Clinical Guidance

Smaller studies have described genotype-phenotype correlations for specific pathogenic variants [, , , ]; however, none of these associations have been firmly established. In general, affected individuals with cysteine-altering pathogenic variants in epidermal growth-factor like repeat (EGFr) domains 1-6 of NOTCH3 have a 12-year earlier onset of stroke, lower survival, and increased white matter hyperintensity volume, consistent with the more severe classic CADASIL presentation, compared to those with a cysteine-altering pathogenic variant in EGFr domains 7-34. The mean survival time was 68.5 and 76.9 years, respectively . There is conflicting evidence about the effect of pathogenic variants in the ligand-binding domain of NOTCH3 (EGFr domains 10 and 11).

Source: GeneReviews — "CADASIL"

Penetrance

Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classic CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGFr domains 7-34 have a much higher population frequency (~1:300) and therefore likely predispose to a milder small-vessel disease and may even be non-penetrant.

Source: GeneReviews — "CADASIL"

Diagnostic Criteria

There are no generally accepted diagnostic criteria for CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). A CADASIL diagnostic screening tool has been proposed by , , and .

Suggestive Findings

CADASIL should be suspected in individuals with unexplained white matter hyperintensities and a family history of stroke and/or vascular dementia; however, lack of an apparent family history of CADASIL does not preclude the diagnosis (see Family history). The following clinical signs and neuroimaging findings can be observed in CADASIL.

Clinical signs

Source: GeneReviews — "CADASIL"

Differential Diagnosis

The differential diagnosis of CADASIL includes and . Sporadic/Multifactorial Disorders The clinical characteristics and MRI abnormalities in these conditions may resemble those of CADASIL. The presence of temporopolar MRI lesions, the absence of optic nerve and spinal cord involvement, the absence of oligoclonal bands in the cerebrospinal fluid, and the absence of hypertension are critical in this regard . Table 2. Clinical Signs and MRI Abnormalities of Sporadic/Multifactorial Disorders in the Differential Diagnosis of CADASIL

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CADASIL, the following evaluations are recommended, if they have not already been completed. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with CADASIL

Source: GeneReviews — "CADASIL"

Clinical Guidance

The treatment effect of thrombolytic therapy (intravenous thrombolysis) is unknown in individuals with CADASIL. Studies performed in non-CADASIL populations show that increasing cerebral microbleed burden and increasing white matter hyperintensity lesion load is associated with an increased risk of intracerebral hemorrhage after thrombolytic therapy ; therefore, individuals with CADASIL may be at increased risk for intracerebral hemorrhage. In case of a thromboembolic large vessel stroke (i.e., unrelated to CADASIL), the benefit of thrombolysis outweighs the potential risk of intracerebral hemorrhage. Oral anticoagulants could lead to an increased risk of intracerebral hemorrhage in individuals with CADASIL due to the presence of microbleeds ; the prescription of anticoagulants should therefore be carefully weighed. In case of a clear indication for anticoagulant therapy, such as atrial fibrillation or deep venous thrombosis, the benefit of the treatment likely outweighs the potential risk of intracerebral hemorrhage. Smoking increases the risk of stroke in individuals with CADASIL and should be avoided .

Source: GeneReviews — "CADASIL"

Therapies Under Investigation

Case reports and small-scale observational studies have suggested a beneficial effect of acetazolamide on migraine . Acetazolamide has also been shown to have a beneficial effect on cerebral perfusion [, , , ]. Acetazolamide is not given to individuals with CADASIL on a routine basis, as no large studies have been performed. Several therapeutic approaches are in pre-clinical development: testing in cells and mouse models including immunotherapy , antisense mediated NOTCH3 exon skipping , and treatment with stem cell factor and granulocyte colony-stimulating factor . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "CADASIL"

Surveillance Guidelines

No standard international surveillance guidelines for CADASIL exist. Several countries have developed CADASIL guidelines, such as the medical guideline for CADASIL published (in French) by the French Health Authority (HAS). The interval at which individuals with CADASIL should be seen for follow up depends on the severity and type of symptoms and the needs of patients and their care givers.

• Follow up by a neurologist with expertise in CADASIL is recommended from the time of diagnosis onward.

• A consultation with a neuropsychiatrist is recommended when there are symptoms of depression, apathy, or other psychiatric manifestations.

• Consultation of other medical specialists (e.g., rehabilitation physician, clinical geneticist, physical therapist, and psychologist) is as required.

Source: GeneReviews — "CADASIL"