(Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)

David Goldemund M.D.
Updated on 20/03/2024, published on 11/05/2023

  • 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.)
  • it typically affects individuals over the age of 30 (onset usually occurring between 40 and 50 years of age); life expectancy is reduced in people with CADASIL.
  • the phenotype is highly variable, and although the full clinical and neuroimaging presentation may be indicative of the disease, genetic testing or skin biopsy is necessary to confirm the diagnosis
  • once diagnosed, genetic counseling should be offered to affected individuals and their families

Definition and pathophysiology

  • CADASIL is the most common small vessel disease caused by a single gene mutation
  • the responsible gene was discovered by Joutel et al. in 1996
    • mutations in the NOTCH 3 gene are located on chromosome 19 – exons 2-24;  > 200 mutations have been identified so far
    • the NOTCH3 protein is a transmembrane receptor with extracellular epidermal growth factor (EGF) repeat domains
    • CADASIL is inherited in an autosomal-dominant (AD) manner, meaning that only one copy of the mutated gene is required for the disease to be passed down from a parent to their child
  • the mutation causes the progressive degeneration of smooth muscle cells of small cerebral vessels due to accumulation of NOTCH 3 in the basal membrane (visible as osmiophilic granules in electron microscopy) ⇒ impaired autoregulation, hypoperfusion, ischemia
  • although angiopathy is generalized and can be detected through skin biopsy, CADASIL is characterized by almost exclusively neurologic manifestations

Clinical presentation

  • migraine (usually with aura) is the most common initial symptom, typically presenting between the ages of 20 and 30 (present in ~ 55% of cases)
  • TIA or strokes occur between the ages of 30 and 45, accompanied by “clinically asymptomatic” lacunar infarcts and white matter lesions (WMLs)
  • progressive subcortical lacunar infarcts and WML are the basis for the development of neuropsychiatric symptoms
    • mood disorders (depression, apathy)
    • impaired psychomotor speed and executive function
    • progressive cognitive impairment leading to dementia and disability
  • additional symptoms may arise depending on the number and location of infarcts
    • paresis
    • ataxia
    • pseudobulbar syndrome
    • urinary incontinence
    • visual and speech disturbances
  • in some cases, acute reversible encephalopathy (sometimes accompanied by epileptic seizures) may occur, with spontaneous resolution and recurrence [Schon, 2003]
  • clinical presentation of CADASIL may be extremely variable, , with some patients exhibiting minimal disturbances and a milder course even at advanced ages
CADASIL - clinical presentation

Diagnostic evaluation

  • CADASIL should be considered in individuals with a strong family history of early-onset stroke, dementia, and typical MRI findings
  • a CADASIL scale (see further) has been proposed to guide the selection of appropriate individuals for genetic testing or skin biopsy
  • definitive diagnosis typically involves serum genetic testing for NOTCH3 mutations
  • for individuals with negative genetic testing, the presence of unidentified genetic mutations may warrant a skin biopsy with histopathologic examination to assess for granular osmiophilic material (GOM) accumulation

Personal history

  • typically early-onset TIA/stroke, often occurring in the absence of traditional vascular risk factors
  • gradual progression of cognitive impairment, leading to dementia
  • migraine with aura
  • positive family history


  • 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]
      • typically extensive, symmetrical, confluent lesions (WML)  → FAZEKAS  or  ARWMC
        in contrast to Binswanger’s disease, there is specific and significant involvement of the external capsule and temporal pole  Compared to Binswanger's disease, CADASIL has significant involvement of the external capsule and temporal lobe Compared to Binswanger's disease, CADASIL has significant involvement of the external capsule and temporal lobe
      • the lesions can be detected even in the presymptomatic phase
    • 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


CADASIL with a typical extensive lesions in temporal poles and external capsule


Laboratory tests

  • genetic testing – the gold standard for definitive diagnosis of CADASIL
    • negative results may be attributed to the presence of a novel 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 highly specific but exhibits 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
  • TIA/lacunar stroke at a 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)  
  • 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 other inherited diseases; therefore, a negative genetic test does not provide complete reassurance for patients
  • genetic testing may sometimes be positive in biopsy-negative patients
  • genetic counseling is needed in case of a positive result
    • genetic counselors can provide detailed information about the disease, its inheritance pattern, and the risk of passing it on to offspring
    • they can also assist families in making informed decisions about their healthcare and reproductive choices
  • a significant number of patients presenting with a phenotype suggestive of CADASIL have no pathogenic mutations on exons 2–23 of the NOTCH3 gene
  • this observation highlights the possibility that the genetic spectrum of the CADASIL phenotype may be broader than previously recognized
    • novel NOTCH3 mutations
      • a new mutation on exon 24 has been reported  (outside the traditional exon 2-23 region) in a patient with CADASIL-like features
      • 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 may be a more reliable method for diagnosing)
    •  other genes causing CADASIL-like hereditary cerebral SVD (NOTCH3-negative)

Differential diagnosis

  • Binswanger’s disease  Leukoareóza
    • typically affects elderly individuals with multiple vascular risk factors and 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-weighted images) CARASIL - arc sign (Roeben, 2016)
    • AD form with one pathologic allele (HTRA1-related disease) has a milder presentation and less pronounced MRI lesions compared to the fully penetrant form
  • Susac syndrome 
    • no temporal lobe involvement
    • characterized by retinopathy and hearing impairment
    • caused by mitochondrial dysfunction and is associated with recurrent stroke-like episodes, seizures, and lactic acidosis
  • primary angiitis of the CNS (PACNS)
    • positive biopsy, wall enhancement on MRI black blood sequences
  • COL4A1/2 related cerebral small-vessel diseases (CSVD) – genetic disorders that affect the collagen IV proteins

    • 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)  – AD inheritance, very rare
  • Fabry disease
    • an X-linked disorder caused by a deficiency in α-galactosidase A, an enzyme responsible for degrading glycosphingolipids
    • 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)
    • characterized by retinal and CNS vascular changes, as well as systemic manifestations
  • 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




  • at present, there is no causal or specific disease-modifying treatment available; therapy is similar to that for traditional small vessel disease
Antithrombotic drugs
  • antiplatelet therapy – no high-quality evidence on safety or efficacy
    • individuals with CADASIL and ischemic stroke/TIA may be considered for antiplatelet therapy
    • cerebral microbleeds are not a contraindication but may increase the risk of bleeding  [Oh, 2008]
    • there is no evidence to support the use of antiplatelet agents without prior ischemic stroke
  • anticoagulation
Recanalization therapy
  • the benefit of intravenous thrombolysis is uncertain (possible increased risk of bleeding) 
    • however, no definitive contraindication to tPA has been established, and decisions should be made on a case-by-case basis
    • careful evaluation of prior microbleeds is suggested, as they may increase the risk of hemorrhagic complications following thrombolysis
    • it is also unknown whether experiences with thrombolytic therapy in CADASIL are applicable to other genetic SVDs
  • thrombectomy may be considered, taking into account the premorbid condition of the patient
Symptomatic therapy
  • therapy trying to improve cerebral perfusion


    • 125-250 mg once daily PO
    • adjust the dose according to renal function
    • off-label use – evidence is limited; some studies suggest that acetazolamide can improve hemodynamics and increase cerebral perfusion [Huang, 2010]  [Park, 2011]
    • beneficial in migraine but its efficacy in stroke prevention is unclear


    • benefit was seen on the cerebral circulation; not used in clinical practice (Peters, 2008)
  • management of neuropsychiatric complications (usually occurring after the 4th decade)
    • neuroleptics
    • antidepressants
    • anxiolytics
    • DONEPEZIL MEMANTINE – no hard data on the effect on cognitive functions in CADASIL  [Dichgans, 2008]
    • cognitive rehabilitation
      • this includes training and support to help individuals with CADASIL maintain their cognitive abilities and function as independently as possible
  • management of migraine  → more here
    • the migrainous aura may be severe and can vary in semiologies (incl. hemiplegia, hemianesthesia, and visual scotoma)
    • those with migraines with aura tend to have a lower stroke risk, less disability, less cognitive insufficiency, and fewer radiographic cerebral microbleeds compared with those without migraine
    • prophylactic medication – antihypertensive drugs, acetazolamide, anticonvulsants (VPA), or antidepressants
      • beta-blockers should be avoided
    • abortive treatment:
      • traditional analgesics such as acetaminophen or NSAIDs
      • vasoconstrictors (especially triptans) are not recommended
    • no robust data exist on the benefit of botulinum toxin-A, wearable devices, acupuncture or acupressure, or calcitonin gene-related peptide modulators
Management of vascular risk factors
  • treat hypertension, dyslipidemia,  diabetes, etc.  → Vascular risk factors
    • controlling hypertension is crucial
    • value of treating comorbid dyslipidemia remains unknown
    • smoking cessation is strongly encouraged
  • administer FOLIC ACID if homocysteine levels are elevated (as high homocysteine levels are associated with an increased risk of stroke and other vascular events)

CADASIL and perioperative managament

  • patients with CADASIL may be at an increased risk of perioperative stroke or delirium (PET studies have shown a significant decrease in cerebral blood flow in white matter, corresponding to WMHs)
  • to minimize these risks, it is suggested to:
    • maintain intraoperative mean arterial pressure (MAP) >60 mmHg (8 kPa)
    • keep end-tidal carbon dioxide at ~ 40 mmHg (5.3 kPa)
    • avoid or restrict head-down positioning during surgery

CADASIL and pregnancy

  • CADASIL is probably not associated with higher rates of complications during pregnancy, peripartum, or postpartum period
  • according to the European Guidelines 2020, antithrombotics are not routinely recommended during pregnancy
  • no evidence suggesting that vaginal birth is unsafe for women with CADASIL

Physical therapy, cognitive training, and psychological support

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