Uncovering genetic mimics in multiple sclerosis: A single-center clinical exome sequencing study.

Background: Multiple sclerosis (MS) shares clinical/radiological features with several monogenic diseases that can mimic MS. Objective: We aimed to determine if exome sequencing can identify monogenic diseases in patients diagnosed with MS according to the McDonald criteria thus uncovering them as being misdiagnosed. Methods: We performed whole exome sequencing in a cohort of 278 patients with MS, clinically or radiologically isolated syndrome without cerebrospinal fluid-specific oligoclonal bands (CSF-OCBs) (n = 228), a positive family history of MS (n = 44), or both (n = 6), thereby focusing on individuals potentially more likely to have underlying monogenic conditions mimicking MS. We prioritized 495 genes associated with monogenic diseases sharing features with MS. Results: A disease-causing variant in NOTCH3 was identified in one patient without CSF-OCBs, no spinal lesions, with non-response to immunotherapy, and a family history of dementia, thereby converting the diagnosis to cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Moreover, 18 patients (6.5% of total) carried variants of unclear significance. Conclusion: Monogenic diseases being misdiagnosed as MS seem rare in patients diagnosed with MS according to the McDonald criteria, even in CSF-OCB negative cases. The detected pathogenic NOTCH3 variant emphasizes CADASIL as a rare differential diagnosis and highlights the relevance of genetic testing in selected MS cases with atypical presentations.

Exome-based gene panel analysis in a cohort of acute juvenile ischemic stroke patients:relevance of NOTCH3 and GLA variants.

BACKGROUND: Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. MATERIAL AND METHODS: We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. RESULTS: Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry's disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). CONCLUSION: Genetic screening for Fabry's disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

Histology of Cerebral Clots in Cryptogenic Stroke Varies According to the Presence of a Patent Foramen Ovale.

Although a pathophysiological impact remains difficult to prove in individual patient care, a patent foramen ovale (PFO) is currently considered of high relevance for secondary prophylaxis in selected patients with cryptogenic ischemic stroke. By quantification of histological clot composition, we aimed to enhance pathophysiological understanding of PFO attributable ischemic strokes. Retrospectively, we evaluated all cerebral clots retrieved by mechanical thrombectomy for acute ischemic stroke treatment between 2011 and 2021 at our comprehensive stroke care center. Inclusion criteria applied were cryptogenic stroke, age (≤60 years), and PFO status according to transesophageal echocardiography, resulting in a study population of 58 patients. Relative clot composition was calculated using orbit image analysis to define the ratio of main histologic components (fibrin/platelets (F/P), red blood cell count (RBC), leukocytes). Cryptogenic stroke patients with PFO (PFO+, n = 20) displayed a significantly higher percentage of RBC (0.57 ± 0.17; p = 0.002) and lower percentage of F/P (0.38 ± 0.15; p = 0.003) compared to patients without PFO (PFO-, n = 38) (RBC: 0.41 ± 0.21; F/P: 0.52 ± 0.20). In conclusion, histologic clot composition in cryptogenic stroke varies depending on the presence of a PFO. Our findings histologically support the concept that a PFO may be of pathophysiological relevance in cryptogenic ischemic stroke.

Ischemic Stroke of Suspected Cardioembolic Origin Despite Anticoagulation: Does Thrombus Analysis Help to Clarify Etiology?

Introduction: Despite sufficient oral anticoagulation (OAC) to prevent cardioembolism, some patients suffer from cerebral ischemic strokes of suspected cardioembolic origin. Reasons for that are not clarified yet. In certain cases, the suspected cardioembolic origin of stroke is questioned. This study aimed to understand the thrombi origin and pathophysiology in patients suffering from stroke despite OAC by the analysis of histologic thrombus composition and imaging characteristics. Materials and Methods: On two distinct cohorts, we retrospectively analyzed histologic (n = 92) and imaging features (n = 64), i.e., thrombus perviousness in admission CT imaging, of cerebral thrombi retrieved by the endovascular treatment for a large vessel occlusion of the anterior circulation. In each group, patients with non-cardioembolic strokes and suspected cardioembolic strokes with or without anticoagulation were compared. Results: Fibrin/platelet content of suspected cardioembolic thrombi (mean/SD 57.2% ± 13) is higher than in non-cardioembolic thrombi (48.9% ± 17; p = 0.01). In suspected cardioembolic thrombi, the fibrin/platelet content does not differ in the subgroups of patients with (57.3% ± 13) and without prior OAC treatment (56.6% ±13; p = 0.8), both with higher values than non-cardioembolic thrombi. Thrombus perviousness (ε) of suspected cardioembolic OAC thrombi (mean/SD: 0.09 ± 0.06) differs significantly from non-cardioembolic thrombi (0.02 ± 0.02; p < 0.001). Further, ε is higher in suspected cardioembolic thrombi with OAC than in cardioembolic thrombi without OAC (0.06 ± 0.03; p = 0.04) and with insufficient OAC (0.04 ± 0.02; p = 0.07). Conclusion: Thrombi of the suspected cardioembolic origin of patients with prior OAC do not differ in their histologic composition from those without prior OAC, but both differ from non-cardioembolic thrombi. These histologic results make a non-cardioembolic etiology for strokes despite prior OAC rather unlikely but favor other reasons for these ischemic events. Perviousness assessment reinforces the histologic findings, with additional information about the OAC thrombi, which present with higher perviousness. This suggests that OAC would not affect the relative histologic thrombus composition but may alter the microstructure, as reflected by perviousness.

Clinical implications of the incidental finding of a free-floating thrombus in the internal carotid artery.

We present an 81-year old male in whom a routine carotid artery ultrasonographic follow-up examination incidentally revealed a large, free-floating thrombus (FFT) of the right internal carotid artery. This case focuses on the clinical decision-making regarding FFTs, which constitute a rare condition lacking a diagnostic gold standard with few available data concerning optimum treatment and natural course-in particular regarding patients in whom FFT is an incidental finding. We were able to demonstrate the accuracy of carotid artery ultrasonography in the detection as well as follow-up of FFT. Of clinical interest is furtherly a possible partial disappearance by spontaneous re-adhesion or resolution of the FFT.