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Microvascular diseases of the brain or cerebral small vessel disease (SVD) is the term commonly used to describe a syndrome of clinical, cognitive, neuroimaging and neuropathological findings thought to arise from disease affecting the perforating cerebral arterioles, capillaries and venules and the resulting brain damage in the cerebral white and deep grey matter. Misleadingly this term is used to describe ischemic consequences but these patients are liable to hemorrhage.
The exact pathogenesis of microvascular diseases of the brain is not known. But many mechanisms are suggested like arteriosclerosis, lipohyalinosis, endothelial dysfunction and failure of blood brain barrier to explain ischemic changes of microvascular diseases of the brain. Cerebral amyloid angiopathy and hypertension are the most common etiologies suggested to explain the hemorrhagic changes.
Leukoaraiosis is an ischaemic demyelination of the immediate periventricular white matter associated with astrogliosis, enlarged extracellular spaces and white matter microcavitations. It is secondary to chronic global reduction of brain perfusion. Leukoaraiosis, which appears as an area of hyperintense signal in the white matter on MR images, is an age-related neurodegenerative condition that when severe correlates with dementia. It is characterized histologically by demyelination, loss of glial cells and spongiosis.
Lacunar infarction may be defined as small subcortical infarcts (less than 15 mm in diameter) in the territory of the deep penetrating arteries and may present with specific lacunar syndromes or may be asymptomatic.It is secondary to lipohyalinosis or microatheroma of the origin of the pentrating artery. MRI is prefered in dignosis as it has more sensitivity to lacunes especially infratentorial lacunes, DWI help in rapid dignosis of new lacunes. They are most numerous in the periventricular gray matter (thalamus and basal ganglia) and the immediate periventricular white matter.
Granular atrophy is defined pathologically as infarctions localized to the cerebral cortex and not extending to the subcortical white matter. It is characterized by the presence of small punched out foci of cavitated cicatricial softening situated entirely in the cortex and accompanied by focal glial scar and thinning of the cortical ribbon. The lesions are bilateral and situated along the crest of the gyri. It is secondary to generalized hypoxia rather than local vascular abnormality. It is seen as a high signal lesion on T1-weighted MR images.
Pathologic dilatation of Virchow-Robin Spaces is most commonly associated with arteriolar abnormalities believed to result from moderate to severe microangiopathy. As the severity of the microangiopathy increases, microvessels demonstrate increasingly severe changes with arterial narrowing, microaneurysms and pseudoaneurysms, onion skinning, mural calcification, thrombotic and fibrotic luminal occlusions as arseult of mechanical trauma due to CSF pulsation or vascular ectasia, distinguished from lacunr infarctions by MRI as they are typically located in some areas (e.g., anterior commissure, vertex) that are different from those of lacunar infarcts and are usually smaller than 1×2 mm and have an isointense appearance with the CSF on proton density sequence.
Microbleeds are small punctate areas of hypointensity on T2* or susceptibility-weighted imaging that are up to 10 mm in diameter and correspond to small collections of haemosiderin laden macrophages around small perforating vessels. Microbleeds are associated with lacunar stroke and white matter hyperintensities and are clearly part of the range of small vessel disease. Many types of hemorrhage result from small vessel disease either lobar or subarachnoid hemorrhage. The most common cause are cerebral amyloid angiopathy and hypertension. CT still the best in diagnosis of cerebral hemorrhage due to its availability and rapid acquisition time however, several recent studies have now shown that GRE MRI sequences are as accurate as CT for the detection of intraparenchymal haemorrhage and far superior to CT for the detection of chronic haemorrhage. Pathoetiologic classification of small vessel disease includes 6 types. Type 1 arteiosclerosis characterised by loss of smooth muscle cells from the tunica media, deposits of fibrohyaline material, narrowing of the lumen, and thickening of the vessel wall this is thought to be secondary to hypertension. Type 2 sporadic and hereditary cerebral amyloid angiopathy characterized by deposition of amyloid protein in vessel wall when severe the vessels become dilated and disrupted with focal wall fragmentation and blood extravasation. Type 3 inherited or genetic small vessel diseases distinct from cerebral amyloid angiopathy like CADASIL. Type 4 Inflammatory and immunologically mediated small vessel diseases are a heterogeneous group of rare diseases characterised by the presence of inflammatory cells in the vessel walls (vasculitis) and are usually part of a systemic disease. Type 5 venous collagenosis characterized by increased thickness of the walls that results in narrowed lumen and, sometimes, occlusion. Type 6 other small vessel disease like post radiation angiopathy.
An abrupt increase in pressure brings about a rapid and reversible vasoconstriction of small resistance vessels due to their inherent myogenic tone. Prolonged elevations of pressure can cause a range of more lasting changes in the microcirculation, two of which remodeling of small arteries and arterioles and rarefaction of arterioles and capillaries. Howevere the role of hypertension in small vessel disease is conflicting.DM and insulin resistance acting via oxidative stress, inflammation and advanced glycation end products, can induce microvascular abnormality through functional and structural microvascular rarefaction. Although obesity through oxidative stress, chronic inflammation and elevation free fatty acids causes microvascular abnormality.
Cerebral amyloid angiopathy, although usually asymptomatic, is an important cause of primary lobar intracerebral hemorrhage limited to cortical and subcortical area of the brain in contrast to hypertensive haemorrhage that occures in deep structure like the the basal ganglia. A less common, but clinically important manifestation of cerebral amyloid angiopathy is transient neurologic symptoms distinguished from true TIAs include the smooth spread of the symptoms, the absence of hemodynamically significant stenosis in the relevant vascular supply and the presence of small hemorrhage in the corresponding region of cortex best shown in GRE-MRI.
CADASIL is autosomal dominant disease caused by mutations in the NOTCH3 gene on chromosome 19. CADASIL presnts by Ischemic episodes, cognitive deficits, migraine with aura or psychiatric disturbances. MRI signs of CADASIL Small circumscribed regions that are isointense to cerebrospinal fluid on T1- and T2-weighted images. CARASIL also known as Maeda Syndrome, is clinically similar to CADASIL but with earlier onset and several extraneurological symptoms like arthropathy and disc herniation.
The rheological changes associated with microvascular brain disease include increase in the whole blood viscosity and thrombotic tendency of the blood. In general a significant increase of blood, plasma and serum viscosity and a decrease of whole blood filterability significantly impair flow in the microcirculation and contribute to the development of the ischemic microvascular brain disease. The microvascular brain disease is the end result of a vicious circle that starts at one end of the circle with loss of the autoregulatory process and restarts at the other end of the circle by increase of the whole blood viscosity.
The antiphospholipid syndrome is a hypercoagulable state characterized by recurrent arterial or venous thromboembolism or pregnancy loss in association with antibodies directed against plasma proteins that may be bound to anionic phospholipids. For patients with cryptogenic ischemic stroke or TIA and positive antiphospholipid antibodies with a target INR of 2 to 3 by warfarin is reasonable. Inherited thrombophilias are hypercoagulable states that include a number of disorders like protein S and protein C defiency. These conditions are thought to be rare causes of ischemic stroke in adults but may be more important causes of ischemic stroke in children. Vascular cognitive impairment associated with small vessel disease has recently received particular attention because this type of cognitive impairment has homogeneous clinical and neuroimaging features and a progressive course. The clinical characteristics of vascular cognitive impairment associated with small vessel disease are gait, mood, behavioural and urinary disturbances. In the early phases, these disturbances can be mild and loosely associated. The final stage is one in which the patient fits the criteria for dementia. Clinical diagnostic criteria show moderate sensitivity (50–70%) and variable specificity (64–98%). Epidemiological studies are hampered by the lack of clear and validated diagnostic criteria, the complexity of brain pathologies, ethnic and geographic variations
Important pathogenic factors of vascular dementia include the volume of brain destruction, its location which is the most important suggesting the concept of strategic sites of infarcts (thalamus, frontobasal, limbic system) and the number of cerebrovascular lesions. Abnormalities in key neurotransmitter systems in particular in the basal forebrain cholinergic system related to diffuse white matter lesions causing widespread disconnection of cholinergic projections to the center which causes decreased cerebral blood flow and hypoperfusion as critical factors in the pathogenesis of vascular dementia. Other neurotransmitters are involved like vasopressin and histamine in the pathogenesis of vascular dementia.Many aspects related to vascular parkinsonism continue to be a source of confusion. Diagnostic criteria are not clearly defined and consequently, patients with widely varied clinical pictures may be diagnosed with parkinsonism. Doubt may be cast on the diagnosis of vascular parkinsonism in most cases and vascular genesis may be attributed to parkinsonism of different aetiology in some other cases. The following types of simultaneous occurrence first, gait disorders of the lower body parkinsonism type are caused mostly by changes in frontal lobes; such disorders may require a diagnosis of vascular origin when alternative causes are excluded. second, if the signs and symptoms are typical for Parkinson disease the coincidence of Parkinson disease and cerebrovascular diseases should be considered, third, if the symptoms of parkinsonism are neither typical for Parkinson disease nor for vascular parkinsonism and there are clinical and/or MR signs of cerebrovascular diseases the vascular parkinsonism should be regarded as possible; fourth, if the symptoms of parkinsonism and clinical and MR signs are typical for vascular parkinsonism, it should be regarded as probable, fifth, if a stroke affecting the contralateral basal ganglia is followed by the occurrence of hemiparkinsonism, the diagnosis of vascular parkinsonism is unambiguous.
The main goals in the initial phase of acute stroke management are to ensure medical stability, begin to uncover the pathophysiologic basis of the neurologic symptoms, and to determine whether patients with acute ischemic stroke are candidates to receive treatment with thrombolysis. Subgroup analysis of trial data suggest that the benefit with thrombolysis is sustained in patients with lacunar stroke. However, patients with lacunar syndromes should be selected for thrombolysis according to current guidelines in the same way as patients with other subtypes of ischemic stroke. Thrombolytic therapy is associated with a 6 percent risk of symptomatic brain hemorrhage but increase to 10 percent in presensce of radiological signs of small vessel disease.
Currently viable strategies of prevention of microvascular diseases of the brain include blood pressure reduction, statins, and antiplatelet therapy. treatment with either clopidogrel 75 mg daily as monotherapy, or aspirin-extended-release dipyridamole 25 mg/200 mg twice a day, rather than aspirin alone is recommended. Some experts still prefer aspirin as the first-line agent, noting that the alternative antiplatelet regimens have an apparent modest advantage in benefit that is potentially offset by a disadvantage in cost.
Statins help in prevention in primary and secondary stroke unlike other drugs used in treatment of dyslipdemia like fibrates. Statins is used even within normal lipid profile as In addition to their cholesterol lowering properties, statins also have a role in plaque stabilization, reducing inflammation, slowing carotid arterial disease progression improving myocardial infarction and left ventricular dysfunction Control of blood pressure is a main strategy in prevention of microvascular diseases of the brain and helps in prevention of microvascular rarefaction and arteriolar remodeling. Recommended drugs to use are acting by vasodilation like ACEI, ARBS and calcium agonist. Control of DM also is important in prevention of microvascular diseases of the brain. This is guided by HbA1c which should be around 7 percent but should individualized to avoid risk of hypoglycemia. Daily fluctuation of blood sugar level should be controlled to prevent release of free radicals and subsequent endothelial dysfunction. Control of vasculitis using steroids and immunosuppressant drugs is also helpful in prevention but side effects of these drugs should be avoided. Control of hyperhomocystinemia by using vitamin B complex in adequate dose is helpful in prevention of microvascular diseases of the brain.
Many trials are done in treatment of vascular dementia caused by microvascular diseases of the brain using memantine, donepzil, rivastagmine and nimodipine but all these trials produced modest results. Results of trial of antiparkinsonian drugs in treatment of vascular parkinsonism were also poor. So control of risk factors still the main strategy to prevent vascular dementia and vascular parkinsonism.