Tales from an old foe – CADASIL

by Kailash Krishnan MRCP (UK), MRCP (Lond), PhD (Stroke Medicine), Stroke, Division of Neuroscience, University of Nottingham and Department of Stroke Medicine, Nottingham University Hospitals NHS Trust, UK

A 55-year-old man was admitted recently to the stroke unit with a 6 hour history of slurred speech, right arm and leg weakness. He recalled having an episode of numbness affecting the face, left arm and leg 8 years ago lasting few hours. His wife reported that since then he was more distracted and forgetful. He had a history of migraine with aura but was not on any treatment. His father had a stroke in his 50’s and was later diagnosed with dementia. Diffusion-weighted MRI scanning confirmed an infarct in the left corona radiata. Fluid-attenuation inversion recovery sequences showed widespread confluent white matter hyperintensities in both basal ganglia. There was also involvement of the anterior temporal lobe, external capsule and some cerebral microbleeds. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was confirmed by genetic testing for NOTCH3 pathogenic mutation. The patient was treated with clopidogrel and atorvastatin. Neuropyschological evaluation revealed mild executive dysfunction and the patient was referred to the memory clinic. Genetic counselling was offered. His general practitioner was advised to closely monitor blood pressure and follow-up was arranged.

Discussion

Since its definition in the 1990’s, CADASIL, a monogenic form of small vessel disease, has emerged as the most common heritable cause of stroke and vascular dementia in young adults. This angiopathy is linked to mutations in the NOTCH-3 gene, on the long arm of chromosome 19. Ischaemic stroke is a cardinal feature, with dysregulation of cerebral blood flow postulated as the primary mechanism.(1) It is noteworthy that risk factors such as hypertension and diabetes mellitus are not common.(1) The age of onset is usually in the 40’s, with most patients presenting with a typical lacunar syndrome (pure motor and/or sensory stroke, dysarthria and clumsy hand syndrome or ataxic hemiparesis). Migraine is often the earliest feature of the disease and the age of onset is variable. Cognitive deficit usually involves information processing and executive functions with dementia reported in upto 40% of patients.(2)

No specific treatment is yet available for CADASIL. Antiplatelets such as Aspirin or Clopidogrel are often used but could increase bleeding risk.(3) Statins have been tested but showed no benefit. (4) There are reasons to favour routine BP lowering in CADASIL(5) but evidence is lacking on type of agent, timing and long-term effects. The management of acute stroke complications, migraine and psychiatric disorders are based on indirect evidence from patients without CADASIL. Cholinergic defect has been linked to cognitive impairment, but a trial of Donepezil showed no benefit in the primary endpoint.(6) Improvements were observed on executive function but the clinical implications need further exploration.(6)

Although progress has been made, our understanding of CADASIL is still limited and more work is needed on pathophysiological mechanisms, risk factors, clinical and imaging predictors of outcome and treatment. Early diagnosis allows patients and their families to receive timely practical information, appropriate multidisciplinary supportive treatment, genetic counselling and psychological support.

REFERENCES

1. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995;346:934-9.
2. Chabriat H. Neuropsychiatric manifestations in CADASIL. Dialogues in clinical neuroscience. 2007;9(2):199-208.
3. Dichigans M, Holtmannspotter M, Herzog J, et al. Cerebral microbleeds in CADASIL. Stroke. 2002;33:67-71.
4. Peters N, Freillinger T, Opherk C, et al. Effects of short term atorvastatin on cerebral haemodynamics in CADASIL. J Neurol Sci. 2007;260(1-2):100-5.
5. Rufa A, Dotti MT, Franchi M, et al. Systemic blood pressure profile in cerebral autosomal dominant arteriopathy with subcortical infacts and leukoencephalopathy. Stroke. 2005;36:2554-8.
6. Dichigans M, Markus HS, Salloway S, et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurology. 2008;7:310-8.