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Show STATE OF THE ART Small Vessel Vasculopathies Affecting the Central Nervous System Marie- Germaine Bousser, MD, and Valerie Biousse, MD Abstract: Small vessel diseases affecting the central nervous system are common causes of ischemic and hemorrhagic stroke. Diseases affecting the small vessels are due either to abnormalities in the content of the vessel or to abnormalities in the vessel wall. Causes include atherosclerosis, inflammatory vasculitides, and noninflammatory vasculopathies such as postpartum angiopathy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL), Susac syndrome, and Sneddon syndrome. ( JNeuro- Ophthalmol 2004; 24: 56- 61) Small vessel diseases of the brain are common causes of ischemic and hemorrhagic stroke and dementia. However, standard classifications of stroke do not usually take account of vessel size. For example, the widely used TOAST classification ( 1) categorizes ischemic stroke into five groups: ( 1) atherosclerotic; ( 2) cardio- embolic; ( 3) lacunar; ( 4) other determined etiology; and ( 5) undetermined etiology. This classification is based on stroke etiology, except for the lacunar group, which is defined by the nature of the cerebral lesion, a small deep infarct ( 2). Because most lacunes are thought to be caused by small vessel disease [ this has been widely debated ( 3)], there has been a confusing trend to consider lacunes and small vessel diseases as almost synonymous. Yet it is now well established that lacunes can also be caused by atherosclerosis of the large arteries ( through embolism or decreased perfusion) or even by cardiac emboli. These mechanisms should therefore both be excluded when evaluating a patient with small vessel disease. Diseases affecting the small vessels are caused by either abnormalities in the vessel content or by abnormalities Department of Neurology ( M- GB), Hopital Lariboisiere, Paris, France; and the Departments of Ophthalmology and Neurology ( VB), Emory University, Atlanta, Georgia. Address correspondence to Marie- Germaine Bousser, MD, Service de Neurologie Hopital Lariboisiere 10 Rue Ambroise Pare 75010 Paris, France; E- mail: Mg. bousser@ lrb. ap- hop- paris. fr Modified from an oral presentation delivered at the 28th Annual Meeting of the North American Neuro- Ophfhalmology Society, Copper Mountain, Colorado, February 9- A, 2002. in the vessel wall. Vessel content abnormalities encompass blood cell disorders such as polycythemia, thrombocythe-mia, hypereosinophilic syndrome, and coagulopathies such as antiphospholipid antibody syndrome and thrombotic thrombocytopenic purpura. Such disorders are easy to recognize with appropriate investigations. Small vessel diseases caused by vessel wall abnormalities are the topic of this article. There is little consensus regarding what constitutes a " small vessel." Capillaries and venules should be included. They are abnormal in such disorders as Behget disease, systemic lupus erythematosus, central nervous system ( CNS) angiitis, and cerebral venous thrombosis. Yet most authors apply the term " small vessel disease" to small arteries ( 4,5) ( 100- 400 urn diameter lumen, with internal elastic lamina and tunica media composed of three or four layers of smooth muscle cells) and arterioles (< 100 urn diameter lumen with continuous elastic lamina and tunica media composed of one or two layers of smooth muscle cells). Small arteries and arterioles arise directly from large parent arteries, such as the middle cerebral and basilar arteries, and penetrate deeply into the brain, where they supply the basal ganglia and deep white matter. They are " end arteries," in that they do not anastomose with other arteries; occlusion therefore readily leads to small deep infarcts or chronic hypoperfusion. It is clinically appropriate, if somewhat simplistic, to separate small vessel disease into acute and chronic types. ACUTE SMALL VESSEL DISEASES OF THE BRAIN These diseases are characterized by the acute or rapidly progressive onset of headache, focal neurologic deficits, seizures, altered cognition, and disorders of consciousness. There is thus no specific pattern of clinical presentation. Neuroimaging findings are also nonspecific. Multiple small infarcts in both gray and white matter are the most frequent findings, but hemorrhages, mass lesions, lepto-meningeal enhancement, and extensive white matter lesions may be seen. Cerebrospinal fluid may be normal or show an " aseptic meningitis" profile. Cerebral angiography may be normal or show segmental vasoconstriction ( Figs. 1 and 2). Acute small vessel diseases can be grouped into two 56 J Neuro- Ophthalmol, Vol. 24, No. 1, 2004 Central Nervous System Vasculopathies FIG. 1. Primary ( granulomatous) angiitis of the central nervous system. A: T2 magnetic resonance imaging shows multiple small hyperdensities consistent with small vessel infarcts. B: Cerebral angiography demonstrates areas of segmental constriction and dilation affecting numerous intracranial arteries, including the posterior cerebral and cerebellar arteries. Leptomeningeal biopsy confirmed the diagnosis of primary angiitis of the CNS. JNeuro- Ophthalmol, Vol. 24, No. 1, 2004 FIG. 2. Postpartum angiopathy. A: T2 magnetic resonance imaging shows hyperdensity { arrow) consistent with small vessel infarct. B: Cerebral angiography demonstrates areas of segmental constriction and dilation ( arrows) affecting numerous intracranial arteries, similar to primary angiitis of the central nervous system. The patient recovered spontaneously a few weeks later. 57 JNeuro- Ophthalmol, Vol. 24, No. 1, 2004 Bousser et al. main categories: inflammatory ( angiitis) and noninflammatory ( Tables 1 and 2). Angiitis of the Central Nervous System This heading includes primary ( granulomatous) angiitis of the CNS, systemic angiitis with CNS involvement, secondary angiitis due to infections ( viral, bacterial, fungal, rickettsial, mycoplasmal, and protozoal), connective tissue diseases, other systemic diseases ( other than vasculitides), and malignancies ( Fig. 1). These diseases all have severe TABLE 1. Classification ofvasculopathies Cerebral angiitis associated with systemic diseases Systemic vasculitides Connective tissue diseases Cerebral angiitis associated with infections Bacterial Bacterial meningitis Bacterial endocarditis Lyme disease Chlamydia pneumoniae Mycoplasma pneumoniae Tuberculosis Syphilis Cat scratch disease ( Bartonella henselae) Viral Herpes zoster and herpes simplex Cytomegalovirus HIV Parasitic Toxoplasmosis Cysticercosis Fungal Aspergillosis Coccidiomycosis Histoplasmosis Cryptococosis Mucormycosis Cerebral angiitis associated with neoplasm Carcinomatous meningitis Lymphoma Cerebral angiopathy associated with toxins Vasoconstrictors Amphetamines Cocaine Primary angiopathy Primary granulomatous angiitis Benign cerebral angiopathy Postpartum benign cerebral angiopathy TABLE 2. Conditions mimicking cerebral angiitis Noninflammatory vasculopathies Benign cerebral angiopathy Cholesterol emboli Susac syndrome Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL) Vasospasm ( subarchnoid hemorrhage, pheochromocytoma, malignant systemic hypertension, ergotism, amphetamines, nasal spray vasoconstrictors) Intracranial dissection Fibromuscular dysplasia Moya- Moya disease Sneddon syndrome Coagulopathies Antiphospholipid antibody syndrome Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Sickle cell disease Hyperviscosity syndrome Cardiac emboli Severe infections Meningococcemia Hemorrhagic fever Malaria Leptospirosis Neoplasia Central nervous system lymphoma Endovascular lymphoma Metabolic disease Fabry disease Cerebrotendinous xanthomatosis Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes ( MELAS) consequences, and need urgent diagnosis, sometimes based on brain biopsy ( as in primary CNS angiitis) and treatment, usually based on corticosteroids and other immunosuppressive agents. Noninflammatory Angiopathies of the Central Nervous System These diseases include poorly understood syndromes such as benign angiopathy of the CNS and postpartum cerebral angiopathy ( Fig. 2), both of which are characterized by spontaneously reversible ( within a few days to several months) vasoconstriction. They therefore need no aggressive treatment. Sneddon syndrome is characterized by multifocal ischemic strokes accompanied by cutaneous livedo 58 © 2004 Lippincott Williams & Wilkins Central Nervous System Vasculopathies JNeuro- Ophthalmol, Vol. 24, No. 1, 2004 reticularis. Susac syndrome consists of small- vessel occlusion in the retina, cochlea, and brain, predominantly affecting young women. Angiopathies caused by recreational or medicinal agents such as vasoconstrictors, cocaine, or external radiation therapy make up another group of noninflammatory angiopathies of the CNS ( Fig. 3). Finally, hypertensive encephalopathy is an acute small vessel disease characterized clinically by headaches, visual disturbances, and seizures, radiologically by widespread white matter edema with diffuse hyperintense signal on MRI- T2 images, and histologically by fibrinoid necrosis. This syndrome is reversible, provided that blood pressure is promptly lowered. CHRONIC SMALL VESSEL DISEASES OF THE BRAIN More common than acute small vessel diseases, clinical presentation of these diseases includes ischemic strokes ( usually small deep infarcts), intracerebral hemorrhages, and dementia ( 6,7). Stepwise or gradual progression of neurologic deficits occurs over years, often leading to pseudobulbar palsy and subcortical dementia. Neuroimag-ing shows small deep infarcts sometimes accompanied by hemorrhages, and widespread white matter abnormalities ( leukoencephalopathy) attributed to chronic ischemia. Cerebrospinal fluid, duplex scanning, cerebral angiography, and cardiac investigations are usually normal. Four main varieties of chronic small vessel diseases have been identified: 1. Arteriolar sclerosis: this occurs invariably with aging but increases in severity with vascular risk factors, particularly hypertension and diabetes. It is characterized by a vessel wall thickening with various degrees of sclerosis, hyalinosis, lipid deposition ( hence the term lipohyalinosis coined by Fisher), microaneurysms and FIG. 3. Susac syndrome. A: T2 magnetic resonance imaging of a patient with cerebral, cochlear, and retinal angiopathy shows multiple small high signal regions affecting cerebral white matter and basal ganglia. B: Retinal fluorescein angiogram demonstrates multiple branch retinal artery occlusions ( left: OD, early phase; right: OS, late phase). K££ f^ , - = ^ ^ i SH mmrm . . - ; - » - . "'.'-• '• y: f^.' yyr~-\^~ gt-^^-<- 1_ p^ r" y ^ ;• N ^ c v^--- .' - ; ;- 59 JNeuro- Ophthalmol, Vol. 24, No. 1, 2004 Bousser et al. luminal narrowing ( 4,5). There may be a severe leukoen-cephalopathy called Binswanger disease when it occurs in patients with severe chronic systemic hypertension. 2. Cerebral amyloid angiopathy, also known as congo-philic angiopathy, characterized by amyloid infiltration of the media and adventitia of small cortical and lepto-meningeal vessels, usually in the absence of systemic amyloidosis ( 8). It can occur in numerous conditions such as Down syndrome, dementia pugilistica, and Alzheimer disease. The clinical presentation is mostly that of recurrent cortical hemorrhages, but small infarcts and leukoencephalopathy with dementia are frequent. Different varieties have been identified based on the accumulated protein ( beta- amyloid, Cystatin C, transthyretin, and gelsolin). The disease is mostly sporadic but familial forms are increasingly recognized and a number of mutations have been identified on chromosomes 1, 13, 20, and 21. 3. Mitochondrial encephalopathy with lactic acidosis and stroke- like episodes ( MELAS) ( 9): characterized by migraine headaches, seizures, and ischemic strokes, usually in the occipital lobes. It usually affects children or young adults. Pial arterioles and small cortical arteries contain markedly increased quantities of giant cortical mitochondria in the smooth muscle cells and endothelial cells. 4. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL): a small vessel disease of the brain characterized by lesions of smooth muscle cells ( Fig. 4). Its clinical manifestations begin during mid- adulthood and include recurrent ischemic subcortical events, attacks of migraine with aura, severe mood disorders, subcortical dementia, and on the MRI, widespread leukoencephalopathy. A specific treatment has yet to be found. Disabling dementia and focal neurologic symptoms usually develop 20 years after the onset of disease. CADASIL is most frequently a familial disorder with an autosomal dominant mode of transmission. Its gene, Notch 3, is located on chromosome 19. This gene, previously unknown in humans, is expressed in the smooth muscle cells of small vessels and encodes for a large transmembrane receptor ( 12). Twenty years ago, most patients with clinical and neuroimaging features of small vessel disease were thought to have arteriosclerosis ( or lipohyalinosis) of penetrating arteries, particularly in the presence of vascular risk factors. Recent identification of conditions such as amyloid angiopathy, MELAS, and CADASIL suggests that there are probably many other varieties of chronic small vessel diseases of yet undetermined nature. From a pathophysiologic FIG. 4. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ( CADASIL). A: T1 MRI shows typical small punctiform hypointensities within the thalamus and external capsules. B: T2 MRI of the same patient shows typical hyperintensities in the same regions. C: Electron microscopy of skin vessels reveals granular osmophilic material ( white stars) at the surface of smooth muscle cells of a symptomatic CADASIL patient. This material is also found within cerebral arterioles. point of view, all these disorders are characterized by major abnormalities of smooth muscle cells that probably play a crucial role in the pathogenesis. The identification of responsible genes for small vessel diseases of the CNS ( as in CADASIL) allows the creation of animal models that will help to understand the pathophysiology of the vessel wall disorder and perhaps lead to development of specific treatments. 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