Frontiers in Cardiovascular Drug Discovery

Volume: 3

Cerebral Small Vessel Disease: A Clinical Review Focusing on Therapeutic Strategies

Author(s): Francisco José Álvarez-Pérez

Pp: 219-278 (60)

DOI: 10.2174/9781681081632116030006

* (Excluding Mailing and Handling)


The term cerebral small vessel disease (CSVD) or microangiopathy includes several pathological processes of different aetiologies which cause an increase of wall thickness (basically the basement membrane), a narrowing of the lumen, and a weakening of walls in arterioles, capillaries and venules. These vascular modifications cause a loss of proteins towards the interstice and a slowness of blood flow, increasing the risk of ischemia and tissue bleeding.

The CSVD may be aetiopathogenically classified in 6 types. The CSVD type 1, called arteriolosclerosis, is the most prevalent form and has a 6 to 10 times higher prevalence than stroke. It is related to aging and classical vascular risk factors, like arterial hypertension and diabetes mellitus. This review will focus on type 1 CSVD.

In the brain, the main pathological findings are loss of smooth muscle cells in the media, accumulation of fibrohyaline material, fibrinoid necrosis, and development of microatheromas and Charcot-Bouchard microaneurysms. The parenchymatous consequences of these vessel modifications are both ischemic (white matter lesions, lacunes) and haemorrhagic (microhaemorrhages, intracerebral haemorrhages). The clinical manifestations of arteriolosclerosis include cognitive deterioration, dementia, mood disorders, gait and motor disturbances, lacunar strokes, and disability. In vivo, the diagnosis of CSVD is supported by neuroimaging findings (lacunes, leukoaraiosis, white matter lesions, microhaemorrhages), especially by use of magnetic resonance techniques. The role of other biomarkers (plasma and cerebrospinal fluid biochemical parameters, resistance indexes in transcranial Doppler study) is not completely defined.

In patients with diagnosis of microangiopathy there are three main therapeutic considerations. First, there are specific risks in these patients during standard clinical management of acute ischemic stroke. Several studies showed an increased risk of intracranial bleeding related to thrombolytic therapy for acute stroke and anticoagulant treatment for secondary prevention. Indeed, the presence of leukoaraiosis raised the probability of peri-operative stroke or death in patients who underwent carotid endarterectomy. Second, the symptomatic management of patients with cognitive impairment related to CSVD, which is currently based on memantine and acetylcholinesterase inhibitors used in Alzheimer's disease. Third, the specific therapy directed to vessel pathology and parenchymatous consequences (secondary prevention). Available data support the use of antiaggregant drugs to reduce the risk of recurrence of lacunar strokes. Aspirin, ticlopidine, aspirin plus clopidogrel, dipiridamol plus aspirin, and cilostazol showed efficacy in this subtype of stroke. The optimal control of arterial pressure and cholesterol level also reduces the risk of stroke, independently if mechanism of disease was macro or microvascular. However, the specific drugs and the optimal goals are not defined and ongoing trials are trying to evaluate different drugs and preventive strategies (cilostazol plus aspirin, aggressive versus standard blood pressure control). Considering the specific treatment of vascular pathology, there are few available data. Experimental studies showed that relaxin may increase the arterial distensibility. In humans, one ongoing trial is investigating the efficacy and safety of an anti-amyloid beta monoclonal antibody in patients with probable cerebral amyloid angiopathy (CSVD type 2).

Keywords: Acetylcholinesterase Inhibitors, Antiaggregants, Cerebral Amyloid Angiopathy, Cerebral Microangiopathy, Cerebral Microhaemorrhages, Cerebral Small Vessel Disease, Deep Brain Infarcts, Deep Intracerebral Haemorrhages, Enlarged Perivascular Spaces, Lacunar Stroke, Memantine, Vascular Dementia, White Matter Lesions.

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