Cerebral small vessel disease

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Gregory Young
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1 Cerebral small vessel disease What is it? What are the clinical syndromes? How do we diagnose it? What is the pathophysiology? New insights from genetics? Possible therapies?

the most common forms distal arterioles of perforating deep vessels Recognised by imaging

2 Small Vessel disease Changes in the small perforating arteries, arterioles and venules Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms distal arterioles of perforating deep vessels Recognised by imaging appearances, best seen with MRI Clinically important as associated with increased risk of stroke,dementia and death

3 Clinical Presentations Asymptomatic white matter disease found on MRI imaging Presenting with cognitive impairment in the memory service Presenting with falls/gait disturbance Presenting with a lacunar stroke syndrome. Cerebrovasc Dis. 2011;32(6): Epub 2011 Dec : A Decade of the LADIS (Leukoaraiosis And DISability) Study: What Have We Learned about White Matter Changes and Small-Vessel Disease? The LADIS Study Group, Poggesi A, Pantoni L, Inzitari D, Fazekas F, Ferro J, O'Brien J, Hennerici M, Scheltens P, Erkinjuntti T, Visser M, Langhorne P, Chabriat H, Waldemar G, Wallin A, Wahlund A.

4 Small vessel disease prognostic marker Triples risk of stroke, doubles risk of dementia and increases risk of death

5 Radiological markers of small vessel disease main difference between symptomatic and silent cerebral infarcts are their size and location STRIVE-Standards for Reporting and Imaging of small Vessel disease STRIVE, STandards for Reporting and Imaging of Small Vessel Disease

Cerebral Microbleeds CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2 * -weighted gradientecho (GRE) or susceptibility-weighted sequences.

6 Cerebral Microbleeds CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2 * -weighted gradientecho (GRE) or susceptibility-weighted sequences. They are most often located in the cortico-subcortical junction, deep grey or white matter in the cerebral hemispheres, brainstem and cerebellum Cerebral microbleeds, potential imaging markers of bleeding-prone small vessel arteriopathies, in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA, ischemic stroke, and intracerebral hemorrhage. However, these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke

7 Lacunar stroke OCSP LACI- pure motor deficit/ pure sensory/sensorimotor or ataxic hemiparesis Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent small infarct <1.5 (or some say 2) cm diameter in the white matter, basal ganglia, pons or brainstem, and is consistent with a lacunar clinical syndrome derived from French for a small fluid-filled cavity that was thought to mark the healed stage of a small deep brain infarct. Oxfordshire Community Stroke Project (OCSP) classification, which uses only clinical features to diagnose the stroke subtype, can predict correctly the size and location of a recent brain infarct on imaging in 75 80% of patients with stroke, however, up to 20% of acute lacunar infarcts can present with cortical symptoms, and conversely cortical infarcts can present with lacunar syndromes

8 Possible mechanisms of lacunar infarction

9 Pathophysiology-insights from the Spontaneously hypertensive stroke prone rat model early endothelial damage in small vessels leads to a compromised blood brain barrier Leakage of plasma into tissue surrounding blood vessels Activation of inflammation, microthrombosis Local vessel occlusion and hypoperfusion Local vessel occlusion and rupture causing microbleeds

10 Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells. J.M. Wardlaw et al. Stroke. 2003;34:

Genetic causes of hereditary small vessel disease Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter

11 Genetic causes of hereditary small vessel disease Cerebral small vessel disease is considered hereditary in about 5% of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI. Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified. CADASIL, CARASIL, collagen type IV mutations (including PADMAL), retinal vasculopathy with cerebral leukodystrophy, Fabry disease, hereditary cerebral hemorrhage with amyloidosis, and forkhead box C1 mutations These monogenic disorders are often characterized by early-age stroke, but also by migraine, mood disturbances, vascular dementia and often gait disturbances. Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys. Many present with clinically recognizable syndromes.

13 Possible therapeutic interventions Blood brain barrier modulation both cgmp (dipyridamole) and camp (cilostazol, pentoxifylline) modulators can improve BBB integrity, at least in experimental studies Nitric oxide donors Aggressive versus standard BP lowering (PRESERVE Trial) Combination cilostazol and ISMN (LACI-2 trial) Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. International Journal of Stroke Volume 10, Issue 4, pages , 2 MAR 2015 DOI: /ijs.12466

14 Summary of clinical manifestations

15 What do we already know and what future study results awaited TARDIS-dual antiplatelets to be avoided as excess harm CROMIS PRESERVE BRIDGE RESTART SoSTART

16 The End Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol (2010) 9: /S (10) Hugh Markus-genetics Joanna Wardlaw-MRI imaging Philip Bath-therapeutics CROMIS-UCL Pof Werring RESTART and SoSTART-Edinburgh

Patient with vertigo, dizziness and depression

Clinical Case - Test Yourself Neuro/Head and Neck Radiology Patient with vertigo, dizziness and depression Michael Mantatzis, Paraskevi Argyropoulou, Panos Prassopoulos Radiology Department, Democritus