Subcortical ischemic events
Migraine, usually with aura, as the first symptom in the third decade of life
Recurrent subcortical ischemic events (transient ischemic attack/stroke) in adulthood
Mood disturbances, apathy and depression among other psychiatric symptoms
Progressive cognitive decline, especially of executive functioning
Seizures, in a smaller but well-defined portion of patients
Pathological gambling 
Recurrent status epilecticus 
Late onset 
Bipolar disorder 
Inflammatory-like presentation 
Acute vestibular syndrome 
Acute confusional migraine 
Sporadic hemiplegic migraine with normal imaging 
Post-partum psychiatric disturbances 
Recurrent transient global amnesia 
Life expectancy, cause of death, and cardiovascular aspects
As prophylaxis, reduces the frequency of migraine attacks
Sodium valproate 
Acetylcholinesterase inhibitor 
Not efficacious on the primary end-point (Vascular Dementia Assessment scale after 18 weeks), but some improvement in relation to frontal-subcortical dysfunction
Primary and secondary stroke prevention
Unproven and debated benefits
No effects on cerebral blood flow , tested with transcranial Doppler
Induced-vasoreactivity , tested with transcranial Doppler
Sapropterin (200–400 mg bid in 24 months)
Final results for the primary end-point (mean difference in reactive hyperemia index) were not significant for any improvement of peripheral vasoreactivity 
Novel molecular therapeutic target (as stem cell factor and granulocyte-colony stimulating factor)
Highlights and key questions for management of CADASIL patients
Clinical presentation: The clinical presentation is usually stereotyped with MA, small subcortical strokes, or cognitive impairment in middle-aged patients with a family history of stroke or dementia, but the spectrum of the disease is wide and atypical phenotypes have been reported. There is wide variation in phenotype both within and between families.
Cognitive impairment: Cognitive impairment is a prominent feature in CADASIL. While its clinical pattern is typically subcortical, several recent data suggest that the cerebral cortex is also involved and contributes to the cognitive profile abnormalities.
Brain MRI: Cerebral MRI in CADASIL shows extensive white matter changes, with frequent involvement of temporal pole and external capsule. No abnormality is pathognomonic, but confluent bilateral anterior temporal pole T2-hyperintensities are highly suggestive. Recent advances in neuroimaging have also revealed involvement of the cortex.
Vascular risk factors: Smoking seems to be clearly associated with an increase in the stroke risk both in cross-sectional and longitudinal studies. Moreover, smoking and hypertension are associated with an earlier onset of stroke and more rapid progression in CADASIL. Evidence is less robust for other risk factors and more study is needed. However, in the absence of effective therapeutic approaches, control of vascular risk factors is recommended. Also, genetic modulating factors other than the NOTCH3 mutation probably play a role, but their nature remains to be determined.
Genetic: More than 200 different NOTCH3 gene mutations have been reported in exons 2–24, involving the loss or gain of cysteine residues. The role of non-canonic NOTCH3 mutations (e.g., cysteine-sparing mutations, mutations outside EGFR domains, frameshift or nonsense mutations) is debated; in these cases, the search for GOMs in skin is mandatory, although in some cases it may be negative. When identifying a non-canonic mutation, sequencing of all EGFR-encoding exons of the NOTCH3 gene is mandatory as well as the cosegregation analysis of the non-canonic mutation with the CADASIL MRI phenotype within the family.
Neuropathology: GOM is the neuropathological hallmark of CADASIL. Specificity is high, but sensitivity is variable. Mutation testing is the gold standard, and the use of skin biopsy should be limited to the rare situations when the diagnosis is strongly suspected despite negative genetic testing.
Genetic counseling: Genetic counseling should always be offered to patients diagnosed with CADASIL and should precede all predictive genetic testing. Predictive genetic testing should only be offered to adults (>18 years) and should be performed by trained staff with genetic counselling experience, using a standard protocol such as that used in Huntington’s disease.
Treatment: In the absence of specific data for CADASIL, most neurologists use aspirin in secondary prevention after ischemic strokes in older patients, for example, those aged over 40, but there is no evidence for or against its use. Whether this strategy is appropriate in CADASIL is undetermined and will require further investigation, given the possible increased hemorrhagic risk. Patients that need to undergo anticoagulation for a clear indication such as high risk atrial fibrillation should be carefully followed given the reported risk of intracerebral hemorrhage. A multicenter randomised controlled trial using donepezil to improve cognitive dysfunction showed no benefit on the primary endpoint and only improvements of uncertain clinical significance on several measures of executive function. New, rational therapeutic interventions for CADASIL are in early phases of pre-clinical development.