variable intervals of deterioration, stabilization, or seeming improvement, and evidence of focal, multifocal, or coalescent white matter lesions on neuroimaging. Unlike CADASIL, the acquired disorders are not characterized by a family history of stroke or dementia. Other clinical features may also help to distinguish them from CADASIL: Clues that point to multiple sclerosis rather than CADASIL include the presence of optic nerve or spinal cord involvement (usually spared in CADASIL) and the pattern of lesions on magnetic resonance imaging (MRI), which are hyperintense on proton density and T2- weighted studies and hypointense if visible at all on T1-weighted images, typically occur in the periventricular region with an ovoid appearance, are arranged at right angles to the corpus callosum (Dawson fingers), and spare the temporal pole white matter (often involved in CADASIL). Another indication suggestive of multiple sclerosis is the detection of oligoclonal bands in the cerebrospinal fluid. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis".) Features suggestive of sporadic forms of small vessel ischemic and lacunar infarction (see "Lacunar infarcts") include the presence of hypertension (the main risk factor for sporadic small vessel disease) and the absence of anterior temporal lobe white matter hyperintensities on T2-weighted MRI sequences ( image 3), which are found in approximately 90 percent of patients with CADASIL and are uncommon in sporadic small vessel disease. https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 12/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate PACNS may cause ischemia and infarction in any part of the central nervous system, often manifesting as multifocal infarcts in different vascular territories (see "Primary angiitis of the central nervous system in adults"). By contrast, the ischemic lesions in CADASIL are typically restricted to the white matter. In most cases, the clinical features and mode of inheritance help to distinguish other inherited disorders in the differential diagnosis from CADASIL: Fabry disease is an X-linked glycolipid storage disorder associated with an increased risk of ischemic stroke and white matter disease, particularly in affected adult males. Other characteristic features include a peripheral neuropathy with severe paroxysmal pain the hands and feet, telangiectasias and angiokeratomas, renal insufficiency, and cardiovascular manifestations such as left ventricular hypertrophy. (See "Fabry disease: Clinical features and diagnosis" and "Fabry disease: Neurologic manifestations" and "Fabry disease: Cardiovascular disease".) CARASIL is a rare disorder suggested by autosomal recessive inheritance, early onset of white matter and external capsule lesions on neuroimaging, and other associated features including alopecia and spondylosis with disk degeneration, osteophyte formation, and episodes of acute low back pain [113]. The diagnosis is made by the detection of causative pathogenic variants in the HTRA1 gene. Heterozygous pathogenic variants in the HTRA1 gene are now recognized as an important cause of familial small vessel disease [114,115]. The clinical and MRI phenotype as well as age of onset very much resemble sporadic small vessel disease. MANAGEMENT There is no specific disease-modifying treatment for CADASIL, and only limited information is available regarding management of the major manifestations of the disorder. Ischemic manifestations Acute stroke and TIA Acute transient ischemic attack and acute stroke in patients with CADASIL are managed following the general principles of stroke medicine. There is no evidence to suggest that systemic intravenous thrombolysis improves outcome after a stroke caused by small vessel occlusion in CADASIL patients. However, if a patient with known or suspected CADASIL has an acute ischemic stroke in the territory of a thromboembolic large vessel occlusion, it is likely unrelated to CADASIL, and the benefit of https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 13/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate thrombolysis and/or mechanical thrombectomy probably outweighs the potential risk of intracerebral hemorrhage. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Initial assessment and management of acute stroke".) Secondary prevention For secondary stroke prevention, patients with CADASIL should be treated with all available risk reduction strategies, including control of hypertension, statin therapy for hyperlipidemia, glucose control, and antiplatelet therapy, although specific evidence that these measures are effective for CADASIL is lacking. Smoking cessation may be particularly important, since there is evidence that active smoking increases the risk of stroke and dementia in patients with CADASIL [116]. Lifestyle modifications that may reduce risk include limited alcohol consumption, weight control, regular aerobic physical activity, and a Mediterranean diet that is rich in fruits, vegetables, and low-fat dairy products. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) Antithrombotic therapy Long-term management includes low-dose aspirin (81 mg daily) in patients who have experienced an ischemic attack and who tolerate the drug. There are no data to support the use of oral anticoagulants, which may put patients at an unnecessarily high risk of developing complications [23,82,96]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Antihypertensive therapy Although there are no studies of blood pressure control in CADASIL, hypertension may be a risk factor for ischemic stroke, progression of brain atrophy, and the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, treatment of hypertension may have an additional benefit in patients with CADASIL. We suggest measures to control blood pressure for all patients with CADASIL who have elevated systolic blood pressure. Treatment of hypertension for secondary stroke prevention is discussed separately. (See "Antihypertensive therapy for secondary stroke prevention".) Glucose control Similarly, although there is no evidence that strict glucose control can slow CADASIL progression, elevated glycated hemoglobin (A1C) levels may be a risk factor for the presence of cerebral microbleeds (see 'Magnetic resonance imaging' above). Thus, glucose control may also have an additional benefit in patients with CADASIL, and we suggest measures to normalize glycemia and A1C levels in patients with elevated A1C levels. The target A1C value should be 7.0 percent or lower for most patients. The goal should be set somewhat higher for older patients and those with a limited life expectancy in whom the risk of hypoglycemia may outweigh the potential https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 14/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate benefit. (See "Glycemic control and vascular complications in type 1 diabetes mellitus" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".) Statin therapy In patients with elevated lipids, the use of statin therapy is suggested because of the beneficial effects for patients with atherosclerotic arterial disease, and because of experimental evidence suggesting they have neuroprotective effects [3,117]. The treatment of dyslipidemia for secondary stroke prevention is reviewed elsewhere. (See "Overview of secondary prevention of ischemic stroke", section on 'Dyslipidemia'.) Symptomatic therapy The specific management of CADASIL focuses on the control of symptoms such as headache, depression, and urinary incontinence. (See "Unipolar major depression in adults: Choosing initial treatment" and "Female urinary incontinence: Treatment" and "Unipolar depression in adults: Choosing treatment for resistant depression".) Cognitive impairment and dementia We offer donepezil to patients with prominent deficits in executive dysfunction and slowed processing speed [118]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and "Treatment of vascular cognitive impairment and dementia".) Pseudobulbar palsy Pseudobulbar palsy is caused by bilateral corticobulbar tract degeneration from lacunar infarcts and rarefaction of the subcortical white matter. Emotional lability (pseudobulbar affect) with pathologic crying and laughing may respond to selective serotonin reuptake inhibitors (eg, a single evening dose of 100 mg fluvoxamine) [119]. When oral hydration and feeding become insufficient, the patient should receive additional tube feeding. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management".) Migraine Migraine attacks can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Triptans are relatively contraindicated in patients with CADASIL based upon the theoretical concern of increased stroke risk due to vasospasm. (See "Acute treatment of migraine in adults".) Since the attack frequency of migraine with aura is low in most patients with CADASIL, few require prophylactic treatment [3]. For those who do, anecdotal evidence suggests that acetazolamide (250 mg per day) may be beneficial [120,121]. Standard prophylactic regimens for migraine can also be used. These are discussed separately. (See "Preventive treatment of episodic migraine in adults".) https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 15/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate CLINICAL COURSE AND PROGNOSIS Clinical progression in CADASIL tends to occur with the sequential development of migraine with aura around age 30 years, transient ischemic attacks, ischemic strokes and mood disorders between 40 and 60 years, dementia between 50 and 60 years, and gait difficulty at approximately 60 years [3,41,42,52]. However, the overall course of CADASIL is highly variable even within affected families. Some patients remain asymptomatic until their seventies [2]. Onset of symptomatic disease in childhood has been reported. (See 'Onset' above.) Early onset does not necessarily predict rapid progression. In a review of 102 patients from 29 families, the duration from onset to death varied from 3 to 43 years, with a mean of 23 years [41]. While individual progression varies, a substantial proportion of adults with CADASIL experience clinical deterioration over a period of three years. This observation emerged from a prospective study of 290 adults (mean age approximately 51 years) with CADASIL who were recruited from two major referral centers in Europe [116]. The major clinical manifestations of the cohort at baseline were the following: Asymptomatic, 4 percent Transient ischemic attack or stroke, 66 percent Migraine with aura, 39 percent Gait disturbance, 30 percent Moderate or severe disability, 18 percent Dementia, 14 percent Mean number of lacunes, 5 At three-year follow-up, with complete information available for 265 patients, the composite outcome of incident stroke, incident dementia, moderate or severe disability, or death occurred in 124 (47 percent) [116]. The proportion affected by individual end points was as follows: New stroke, 20 percent; of these, most (approximately 80 percent) strokes occurred in patients with a history of stroke Development of dementia in subjects without dementia at baseline, 21 percent Progression to moderate or severe disability in subjects with no or mild disability at baseline, 9 percent Death, 5 percent https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 16/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate Baseline factors independently associated with the composite endpoint in different multivariable models included gait disturbance, active smoking, a history of stroke, and more than three lacunar strokes or presence of brain atrophy on magnetic resonance imaging (MRI) [116]. In a retrospective analysis of 411 patients with CADASIL, the median age at death was 65 years in men and 71 years in women [2]. SCREENING ASYMPTOMATIC FAMILY MEMBERS Asymptomatic family members should receive genetic counseling prior to any procedures, such as brain magnetic resonance imaging (MRI), which might detect subclinical signs of CADASIL. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.) Predictive genetic testing should be carried out according to published guidelines dealing with ethical, legal, and psychosocial issues in other late-onset neurologic conditions for which no disease-modifying treatment is available. Asymptomatic children should not be tested, while adults at risk should be referred to a genetic counselor for an educational meeting. Pre- and post-test counseling should be performed irrespective of the result of the test. (See "Genetic testing".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by pathogenic variants in the NOTCH3 gene. The underlying vascular lesion in CADASIL is a nonatherosclerotic angiopathy involving small arteries and capillaries, primarily in the brain, characterized by the presence of electron-dense granular osmiophilic material (GOM) within the arterial media surrounding the smooth muscle cells. (See 'Pathophysiology' above.) The major clinical manifestations of CADASIL are transient ischemic attack and ischemic stroke predominately involving small vessels, cognitive deficits with early executive dysfunction, migraine with aura, and neuropsychiatric disturbances. Stroke and vascular https://www.uptodate.com/contents/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy-cadasil/print 17/32 7/5/23, 12:35 PM Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) - UpToDate cognitive impairment are the main causes of morbidity and mortality. (See 'Clinical features' above.) Brain magnetic resonance imaging (MRI) ( image 1) shows lacunar infarcts and less well demarcated T2 hyperintensities primarily located in the subcortical white matter, but also in the brainstem and subcortical gray matter. White matter T2 hyperintensities in the anterior temporal lobe and external capsule are additional features suggestive of CADASIL. (See 'Magnetic resonance imaging' above.) The diagnosis of CADASIL is suspected based upon a combination of suggestive clinical and neuroimaging features, particularly when there is a positive family history for stroke or dementia. The diagnosis of CADASIL is established by genetic analysis with documentation of a typical NOTCH3 pathogenic variant, or by skin biopsy showing granular osmiophilic material (GOM) within small blood vessels. Skin biopsy is indicated if genetic testing is negative. (See 'Evaluation' above.) There is no specific disease-modifying treatment for CADASIL. For patients with CADASIL who are symptomatic with ischemic stroke or transient ischemic attack, we suggest antiplatelet therapy (aspirin 81 mg daily) for secondary stroke prevention (Grade 2C). However, there are no data establishing that antiplatelet therapy is effective for preventing stroke related to CADASIL. (See 'Management' above and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Although specific evidence of benefit for patients with CADASIL is lacking, we employ all available risk reduction strategies for secondary stroke prevention, including low-dose aspirin (81 mg daily), control of hypertension, statin therapy for dyslipidemia, and strict control blood glucose. (See 'Ischemic manifestations' above.) The management of CADASIL otherwise focuses on the control of symptoms related to progressive dementia, migraine, depression, and urinary incontinence. (See 'Symptomatic therapy' above.) Clinical progression in CADASIL tends to occur with the sequential development of migraine with aura around age 30 years, transient ischemic attacks, ischemic strokes and mood disorders between 40 and 60 years, dementia between 50 and 60 years, and gait difficulty at approximately 60 years. However, the clinical course of CADASIL is highly variable even within affected families. (See 'Clinical course and prognosis' above.) 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