Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers

Objectives: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity. Methods: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain). Results: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had 65 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls. Interpretation: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious

Gray Matter Changes in Parkinson's and Alzheimer's Disease and Relation to Cognition

Purpose of Review We summarize structural (s)MRI findings of gray matter (GM) atrophy related to cognitive impairment in Alzheimer's disease (AD) and Parkinson's disease (PD) in light of new analytical approaches and recent longitudinal studies results. Recent Findings The hippocampus-to-cortex ratio seems to be the best sMRI biomarker to discriminate between various AD subtypes, following the spatial distribution of tau pathology, and predict rate of cognitive decline. PD is clinically far more variable than AD, with heterogeneous underlying brain pathology. Novel multivariate approaches have been used to describe patterns of early subcortical and cortical changes that relate to more malignant courses of PD. New emerging analytical approaches that combine structural MRI data with clinical and other biomarker outcomes hold promise for detecting specific GM changes in the early stages of PD and preclinical AD that may predict mild cognitive impairment and dementia conversion

Impact of e-ASPECTS software on the performance of physicians compared to a consensus ground truth: a multi-reader, multi-case study

BackgroundThe Alberta Stroke Program Early CT Score (ASPECTS) is used to quantify the extent of injury to the brain following acute ischemic stroke (AIS) and to inform treatment decisions. The e-ASPECTS software uses artificial intelligence methods to automatically process non-contrast CT (NCCT) brain scans from patients with AIS affecting the middle cerebral artery (MCA) territory and generate an ASPECTS. This study aimed to evaluate the impact of e-ASPECTS (Brainomix, Oxford, UK) on the performance of US physicians compared to a consensus ground truth.MethodsThe study used a multi-reader, multi-case design. A total of 10 US board-certified physicians (neurologists and neuroradiologists) scored 54 NCCT brain scans of patients with AIS affecting the MCA territory. Each reader scored each scan on two occasions: once with and once without reference to the e-ASPECTS software, in random order. Agreement with a reference standard (expert consensus read with reference to follow-up imaging) was evaluated with and without software support.ResultsA comparison of the area under the curve (AUC) for each reader showed a significant improvement from 0.81 to 0.83 (p = 0.028) with the support of the e-ASPECTS tool. The agreement of reader ASPECTS scoring with the reference standard was improved with e-ASPECTS compared to unassisted reading of scans: Cohen's kappa improved from 0.60 to 0.65, and the case-based weighted Kappa improved from 0.70 to 0.81.ConclusionDecision support with the e-ASPECTS software significantly improves the accuracy of ASPECTS scoring, even by expert US neurologists and neuroradiologists

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality among Patients with COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 � 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 �103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7) were included in the primary analysis (median interquartile range age, 62 50-71 years; 237 42.2% women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% 95% CI,-6.6% to 9.8%; odds ratio, 1.06 95% CI, 0.76-1.48; P =.70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% 1-sided 97.5% CI,-� to 3.4%; odds ratio, 1.83 1-sided 97.5% CI, 0.00-5.93), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% 95% CI, 0.4%-3.8%; P =.01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508. © 2021 American Medical Association. All rights reserved

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications

Co-existing fast CSF leaks and CSF-venous fistulas on dynamic CT myelography

Spontaneous intracranial hypotension can be caused by spinal dural tears or CSF-venous fistulas. It is rare for patients to have more than one type of leak at any given time. Here, we illustrate 3 examples of dural tears that co-existed with CSF-venous fistulas, with both being seen on dynamic CT myelography. To our knowledge, coexistent CSF-venous fistulas and dural tears have not been previously illustrated on dynamic CT myelography, even though this is one of the most commonly used modalities to work-up patients with CSF leaks. We discuss the clinical importance of the rare co-occurrence of these leaks with regard to diagnosis and treatment, as well as implications for understanding and classifying CSF leaks

Comparison of 1.5 Tesla and 3.0 Tesla Magnetic Resonance Imaging in the Evaluation of Acute Demyelinating Optic Neuritis

Background: Optic neuritis (ON) is the most common optic neuropathy in young adults. MRI is reported to have a high sensitivity for ON. Higher signal strengths of MRI may enhance resolution and lead to better detection of ON. We sought to compare the sensitivity of 3.0 Tesla (T) MRI to that of 1.5 T MRI in detecting acute demyelinating ON. Methods: A retrospective chart review was performed on patients with a clinical diagnosis of optic neuritis at Mayo Clinic Health System from January 2010 to April 2020. Among 1,850 patients identified, 126 patients met the eligibility criteria. Exclusion criteria comprised questionable or alternative diagnosis, diagnosis of ON before the study period, eye examinations performed elsewhere, or absence of fat-saturated head and orbits MRIs performed locally within 30 days of symptom onset. Gadolinium contrast enhancement, T2 hyperintensity, and the radiologic diagnosis of ON were recorded by a neuro-radiologist who was masked to the clinical history and the magnet strength of the MRI. Results: Fifty-three patients (42.1%) had 3.0 T MRI, and 73 patients (57.9%) had 1.5 T MRI. Overall, 88.9% (112/126) of patients were determined to have a positive MRI for ON. The radiographic sensitivity for ON was higher in the 3.0 T group compared with the 1.5 T group (98.1% vs 82.2%, respectively [ P = 0.004]). The frequency of gadolinium enhancement was found to be greater in the 3 T group compared with the 1.5 T group (98.1% vs 76.7%, respectively [ P < 0.001]). T2 hyperintensity was also more often seen in the 3.0 T group compared with the 1.5 T group (88.7% vs 68.5%, respectively [ P = 0.01]). Conclusions: 3.0 T MRI is more sensitive than 1.5 T MRI in detecting ON. This finding suggests that 3.0 T MRI is a preferred imaging modality for the confirmation of ON

Voxel-level imaging findings in lvPPA and DAT when compared to controls.

<p>Three dimensional renderings show regions of reduced FDG metabolism and gray matter (GM) volume in lvPPA compared to controls and in DAT compared to controls. All images were generated using an FDR corrected statistical threshold of p<0.0005 and an extent threshold of 100 voxels. A decrease in brightness of the render reflects increased distance from the surface of the tissue.</p