Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

INTRODUCTION — Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited angiopathy caused by pathogenic variants in the NOTCH3 gene on chromosome 19 [1]. CADASIL is now recognized as an important cause of stroke in the young [2,3].

Stroke and vascular cognitive impairment remain the main causes of morbidity and mortality in patients with CADASIL. Previous descriptions of families with "hereditary multi-infarct dementia," "chronic familial vascular encephalopathy," and "familial subcortical dementia" represent early reports of the same condition.

PATHOPHYSIOLOGY — CADASIL is caused by cysteine-altering pathogenic variants in the NOTCH3 gene, which lead to vasculopathic changes predominantly involving small penetrating arteries, arterioles, and brain capillaries [3]. The underlying vascular lesion is a specific nonatherosclerotic, amyloid-negative angiopathy involving small arteries (100 to 400 microns in diameter) and capillaries, primarily in the brain but also in other organs [4].

Genetics — The NOTCH3 gene on chromosome 19p13.2-p13.1 is one of four mammalian homologs of the Drosophila NOTCH gene [5]. NOTCH genes code for large transmembrane receptors involved in cell fate decisions during embryonic development [6]. The protein product Notch3 is critical for vascular smooth muscle cell (VSMC) differentiation and vascular development [7]. In adults, expression of NOTCH3 is largely restricted to VSMCs and capillary pericytes.

More than 200 different pathogenic variants in NOTCH3 have been reported in patients with CADASIL from all over the world [8,9]. All described pathogenic variants are located in the extracellular region of the Notch3 transmembrane receptor within epidermal growth factor (EGF)-like repeat domains. The spectrum includes missense variants, splice site variants, and small in-frame deletions [10,11].

Approximately 95 percent of patients have pathogenic missense variants. Some of these variants are particularly prevalent, but many families have private pathogenic variants. Pathogenic variants show a highly stereotyped nature since all involve cysteine residues. The usual number of six cysteine residues within wild type EGF-like repeat domains is changed toward an odd number.

There have been reports of atypical "mutations" not involving cysteine residues [12,13]. However, there is no experimental evidence to demonstrate the pathogenicity of these sequence variants, which may represent rare polymorphisms.

CADASIL pathogenic variants are strongly clustered at the N-terminus; approximately 60 percent are located in exon 4 and approximately 85 percent in exons 2 to 6, thereby enabling targeted screening strategies [10]. (See 'Genetic analysis' below.)

Molecular mechanisms — Like all Notch receptors, the Notch3 receptor is proteolytically processed in the trans-Golgi network as it traffics from the endoplasmic reticulum to the plasma membrane. Proteolytic cleavage results in a large extracellular fragment and a small intracellular fragment that contains the transmembrane region.

In CADASIL, the extracellular domain of the Notch3 receptor accumulates within blood vessels. Accumulation takes place at the cytoplasmic membrane of VSMCs and pericytes in close vicinity to the granular osmiophilic material (GOM) that characterize the disease [14]. Notch3 recruits other proteins into the extracellular deposits, among them vitronectin and tissue inhibitor of metalloproteinase-3 (TIMP3), which may be relevant for disease pathogenesis [15]. Evidence from transgenic mice suggests that Notch3 accumulation in cerebral pericytes leads to a significant reduction in pericyte number, a progressive loss of astrocytic end-foot process contact with capillaries, disruption of the blood-brain barrier, and functional impairment of microvessels [16].

Apart from its role in vessel development, the Notch3 receptor seems to be involved in vascular remodeling following injury [17,18]. An interesting observation potentially relating to the frequent occurrence of migraine with aura in CADASIL is that transgenic mice expressing a CADASIL-typical NOTCH3 pathogenic variant show an enhanced susceptibility to experimentally induced cortical spreading depression [19].

Vascular complications in the brain — The underlying vascular lesion is a specific nonatherosclerotic, amyloid-negative angiopathy involving small arteries (100 to 400 microns in diameter) and capillaries, primarily in the brain but also in other organs [4]. Although CADASIL is a generalized angiopathy, the vascular complications are largely limited to the brain. This discrepancy might, in part, be related to the predominant involvement of leptomeningeal and long penetrating arteries of the brain [20]. Morphometric studies have revealed a significant reduction of the internal diameter of small penetrating arteries and an increased thickness of the arteriolar wall in both the gray and white matter of the brain.

Another potential factor contributing to the preferential involvement of the brain is the specific anatomy of the blood-brain barrier [4,21]. Normally, brain endothelial cells are connected via tight junctions that typically prevent the bidirectional exchange of hydrophilic substances between the blood and the brain. Also, brain microvessels are covered by astrocytic end-feet, which contribute to integrity of the blood-brain barrier and relay energy demand from neurons to the vasculature. As mentioned above, experimental studies in CADASIL transgenic mice have shown profound alterations of cerebral microvessels, with detachment of astrocytic end-feet from microvessels, leakage of plasma proteins, and reduced microvascular reactivity [16].

Pathology — Most autopsy studies have been carried out in patients with advanced disease. Macroscopic examination of the brain reveals rarefaction of the subcortical white matter with periventricular preference [4]. Another consistent finding is lacunar infarcts predominantly within the basal ganglia, thalamus, and brainstem, particularly in the pons. (See "Lacunar infarcts".)

Histologically, various degrees of demyelination, axonal loss, enlargement of the extracellular space, and mild astrocytic gliosis are found; these findings are compatible with chronic ischemia [4]. In a neuropathologic study of four patients who died from complications of CADASIL, neuronal apoptosis was seen in layers 3 and 5 of the cerebral cortex [22].

Genotype-phenotype correlations — There are several reports on associations between specific NOTCH3 pathogenic variants and particular disease manifestations or accelerated disease progression [2,23-26]. While the association with specific disease manifestations is still disputed, there is reasonably strong evidence that pathogenic variants in the first six epidermal growth factor-like repeat domains (EGFRs 1 to 6) of the Notch3 protein are associated with an earlier age of stroke onset, a more severe clinical phenotype, increased white matter hyperintensity volume, and lower survival compared with pathogenic variants in EGFRs 7 to 34 [27-30]. Within the latter group, limited data based on small patient numbers suggest that variants in EGFRs 7 to 9 and EGFRs 18 to 34 are also associated with more severe disease [30]. Another report analyzed data from CADASIL and population cohorts and classified NOTCH3 EGFR domains into three risk categories (high, medium, and low) that predicted small vessel disease severity; high-risk EGFR domains included EGFRs 1 to 6 and also domains 8, 11, and 26 [31]. Further studies are needed to confirm these correlations.

EPIDEMIOLOGY — Although most studies come from Europe, CADASIL has been reported worldwide [32]. Based upon data from single referral centers and regional databases, the estimated prevalence of individuals harboring pathogenic variants in NOTCH3 from earlier studies was 0.8 to 5 per 100,000 individuals [33-36]. Subsequent reports suggest that the prevalence of NOTCH3 cysteine-altering pathogenic variants is substantially higher, and may be as high as 1 in 300 worldwide [27,37-39]. In one report, cysteine-altering NOTCH3 variants were associated with an increased risk of vascular dementia and stroke, and increased white matter hyperintensity volume, particularly involving the anterior temporal lobes [39]. Hence, the phenotypic spectrum of NOTCH3 cysteine-altering pathogenic variants is very broad and includes classic CADASIL, mild small vessel disease, and nonpenetrance [32,38-40].

Pathogenic variants in single genes, including those in NOTCH3, are thought to be rare cause of lacunar stroke [41].

CLINICAL FEATURES — Patients with CADASIL usually present with one or more of the following manifestations [3,42-44]:

●Migraine with aura

●Acute reversible encephalopathy

●Ischemic episodes

●Cognitive impairment and dementia

●Psychiatric disturbances

Onset — The onset of symptomatic disease in patients with CADASIL typically occurs in adulthood [3,45]. However, there are case reports of children and adolescents with genetically confirmed CADASIL [46-50]. One of the earliest onset cases of symptomatic CADASIL involved a three-year-old boy who presented with global developmental delay [47]. Brain MRI showed multiple foci of increased T2 signal on brain MRI and genetic sequencing identified a NOTCH3 pathogenic variant.

Migraine with aura — Migraine with aura occurs in nearly one-half of CADASIL cases and is often the initial manifestation of the disease [43,51,52]. In a minority, migraine with aura is the sole symptom of CADASIL [52]. The average age at onset of migraine with aura is approximately 30 years [53,54]. Aura symptoms tend to involve the visual and sensory system. However, one-half or more of patients have at least one atypical aura with manifestations such as motor symptoms (hemiplegic migraine), confusion, altered consciousness, hallucinations, or basilar symptoms (migraine with brainstem aura), acute onset aura, or long-lasting aura [52]. These may be difficult to differentiate from ischemic episodes [42,53].

Isolated migraine aura (ie, never accompanied by headache) affects approximately 20 percent of patients with CADASIL [52]. The frequency of migraine attacks seems to decrease after the first stroke [42]. At younger ages (≤50 years), migraine with aura in patients with CADASIL may be more prevalent in women than in men [55]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura' and "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine subtypes'.)

Acute reversible encephalopathy — Acute reversible encephalopathy (also known as CADASIL encephalopathy or "CADASIL coma") occurs in up to 10 percent of cases [44,56-58]. Manifestations may include altered consciousness, visual hallucinations, seizures, and focal neurologic deficits including unilateral weakness or sensory deficits, dysarthria, aphasia, neglect and inattention, apraxia, or visual agnosia.

In one report of 33 patients with 50 episodes of encephalopathy, the encephalopathic event was the first major symptom that led to the diagnosis of CADASIL in 94 percent; complete recovery occurred within one month in 74 percent and within three months in 96 percent of episodes [44]. A majority of affected patients had a history of migraine or migraine aura directly preceding the encephalopathy.

The underlying mechanisms are not fully understood. Some experts consider CADASIL encephalopathy to be a severe form of migraine, as the episodes often begin with a migraine headache accompanied by nausea, vomiting, seizures, fever, and/or hallucinations [59,60].

Ischemic stroke and transient ischemic attacks — Ischemic stroke and transient ischemic attacks are frequent manifestations of CADASIL, occurring in approximately 85 percent of symptomatic individuals [42,43]. In a large retrospective study, the age at onset for ischemic stroke ranged from 19 to 67 years, and the median age for ischemic stroke onset in men and women was 51 and 53 years, respectively [2]. At younger ages (≤50 years), ischemic stroke in patients with CADASIL may be more prevalent in men than in women [55]. In one prospective report of over 200 subjects with CADASIL who were followed for a mean of 3.4 years, incident lacunes developed in approximately 25 percent and were predicted by the number of prevalent lacunes and systolic blood pressure at baseline [61].

In many cases, ischemic episodes present as a classic lacunar syndrome (pure motor stroke, ataxic-hemiparesis, dysarthria-clumsy hand syndrome, pure sensory stroke, sensorimotor stroke), but other lacunar syndromes (brainstem or hemispheric) are also observed. Strokes are often recurrent, leading to motor and cognitive decline, and sometimes to severe disability with gait disturbance, urinary incontinence, and pseudobulbar palsy. (See "Lacunar infarcts".)

Cortical infarcts involving the territory of a large artery are atypical but occasionally have been reported [62], and a study that evaluated 13 patients from Korea with CADASIL found angiographic large artery stenosis in five (38 percent) [63]. However, these observations may be coincidental.

The presence of conventional stroke risk factors may exacerbate disease severity in CADASIL. In a study of 200 patients with CADASIL, the risk of stroke was significantly higher in those with hypertension (odds ratio [OR] 2.57, 95% CI 1.29-5.14) [58]. In addition, the risk of stroke increased with pack-years of smoking (OR 1.07, 95% CI 1.03-1.11).

Cognitive impairment and dementia — Cognitive deficits are the second most frequent feature of CADASIL. In a report of 176 patients with genetically confirmed CADASIL and a mean age of 51 years, vascular cognitive impairment was observed in approximately 50 percent [64]. Approximately 75 percent eventually develop dementia [2,42]. In different studies, history of stroke, lacunar lesion volume, lacune count, global brain atrophy on brain MRI (see 'Magnetic resonance imaging' below), and older age have been identified as predictors of cognitive impairment [64-66]. Another important aspect is lesion location, particularly involvement of frontal-subcortical circuits [67].

The cognitive syndrome in CADASIL is characterized by deficits in multiple domains [68]. Early impairment of executive function is followed by deterioration in other cognitive domains with aging [69,70]. In most cases, cognitive decline is slowly progressive with additional stepwise deterioration [71]. Neuropsychologic testing usually shows pronounced deficits in executive function, cognitive processing speed, and verbal fluency [72].

Neuropsychiatric symptoms — Mood disorders occur in approximately 25 to 30 percent of patients with CADASIL [42,43,73]. Many patients develop adjustment disorder or moderate depression, but major depression is also seen. Other manifestations include bipolar disorder, panic disorder, hallucinatory syndrome, and delusional episodes. Rarely, CADASIL presents with a picture of schizophrenia [74].

Apathy is another common problem in CADASIL [75], and appears to be more common in men than women with the disorder [55]. Apathy has been defined as a primary loss of motivation, characterized by diminished speech, motor activity, and emotional expression. This definition of apathy is similar to that of abulia, defined as a loss of the impulse, will, or motivation to think, speak, and act. Diminished motivation is the key concept in both apathy and abulia. Although apathy frequently occurs with depression, apathy can develop in the absence of depression.

In a prospective cohort study of 132 patients with CADASIL, apathy was present in 54 (41 percent), similar to the frequencies of depression, disturbed sleep, and irritability (46, 45, and 43 percent, respectively) [75].

Seizures — Seizures occur in 5 to 10 percent of patients with CADASIL [36,42,76,77]; seizures may accompany episodes of acute reversible encephalopathy [44]. (See 'Acute reversible encephalopathy' above.)

Other manifestations — Less common manifestations include the following:

●Spinal cord involvement or infarction has been noted in case reports [78-82].

●Intracerebral hemorrhage has been rarely described in patients with CADASIL [83-85]. However, an exception is a case series of 20 consecutive symptomatic patients with CADASIL from Korea [86]. Intracerebral hemorrhage was the presenting sign in two patients (10 percent), while high susceptibility brain MRI sequences (T2*-weighted images) detected seven intracerebral hemorrhages in five patients (25 percent). Hemorrhages were located in the basal ganglia, thalamus, cerebellum, and parietal lobe; their largest diameters ranged from 1.2 to 2.8 cm.

Complications with pregnancy — Affected women with CADASIL may develop complications during pregnancy, but data regarding pregnancy in women with CADASIL are limited and inconsistent. In a retrospective analysis, 12 of 25 mothers (48 percent) developed neurologic symptoms in 40 percent of their pregnancies [87]. Complications included transient ischemic episodes, migraine, and preeclampsia-like symptoms. In most cases, these complications were the initial disease manifestation. However, another retrospective report of 93 pregnancies involving 56 women with CADASIL reported that none had disease onset or ischemic events during pregnancy [88]. There were 16 miscarriages (17 percent), a rate that is within the range of miscarriage observed in the general population. The investigators concluded that CADASIL did not appear to be associated with an unfavorable outcome for the mother or the fetus.

EVALUATION

When to suspect the diagnosis — CADASIL is usually suspected when patients present with typical clinical signs (eg, TIA, small vessel stroke, migraine, cognitive impairment, psychiatric symptoms, seizures), particularly when there is a positive family history for stroke or dementia, or when there are typical findings on brain magnetic resonance imaging (MRI). However, the diagnosis is not excluded by the apparent lack of a family history [32].

Because the individual clinical features of CADASIL are nonspecific, patients may come to attention from stroke services, memory clinics, headache clinics, psychiatry services, or others. In many cases, suspicion for CADASIL is first raised by findings from brain MRI that is ordered for the evaluation of stroke, cognitive decline, or other indications. (See 'Clinical features' above and 'Neuroimaging' below.)

History and examination — In addition to a history of the presenting illness and past medical history, it is important to obtain a thorough family history focused on stroke, migraine, mood disorders, seizures, and dementia. A detailed neurologic examination includes an assessment for manifestations of CADASIL including cognitive impairment and focal neurologic deficits.

Neuroimaging — We obtain brain MRI for all patients with suspected CADASIL. Brain MRI is the most useful imaging method to demonstrate the radiologic features of CADASIL, including recent lacunar infarctions, chronic lacunes, and white matter hyperintensities. Head computed tomography (CT) may show lacunar infarctions and leukoaraiosis (reflecting white matter changes) but is less sensitive than MRI.

Magnetic resonance imaging — MRI of the brain (image 1) shows two major types of abnormalities [89,90]:

●Small, circumscribed regions that are isointense to cerebrospinal fluid (CSF) on T1- and T2-weighted images. Most of these lesions are consistent with lacunes in terms of their size, shape, and location.

●Less well demarcated T2 hyperintensities of variable size that may show different degrees of hypointensity on T1-weighted images but are clearly distinct from CSF.

The majority of these lesions are located in the subcortical white matter (image 2), but similar lesions may be seen in other brain regions, including the brainstem and subcortical gray matter [89,90]. While the brain lesions of CADASIL are characteristically bilateral, at least one atypical case of unilateral leukoencephalopathy (image 3) has been reported [91].

The onset of MRI-visible lesions and the rate of lesion progression are variable [43,92,93], but by age 35 years all carriers of NOTCH3 pathogenic variants have developed MRI lesions [43]. Small irregular T2 hyperintensities involving the periventricular and deep white matter are usually the first sign in younger individuals.

The following MRI signs may help to identify patients with CADASIL:

●Temporal lobe and external capsule hyperintensities – Anterior temporal lobe (temporal pole) white matter hyperintensities seen on T2-weighted sequences (image 4) are found in approximately 90 percent of patients with CADASIL, whereas such lesions are uncommon in sporadic small vessel disease [90,94]. External capsule and corpus callosum hyperintensities seen on T2-weighted sequences are also characteristic findings [94].

●Subcortical lacunar lesions – Subcortical lacunar lesions are linearly arranged groups of rounded circumscribed lesions that are just below the cortex at the gray-white matter junction with a signal intensity identical to CSF [95]. These lacunar lesions are very small and are best differentiated from surrounding white matter hyperintensity with fluid-attenuated inversion recovery (FLAIR) sequences [96].

●Cerebral microbleeds – Cerebral microbleeds (also known as microhemorrhages) have been reported in 31 to 69 percent of patients [23,97-99]. Microbleeds are small, 2 mm to 5 mm focal or multifocal areas of hemosiderin deposition and are the remnants of subclinical leaks of blood. They are best detected as small, rounded dark lesions on gradient echo or T2*-weighted MRI images that are sensitive to iron (image 1). Microbleeds are not specific for CADASIL since they are also found in patients with other types of small vessel disease.

In a multicenter cohort study that evaluated 147 patients with CADASIL, the presence of cerebral microbleeds was independently associated with increased blood pressure, glycated hemoglobin (A1C) levels, lacunar infarct volume, and the extent of white matter hyperintensities [98]. In addition, the number of cerebral microbleeds was independently associated with poor functional outcome. In a later study, cerebral microbleeds were detected in 36 percent of 369 patients with CADASIL and were independently associated with an increased risk of incident ischemic stroke [99].

These findings suggest that cerebral microbleeds are a marker for a subgroup of patients with CADASIL who have a more severe or advanced form of the disease [98,99].

●Brain atrophy – Brain atrophy as measured on MRI is another important feature of CADASIL. Brain atrophy may be due in part to secondary neurodegeneration of cortical regions caused by ischemic lesions in subcortical regions that disrupt connecting fibers [100]. In a prospective longitudinal cohort study of 76 patients with CADASIL, brain atrophy was significantly correlated with measures of disability and cognitive impairment both at baseline and follow-up [66]. Age and male sex were independent risk factors for brain atrophy at baseline, while age and systolic blood pressure predicted change (loss) in brain volume over time.

In contrast to the loss of overall brain volume, brain lesion volume on T2-weighted MRI did not correlate with changes in clinical measures over time [66,101].

Other imaging studies — Perfusion MRI, Doppler sonography, and nuclear medicine techniques may show reductions of cerebral blood flow, mean flow velocity, cerebral blood volume, and cerebral metabolism, but are less helpful in establishing the diagnosis [102-104]. Postmortem high-field MRI at 7 Tesla has revealed small intracortical infarcts in a patient with CADASIL [105]. Cortical involvement also has been reported in other patients with sporadic small vessel disease and may be clinically important.

Conventional angiography is not contributory and potentially harmful, as patients with CADASIL appear to have a high risk of developing angiographic complications [106].

Lumbar puncture — Lumbar puncture with cerebrospinal fluid analysis (CSF) is not required for the evaluation of CADASIL, but may be helpful when multiple sclerosis is a consideration in the differential diagnosis (see 'Differential diagnosis' below). In a report of 87 patients with CADASIL who had lumbar puncture with CSF examination, none had a pleocytosis, and oligoclonal bands were detected in only 1 percent [21]. A mildly elevated protein level was present in 29 percent; the mean protein level was 40 mg/dL (range 10.2 to 75 mg/dL).

By contrast, most patients with multiple sclerosis have CSF oligoclonal bands and a mild CSF pleocytosis. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)

DIAGNOSIS

Confirming the diagnosis — In order to firmly establish a diagnosis of CADASIL, one of the following is required:

●Documentation of a pathogenic variant in the NOTCH3 gene by genetic analysis

●Documentation of characteristic ultrastructural deposits within small blood vessels by skin biopsy if genetic analysis is not definitive

There have been efforts to define screening scales for CADASIL [107]. However, the utility of these scales remains to be confirmed in other populations.

Genetic analysis — Molecular genetic testing establishes the diagnosis of CADASIL by identifying a heterozygous pathogenic variant in NOTCH3 [32]. The approach may involve single-gene testing (sequence analysis of NOTCH3 and gene-targeted deletion/duplication analysis) or a multigene panel (where available) that includes NOTCH3 and other genes of interest associated with stroke risk.

Apart from establishing the diagnosis, identification of the pathogenic variant is critical for genetic counseling and testing of relatives at risk. (See 'Screening asymptomatic family members' below.)

Genetic testing does not detect all patients with CADASIL. In up to 4 percent of patients, sequencing of all exons encoding EGF-like domains fails to identify a pathogenic variant [10]. As a result, skin biopsy is indicated if genetic testing is negative (or unavailable) when there is a high index of clinical suspicion for the diagnosis of CADASIL.

Skin biopsy — The angiopathy in CADASIL is characterized by two main features, which are highly specific for this condition:

●Granular osmiophilic material (GOM) within the vascular basal lamina of arteries, arterioles, and precapillaries on electron microscopy [108-111]. The deposits are typically located at the surface of vascular smooth muscle cells.

●Deposition of the extracellular domain of the Notch3 receptor in the vascular media of arteries and arterioles [112].

These changes are present in all organs, enabling a firm diagnosis by biopsy. The sensitivity and specificity of skin biopsy with subsequent ultrastructural examination has not been formally addressed. According to the author's experience, the specificity of typical GOM deposits is 100 percent. The sensitivity is less than 100 percent and largely depends upon the quality of the sample and the number of available arterioles and arteries. We usually request investigation of three arteries or arterioles before claiming a biopsy "negative."

The diagnostic value of Notch3 immunostaining is less clear [112,113]. In one series, the sensitivity was less than 90 percent with incomplete specificity [113]. In addition, the respective antibody has not been approved for diagnostic purposes.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of CADASIL includes the following conditions:

●Acquired disorders:

•Sporadic small vessel disease with or without hypertension as the main risk factor

•Multiple sclerosis

•Primary angiitis of the central nervous system (PACNS)

●Inherited disorders:

•Fabry disease, caused by pathogenic variants in the GAL gene

•Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and other forms of familial symptomatic small vessel disease due to pathogenic variants in the HTRA1 gene

•Some forms of leukodystrophy

These disorders have clinical features that may overlap with CADASIL, including focal, multifocal, or global symptoms and signs of cerebral dysfunction, a clinical course that can be marked by variable intervals of deterioration, stabilization, or seeming improvement, and evidence of focal, multifocal, or coalescent white matter lesions on neuroimaging [114].

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 4), which are found in approximately 90 percent of patients with CADASIL and are uncommon in sporadic small vessel disease.

●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 [115]. 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 [116,117]. 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 patients with CADASIL [114]. European guidelines state that patients with CADASIL should not receive thrombolysis for acute small vessel ischemic stroke, which is the typical stroke type associated with CADASIL [118]. 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 mechanical thrombectomy without thrombolysis 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".)

Preventive measures — 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 [119]. 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. However, there are no data establishing that antiplatelet therapy is effective for preventing stroke related to CADASIL [114]. There are no data to support the use of oral anticoagulants, which may put patients at an unnecessarily high risk of developing complications [23,83,97]. (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. Intensive blood pressure control is indicated for all patients with CADASIL who have elevated systolic blood pressure [114]. 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 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 [3,120]. The treatment of dyslipidemia for secondary stroke prevention is reviewed elsewhere. (See "Overview of secondary prevention of ischemic stroke", section on 'Dyslipidemia'.)

●Perioperative management – Measures to maintain hemodynamic stability and avoid hypotension and cerebral ischemia during anesthesia and surgery are advised for patients with CADASIL [118]. An AHA practice statement recommends maintaining a mean arterial pressure of >60 mmHg (8 kPa) and an end-tidal carbon dioxide at approximately 40 mmHg (5.3 kPa) during surgery; avoidance of head-down positioning may help to maintain cerebral venous return [114,121].

●Avoidance of catheter angiography – Conventional catheter angiography has been associated with prolonged neurologic symptoms in patients with CADASIL and therefore is best avoided [106], with the exception of angiography performed for patients with acute ischemic stroke caused by a large vessel occlusion [114].

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 [114,122]. (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) [123]. 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 avoided by some experts in patients with CADASIL based upon the theoretical concern of increased stroke risk due to vasospasm. However, available evidence suggests that acute treatment with triptans is safe [59,114,118,124]. (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 [125,126]. Standard prophylactic regimens for migraine can also be used for patients with CADASIL, although limited data suggest that beta-blocker therapy is associated with unfavorable outcomes [114,124]. These are discussed separately. (See "Preventive treatment of episodic migraine in adults".)

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 [3,42,43,53]. 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 [42].

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 [119]. 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) [119]. 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

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) [119].

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 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.)