of pathologies that affect the perforating arteries and arterioles located in the brain parenchyma or in the leptomeningeal vessels. Sporadic SVD is characterized by two main forms that mainly differ for their localization within the brain. The first one is arteriolosclerosis, also known as hypertensive-SVD, which has a predilection for the deep lenticulostriate arteries that are vulnerable to poorly controlled and long-standing hypertension or diabetes. The second most common form is cerebral amyloid angiopathy that is a pathological process characterized by the progressive accumulation of ß-amyloid protein in the wall of small cortical and leptomeningeal arterioles and arteries. It is clinically relevant to distinguish these two forms of SVD because they differ in terms of hemorrhagic risk with important consequences when antithrombotic decisions need to be taken. In our review, we aimed to provide a comprehensive overview of the main clinical manifestations of SVD that could help stroke physicians in their daily practice.

Dr. Grewal: Can you explain why it is important for physicians to pay attention to manifestations of SVD?

Dr. Pasi: SVD can manifest with a widespread and heterogenous range of clinical manifestations that often lead to functional disability in the late stages of the disease. It can manifest abruptly and dramatically, like in intracerebral hemorrhage and lacunar stroke. Differently, an insidious clinical course may be associated with progressive cognitive decline, development of mood disorders and motor problems. Furthermore, with an increasing use of the MRI, as stroke physicians, we often encounter incidental findings of imaging markers of SVD. Accumulating evidence suggests that the presence of SVD imaging markers are associated with subtle neurological symptoms, and they confer an increased risk of stroke and cognitive impairment. Finally, the two main forms of SVD, arteriolosclerosis and cerebral amyloid angiopathy, are associated with both ischemic and hemorrhagic consequences. Hence, stroke specialists may face challenging clinical situations in balancing hemorrhagic and ischemic risk, especially when antithrombotic medication may be needed.

Dr. Grewal: Is there a genetic, racial or sex difference in SVD prevalence?

Dr. Pasi: Accumulating evidence suggests that SVD is not only related to the presence of vascular risk factors, but also that genetic factors influence its expression. For a detailed overview of the genetic factors related to SVD, I suggest reading the review written by Marini et al. that is published in this same issue of the Stroke journal. In some racial and ethnic categories,such as black, Hispanic and Asian populations, SVD might be more prevalent and aggressive. This aspect has important clinical implications, as in certain racial and ethnic groups,the presenceofSVD imaging markers and clinical manifestations needs to be carefully excluded and sometimes more aggressively treated. Right now, a clear sex difference in SVD prevalence has not been consistently reported, but this remains an aspect that has been understudied. More research is needed in the coming years.

Dr. Grewal: In your paper, you mention intracranial hemorrhage risk in patients with SVD. How do you manage patients with probable cerebral amyloid angiopathy who need to be on antithrombotic or anticoagulant agents in your practice?

Dr. Pasi: While recurrent ICH in cerebral amyloid angiopathy is one of the major fears of stroke specialists, the risk of intracranial, but also extracranial, ischemic events is frequent in ICH patients, also in CAA-related ones. Limited observational evidence suggests that restarting anticoagulation in ICH patients with atrial fibrillation is not associated with a higher rate of ICH recurrence and may even be related with better vital and functional outcome, even in patients with lobar ICH related to CAA. However, these are non-randomized, observational data. Several randomized controlled trials are ongoing (including one led in CHU Lille – A3ICH, NCT03243175) and will evaluate the possible impact of underlying SVD on the net clinical benefit of antithrombotic treatments. Therefore, in the absence of evidence-based data, my suggestion is to randomize in one of the several ongoing trials.

Dr. Grewal: Could you discuss in detail the impact of white matter hyperintensities seen on imaging?

Dr. Pasi: White matter burden is associated with more than a doubled risk of ischemic stroke and a 3-folds higher risk for intracerebral hemorrhage in elderly populations. Furthermore, it is associated with a significant risk of developing subsequent dementia in both the general population and a population at high risk of vascular events. These numbers are not reassuring and suggest that white matter hyperintensities are not an innocuous bystander.

The increased risk of both ischemic and hemorrhagic cerebral events in patients with white matter hyperintensities raises the questions of whether antithrombotic medications may be considered as a valid therapeutic option in primary stroke prevention. In the absence of a randomized controlled trial, guidelines on prevention of stroke in patients with silent cerebrovascular disease state that it is not clear whether WMH or silent brain infarcts are a sufficient reason for aspirin therapy in prevention of future ischemic stroke.

Dr. Grewal: In your opinion, what would be some of the future strategies to prevent SVD clinical manifestations?

Dr. Pasi: Until now the most valuable way to prevent the progression of SVD is a strict control of vascular risk factors. Because many vascular risk factors are modifiable, it is possible to slow SVD progression by their optimal control. Maintaining a low risk factor profile earlier in life showed promising results with a better cognition in midlife. However, future research effort and randomized control trials are warranted to evaluate interventions that may prevent or mitigate the wide spectrum of clinical symptoms related to SVD. 

Dr. Grewal: What advice do you have for investigators interested in further investigating the field of SVD?

Dr. Pasi: Always remember that SVD is not only a neuropathological or radiological construct, but it is also a key player in some of the most devastating clinical manifestations that we encounter as stroke physicians! It is an exciting research field in continuous expansion with certainly many new discoveries in the years to come!

Dr. Pasi would like to thank Prof. Charlotte Cordonnier for her assistance in the interview.