CADASIL

Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy

Fact Sheet

• CADASIL [PDF]

Genetics

• Error in the NOTCH3 Gene on Chromosome 19. This gene is responsible for the development of smooth muscle in the walls of blood vessels.

Cause

• Although CADASIL affects all blood vessels, the complications are largely limited to the long penetrating arteries of the brain. The blood-brain barrier is also affected.

Pathology

• Autopsies of brains with CADASIL show lacunar infarcts (strokes deep in the brain in the pons, thalamus and brain stem).

Incidence

• The rate of disease-causing variants however is somewhere between 1 to 5 in 100,000 people. The prevalence of all NOTCH3 gene variants might be as high as 1 in 300 people.

Onset

• Early adulthood but some cases reported in children and adolescents

Clinical Features

CADASIL usually presents with one or more of:

• Migraine with aura

  • Occurs in 50% of patients, usually the first sign, more common in women

  • The average age is 30 years

  • Aura usually involves the visual and sensory systems (flashing lights) but 50% have other symptoms as well including hemiplegia, confusion, and hallucinations)

• Acute reversible encephalopathy

  • Occurs in 10% of patients

  • Manifests as altered consciousness, hallucinations, seizures, weakness, numbness, loss of speech

  • Usually the symptoms that leads to a diagnosis

• Ischemic episodes

  • Strokes and Transient Ischaemic Attacks (Mini strokes)

  • Occurs in 85% of patients, the median age is 52 years

  • Usually a classic lacunar stroke syndrome (Pure motor or sensory symptoms, Hemiparesis, Ataxia-hemiparesis, Dysarthria-clumsy hand syndrome, Sensorimotor stroke)

• Cognitive impairment and dementia

  • Occur in 60% of patients

  • Lacunar lesions and global brain atrophy on MRI

  • Usually slow cognitive decline

• Psychiatric disturbances

  • Mood disorders occur in 25 %of patients

  • Commonly moderate depression, sometimes bipolar, panic disorder, hallucinations or delusions

  • Apathy is a common symptom, more common in men

• Seizures

  • Occur in 5 to 10% of patients

Evaluation

• Suspect CADASIL when classical symptoms present, particularly when there is a positive family history of stroke or dementia, or when there are typical findings on brain MRI. A lack of family history doesn’t exclude a diagnosis.

History and Examination

• Thorough standard history with a focus on a family history of stroke, migraine, mood disorders, seizures and dementia. Detailed neurological examination documenting all findings.

Imaging

• MRI brain for all patients with suspected CADASIL.

• MRI usually shows recent lacunar infarcts, chronic lacunes, and white matter hyperintensities.

• There are also temporal lobe and external capsule hyperintensities, subcortical lacunar lesions, cerebral microbleeds and brain atrophy.

Diagnosis

• Either genetic analysis or if not available or conclusive, then skin biopsy looking for characteristic changes.

Differentials

• Acquired Disorders such as small vessel disease, multiple sclerosis, and PACNS (primary angiitis of the central nervous system)

• Inherited Disorders such as Fabry disease, CARASIL, and leukodystrophy.

Management

• There is currently no specific disease-modifying treatment for CADASIL :(

Acute Stroke

• Managed as you normally would. No evidence systemic thrombolysis improves outcomes after a small vessel stroke in CADASIL but if the stroke is in the territory of a thromboembolic large vessel then it can be considered.

Secondary Stroke Prevention

• Control hypertension

• Statin therapy if high blood cholesterol

• Glucose control if Diabetic

• Antiplatelet therapy such as low-dose Aspirin 100mg daily

• Smoking cessation

• Limit alcohol consumptions

• Weight control

• Regular aerobic exercise

• A Mediterranean diet that is rich in fruits, vegetables, grains, nuts, fish and low-fat dairy.

Symptomatic Therapy

• Doneprezil in patients with slowed executive function and processing speed

• SSRI for emotional lability in pseudobulbar palsy

• Migraine attacks are treated with NSAIDs. Triptans are contraindicated.

Prognosis

• Migraine with aura around age 30.

• Strokes, TIAs and mood disorders from age 40 to 60.

• Dementia between ages 50 and 60

• Gait difficulty at age 60

• Can be highly variable with some patients being completely asymptomatic until their seventies

• Early onset doesn't necessarily mean rapid progression

Life Expectancy

• The average life expectancy is 65 years for men and 70 years for women.

References

• CADASIL Up To Date

• CADASIL NORD

• CADASIL Rare Diseases

Fact Sheet

• CADASIL [PDF]