Safety and Effectiveness of Intravenous Thrombolysis in Patients With CADASIL: A Multicenter Study

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by NOTCH3 mutations, is the most common hereditary cerebral small vessel disease. Recently, a higher-than-expected prevalence of NOTCH3 mutations, up to 0.3%, has been identified in general population.¹ One clinical challenge in managing acute ischemic stroke in CADASIL is the high number of cerebral microbleeds, averaging 5 per patient,² which complicates the acute reperfusion therapy. Current guidelines including the American Heart Associations and the European Academy of Neurology do not recommend intravenous thrombolysis (IVT) in CADASIL due to unknown safety and efficacy.^3,4 This highlights a gap in IVT use in patients with stroke with known NOTCH3 mutation.⁵ Therefore, we aim to evaluate the safety and efficacy of IVT in CADASIL patients by providing the largest case number to date and comprehensive neuroimaging makers evaluation.

This was a retrospective, multicenter study of CADASIL patients who had received IVT for acute ischemic stroke from 4 different CADASIL cohorts, including Taiwan, Japan, and Korea. Relevant clinical information and outcomes were collected. Neuroimaging markers of small vessel disease were assessed on the corresponding brain magnetic resonance imaging. The data of this study are available from the corresponding author upon reasonable request.

Out of 609 patients with CADASIL from the 4 registries, 224 had a stroke history, and 12 (5%) received IVT. The median age was 60 years, with 67% being male. Common vascular risk factors included hypertension (67%), hyperlipidemia (67%), and diabetes (25%). Ten patients carried the NOTCH3 R544C mutation, while 1 had the R141C and another the C1250R mutation. Of note, 3 patients were diagnosed with CADASIL before receiving thrombolysis, and their magnetic resonance imaging, which was done 2, 4, and 7 years before IVT showed 2, 0, and 3 cerebral microbleeds, respectively.

The median National Institutes of Health Stroke Scale score was 5, and onset-to-IVT time was 94 minutes. Four patients received low-dose (0.6 mg/kg) alteplase. Post-thrombolysis magnetic resonance imaging showed visible diffusion-weighted imaging lesions in 8 patients, primarily small subcortical infarcts (Figure). Most patients had moderate-to-severe periventricular and deep white matter hyperintensity, with 33% showing anterior temporal white matter hyperintensity and 50% showing external capsule white matter hyperintensity. The median number of lacunes was 3 (range, 0–18), and the median number of cerebral microbleed was 5 (range, 0–23). No patients developed postthrombolytic intracerebral hemorrhage. At 90 days poststroke, 83% of patients achieved a modified Rankin Scale score of 0 or 1.

Figure.

Overview of the 12 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) who received intravenous thrombolysis. A, Clinical information and imaging markers of cerebral small vessel diseases. B, On postthrombolysis brain magnetic resonance imaging, diffusion restriction lesions can be seen (yellow arrows or yellow circle) in 8 patients, and all are <2 cm in diameter. C, Severity of white matter hyperintensities shown on FLAIR imaging. CMB indicates cerebral microbleed; ICH, intracerebral hemorrhage; NIHSS, National Institutes of Health Stroke Scale; and WMH, white matter hyperintensity.

Our findings suggest that IVT can be administered safely in this patient population whether the diagnosis of CADASIL was made before or after. Despite the high burden of SVD markers, most patients achieved excellent functional outcomes without experiencing hemorrhagic complications. The majority of patients had small subcortical infarcts, compatible with the most common stroke type in CADASIL. With a smaller infarct size and a relatively low burden of microbleeds, the risk of postthrombolysis hemorrhage may be low. Our study limitations included the retrospective nature of analysis, variations in clinical practice across different centers (such as alteplase dose and use of magnetic resonance imaging before IVT), and lack of a control group of patients with CADASIL who did not receive IVT.

In conclusion, this study provides evidence supporting the safety and feasibility of IVT in patients with CADASIL. Given the rising discovery of NOTCH3 variants worldwide, there is an urgent need to re-evaluate existing recommendations and provide more nuanced guidance for clinicians managing acute ischemic stroke in this unique patient population.

Article Information

Sources of Funding

This study was supported by grants from Academia Sinica (AS-GC- 111-L04), Taipei Veterans General Hospital (V113C-018), Taiwan, and JSPS KAKENHI (JP24KK0156), AMED (JP24ek0109737), Japan.

Disclosures

None.