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]
  - 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
  - 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

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

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)

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
- 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)

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

Antithrombotic drugs

antiplatelet therapy – no high-quality evidence on safety or efficacy
- people 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
- patients with CHA₂DS₂-VASc score >2 + AFib or other indications for anticoagulation should preferably receive a DOAC (if possible)
- left atrial appendage device closure may be a reasonable alternative to long-term anticoagulation

Recanalization therapy

the benefit of intravenous thrombolysis is uncertain (possible increased risk of bleeding)
- however, no contraindication to tPA has been established, and decisions should be made on a case-by-case basis
- careful evaluation of prior microbleeds is suggested
- it is also unknown whether experiences with thrombolytic therapy in CADASIL are relevant to other genetic CSVDs
thrombectomy may be performed, taking into account the premorbid condition of the patient

Symptomatic therapy

therapy trying to improve cerebral perfusion

ACETAZOLAMIDE (DILURAN)

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

L-ARGININE

- 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 [Dichgans, 2008]
- cognitive rehabilitation

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
  - avoid beta-blockers
- 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
- hypertension is associated with incident stroke, ICH, dementia, and overall disability
- value of treating comorbid dyslipidemia remains unknown
- strongly encourage smokers to quit
administer FOLIC ACID if homocysteine levels are elevated

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