ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

CADASIL

(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

Created 11/05/2023, last revision 17/05/2023

  • 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

  • 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 reported
    • CADASIL is the most common small vessel disease caused by mutations involving a single gene
    • 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 the older ages
CADASIL - clinical presentation

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
  • MRI detects hypointensities in T1 and hyperintensities in T2  [Stojanov, 2015]
    • typically extensive confluent white matter lesions (WML) → FAZEKAS  or  ARWMC
      in contrast to Binswanger’s disease, there is significant involvement of the external capsule and temporal pole Compared to Binswanger's disease, CADASIL has significant involvement of the external capsule and temporal lobeCompared to Binswanger's disease, CADASIL has significant involvement of the external capsule and temporal lobe
    • the lesions can be detected in the presymptomatic phase
  • lacunar infarcts in the 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
CADASIL

CADASIL

Neurosonology

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

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
  • TIA/lacunar stroke at younger age
  • progressive dementia
  • typical findings on MRI
  • suspicious family history (unreliable data)
Diagnosis is probable
  • positive skin biopsy
    • GOM in the tunica media on ELM examination
    • immunohistochemical examination
  • family history (reliable data)
Diagnosis is certain
  • detection of pathological NOTCH3 mutation on chromosome 19
 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)  

Genetic testing

  • 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

CADASIL-like patients

  • 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)
    •  other genes causing CADASIL-like hereditary cerebral SVD (NOTCH3-negative)

Differential diagnosis

  • Binswanger´s disease  Leukoareóza
    • 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) CARASIL - arc sign (Roeben, 2016)
  • 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 cerebral small-vessel disease (CSVD)
  • CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy)
  • 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

  • no causal or disease-modifying treatment is available; therapy is similar to that for traditional small vessel disease
  • management of modifiable vascular risk factors
    • blood pressure, dyslipidemia, and diabetes management
    • administer folic acid if homocysteine levels are elevated
    • smoking cessation
  • antiplatelets and statins
    • clinical efficacy is not proven, but both are used
    • presence of microbleeds on MRI may increase the risk of bleeding with antiplatelet therapy [Oh, 2008]
  • acetazolamide (DILURAN) 250mg daily
    • according to some studies, acetazolamide improves hemodynamics and increases CBF [Huang, 2010]  [Park, 2011]
    • beneficial in migraine, efficacy in stroke prevention is unclear
  • symptomatic therapy of psychiatric disorders
    • neuroleptics
    • antidepressants
    • no data on the symptomatic effect of donepezil on cognitive function  [Dichgans, 2008]
  • the benefit of tPA and anticoagulation is uncertain (due to increased risk of bleeding)
  • triptans are rather not recommended for the treatment of migraine (may provoke stroke)

Physical therapy, cognitive training

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CADASIL
link: https://www.stroke-manual.com/cadasil/