ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY
CARASIL
(Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
Created 12/05/2023, last revision 12/05/2023
Definition
- CARASIL is a very rare (probably underdiagnosed) hereditary disease affecting the small cerebral vessels, spine, and hair follicles
- it is caused by a mutation in the HTRA1 gene on chromosome 10q (10q25.3-q26.2)
- there are 2 forms (Onodera, 2010)
- classic CARASIL – with biallelic pathogenic variants (AR inheritance)
- HTRA1-CSVD – with heterozygous HTRA1 pathogenic variant (AD inheritance)
- classic CARASIL is characterized by early-onset changes in the deep white matter on MRI and associated neurologic symptoms (early-onset gait disturbance, scalp alopecia, cognitive impairment)
- HTRA1-CSVD may be oligosymptomatic or asymptomatic (with positive neuroimaging only)
Clinical presentation
CLASSIC CARASIL
- premature alopecia (starting in the teenage years; one of the initial symptoms)
- musculoskeletal symptoms (before the age of 30)
- deforming spondylosis (cervical spine and/or thoracolumbar spine). disk herniation
- knee or elbow osteoarthritis
- deforming spondylosis (cervical spine and/or thoracolumbar spine). disk herniation
- spastic gait (between 20 and 40 years of age)
- recurrent ischemic stroke-like episodes (typically before age 40) with gradually progressive vascular dementia and mood changes (apathy) (between the ages 20 and 50)
- symptomatic poststroke epilepsy
- in contrast to CADASIL, migraine is not present
HTRA1-CSVD
- slowly progressive gait disturbance and stroke-like episodes (usually after the age of 40)
- may be followed by mood changes and cognitive dysfunction
- spondylosis and alopecia are less common
Diagnostic evaluation
CARASIL should be suspected if the combination of diffuse vascular leukoencephalopathy, alopecia, and disk herniations occur at a young age
Neuroimaging
- CT shows nonspecific hypodensities in the white matter (leukoaraiosis)
- MRI detects hypointensities on T1 and hyperintensities on T2
- white matter lesions (WML)
- U-fibers are relatively preserved
- it is not clear whether the anterior temporal pole and external capsule lesions are observed in the early stages of CARASIL
- lacunar infarcts in the basal ganglia, thalamus, and pons
- arc sign – increased T2 signal across the pons at the level of middle cerebellar peduncles (Röben, 2016)
- cerebral microbleeds (CMBs) → see here
- white matter lesions (WML)
Laboratory tests
- genetic testing – the gold standard for definitive diagnosis
- mutation affects the HTRA1 gene on chromosome 10q (10q25.3-q26.2
- once the HTRA1 pathogenic variant(s) have been identified in family members, prenatal and preimplantation testing is possible
- skin biopsy does not help establish the diagnosis
Differential diagnosis
- Binswanger´s disease
- elderly individuals, multiple vascular risk factors, systemic atherosclerosis
- absence of typical temporal lobe lesions
- CADASIL
- symptoms appear 10-15 years earlier in patients with classic CARASIL
- migraine and depression are not present in CARASIL
- Susac syndrome
- no temporal lobe involvement
- retinopathy, hearing impairment
- MELAS
- primary angiitis of the CNS (PACNS)
- progressive multiple sclerosis
- COL4A1 cerebral small-vessel disease
- CARASAL (cathepsin A-related arteriopathy with strokes and leukoencephalopathy)
Management
- no causal or disease-modifying treatment is available; therapy is similar to that for traditional small vessel disease
- management of modifiable vascular risk factors
- antiplatelets and statins
- clinical efficacy is not proven
- symptomatic treatment of psychiatric disorders and spasticity
- risk/benefit ratio of tPA and anticoagulation is uncertain
- physical therapy, walking aids, cognitive training
- standard treatment of spinal spondylosis and mood disorders
- genetic counseling
