Reversible cerebral vasoconstriction syndrome with concurrent bilateral carotid artery dissection

Background: The pathophysiological basis of reversible cerebral vasoconstriction syndrome is poorly understood but carotid artery dissection has been discussed as a rare possible cause. So far, only single cases of unilateral carotid artery dissection and reversible cerebral vasoconstriction syndrome have been reported. Case: Here, we describe the case of a 54-year old patient presenting to the emergency department with right hemiparesis, hypaesthesia and dysarthria. Furthermore, he reported two episodes of thunderclap headache after autosexual activity. Cerebral imaging showed ischaemic infarcts, slight cortical subarachnoid haemorrhage, bilateral carotid artery dissection and fluctuating intracranial vessel irregularities, compatible with reversible cerebral vasoconstriction syndrome. An extensive diagnostic work-up was normal. No typical trigger factors of reversible cerebral vasoconstriction syndrome could be found. The patient received intravenous heparin and the calcium channel blocker nimodipine. Follow-up imaging revealed no vessel irregularities, the left internal carotid artery was still occluded. Conclusion: This case supports the assumption that carotid artery dissection should be considered as a potential trigger of reversible cerebral vasoconstriction syndrome, possibly by altering sympathetic vascular tone

The carotid plaque imaging in acute stroke (CAPIAS) study:

Background: In up to 30% of patients with ischemic stroke no definite etiology can be established. A significant proportion of cryptogenic stroke cases may be due to non-stenosing atherosclerotic plaques or low grade carotid artery stenosis not fulfilling common criteria for atherothrombotic stroke. The aim of the CAPIAS study is to determine the frequency, characteristics, clinical and radiological long-term consequences of ipsilateral complicated American Heart Association lesion type VI (AHA-LT VI) carotid artery plaques in patients with cryptogenic stroke. Methods/Design: 300 patients (age > 49 years) with unilateral DWI-positive lesions in the anterior circulation and non- or moderately stenosing (<70% NASCET) internal carotid artery plaques will be enrolled in the prospective multicenter study CAPIAS. Carotid plaque characteristics will be determined by high-resolution black-blood carotid MRI at baseline and 12 month follow up. Primary outcome is the prevalence of complicated AHA-LT VI plaques in cryptogenic stroke patients ipsilateral to the ischemic stroke compared to the contralateral side and to patients with defined stroke etiology. Secondary outcomes include the association of AHA-LT VI plaques with the recurrence rates of ischemic events up to 36 months, rates of new ischemic lesions on cerebral MRI (including clinically silent lesions) after 12 months and the influence of specific AHA-LT VI plaque features on the progression of atherosclerotic disease burden, on specific infarct patterns, biomarkers and aortic arch plaques. Discussion: CAPIAS will provide important insights into the role of non-stenosing carotid artery plaques in cryptogenic stroke. The results might have implications for our understanding of stroke mechanism, offer new diagnostic options and provide the basis for the planning of targeted interventional studies

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [&lt;1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Reversible cerebral vasoconstriction syndrome with concurrent bilateral carotid artery dissection

Background: The pathophysiological basis of reversible cerebral vasoconstriction syndrome is poorly understood but carotid artery dissection has been discussed as a rare possible cause. So far, only single cases of unilateral carotid artery dissection and reversible cerebral vasoconstriction syndrome have been reported. Case: Here, we describe the case of a 54-year old patient presenting to the emergency department with right hemiparesis, hypaesthesia and dysarthria. Furthermore, he reported two episodes of thunderclap headache after autosexual activity. Cerebral imaging showed ischaemic infarcts, slight cortical subarachnoid haemorrhage, bilateral carotid artery dissection and fluctuating intracranial vessel irregularities, compatible with reversible cerebral vasoconstriction syndrome. An extensive diagnostic work-up was normal. No typical trigger factors of reversible cerebral vasoconstriction syndrome could be found. The patient received intravenous heparin and the calcium channel blocker nimodipine. Follow-up imaging revealed no vessel irregularities, the left internal carotid artery was still occluded. Conclusion: This case supports the assumption that carotid artery dissection should be considered as a potential trigger of reversible cerebral vasoconstriction syndrome, possibly by altering sympathetic vascular tone

Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro

Background and Purpose—Mutations in NOTCH3 cause cerebral autosomal–dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic cause of stroke and vascular dementia. Misfolding and aggregation of NOTCH3 proteins triggered by cysteine-affecting mutations are considered to be the key disease mechanisms. However, the significance of cysteine-sparing mutations is still debated.&lt;p&gt;&lt;/p&gt; Methods—We studied a family with inherited small vessel disease by standardized medical history, clinical examination, MRI, ultrastructural analysis of skin biopsies, and Sanger sequencing of all NOTCH3 exons. In addition, we performed in vitro characterization of NOTCH3 variants using recombinant protein fragments and a single-particle aggregation assay.&lt;p&gt;&lt;/p&gt; Results—We identified a novel cysteine-sparing NOTCH3 mutation (D80G) in 4 family members, which was absent in a healthy sibling. All mutation carriers exhibited a CADASIL typical brain imaging and clinical phenotype, whereas skin biopsy showed inconsistent results. In vitro aggregation behavior of the D80G mutant was similar compared with cysteine-affecting mutations. This was reproduced with cysteine-sparing mutations from previously reported families having a phenotype consistent with CADASIL.&lt;p&gt;&lt;/p&gt; Conclusions—Our findings support the view that cysteine-sparing mutations, such as D80G, might cause CADASIL with a phenotype largely indistinguishable from cysteine mutations. The in vitro aggregation analysis of atypical NOTCH3 mutations offers novel insights into pathomechanisms and might represent a tool for estimating their clinical significance.&lt;p&gt;&lt;/p&gt