ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY
CADASIL
(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
Created 11/05/2023, last revision 27/09/2023
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease characterized almost exclusively by neurological manifestations (premature small vessel disease, migraines, etc.)
- affects individuals over 30 years of age (onset usually between 40 and 50 years of age); life expectancy is reduced
- the phenotype is highly variable, and although the full clinical-neuroimaging picture may be suggestive of the disease, diagnosis is made by genetic testing or skin biopsy
- once diagnosed, genetic counseling should be offered
Definition and pathophysiology
- CADASIL is the most common small vessel disease caused by mutations involving a single gene
- the gene responsible for the pathogenesis of CADASIL was discovered by Joutel et al. in 1996
- mutations in the NOTCH 3 gene on chromosome 19 – exons 2-24; > 200 mutations have been reported
- the NOTCH3 protein is a single-pass transmembrane receptor with extracellular epidermal growth factor (EGF) repeat domains
- CADASIL is inherited in an autosomal-dominant fashion
- the mutation causes the progressive degeneration of smooth muscle cells of small cerebral vessels due to pathological accumulation of NOTCH 3 in the basal membrane (osmiophilic granules in electron microscopy) ⇒ impaired autoregulation, hypoperfusion, ischemia
- angiopathy is generalized (positive skin biopsy); it is, however, characterized by almost exclusively neurologic manifestations
Clinical presentation
- migraine (usually with aura) is the most common initial symptom (between 20-30 years of age) – present in approx. 55%
- TIA or stroke occurs between 30-45 years of age, including “clinically asymptomatic” lacunar infarcts and white matter lesions (WML)
- progressive subcortical lacunar infarcts and WML are the basis for neuropsychiatric symptoms
- mood disorders, depression, apathy
- decreased psychomotor speed with impaired executive function
- cognitive impairment leading to progressive dementia and disability
- other symptoms depend on the number and location of the infarcts
- paresis, ataxia
- pseudobulbar syndrome
- urinary incontinence
- visual and speech disturbances
- acute reversible encephalopathy (sometimes with epileptic seizures) is described; these may spontaneously resolve and recur [Schon, 2003]
- clinical presentation may be extremely variable, and some patients may have few disturbances and a milder course even at older ages

Diagnostic evaluation
- CADASIL should be suspected in patients with a strong family history of early stroke, dementia, and typical MRI findings
- a CADASIL scale (see further) has been proposed to select the right patients for genetic testing or skin biopsy
- definitive diagnosis begins with serum genetic testing for a NOTCH3 mutation; negative patients may have unidentified genetic mutations, and the next step is a skin biopsy with histopathologic examination for GOM accumulation
Personal history
- typically TIA/stroke at a younger age, often in the absence of traditional vascular risk factors
- gradual progression of cognitive impairment
- migraine with aura
- positive family history
Neuroimaging
- CT shows nonspecific hypodensities in the white matter (leukoaraiosis)
- MR is crucial in the diagnosis of inherited CSVDs
- white matter hyperintensities (lesions) in T2/FLAIR [Stojanov, 2015]
- subcortical lacunar infarcts (basal ganglia, periventricular white matter, and pons)
- cerebral microbleeds (CMBs) → see here
- best seen on GRE or SWI sequences as multiple punctate foci of susceptibility/hypointensity
- dilated perivascular spaces (T2-weighted MRI)
- brain atrophy
Neurosonology
- intracranial flow is decreased together with decreased VMR [Pfefferkorn,2001] [Engelter, 2002]
Laboratory tests
- genetic testing – the gold standard for definitive diagnosis
- negative results may be related to the presence of a new NOTCH3 mutation
- skin biopsy (systemic arteriolopathy) – it is necessary to obtain subcutaneous tissue with blood vessels; the sample should be fixed in glutaraldehyde
- electron microscopy – granular osmiophilic material (GOM) in the vessel wall
- immunohistochemistry – detection of intravascular deposits in the smooth muscle of the vessel wall using molecular antibodies against NOTCH3 [Joutel, 2001]
- skin biopsy is specific but has a variable sensitivity
The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and, therefore to be subjected to the genetic testing
Diagnosis is possible
Diagnosis is probable
Diagnosis is certain
|
CADASIL Scale [Pescini, 2012] Max 25 points, a total score of ≥15 predicts CADASIL diagnosis |
|
Migraine | 1 |
Migraine with aura | 3 |
TIA/stroke | 1 |
TIA/stroke onset <50 y | 2 |
Psychiatric disturbances | 1 |
Cognitive decline/dementia | 3 |
Leukoencephalopathy | 3 |
Leukoencephalopathy extending to the temporal pole | 1 |
Leukoencephalopathy extending to the external capsule | 5 |
Subcortical infarcts | 2 |
Family history* in at least 1 generation | 1 |
Family history* in at least 2 generations | 2 |
* at least 1 of the typical disturbances (headache, transient ischemic attack/stroke, cognitive decline, psychiatric disturbances) |
- the gold standard for confirming the diagnosis (may be positive in biopsy-negative patients)
- careful selection of patients (e.g., using the CADASIL score above) is required
- the analysis of the NOTCH3 gene is costly and time-consuming
- the negativity of the test does not exclude the presence of other inherited diseases and, therefore, is not entirely reassuring for the patients
- genetic counseling is needed in case of a positive result
- a significant number of patients with a phenotype suggestive of CADASIL have no pathogenic mutations on exons 2–23 of the NOTCH3 gene
- the identification of this group is important because the genetic spectrum of the CADASIL phenotype may be broader than previously thought
- novel NOTCH3 mutations
- a new mutation on exon 24 has been reported
- a novel activating mutation on exon 25 has been described in a patient with cerebral SVD but without GOM deposits and NOTCH3 receptor accumulation (genetic testing is superior to skin biopsy in this case)
- a new mutation on exon 24 has been reported
- other genes causing CADASIL-like hereditary cerebral SVD (NOTCH3-negative)
- novel NOTCH3 mutations
Differential diagnosis
- Binswanger’s disease
- elderly individuals, multiple vascular risk factors, systemic atherosclerosis
- absence of typical temporal lobe lesions
- CARASIL (Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
- mutation of HTRA1 serine peptidase gene on chromosome 10q (10q25.3-q26.2)
- early onset, no migraine
- clinically similar to CADASIL + early alopecia and spondylosis deformans
- no GOM granules in the skin biopsy
- arteriolopathic changes on MRI + arc sign (hyperintensity connecting peduncles across the pons in T2)
- AD form with one pathologic allele (HTRA1-related disease) has milder presentation and less pronounced MRI lesions
- Susac syndrome
- no temporal lobe involvement
- retinopathy, hearing impairment
- MELAS
- primary angiitis of the CNS (PACNS)
- positive biopsy, wall enhancement on MRI black blood sequences
- COL4A1/2 related cerebral small-vessel diseases (CSVD)
- HANAC syndrome (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) (Alamowitch, 2009)
- PADMAL (pontine autosomal dominant microangiopathy with leukoencephalopathy)
- CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy)
- prominent brainstem symptoms (tinnitus, hearing loss, and dysphagia)
- Fabry disease
- an X-linked disorder caused by a deficiency in α-galactosidase A
- albuminuria, angiokeratomas, renal disease, cardiomyopathy, and autonomic and painful peripheral neuropathies
- RVCL-S (retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations)
- TREX1 gene mutation (Wilms, 2022)
- TREX1 gene mutation (Wilms, 2022)
- Behcet’s disease
- acute disseminated encephalomyelitis
- HIV encephalopathy and AIDS dementia complex
- Lyme disease
- multiple sclerosis
- different MRI appearance and involvement of the optic nerves and spinal cord ( not be expected in CADASIL)
- neurosarcoidosis
- neurosyphilis
Management
Medication
- at present, there is no causal or specific disease-modifying treatment available; therapy is similar to that for traditional small vessel disease
CADASIL and perioperative managament
- patients could be at increased risk of perioperative stroke or delirium (PET studies have shown a significant decrease in cerebral blood flow in white matter, corresponding to WMHs)
- it is suggested to
- keep intraoperative MAP >60 mmHg (8 kPa)
- keep end-tidal carbon dioxide at approx. 40 mm Hg (5.3 kPa)
- avoid or restrict head-down positioning
CADASIL and pregnancy
- CADASIL is probably not associated with higher rates of complications during pregnancy, peripartum, or postpartum
- according to the European Guidelines 2020, no antithrombotics are needed during pregnancy
- no data show that vaginal birth is unsafe