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CADASIL is an autosomal dominant form of arteriopathy, primarily affecting cerebral vessels, and predominantly caused by point mutations in the Notch3 gene on the short arm of chromosome 19.1 Affected individuals develop subcortical strokes and cognitive deficits in their 50s and 60s.2 Brain magnetic resonance imaging (MRI) shows large areas of leukoencephalopathy and multiple subcortical lacunar infarcts. Small arteries and capillaries are characterised histologically by a non-atherosclerotic, non-amyloid angiopathy with accumulation of granular osmiophilic material (GOM) within the smooth muscle cell basement membranes and extracellular matrix.3 While CADASIL is considered a primarily ischaemic form of vascular dementia, microhaemorrhages have recently been reported in 31% of symptomatic Notch3 mutation carriers, suggesting that structural fragility of the arterial walls may lead to leaking of haem products.4 Lobar haemorrhage in the absence of other risk factors for haemorrhage has previously been reported in one patient with CADASIL.5 Here we report a second case.
A 56 year old man who had been diagnosed with multiple sclerosis six years earlier was admitted to the hospital with an acute change in mental state. He had collapsed at home and was unresponsive when rescue arrived. In the emergency room he had a depressed level of consciousness and difficulty following commands, with paucity of speech, dysarthria, and hypophonia. There was no evidence of head trauma. His blood pressure was 100/63 mm Hg and his temperature was 36.1°C.
Past medical history included chronic obstructive pulmonary disease, prostate resection for prostate cancer, and a history of nicotine and alcohol dependence. He had no history of hypertension, diabetes mellitus, or coagulopathy. His drug treatment included ipratropium, ranitidine, methyprednisolone, and albuterol. His mother, now deceased, had been diagnosed as having multiple sclerosis and had migraines with auras, stroke-like symptoms, and dementia. He had eight siblings, three with headaches and one with recent transient ischaemic events.
Computed tomography (CT) of the head in the emergency department showed an area of high attenuation in the right frontal lobe consistent with an acute intraparenchymal haemorrhage (fig 1A). There was no evidence of trauma on head CT. Gradient echo MRI sequences of the brain done on hospital day 2 showed a 2×2.5 cm area of haemorrhage in the superior-anterior aspect of the right frontal lobe white matter as well as a microhaemorrhage in the right parietal region (fig 1B). The area of haemorrhage was hypointense on T2 (fig 1C) and isointense on T1 weighted sequences (fig 1D), consistent with acute haemorrhage. There was no MRI evidence of a cavernous haemangioma, arteriovenous malformation, or tumour. Magnetic resonance angiography was not done.
A brain biopsy of the right frontal lobe done on the seventh hospital day showed degeneration of small and medium sized arteries. Vessel walls were thick and hyalinised in the grey matter, white matter, and meninges. PAS staining was positive and the muscular coat of the large vessels revealed degenerative changes. Electron microscopy showed the granular osmiophilic material characteristic of CADASIL. Notch3 gene testing revealed a R133C mutation in exon 4, consistent with the diagnosis of CADASIL. The patient remained normotensive throughout his hospital stay. On the fifth hospital day he developed aspiration pneumonia requiring mechanical ventilation. He died eight days later as a result of this pneumonia.
This is the second report of spontaneous cerebral haemorrhage in a patient with CADASIL. In 1977, Sourander and Walinder reported a 29 year old man with hereditary multi-infarct dementia on anticoagulants, with a large haemorrhage in the right hemisphere.5 This family was thought to be one of the first with CADASIL; however, recent testing for Notch3 mutations in the family has not confirmed that diagnosis.6 In 1992, Baudrimont et al reported a case of massive left cerebral haematoma involving the caudate nucleus, internal capsule, and thalamus in a 40 year old normotensive woman who was a member of a large CADASIL family. She had no known history of other risk factors for haemorrhage.7
The index patient in this report had no evidence of coagulopathy and no history of previous hypertension, cerebral haemorrhage, or anticoagulant therapy. The patient could have experienced a haemorrhagic contusion related to a closed head injury during his unwitnessed fall before admission, but there was no evidence of trauma on physical examination or on head CT. On MRI there was no evidence of a cavernous haemangioma, arteriovenous malformation, or neoplasm. Necropsy was not carried out.
Ultrastructural analysis of small arteries in human postmortem brain and skin in patients with CADASIL shows breakdown of the arterial wall cytoarchitecture, which may help explain the propensity for microhaemorrhages.8 The first notch3 transgenic mouse shows early widening of the subendothelial and intra-smooth-muscle spaces in the vascular smooth muscle cells, denoting weakening of the arterial wall and increasing susceptibility to micro- and macrohaemorrhages.9
This case report supports the growing evidence for both ischaemia and haemorrhage in a variety of small artery diseases including amyloid angiopathy and CADASIL.10,11 Clinicians may need to consider the possibility of haemorrhage when evaluating new events and deciding on treatment for stroke prevention in patients with CADASIL.
Supported by grants P20 RR015578 and K08MH001487.
Competing interests: none declared