CADASIL

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Learning objectives

  • Understand the aetiology and risk factors for CADASIL
  • Be able to recognise the clinical presentation of CADASIL
  • Discuss diagnostics and treatment strategies

Introduction

CADASIL is the acronym for Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. CADASIL causes a small vessel non-arteriosclerotic non-amyloid microangiopathy. It is a hereditary disease of small cerebral arteries affecting middle-aged adults leading to disability and dementia and causing migraine with aura in less than half.

Aetiology/Genetics

The disease was mapped to the 19th Chromosome and linkage studies identified a mutated notch 3 gene at chromosome 19p13.1. It can be inherited as an Autosomal dominant or Autosomal recessive (CARASIL). A mouse model of CADASIL has shown increased susceptibility to cortical spreading depression. [Eikermann-Haerter K 2011]. CADASIL mutations cause gradual accumulation of NOTCH3 protein around vascular smooth muscle cells and pericytes along with Granular osmiophilic material (GOM) within media and adventitia.

Clinical

FindingsProgressive symptoms and signs
Migraine with aura

is seen in up to 40% of patients and is often the first pinpoint signs. It is seen in a minority so one should not rely on its presence to

suspect the diagnosis. In some patients with CADASIL Migraine with aura is severe and predominant.
Subcortical ischaemic lesions presenting as lacunar syndromes are usually found in the late 40s/50s. May be compounded by other vascular risk factors e.g smoking, diabetes and hypertension.
PsychiatricMood disturbance may be seen with mania/depressive periods. Apathy is common.
Cognitive impairment may be detectable from the 40s onwards [Chabriat H et al 2009]. There can be progressive gait dyspraxia, urinary incontinence, and pseudobulbar palsy. By the late 60s dementia is severe.
Othersseizures and parkinsonism can occur.

Investigations

  • CT Brain:may just show small vessel changes with periventricular changes
  • MRI Brain:is useful and demonstrates prominent subcortical white matter changes and lacunar infarcts are often symmetrical and periventricular and particularly located to anterior temporal lobes and external capsule. These may be detectable from the mid-30s onwards. These locations are quite specific for CADASIL. Lesions may also be found in basal ganglia and thalamus. Microbleeds are also found in approximately 50% on gradient echo (T2*). There is progressive brain atrophy.
  • Brain Histology: very rarely available premortem. Shows chronic small artery disease in periventricular space, centrum semiovale and basal ganglia. Cortical layers 3 and 5 show apoptosis. Vessels show eosinophilic deposits in tunica media of arteries in the brain . There is progressive luminal stenosis and occlusion. These changes are also found in skeletal muscle and skin.
  • Skin biopsy for diagnosis with staining with NOTCH3 monoclonal antibody reveals excess NOTCH3 protein in the vessel wall. This is highly sensitive(85-95%) and specific (95-100%). A skin biopsy also demonstrates the presence of Granular osmiophilic material (GOM) which is best seen by electron microscopy within media and adventitia of the small subcutaneous arterioles which is diagnostic for CADASIL.
  • Genetic Testing: should be done on those with the classical phenotype of family history and migraine with aura and subcortical strokes. Without a family history care must be taken. The presence in patients with migraine with aura of some T2 hyperintensities is not uncommon. There is no specific disease-altering therapy and an affected 30-year-old patient with a new migraine with aura may wait 30 years for their first stroke. Unless the patient requests it some stroke physicians/neurologists would see little benefit in testing. Patients who are tested need to understand that it will not alter outcome [Chabriat H et al 2009]. The role of prenatal screening is unclear.

CARASIL

CARASIL Is an acronym for Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL) and is similar to CADASIL but autosomal recessive and very rare. Identified mainly in China and Japan. CARASIL is caused by mutations in the HTRA1 gene. Patients present with ischaemic stroke or a stepwise deterioration in brain functions. There is progressive dementia, premature baldness, and attacks of severe low back pain or spondylosis deformans/disk herniation. Imaging by MRI shows diffuse white matter changes and multiple lacunar infarctions in the basal ganglia and thalamus.Histopathologically identifies intense arteriosclerosis, mainly in the small penetrating arteries, without granular osmiophilic materials or amyloid deposition [Fukutake T 2011].