MRI evidence of gray matter loss in COVID-19 patients with cognitive and olfactory disorders.

OBJECTIVE: The aim of this study was to assess COVID-19-related gray matter (GM) structural alterations in two distinct groups of patients presenting with the prevailing and distinctive COVID-19-related neurological symptoms - isolated olfactory disorders as sole neurological manifestation (COVID-OD) and cognitive disorders (COVID-CD) - as compared to a control group of unaffected individuals. METHODS: The study included 61 COVID-CD patients (57 [60-63] years, 62% females), 84 COVID-OD patients (49 [35-57] years, 60% females), and 17 controls (51 [41-52] years, 41% females). Region-based morphometry (RBM) and voxel-based morphometry (VBM) were performed on T1-weighted MRI scans to assess GM regional volume and voxel-wise density differences between COVID-19 patients and controls. Surface-based morphometry (SBM) was applied to investigate cortical thickness alterations. The statistical models built to assess GM structural differences among groups included total intracranial volume and age as nuisance variables. RESULTS: The multi-morphometric analysis revealed statistically significant (p < 0.05 corrected for multiple comparisons) reduction in GM regional volumes, in voxel-wise GM density and in cortical thickness in both COVID-CD and COVID-OD patient groups as compared to controls. Across all three analyses, COVID-CD patients showed more distributed and severe GM loss than COVID-OD patients. The most prominently affected GM regions in the COVID-CD group included the hippocampus, putamen, cingulate gyrus, precuneus, precentral and postcentral gyri, amygdala, lingual gyrus, and caudate nucleus. INTERPRETATION: Our MRI findings show that COVID-19-related olfactory and cognitive disorders both induce GM atrophy, although at different degrees of severity, likely indicative of neurodegeneration and neuroinflammation.

Presentation and Outcome in S1P-RM and Natalizumab-Associated Progressive Multifocal Leukoencephalopathy: A Multicenter Cohort Study.

BACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. METHODS: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. RESULTS: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). DISCUSSION: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Muscle hypertrophy following acquired neurogenic injury: systematic review and analysis of existing literature.

OBJECTIVES: Neurogenic muscle hypertrophy (NMH) is a rare condition characterized by focal muscle hypertrophy caused by chronic partial nervous injury. Given its infrequency, underlying mechanisms remain poorly understood. Inspired by two clinical cases, we conducted a systematic review to gain insights into the different aspects of NMH. METHODS: We systematically searched online databases up until May 30, 2023, for reports of muscle hypertrophy attributed to acquired neurogenic factors. We conducted an exploratory analysis to identify commonly associated features. We also report two representative clinical cases. RESULTS: Our search identified 63 reports, describing 93 NMH cases, to which we added our two cases. NMH predominantly affects patients with compressive radiculopathy (68.4%), negligible muscular weakness (93.3%), and a chronic increase in muscle bulk. A striking finding in most neurophysiological studies (60.0%) is profuse spontaneous discharges, often hindering the analysis of voluntary traces. Some patients exhibited features consistent with more significant muscle damage, including higher creatine phosphokinase levels, muscle pain, and inflammatory muscle infiltration. These patients are sometimes referred to in literature as "focal myositis." Treatment encompassed corticosteroid, Botulinum Toxin A, decompressive surgery, antiepileptic medications, and nerve blocks, demonstrating varying degrees of efficacy. Botulinum Toxin A yielded the most favorable response in terms of reducing spontaneous discharges. INTERPRETATION: This systematic review aims to provide a clear description and categorization of this uncommon presentation of an often-overlooked neurological disorder. Though questions remain about the underlying mechanism, evidence suggests that aberrant fiber overstimulation along with increased workload that promotes focal damage may result in muscle hypertrophy. This may serve as a guide for therapeutic interventions.

Expanding the Neurological Phenotype of Anderson-Fabry Disease: Proof of Concept for an Extrapyramidal Neurodegenerative Pattern and Comparison with Monogenic Vascular Parkinsonism.

Anderson-Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson's disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients' information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations.

Intracranial Pressure Thresholds for Cerebral Autoregulation Impairment: Age-Stratified Analysis of Ultra-Low-Frequency Pressure Reactivity Index (UL-PRx) in Traumatic Brain Injury.

BACKGROUND: The study investigated the effectiveness of low-frequency sampling in detecting alterations in cerebrovascular reactivity (CVR) associated with changes in intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across different age groups. The primary objective was to investigate an ICP threshold that indicates a decrease in CVR as evidenced by a significant increase in the ultra-low-frequency pressure reactivity index (UL-PRx). Additionally, the study aimed to develop an age-based categorization method for patients with TBI to investigate the differences between these ICP thresholds in different age groups. METHODS: In this retrospective analysis, data from 263 patients with TBI were prospectively collected. ICP and mean arterial pressure were extracted from the hospital database at 5-min intervals. Demographic details, clinical presentation, computed tomography scans, neurosurgical interventions, and 12-months outcome were recorded. ICP versus UL-PRx values were categorized into ICP bins and graphically represented with boxplots for each age group, illustrating how as ICP values rise, there is a bin (age-tailored ICP [AT-ICP]) beyond which UL-PRx shows a sudden increase, indicating CVR loss. Homogeneous age groups were established to obtain a consistent AT-ICP threshold. The discriminatory ability of the AT-ICP thresholds was compared with the guideline-recommended thresholds by calculating the area under the Receiver Operating Characteristic curve of the ICP-derived indices (dose above threshold, and the hourly dosage above threshold). RESULTS: Age groups 0-5, 6-20, 21-60, 61-70, and 71-85 years were the best age subdivisions, corresponding to AT-ICP thresholds of 20, 30, 35, 25, and 30 mmHg, respectively. The AT-ICP thresholds exhibited better discriminative ability compared with the guideline-recommended thresholds. CONCLUSIONS: The AT-ICP thresholds offer a novel approach for estimating CVR impairment and the developed method represents an alternative solution to address the age stratification issue in patients with TBI.

Brain microstructure and connectivity in COVID-19 patients with olfactory or cognitive impairment.

INTRODUCTION: The COVID-19 pandemic has affected millions worldwide, causing mortality and multi-organ morbidity. Neurological complications have been recognized. This study aimed to assess brain structural, microstructural, and connectivity alterations in patients with COVID-19-related olfactory or cognitive impairment using post-acute (time from onset: 264[208-313] days) multi-directional diffusion-weighted MRI (DW-MRI). METHODS: The study included 16 COVID-19 patients with cognitive impairment (COVID-CM), 35 COVID-19 patients with olfactory disorder (COVID-OD), and 14 controls. A state-of-the-art processing pipeline was developed for DW-MRI pre-processing, mean diffusivity and fractional anisotropy computation, fiber density and cross-section analysis, and tractography of white-matter bundles. Brain parcellation required for probing network connectivity, region-specific microstructure and volume, and cortical thickness was based on T1-weighted scans and anatomical atlases. RESULTS: Compared to controls, COVID-CM patients showed overall gray matter atrophy (age and sex corrected p = 0.004), and both COVID-19 patient groups showed regional atrophy and cortical thinning. Both groups presented an increase in gray matter mean diffusivity (corrected p = 0.001), decrease in white matter fiber density and cross-section (corrected p < 0.05), , and COVID-CM patients also displayed an overall increased diffusivity (p = 0.022) and decreased anisotropy (corrected p = 0.038) in white matter. Graph-based analysis revealed reduced network modularity, with an extensive pattern of connectivity increase, in conjunction with a localized reduction in a few connections, mainly located in the left hemisphere. The left cingulate, anterior cingulate, and insula were primarily involved. CONCLUSION: Expanding upon previous findings, this study further investigated significant alterations in brain morphology, microstructure, and connectivity in COVID-19 patients with olfactory or cognitive disfunction. These findings suggest underlying neurodegeneration, neuroinflammation, and concomitant compensatory mechanisms. Future longitudinal studies are required to monitor the alterations over time and assess their transient or permanent nature.

Neuroradiological manifestations in hospitalized patients with COVID-19: An Italian national multicenter study on behalf of AINR (Associazione Italiana di Neuroradiologia) and SIRM (Società Italiana di Radiologia Medica).

PURPOSE: This multicentric study aims to characterize and assess the occurrence of neuroradiological findings among patients with SARS-CoV-2 infection during the first Italian wave of the pandemic outbreak. MATERIALS AND METHODS: Patients' data were collected between May 2020 and June 2020. Clinical and laboratory data, chest imaging, brain CT, and MRI imaging were included. Acquired data were centralized and analyzed in two hospitals: ASST Spedali Civili, Brescia, and IRRCS San Raffaele Research Hospital, Milan, Italy. COVID-19 patients were classified into two different subgroups, vascular and nonvascular. The vascular pattern was further divided into ischemic and hemorrhagic stroke groups. RESULTS: Four hundred and fifteen patients from 20 different Italian Centers were enrolled in the study. The most frequent symptom was focal neurological deficit, found in 143 patients (34.5%). The most frequent neuroradiological finding was ischemic stroke in 122 (29.4%) patients. Forty-four (10.6%) patients presented a cerebral hemorrhage. Forty-seven patients had non-stroke neuroimaging lesions (11.3%). The most common was PRES-like syndrome (28%), SWI hypointensities (22%), and encephalitis (19%). The stroke group had higher CAD risk (37.5% vs 20%, p = .016) and higher D-dimer levels (1875 ng/mL vs 451 ng/mL, p < .001) compared to the negative group. CONCLUSION: Our study describes the biggest cohort study in Italy on brain imaging of COVID-19 patients and confirms that COVID-19 patients are at risk of strokes, possibly due to a pro-thrombotic microenvironment. Moreover, apart from stroke, the other neuroradiological patterns described align with the ones reported worldwide.

Cerebral autoregulation in traumatic brain injury: ultra-low-frequency pressure reactivity index and intracranial pressure across age groups.

BACKGROUND: The ultra-low-frequency pressure reactivity index (UL-PRx) has been established as a surrogate method for bedside estimation of cerebral autoregulation (CA). Although this index has been shown to be a predictor of outcome in adult and pediatric patients with traumatic brain injury (TBI), a comprehensive evaluation of low sampling rate data collection (0.0033 Hz averaged over 5 min) on cerebrovascular reactivity has never been performed. OBJECTIVE: To evaluate the performance and predictive power of the UL-PRx for 12-month outcome measures, alongside all International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) models and in different age groups. To investigate the potential for optimal cerebral perfusion pressure (CPPopt). METHODS: Demographic data, IMPACT variables, in-hospital mortality, and Glasgow Outcome Scale Extended (GOSE) at 12 months were extracted. Filtering and processing of the time series and creation of the indices (cerebral intracranial pressure (ICP), cerebral perfusion pressure (CPP), UL-PRx, and deltaCPPopt (ΔCPPopt and CPPopt-CPP)) were performed using an in-house algorithm. Physiological parameters were assessed as follows: mean index value, % time above threshold, and mean hourly dose above threshold. RESULTS: A total of 263 TBI patients were included: pediatric (17.5% aged ≤ 16 y) and adult (60.5% aged > 16 and < 70 y and 22.0% ≥ 70 y, respectively) patients. In-hospital and 12-month mortality were 25.9% and 32.7%, respectively, and 60.0% of patients had an unfavorable outcome at 12 months (GOSE). On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month outcomes. The cutoff of ~ 20-22 for mean ICP and of ~ 0.30 for mean UL-PRx were confirmed in all age groups, except in patients older than 70 years. Mean UL-PRx remained significantly associated with 12-month outcomes even after adjustment for IMPACT models. This association was confirmed in all age groups. UL-PRx resulted associate with CPPopt. CONCLUSIONS: The study highlights UL-PRx as a tool for assessing CA and valuable outcome predictor for TBI patients. The results emphasize the potential clinical utility of the UL-PRx and its adaptability across different age groups, even after adjustment for IMPACT models. Furthermore, the correlation between UL-PRx and CPPopt suggests the potential for more targeted treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05043545, principal investigator Paolo Gritti, date of registration 2021.08.21.

An optimized 1.5 Tesla MRI protocol of the brachial plexus.

PURPOSE: Creating an effective MRI protocol for examining the brachial plexus poses significant challenges, and despite the abundance of protocols in the literature, there is a lack of reference standards for basic sequences and essential parameters needed for replication. The aim of this study is to establish a reproducible 1.5 T brachial plexus imaging protocol, including patient positioning, coil selection, imaging planes, and essential sequence parameters. METHODS: We systematically investigated MRI sequences, testing each parameter through in vivo experiments, examining their effects on signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), visual quality scores, and acquisition time. Sequences were refined based on optimal quality and timing scores. The final protocol was tested on scanners from two other vendors for reliability. RESULTS: The final protocol included a combination of 2D turbo-spin-echo and 3D SPACE T1, SPACE STIR, and VIBE DIXON sequences. Recommendations for imaging planes, phase encoding, field of view, TR, TE, resolution, number of slices, slice thickness, fat and blood suppression, and acceleration strategies are provided. The protocol was successfully translated to other vendor's scanners with comparable quality. CONCLUSION: We present an optimized protocol detailing the essential parameters for reproducibility. Our comprehensive list of experiments describes the impact of each parameter on image quality and scan time, addressing common artifacts and potential solutions. This protocol can benefit both young radiologists new to the field and experienced professionals seeking to refine their existing protocols.

Neuromuscular imaging in clinical practice: an ESNR survey of 30 centers.

PURPOSE: We assessed the current clinical imaging practice in the primary evaluation of neuromuscular disorders (NMD), with respect to standardized imaging, evaluation and reporting through a European and extra-European-wide survey. METHODS: An online questionnaire was emailed to all European Society of Neuroradiology (ESNR) members (n = 1662) who had expressed their interest in NMD. The questionnaire featured 40 individual items. Information was gathered on the context of the practices, available and preferred imaging modalities, applied imaging protocols and standards for interpretation, reporting and communication. RESULTS: A total of 30 unique entries from European and extra-European academic and non-academic institutions were received. Of these, 70% were neuroradiologists, 23% general radiologists and 7% musculoskeletal radiologists. Of the 30 responding institutes, 40% performed from 20 to 50 neuromuscular scans per year for suspected NMD. The principal modality used for a suspected myopathy was magnetic resonance imaging (MRI) (50%) or "mainly MRI" (47%). The primary imaging modality used for the evaluation of patients suspected of a neuropathy was MRI in 63% of all institutions and "mainly MRI" in 37%. For both muscle and nerve pathology, pelvic girdle and inferior limbs are the most scanned parts of the body (28%), followed by the thigh and leg (24%), whole body MR (24%), scapular girdle (16%), and the thigh in just 8% of institutions. Multiplanar acquisitions were performed in 50% of institutions. Convectional sequences used for muscle MRI included T2-STIR (88%), 2D T1weighted (w) (68%), T1 Dixon or equivalent (52%), T2 Dixon (40%), DWI (36%), 2D T2w (28%), T1 3D and T2 3D (20% respectively). For nerve MRI conventional sequences included T2-STIR (80%), DWI (56%), T2 3D (48%), 2D T2w (48%), T1 3D (44%), T1 Dixon or equivalent (44%), 2D T1 (36%), T2 Dixon (28%). Quantitative sequences were used regularly by 40% respondents. While only 28% of institutions utilized structured reports, a notable 88% of respondents expressed a desire for a standardized consensus structured report. Most of the respondents (93%) would be interested in a common MRI neuromuscular protocol and would like to be trained (87%) by the ESNR society with specific neuromuscular sessions in European annual meetings. CONCLUSIONS: Based on the survey findings, we can conclude that the current approach to neuromuscular imaging varies considerably among European and extra-European countries, both in terms of image acquisition and post-processing. Some of the challenges identified include the translation of research achievements (related to advanced imaging) into practical applications in a clinical setting, implementation of quantitative imaging post-processing techniques, adoption of structured reporting methods, and communication with referring physicians.

Neuroimaging findings in 4342 hospitalized COVID-19 subjects: A multicenter report from the United States and Europe.

BACKGROUND AND PURPOSE: To determine the incidence of acute neuroimaging (NI) findings and comorbidities in the coronavirus disease of 2019 (COVID-19)-infected subjects in seven U.S. and four European hospitals. METHODS: This is a retrospective study of COVID-19-positive subjects with the following inclusion criteria: age >18, lab-confirmed COVID-19 infection, and acute NI findings (NI+) attributed to COVID-19 on CT or MRI brain. NI+ and comorbidities in total hospitalized COVID-19-positive (TN) subjects were assessed. RESULTS: A total of 37,950 COVID-19-positive subjects were reviewed and 4342 underwent NI. NI+ incidence in subjects with NI was 10.1% (442/4342) including 7.9% (294/3701) in the United States and 22.8% (148/647) in Europe. NI+ incidence in TN was 1.16% (442/37,950). In NI (4342), incidence of ischemic stroke was 6.4% followed by intracranial hemorrhage (ICH) (3.8%), encephalitis (0.5%), sinus venous thrombosis (0.2%), and acute disseminated encephalomyelitis (ADEM) (0.2%). White matter involvement was seen in 57% of NI+. Hypertension was the most common comorbidity (54%) before cardiac disease (28.8%) and diabetes mellitus (27.7%). Cardiac disease (p < .025), diabetes (p < .014), and chronic kidney disease (p < .012) were more common in the United States. CONCLUSION: This multicenter, multinational study investigated the incidence and spectrum of NI+ in 37,950 hospitalized adult COVID-19 subjects including regional differences in incidences of NI+, associated comorbidities, and other demographics. NI+ incidence in TN was 1.16% including 0.95% in the United States and 2.09% in Europe. ICH, encephalitis, and ADEM were common in Europe, while ischemic strokes were more common in the United States. In this cohort, incidence and distribution of NI+ helped characterize the neurological complications of COVID-19.

Brain diffusion alterations in patients with COVID-19 pathology and neurological manifestations.

BACKGROUND AND OBJECTIVE: COVID-19 neurological manifestations have been progressively recognized. Among available MRI techniques, diffusion weighted imaging (DWI) shows promise to study microstructure, inflammation, and edema. Previous DWI studies reported alterations in brain diffusivity in COVID-19 patients, as assessed by morphologic evaluation of brain DWI scans only. The aim of this study was to assess and quantify brain diffusion alterations in COVID-19 patients with neurological manifestations. METHODS: 215 COVID-19 patients with neurological manifestations (olfactory and/or other neurological disorders) and 36 normal controls were compared and studied with DWI and T1-weighted MRI scans. MRI scans were processed by a semi-automatic processing procedure specifically developed for the purpose of this study, and the Apparent Diffusion Coefficient (ADC) was quantified in different brain tissues and individual white matter (WM) and gray matter (GM) regions. Differences in ADC values were assessed between COVID-19 patients and normal controls, as well as in the COVID-19 patient population grouped by hospitalization and neurological symptoms. RESULTS: Among COVID-19 patients (median [IQR] = 52 [42 - 60] years of age, 58 % females), 91 were hospitalized and 26 needed intensive care. 84 patients had hyposmia/ageusia only, while 131 ones showed other neurological disorders. COVID-19 patients showed significantly increased ADC values in the WM and in several GM regions (p < 0.001). ADC values were significantly correlated with MRI time from disease onset (p < 0.05). Hospitalized patients showed significantly higher ADC alteration than non-hospitalized patients in all brain tissues; similarly, COVID-19 patients with neurological disorders showed significantly higher ADC values than those with olfactory loss only. ADC alteration was highest in patients with cognitive or memory disorder and in those with encephalitis or meningitis. ADC values were neither associated with the duration of hospitalization nor with the need for intensive care. CONCLUSION: Current findings suggest DWI potential as a non-invasive marker of neuroinflammation in COVID-19, and the transient nature of the same. Future longitudinal studies are needed to confirm our findings.

MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms.

BACKGROUND AND OBJECTIVE: Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system's morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. METHODS: 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. RESULTS: COVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. CONCLUSIONS: Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology.

Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene.

Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.

Cerebral Microbleeds Assessment and Quantification in COVID-19 Patients With Neurological Manifestations.

It is increasingly acknowledged that Coronavirus Disease 2019 (COVID-19) can have neurological manifestations, and cerebral microbleeds (CMBs) have been observed in this setting. The aim of this study was to characterize CMBs patterns on susceptibility-weighted imaging (SWI) in hospitalized patients with COVID-19 with neurological manifestations. CMBs volume was quantified and correlated with clinical and laboratory parameters. The study included patients who were hospitalized due to COVID-19, exhibited neurological manifestations, and underwent a brain MRI between March and May 2020. Neurological, clinical, and biochemical variables were reported. The MRI was acquired using a 3T scanner, with a standardized protocol including SWI. Patients were divided based on radiological evidence of CMBs or their absence. The CMBs burden was also assessed with a semi-automatic SWI processing procedure specifically developed for the purpose of this study. Odds ratios (OR) for CMBs were calculated using age, sex, clinical, and laboratory data by logistic regression analysis. Of the 1,760 patients with COVID-19 admitted to the ASST Papa Giovanni XXIII Hospital between 1 March and 31 May 2020, 116 exhibited neurological symptoms requiring neuroimaging evaluation. Of these, 63 patients underwent brain MRI and were therefore included in the study. A total of 14 patients had radiological evidence of CMBs (CMBs+ group). CMBs+ patients had a higher prevalence of CSF inflammation (p = 0.020), a higher white blood cell count (p = 0.020), and lower lymphocytes (p = 0.010); the D-dimer (p = 0.026), LDH (p = 0.004), procalcitonin (p = 0.002), and CRP concentration (p < 0.001) were higher than in the CMBs- group. In multivariable logistic regression analysis, CRP (OR = 1.16, p = 0.011) indicated an association with CMBs. Estimated CMBs volume was higher in females than in males and decreased with age (Rho = -0.38; p = 0.18); it was positively associated with CRP (Rho = 0.36; p = 0.22), and negatively associated with lymphocytes (Rho = -0.52; p = 0.07). CMBs are a frequent imaging finding in hospitalized patients with COVID-19 with neurological manifestations and seem to be related to pro-inflammatory status.

Neuroimaging in patients with COVID-19: a neuroradiology expert group consensus.

Neurological and neuroradiological manifestations in patients with COVID-19 have been extensively reported. Available imaging data are, however, very heterogeneous. Hence, there is a growing need to standardise clinical indications for neuroimaging, MRI acquisition protocols, and necessity of follow-up examinations. A NeuroCovid working group with experts in the field of neuroimaging in COVID-19 has been constituted under the aegis of the Subspecialty Committee on Diagnostic Neuroradiology of the European Society of Neuroradiology (ESNR). The initial objectives of this NeuroCovid working group are to address the standardisation of the imaging in patients with neurological manifestations of COVID-19 and to give advice based on expert opinion with the aim of improving the quality of patient care and ensure high quality of any future clinical studies. KEY POINTS: • In patients with COVID-19 and neurological manifestations, neuroimaging should be performed in order to detect underlying causal pathology. • The basic MRI recommended protocol includes T2-weighted, FLAIR (preferably 3D), and diffusion-weighted images, as well as haemorrhage-sensitive sequence (preferably SWI), and at least for the initial investigation pre and post-contrast T1 weighted-images. • 3D FLAIR should be acquired after gadolinium administration in order to optimise the detection of leptomeningeal contrast enhancement.

SARS-CoV-2 infection and acute ischemic stroke in Lombardy, Italy.

OBJECTIVE: To characterize patients with acute ischemic stroke related to SARS-CoV-2 infection and assess the classification performance of clinical and laboratory parameters in predicting in-hospital outcome of these patients. METHODS: In the setting of the STROKOVID study including patients with acute ischemic stroke consecutively admitted to the ten hub hospitals in Lombardy, Italy, between March 8 and April 30, 2020, we compared clinical features of patients with confirmed infection and non-infected patients by logistic regression models and survival analysis. Then, we trained and tested a random forest (RF) binary classifier for the prediction of in-hospital death among patients with COVID-19. RESULTS: Among 1013 patients, 160 (15.8%) had SARS-CoV-2 infection. Male sex (OR 1.53; 95% CI 1.06-2.27) and atrial fibrillation (OR 1.60; 95% CI 1.05-2.43) were independently associated with COVID-19 status. Patients with COVID-19 had increased stroke severity at admission [median NIHSS score, 9 (25th to75th percentile, 13) vs 6 (25th to75th percentile, 9)] and increased risk of in-hospital death (38.1% deaths vs 7.2%; HR 3.30; 95% CI 2.17-5.02). The RF model based on six clinical and laboratory parameters exhibited high cross-validated classification accuracy (0.86) and precision (0.87), good recall (0.72) and F1-score (0.79) in predicting in-hospital death. CONCLUSIONS: Ischemic strokes in COVID-19 patients have distinctive risk factor profile and etiology, increased clinical severity and higher in-hospital mortality rate compared to non-COVID-19 patients. A simple model based on clinical and routine laboratory parameters may be useful in identifying ischemic stroke patients with SARS-CoV-2 infection who are unlikely to survive the acute phase.