Encephalopathy in a Large Cohort of British Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients

Abstract

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode.

Keywords: brain; encephalopathy; leukoencephalopathy; magnetic resonance imaging; migraine with aura.

Figure 1.

Histogram shows the percentage of patients in each age group during the first and all encephalopathic events.

Figure 2.

Distribution of mutations in the NOTCH3 protein among patients with history of encephalopathy (top) and without history of encephalopathy (bottom). x axis: amino acids along the protein; including 34 epidermal growth factor repeat (EGFr) domains in the extracellular domain(marked); y axis: number of cases where each lollipop represents a different mutation site. Three most frequent mutations marked. Image created with C-bioportal. Mapper. (http://www.cbioportal.org/mutation_mapper.jsp).

Figure 3.

Patient 1 during first episode. Flair images revealing increased signal and swelling in the right temporal and parietal regions (approximate area of changes marked) (A) with near complete resolution of changes on follow-up images 40 days later (B). Patient 1 during the second episode. T2 weighted and flair images (C) revealing cortical swelling and signal abnormalities in the left parietal and temporal region (marked area). Diffusion-weighted image (DWI) images are showing mild increase in signal with corresponding low signal on apparent diffusion coefficient map (D).