Laboratory Studies
Genetic Testing
Genetic testing is commercially available to detect mutations in NOTCH3. A small amount of venous blood is needed for the test (10 mL of whole blood in Lavender top tube, refrigerated). More than 90% of patients with CADASIL have mutations (mostly missense) in the NOTCH3 gene. [18] Also, approximately 90% of mutations could be detected within a few exons (exons 2-6). [19] Thus, genetic testing should initially be focused on these exons. Currently available genetic testing has a sensitivity approaching 100%.
Genetic testing for CADASIL is indicated when clinical findings (migraines with early-onset strokes and dementia) and radiographic (MRI) findings raise a high index of suspicion. Diffuse white matter disease in a young patient who suffers from migraines and who has a family history of early stroke raises the suspicion of CADASIL. Genetic testing for asymptomatic family members of CADASIL patients is available. However, the affected family member must be tested first to assess the sensitivity of the test.
A newly developed screening tool, the CADASIL scale, was designed to select patients with a high probability of being affected who should undergo genetic testing. While the scale needs validation, it is a good first step and highlights the prominent features of the disease. [20]
Imaging Studies
Magnetic resonance imaging (MRI)
Hyperintensities on T2-weighted imaging or FLAIR are seen in the periventricular and deep white matter. [21] These white matter hyperintensities on MRI can be visualized in those aged 21 years and older. [22] MRI lesion volume correlates with the level of disability associated with CADASIL. [23] A characteristic finding on the MRI in patients with CADASIL is the presence of isolated T2 hyperintensities involving the temporal poles (see image below), a feature that can differentiate the condition from chronic microvascular ischemia due to hypertension. This finding is associated with a sensitivity and specificity of 95% and 80% respectively. [24]
FLAIR MRI of the brain showing hyperintensities involving the temporal poles in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)
Another relatively conspicuous MRI feature is involvement of the external capsules (see image below), which has a sensitivity of 93% and a specificity of 45%. [25] In association with age, volume of lacunar lesions is a strong and independent MRI predictor of cognitive and motor disability in CADASIL. [26] MRI studies in patients with CADASIL have also shown an age-related increased risk of intracerebral microbleeds. [27]
FLAIR MRI of the brain showing hyperintensities involving bilateral external capsules in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)
Other Tests
Skin biopsy
Pathologic evaluation of skin biopsy (see Histologic Findings) in patients with CADASIL has a sensitivity of 45% and specificity of 100%. [25] Preliminary data demonstrate that immunostaining skin biopsy specimens for NOTCH3 protein is highly sensitive (96%) and specific (100%) for the diagnosis of CADASIL. [28]
Histologic Findings
Pathologically, CADASIL is characterized by degeneration and thickening of the arterial walls (especially cerebral vasculature) with deposition in the media of a nonatheromatous, nonamyloidotic substance that is characteristically periodic acid-Schiff (PAS) positive. Under the electron microscope (EM), this substance appears as a granular osmiophilic material (GOM), pathognomonic for the disease. [29] Skin biopsy typically shows ultrastructural alterations of skin vessels similar to those of brain arteries. [30] Recent reports indicate that these morphologic abnormalities may also involve the kidney. [31]
-
FLAIR MRI of the brain showing hyperintensities involving the temporal poles in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)
-
FLAIR MRI of the brain showing hyperintensities involving bilateral external capsules in a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). (Reprinted with permission from Mayo Clin Proc, Meschia, 2005.)
