De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

Current State and Future Directions in the Therapy of ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.

Acute Middle Cerebral Artery Occlusion Detection Using Mobile Non-Imaging Brain Perfusion Ultrasound-First Case.

Mobile brain perfusion ultrasound (BPU) is a novel non-imaging technique creating only hemispheric perfusion curves following ultrasound contrast injection and has been specifically designed for early prehospital large vessel occlusion (LVO) stroke identification. We report on the first patient investigated with the SONAS® system, a portable point-of-care ultrasound system for BPU. This patient was admitted into our stroke unit about 12 h following onset of a fluctuating motor aphasia, dysarthria and facial weakness resulting in an NIHSS of 3 to 8. Occlusion of the left middle cerebral artery occlusion was diagnosed by computed tomography angiography. BPU was performed in conjunction with injection of echo-contrast agent to generate hemispheric perfusion curves and in parallel, conventional color-coded sonography (TCCS) assessing MCAO. Both assessments confirmed the results of angiography. Emergency mechanical thrombectomy (MT) achieved complete recanalization (TICI 3) and post-interventional NIHSS of 2 the next day. Telephone follow-up after 2 years found the patient fully active in professional life. Point-of-care BPU is a non-invasive technique especially suitable for prehospital stroke diagnosis for LVO. BPU in conjunction with prehospital stroke scales may enable goal-directed stroke patient placement, i.e., directly to comprehensive stroke centers aiming for MT. Further results of the ongoing phase II study are needed to confirm this finding.

Recurrent vertebrobasilar strokes and transient-ischemic attacks with challenging workup: Case report.

Detecting the stroke etiology in young patients can be challenging. Among others, determining causality between ischemic stroke and patent foramen ovale (PFO) remains a complicated task for stroke neurologists, given the relatively high prevalence of PFOs. Thorough diagnostic workup to identify incidental vascular risk factors and rare embolic sources is crucial to avoid premature PFO closure suggesting successful secondary stroke prevention. In this paper, we report on a 38-year-old patient with recurrent vertebrobasilar territory, especially right posterior inferior cerebellar artery (PICA) territory strokes. After the initial suspicion of a left vertebral artery (VA) dissection was not confirmed by ultrasound and magnetic resonance imaging (MRI) and other major risk factors were excluded, a PFO was detected and closed. Successful PFO closure was confirmed by transesophageal echocardiography, yet recurrent transient-ischemic attacks and vertebrobasilar strokes, especially during nighttime and in the early morning, occurred despite various antiplatelet and antithrombotic regimes and a persistent right-to-left shunt was detected by bubble transcranial Doppler. Finally, MRI after another vertebrobasilar infarction detected a transient left VA occlusion that finally led to the diagnosis of a left VA pseudoaneurysm from an incident emboligenic dissection in the atlas segment. This pseudoaneurysm together with an anatomical variant of the right PICA originating with the right anterior inferior cerebellar artery from the basilar artery finally explained the recurrent ischemic events of the patient. After successful treatment with coil occlusion, the patient suffered no further stroke and recovered completely. In summary, stroke in the young remains a diagnostic challenge. The incidental finding of a PFO should not deter from thorough stroke workup and the follow-up of these patients including PFO closure verification should be performed under the guidance of vascular neurologists.

Index event of cerebral amyloid angiopathy (CAA) determines long-term prognosis and recurrent events (retrospective analysis and clinical follow-up).

BACKGROUND: The modified Boston criteria (mBC) define the probability for the diagnosis of cerebral amyloid angiopathy (CAA). Its initial clinical presentation differs from asymptomatic cerebral microbleedings (cMBs), acute ischemic stroke (AIS), cortical hemosiderosis (cSS), to lobar ICH (lICH). METHODS: Retrospective analyses and clinical follow-ups of individuals with at least mBC "possible" CAA from 2005 to 2018. RESULTS: 149 patients were classified in subgroups due to the index event: lICH (n = 91), AIS (n = 32), > 3 cMBs only (n = 16) and cSS (n = 10). Patients in the lICH subgroup had a significantly higher percentage of single new lICHs compared to other groups, whereas patients in the AIS-group had a significantly higher percentage of multiple new AIS. cMBs as index event predisposed for AIS during follow up (p < 0.0016). Patients of the cMBs- or cSS-group showed significantly more TFNEs (transient focal-neurological episodes) and lower numbers of asymptomatic patients (for epilepsy and TFNEs) at the index event than patients with lICH or AIS (p < 0.0013). At long-term follow-up, the cMBs- and cSS-group were characterized by more TFNEs and fewer asymptomatic patients. CONCLUSIONS: A new classification system of CAA should add subgroups according to the initial clinical presentation to the mBCs allowing individual prognosis, acute treatment and secondary prophylaxis.

Cerebrovascular Risk Factors in Possible or Probable Cerebral Amyloid Angiopathy, Modifier or Bystander?

Goal: Cerebral amyloid angiopathy (CAA) is a frequent cause of atypical intracerebral hemorrhage (ICH) in the elderly. Stroke risk factors such as arterial hypertension (AHT), atrial fibrillation (AFib), diabetes mellitus (DM), and renal dysfunction (RD) are increasingly apparent in these patients. In this retrospective study, we analyzed the presence of these stroke risk factors in different initial CAA presentations comprising cerebral microbleeds (CMB), acute ischemic stroke (AIS), cortical superficial hemosiderosis (cSS), or lobar ICH (LICH) and evaluated their influence on the initial clinical presentation of patients with CAA. Material and Methods: We identified patients with at least possible CAA defined by the modified Boston criteria admitted to the Department of Neurology or Neurosurgery from 2002 to 2018. Findings: In the overall cohort of 209 patients, we analyzed the correlation between the number of stroke risk factors and the initial clinical presentation of patients with CAA and could show the high multimorbidity of the collective. There are large differences between the subgroups with different initial clinical presentations, e.g., patients with CMB as initial CAA presentation have the highest number of cerebrovascular risk factors and recurrent AIS, whereas AFib is more frequent in the Neurosurgery Department. Conclusion: There is a distinct overlap between the subgroups of CAA manifestations and stroke risk factors that need to be verified in larger patient collectives. Since these comorbidities are likely to influence the clinical course of CAA, they represent possible targets for secondary prevention until specific treatment for CAA becomes available.

Decline and Recurrence of Stroke Consultations during the COVID-19 Pandemic Lockdown Parallels Population Activity Levels.

BACKGROUND: The COVID-19 pandemic lockdown (CPL) lead to a significant decrease in emergency admissions worldwide. We performed a timely analysis of ischemic stroke (IS) and related consultations using the telestroke TEMPiS "working diagnosis" database prior (PL), within (WL), and after easing (EL) of CPL. METHODS: Twelve hospitals were selected and data analyzed regarding IS (including intravenous thrombolysis [intravenous recombinant tissue plasminogen; IV rtPA] and endovascular thrombectomy [EVT]) and related events from February 1 to June 15 during 2017-2020. In addition, we aimed to correlate events to various mobile phone mobility data. RESULTS: Following the significant reduction of IS, IV rtPA, and EVT cases during WL compared to PL in 2020 longitudinally (p values <0.048), we observed increasing numbers of consultations, IS, recommendations for EVT, and IV rtPA with the network in EL over WL not reaching PL levels yet. Absolute numbers of all consultations paralleled best to mobility data of public transportation over walking and driving mobility. CONCLUSIONS: While the decrease in emergency admissions including stroke during CPL can only be in part attributed by patients not seeking medical attention, stroke awareness in the pandemic, and direct COVID-19 triggered stroke remains of high importance. The number of consultations in TEMPiS during the lockdown parallels best with mobility of public transportation. As a consequence, exposure to common viruses, well-known triggers for acute cerebrovascular events and other diseases, are reduced and may add to the decline in stroke consultations. Further studies comparing national responses toward the course of the COVID-19 pandemic and stroke incidences are needed.