Evaluation of the quality and the productivity of neuroradiological reading of multiple sclerosis follow-up MRI scans using an intelligent automation software.

PURPOSE: The assessment of multiple sclerosis (MS) lesions on follow-up magnetic resonance imaging (MRI) is tedious, time-consuming, and error-prone. Automation of low-level tasks could enhance the radiologist in this work. We evaluate the intelligent automation software Jazz in a blinded three centers study, for the assessment of new, slowly expanding, and contrast-enhancing MS lesions. METHODS: In three separate centers, 117 MS follow-up MRIs were blindly analyzed on fluid attenuated inversion recovery (FLAIR), pre- and post-gadolinium T1-weighted images using Jazz by 2 neuroradiologists in each center. The reading time was recorded. The ground truth was defined in a second reading by side-by-side comparison of both reports from Jazz and the standard clinical report. The number of described new, slowly expanding, and contrast-enhancing lesions described with Jazz was compared to the lesions described in the standard clinical report. RESULTS: A total of 96 new lesions from 41 patients and 162 slowly expanding lesions (SELs) from 61 patients were described in the ground truth reading. A significantly larger number of new lesions were described using Jazz compared to the standard clinical report (63 versus 24). No SELs were reported in the standard clinical report, while 95 SELs were reported on average using Jazz. A total of 4 new contrast-enhancing lesions were found in all reports. The reading with Jazz was very time efficient, taking on average 2min33s ± 1min0s per case. Overall inter-reader agreement for new lesions between the readers using Jazz was moderate for new lesions (Cohen kappa = 0.5) and slight for SELs (0.08). CONCLUSION: The quality and the productivity of neuroradiological reading of MS follow-up MRI scans can be significantly improved using the dedicated software Jazz.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma.

ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

A rare neuromyelitis optica mimic: Primary CNS histiocytic sarcoma.

Primary central nervous system (CNS) histiocytic sarcoma is a rare hematolymphoid malignancy with features of mature histiocytes and carries a poor prognosis. We describe a unique case in which a 50-year-old woman presented with recurrent acute brainstem syndrome, area postrema syndrome, and myelitis with corresponding magnetic resonance imaging (MRI) lesions meeting diagnostic criteria for seronegative neuromyelitis optica spectrum disorder (NMOSD). Despite initial improvement with steroids and plasma exchange, she experienced recurrent symptoms over 10 months referable to new and persistently enhancing lesions. At autopsy, neuropathology revealed a diffusely infiltrative primary CNS histiocytic sarcoma. This case represents a rare clinicoradiologic mimic of NMOSD, underscoring the importance of evaluation for infiltrative diseases in cases of atypical seronegative NMOSD.

KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM.

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Novel Foveal Features Associated With Vision Impairment in Multiple Sclerosis.

Purpose: To characterize scattering and hyperreflective features in the foveal avascular zone of people with multiple sclerosis (MS) using adaptive optics scanning laser ophthalmoscopy (AOSLO) and to evaluate their relationship with visual function and MS disease characteristics. Methods: Twenty subjects with MS underwent confocal reflectance and non-confocal split-detection AOSLO foveal imaging. Peripapillary retinal nerve fiber layer thickness was measured using optic nerve optical coherence tomography. Blood pressure, intraocular pressure (IOP), and best-corrected high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA) were measured. AOSLO images were graded to determine the presence and characteristics of distinct structures. Results: Two distinct structures were seen in the avascular zone of the foveal pit. Hyperreflective puncta, present in 74% of eyes, were associated with IOP and blood pressure. Scattering features, observed in 58% of eyes, were associated with decreased HCVA and LCVA, as well as increased MS duration and disability, but were not associated with retinal nerve fiber layer thickness. Hyperreflective puncta and scattering features were simultaneously present in 53% of eyes. Conclusions: Hyperreflective puncta were associated with parameters affecting ophthalmic perfusion, but they were not associated with MS disease parameters. Scattering features were associated with parameters corresponding to advanced MS, suggesting that they may be related to disease progression. Scattering features were also correlated with reduced visual function independent from ganglion cell injury, suggesting the possibility of a novel ganglion cell-independent mechanism of impaired vision in people with MS.

Feasibility and acceptability of virtually coaching residents on communication skills: a pilot study.

BACKGROUND: Developing communication skills is a key competency for residents. Coaching, broadly accepted as a training modality in medical education, has been proven a successful tool for teaching communication skills. Little research is available thus far to investigate virtual coaching on communication skills for telemedicine encounters. The purpose of the study was to test the hypothesis that virtually coaching residents on communication skills is feasible and acceptable. We surveyed 21 resident-faculty pairs participating in a "fully virtual" coaching session (patient, coach, and resident were virtual). METHODS: We asked 50 neurology resident-faculty coach pairs to complete one "fully virtual" coaching session between May 20 and August 31, 2020. After each session, the resident and coach completed a 15-item survey, including Likert-style scale and open-ended questions, assessing feasibility and acceptability. Descriptive statistics and qualitative content and thematic analyses were performed. RESULTS: Forty-two percent (21/50) of all eligible residents completed "fully virtual" coaching sessions. The overall survey response rate was 91 % (38/42). The majority of respondents agreed that the direct observation and debriefing conversation were easy to schedule and occurred without technical difficulties and that debriefing elements (self-reflection, feedback, takeaways) were useful for residents. Ninety-five percent of respondents rated the coach's virtual presence to be not at all disruptive to the resident-patient interaction. Virtual coaching alleviated resident stress associated with observation and was perceived as an opportunity for immediate feedback and a unique approach for resident education that will persist into the future. CONCLUSIONS: In this pilot study, residents and faculty coaches found virtual coaching on communication skills feasible and acceptable for telemedicine encounters. Many elements of our intervention may be adoptable by other residency programs. For example, residents may share their communication goals with clinic faculty supervisors and then invite them to directly observe virtual encounters what could facilitate targeted feedback related to the resident's goals. Moreover, virtual coaching on communication skills in both the in-person and telemedicine settings may particularly benefit residents in challenging encounters such as those with cognitively impaired patients or with surrogate decision-makers.

Human KIR + CD8 + T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19.

Previous reports show that Ly49 + CD8 + T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8 + T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR + CD8 + T cells can efficiently eliminate pathogenic gliadin-specific CD4 + T cells from Celiac disease (CeD) patients' leukocytes in vitro . Furthermore, we observe elevated levels of KIR + CD8 + T cells, but not CD4 + regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR + CD8 + T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8 + T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells. ONE-SENTENCE SUMMARY: Here we identified KIR + CD8 + T cells as a regulatory CD8 + T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4 + T cells.

Reduced neurite density in the brain and cervical spinal cord in relapsing-remitting multiple sclerosis: A NODDI study.

BACKGROUND: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). OBJECTIVE: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing-remitting MS (RRMS) patients. METHODS: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). RESULTS: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. CONCLUSION: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.

A case of GFAP-astroglial autoimmunity presenting with reversible parkinsonism.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a newly recognized autoimmune central nervous system (CNS) inflammatory disorder, presenting with an array of neurological symptoms in association with autoantibodies against GFAP, a hallmark protein expressed on astrocytes. Limited knowledge is available on the disease pathogenesis and clinical outcome. Here, we report a case of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism. Our patient was a 66-year old male who experienced progressive somnolence, apathy, anxiety, right arm tremor, urinary retention, progressive weakness, and falls over the course of three months, followed by acute delusional psychosis. His neurologic exam on hospital admission was notable for cognitive impairment, myoclonus, rigidity, right hand action tremor, bradykinesia, shuffling gait, and dysmetria. Cerebrospinal fluid examination showed elevated protein, lymphocytic pleocytosis, and one unique oligoclonal band. Magnetic resonance imaging (MRI) revealed non-specific T2/FLAIR hyperintensities in the brain and longitudinally extensive transverse myelitis in the cervical spine. FDG-PET showed a pattern of brain uptake suspicious for limbic encephalitis. Serum and CSF paraneoplastic panel showed presence of GFAP immunoglobulin G (IgG). Treatment with corticosteroids resulted in clinical and radiographic improvement. However, the patient was treated with anti-CD20 immunotherapy due to steroid-dependence. This case exemplifies the recently described neurologic syndrome of autoimmune GFAP astrocytopathy presenting with encephalomyelitis and parkinsonism, reversed by B lymphocyte depletion.

Immunomodulatory receptors are differentially expressed in B and T cell subsets relevant to autoimmune disease.

Inhibitory cell-surface receptors on lymphocytes, often called immune checkpoints, are powerful targets for cancer therapy. Despite their direct involvement in autoimmune pathology, they are currently not exploited therapeutically for autoimmune diseases. Understanding the expression pattern of these receptors in health and disease is essential for targeted drug design. Here, we designed three 23-colour flow cytometry panels for peripheral-blood T cells, including 15 lineage-defining markers and 21 immunomodulatory cell-surface receptors, and a 22-marker panel for B cells. Blood samples from healthy individuals, multiple sclerosis (MS), and lupus (SLE) patients were included in the study. Several receptors show differential expression on regulatory T cells (Treg) compared to T helper (Th) 1 and Th17 cells, and functional relevance of this difference could be shown for BTLA and CD5. Unbiased multiparametric analysis revealed a subset of activated CD8+ T cells and a subset of unswitched memory B cells that are diminished in MS and SLE, respectively.

Coexistence of Neuromyelitis Optica and Amyotrophic Lateral Sclerosis: A Case Report.

The occurrence of amyotrophic lateral sclerosis (ALS) and neuromyelitis optica (NMO) in a single patient is exceedingly rare. We report a case of a 54-year-old woman of East Asian descent with a prior diagnosis of ALS who developed an episode of unexplained hiccups and nausea and vomiting consistent with area postrema syndrome 3 months prior to the onset of acute transverse myelitis. Magnetic resonance imaging revealed abnormal T2 hyperintensity and gadolinium enhancement at the cervicomedullary junction with extension to C3. Imaging was also notable for nonenhancing central cord T2 hyperintensity from T6 to T8 suggesting previous demyelination. The patient's cerebrospinal fluid analysis was mildly inflammatory. She was found to have a positive NMO/aquaporin-4 immunoglobulin G titer (cell-based assay) greater than 1:100 000, consistent with a diagnosis of NMO. The unusual coexistence of ALS and NMO prompts consideration of potential common pathological neuroinflammatory processes.

Patient-Reported Benefits of Extracranial Venous Therapy: British Columbia CCSVI Registry.

Objective Chronic cerebrospinal venous insufficiency (CCSVI) has been hypothesized to be a risk factor for multiple sclerosis (MS). Venoplasty has been proposed as a treatment for CCSVI. The aim of our study was to gain a better understanding of the "real-world" safety and longitudinal effectiveness of venoplasty Methods: British Columbia residents who self-reported having had venoplasty and consented to participate in the study were interviewed and followed for up to 24 months post-therapy using standardized structured questionnaires Results: Participants reported procedure-related complications (11.5%) and complications within the first month after the procedure (17.3%). Initially, more than 40% of participants perceived that the venoplasty had had positive effects on their health conditions, such as fatigue, numbness, balance, concentration/memory and mobility. However, this improvement was not maintained over time Conclusions: Follow-up patient-reported outcomes indicated that the initial perception of the positive impact of venoplasty on the health conditions of MS patients was not sustained over time. In addition, venoplasty was not without associated morbidity.

Positive perception of pharmacogenetic testing for psychotropic medications.

INTRODUCTION: Pharmacogenetics attempts to identify inter-individual genetic differences that are predictive of variable drug response and propensity to side effects, with the prospect of assisting physicians to select the most appropriate drug and dosage for treatment. However, many concerns regarding genetic tests exist. We sought to test the opinions of undergraduate science and medical students in southern Ontario universities toward pharmacogenetic testing. METHODS AND RESULTS: Questionnaires were completed by 910 undergraduate medicine and science students from 2005 to 2007. Despite students' concerns that the results of genetic tests may be used for other purposes without consent (71%) or lead to discrimination (78%), an overwhelming number of students were in favor of pharmacogenetic testing (90%). DISCUSSION: To our knowledge, this study is the first to survey a large sample for their attitude toward pharmacogenetic testing for psychotropic medications. Our results indicate that, although concerns remain and scientific advancements are required, respondents were in support of pharmacogenetic testing for medications used to treat schizophrenia. © 2014 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.