Shifting our attention earlier in the multiple sclerosis disease course.

PURPOSE OF REVIEW: Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS. RECENT FINDINGS: MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of clinical disease. SUMMARY: Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.

The Impact of Positive Fluid Balance on Sepsis Subtypes: A Causal Inference Study.

Introduction: Sepsis, the leading cause of death in hospitalized patients globally, was investigated in this study, examining the varying effects of positive fluid balance on sepsis subtypes through causal inference. Methods: In this study, data from the eICU database were utilized, extracting 35 features from sepsis patients. Fluid balance during ICU stay was the treatment, and ICU mortality was the primary outcome. Data preprocessing ensured linear assumptions for logistic regression. Binarized positive fluid balance with mortality was examined using DoWhy's logistic regression, while continuous data were analyzed with random forest T-learner. ATE served as the primary metric. Results: Results revealed that septic patients with higher fluid balance had worse mortality outcomes, with an ATE of 0.042 (95% CI: (0.034, 0.047)) using logistic regression and an ATE of 0.0340 (95% CI: (0.028-0.040)) using T-learner. In the pulmonary sepsis subtype, higher mortality was associated with increased fluid balance, showing an ATE of 0.047 (95% CI: (0.037, 0.055)) using logistic regression and an ATE of 0.28 (95% CI: (0.22, 0.34)) with T-learner. Conversely, urinary sepsis patients had improved mortality with higher fluid balance, presenting an ATE of -0.135 (95% CI: (-0.024, -0.0035)) using logistic regression and an ATE of -0.28 (95% CI: (-0.34, -0.22)) with T-learner. Conclusion: Our research implies that fluid balance impact on ICU mortality differs among sepsis subtypes. Positive fluid balance raises mortality in sepsis and pulmonary sepsis but may protect against urinary sepsis. Further trials are needed to confirm these findings.

A structured evaluation of cryopreservation in generating single-cell transcriptomes from cerebrospinal fluid.

Single-cell transcriptomics allows characterization of cerebrospinal fluid (CSF) cells at an unprecedented level. Here, we report a robust cryopreservation protocol adapted for the characterization of fragile CSF cells by single-cell RNA sequencing (RNA-seq) in moderate- to large-scale studies. Fresh CSF was collected from twenty-one participants at two independent sites. Each CSF sample was split into two fractions: one was processed fresh, while the second was cryopreserved for months and profiled after thawing. B and T cell receptor sequencing was also performed. Our comparison of fresh and cryopreserved data from the same individuals demonstrates highly efficient recovery of all known CSF cell types. We find no significant difference in cell type proportions and cellular transcriptomes between fresh and cryopreserved cells. Results were comparable at both sites and with different single-cell sequencing chemistries. Cryopreservation did not affect recovery of T and B cell clonotype diversity. Our CSF cell cryopreservation protocol provides an important alternative to fresh processing of fragile CSF cells.

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

Compassionate-use pocapavir and immunoglobulin therapy for treatment of rituximab-associated enterovirus meningoencephalitis.

A 71-year-old woman previously on rituximab treatment for rheumatoid arthritis presented with 2 years of progressive neurologic symptoms. She was found to have persistent hypogammaglobulinemia and B cell depletion despite rituximab discontinuation a year prior. MRI revealed diffuse meningeal enhancement along the entire neuroaxis. LP showed a CSF lymphocytic pleocytosis, elevated protein, and presence of enterovirus by PCR. The patient was hospitalized several times for progressive clinical and radiologic decline, though she had transient improvements following treatment with immunoglobulin therapy. Her CSF remained positive for enterovirus PCR for at least 12 months. Though two brain biopsies were non-diagnostic, pan-Enterovirus was ultimately identified using a high-throughput next-generation sequencing technique. She was treated with compassionate-use pocapavir with clinical stabilization at 4-month follow-up; however, she expired 8 months later from a bacterial pneumonia.

Vaccination Against SARS-CoV-2 in Neuroinflammatory Disease: Early Safety/Tolerability Data.

BACKGROUND: Patients with autoimmune disease and on immunotherapy were largely excluded from seminal anti-SARS-CoV-2 vaccine trials. This has led to significant vaccine hesitancy in patients with neuroinflammatory diseases (NID); including, but not limited to: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), neurosarcoidosis and myelin oligodendrocyte antibody-mediated disease (MOG-AD). Data is urgently needed to help guide clinical care in the NID population. METHODS: This was a cross-sectional observational study evaluating adults with a neurologist-confirmed diagnosis of a neuroinflammatory disease (NID) and a neurologically asymptomatic control population. Participants were recruited from multiple academic centers participating in the MS Resilience to COVID-19 Collaborative study. We analyzed participant responses from a vaccine-specific questionnaire collected between February and May 2021. RESULTS: 1164 participants with NID and 595 controls completed the vaccine survey. Hesitancy rates were similar between NID and control groups (n = 134, 32.7% NID vs. n = 56, 30.6% control; p = 0.82). The most common reasons for hesitancy in NID participants were lack of testing in the autoimmune population and fear of demyelinating/neurologic events. Unvaccinated patients who had discussed vaccination with their doctor were less likely to be hesitant (n=184, 73.6% vs. n=83, 59.7%; p = 0.007). 634 NID patients and 332 controls had received at least one dose of a vaccine against SARS-CoV-2 at the time of survey completion. After adjusting for age, BMI, and comorbidities, there was no difference in self-reported side effects (SE) between groups with the first dose (n = 256, 42.2% NID vs. 141, 45.3% control; p = 0.20) or second dose (n = 246, 67.0% NID vs. n = 114, 64.8% control, p = 0.85) of the mRNA vaccines nor with the viral-vector vaccines (n = 6, 46% NID vs. n = 8, 66% control; p = 0.39). All reported SEs fell into the expected SE profile. There was no difference in report of new/recurrent neurologic symptoms (n = 110, 16.2% vaccinated vs. 71, 18.2% unvaccinated; p = 0.44) nor radiologic disease activity (n = 40, 5.9% vaccinated vs. n = 30, 7.6% unvaccinated) between vaccinated and unvaccinated NID participants. CONCLUSIONS: We found no difference in patient-reported vaccine side effects and no evidence of NID worsening after vaccination. Large-scale real-world evidence is needed for further validation.

Neurologic Safety Monitoring of COVID-19 Vaccines: Lessons From the Past to Inform the Present.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).

Myelin oligodendrocyte glycoprotein (MOG) antibody-mediated disease: The difficulty of predicting relapses.

BACKGROUND: While many patients with myelin oligodendrocyte glycoprotein antibody-mediated disease (MOG-AD) will have a monophasic course, 30-80% of patients will relapse after the initial attack. It is not known which factors predict relapse. Here we describe our clinical experience with MOG-AD and evaluate for factors that correlate with relapsing disease. METHODS: This was a retrospective, multi-institutional study of 54 patients with MOG-AD, including 17 children and 37 adults. Mann-Whitney U and Fischer's Exact tests were used for comparisons and logistic regression for correlations. RESULTS: Incident attack phenotype included acute disseminated encephalomyelitis (15%), unilateral optic neuritis (ON; 39%), bilateral ON (24%), transverse myelitis (TM; 11%) and ON with TM (11%). Pediatric patients were more likely than adults to present with ADEM (p = .009) and less likely to present with unilateral ON (p = .04). 31 patients (57%) had a relapsing disease course, with time to first relapse of 8.2 months and median annualized relapse rate of 0.97 months. In 40% of patients (n = 22) the first relapse occurred following the withdrawal of treatment for the incident attack. 5 patients converted to seronegative at follow up, 2 of whom later relapsed. Logistic regression revealed no significant relationship between age, gender, race, presentation phenotype, antibody titer, or cerebrospinal fluid results with risk of relapse. For patients who started disease modifying therapy (DMT) prior to the first relapse (n = 11), 64% remained monophasic. 50% (n = 15) of patients on DMT continued to have disease activity, requiring treatment adjustment. CONCLUSIONS: It is difficult to predict which patients with MOG-AD will relapse. Research is needed to determine the optimal timing and choice of treatment.

Evaluation of ocrelizumab in older progressive multiple sclerosis patients.

BACKGROUND: Seminal trials evaluating anti-CD20 therapy in progressive MS primarily found benefit in younger, less-disabled patients with more inflammatory disease activity. The risks and benefits of ocrelizumab use in older patients with progressive froms of MS are not known. METHODS: Retrospective chart review was performed for patients older than 55 with primary or secondary progressive MS at the time of ocrelizumab initiation. Clinical endpoints from 2 years prior to anti-CD20 therapy served as a within-subject control. RESULTS: Data was reviewed for 56 patients older than the age of 55 at the time of ocrelizumab initiation. Of 37 patients with 2-years of follow up on ocrelizumab, 40%(n=15) experienced confirmed disability progression (CDP) while 60% (n=22) remained stable or improved. 24 patients had data available for the within-subject control; for these patients, median age was 67, baseline EDSS 6.3, and disease duration 20.5 years. Prior to anti-CD20 therapy, 58% (n=14) of patients remained stable and 42% (n=10) experienced CDP. After ocrelizumab initiation, 71% (n=17) remained stable and 29% (n=7) experienced CDP. There was no difference between CDP (p=0.54) or change in EDSS (p=0.09) between time periods. Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control. CONCLUSIONS: We found no difference in clinical endpoints for patients on ocrelizumab compared to prior to anti-CD20 therapy; however, we could not exclude a modest effect given our sample size. Larger trials are needed to evaluate ocrelizumab use in this understudied MS subpopulation.

Critical Analysis of a Challenging Case of Post-Infectious N-Methyl-D-Aspartate Receptor Encephalitis.

Infections are increasingly recognized as a common trigger of autoimmune disease, including autoimmune encephalitis. A significant association is particularly shown between HSV-1 encephalitis (HSVE) and a post-infectious autoimmune encephalitis mediated by neuronal autoantibodies, most notably anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. The clinical significance of these and other novel post-infectious autoantibodies has led to new diagnostic and treatment challenges for clinicians. Here we present a case of a 19-year-old female with premorbid psychiatric disease and neuropsychiatric sequelae from HSVE who presented over a year after her initial HSVE with behavioral changes and positive anti-NMDAR antibodies. The clinical challenges encountered during this case are explored in detail based on a review of the literature. Research is needed to help guide management in these complex clinical situations.

Atypical Pneumonia: Definition, Causes, and Imaging Features.

Pneumonia is among the most common causes of death worldwide. The epidemiologic and clinical heterogeneity of pneumonia results in challenges in diagnosis and treatment. There is inconsistency in the definition of the group of microorganisms that cause "atypical pneumonia." Nevertheless, the use of this term in the medical and radiologic literature is common. Among the causes of community-acquired pneumonia, atypical bacteria are responsible for approximately 15% of cases. Zoonotic and nonzoonotic bacteria, as well as viruses, have been considered among the causes of atypical pneumonia in a patient who is immunocompetent and have been associated with major community outbreaks of respiratory infection, with relevant implications in public health policies. Considering the difficulty of isolating atypical microorganisms and the significant overlap in clinical manifestations, a targeted empirical therapy is not possible. Imaging plays an important role in the diagnosis and management of atypical pneumonia, as in many cases its findings may first suggest the possibility of an atypical infection. Clarifying and unifying the definition of atypical pneumonia among the medical community, including radiologists, are of extreme importance. The prompt diagnosis and prevention of community spread of some atypical microorganisms can have a relevant impact on local, regional, and global health policies. ©RSNA, 2021.

Deep Learning-based Quantification of Abdominal Subcutaneous and Visceral Fat Volume on CT Images.

RATIONALE AND OBJECTIVES: Develop a deep learning-based algorithm using the U-Net architecture to measure abdominal fat on computed tomography (CT) images. MATERIALS AND METHODS: Sequential CT images spanning the abdominal region of seven subjects were manually segmented to calculate subcutaneous fat (SAT) and visceral fat (VAT). The resulting segmentation maps of SAT and VAT were augmented using a template-based data augmentation approach to create a large dataset for neural network training. Neural network performance was evaluated on both sequential CT slices from three subjects and randomly selected CT images from the upper, central, and lower abdominal regions of 100 subjects. RESULTS: Both subcutaneous and abdominal cavity segmentation images created by the two methods were highly comparable with an overall Dice similarity coefficient of 0.94. Pearson's correlation coefficients between the subcutaneous and visceral fat volumes quantified using the two methods were 0.99 and 0.99 and the overall percent residual squared error were 5.5% and 8.5%. Manual segmentation of SAT and VAT on the 555 CT slices used for testing took approximately 46 hours while automated segmentation took approximately 1 minute. CONCLUSION: Our data demonstrates that deep learning methods utilizing a template-based data augmentation strategy can be employed to accurately and rapidly quantify total abdominal SAT and VAT with a small number of training images.

Inpatient Neurology Consultations During the Onset of the SARS-CoV-2 New York City Pandemic: A Single Center Case Series.

Objective: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily causes respiratory illness. However, neurological sequelae from novel coronavirus disease 2019 (COVID-19) can occur. Patients with neurological conditions may be at higher risk of developing worsening of their underlying problem. Here we document our initial experiences as neurologic consultants at a single center quaternary hospital at the epicenter of the COVID-19 pandemic. Methods: This was a retrospective case series of adult patients diagnosed with SARS-CoV-2 who required neurological evaluation in the form of a consultation or primary neurological care from March 13, 2020 to April 1, 2020. Results: Thirty-three patients (ages 17-88 years) with COVID-19 infection who required neurological or admission to a primary neurology team were included in this study. The encountered neurological problems associated with SARS-CoV-2 infection were encephalopathy (12 patients, 36.4%), seizure (9 patients, 27.2%), stroke (5 patients, 15.2%), recrudescence of prior neurological disease symptoms (4 patients, 12.1%), and neuromuscular (3 patients, 9.1%). The majority of patients who required evaluation by neurology had elevated inflammatory markers. Twenty-one (63.6%) patients were discharged from the hospital and 12 (36.4%) died from COVID-19 related complications. Conclusion: This small case series of our initial encounters with COVID-19 infection describes a range of neurological complications which are similar to presentations seen with other critical illnesses. COVID-19 infection did not change the overall management of neurological problems.

Papillary Thyroid Carcinoma Recurrence: Low Yield of Neck Ultrasound With an Undetectable Serum Thyroglobulin Level.

OBJECTIVES: To assess the yield of neck ultrasound (US) when serum thyroglobulin (Tg) is undetectable (<0.1 ng/mL) compared to elevated serum Tg in patients with differentiated papillary thyroid carcinoma (PTC) treated with thyroidectomy and radioactive iodine 131 (RAI) ablation. METHODS: A retrospective chart review was conducted from 2010 through 2015 at an academic institution evaluating US results in patients with serum Tg levels obtained within 6 months of a neck US examination after thyroidectomy and RAI. The reference standard for recurrence was pathologic results from US-guided fine-needle aspiration (FNA) or follow-up for at least 1 year. RESULTS: Among 76 patients with undetectable serum Tg levels, there were 19 examinations in 18 patients in which US raised the possibility of recurrence. None of these 18 patients had recurrence by FNA (n = 8) or clinical follow-up of at least 1 year (n = 10). Among 65 patients with elevated serum Tg levels, there were 24 examinations in 22 patients in which US raised the possibility of recurrence. Twelve patients underwent FNA, with 9 patients (34.6%) showing PTC; 7 patients had follow-up neck US examinations showing stability of findings; and 3 patients were lost to follow up. The yield of neck US was significantly lower when serum Tg was undetectable compared to when levels were elevated (P = .001). CONCLUSIONS: Neck US did not identify recurrent PTC when the serum Tg level was undetectable in patients who underwent total thyroidectomy and RAI therapy. Eliminating neck US when serum TG levels are undetectable could decrease unnecessary imaging examinations without negatively affecting the ability to detect recurrent disease.

Near-peer teaching programme for medical students.

BACKGROUND: Near-peer teaching (NPT) is increasingly recognised as an effective method for teaching and learning within medical education. We describe a student-as-teacher programme developed for fourth-year students (MS4s) helping to deliver the second-year Respiratory Pathophysiology course at our medical school. METHODS: Twelve MS4s were paired with faculty members to co-teach one or two small group case-based sessions for second-year students (MS2s). Beforehand, MS4s attended an orientation session and workshop, reviewing skills and strategies for teaching effectively. Following each teaching session co-taught by MS4s, both MS4s and MS2s completed multiple-choice surveys evaluating the MS4's teaching skills and the experience overall. MS4s also wrote reflection essays describing their experiences. Faculty member co-teachers completed a 12-question feedback form for MS4s during the session. RESULTS: We received 114 post-session MS2 surveys, 13 post-session MS4 surveys and 13 post-session faculty staff evaluations. The majority of MS2s reported that MS4s enhanced their understanding of the material, and considered the quality of MS4 teaching to be 'good' or 'outstanding'. Nearly all of the MS4s enjoyed their experiences and believed that the programme improved their teaching skills. Time management was the most common challenge cited by both MS4s and faculty member co-teachers. DISCUSSION: These data demonstrate that NPT is valuable for both MS2s and MS4s: MS2s benefited from the social and cognitive congruence afforded by near-peer teachers, whereas MS4s used this experience to build and enhance their skills as educators. These results support the continued involvement of MS4s in this second-year course, as well as broadening the scope of and opportunities for student teaching at our medical school and beyond. Near-peer teaching is recognised as an effective method for teaching and learning within medical education.

Prosthetic hip infection with Edwardsiella tarda in sickle cell beta thalassemia disease: A case report.

Periprosthetic infection following total hip arthroplasty is a devastating complication that has been reported to occur in up to 1.6% of all primary total hip arthroplasties. We report a previously unrecognized gram-negative bacillus as the infecting agent in a patient with bilateral total hip arthroplasties for stage IV osteonecrosis. A 22-year-old male with combined sickle cell disease and beta thalassemia with a prior history of unknown hip surgeries and treatment for distal tibial osteomyelitis in Africa developed a periprosthetic joint infection; intra-operative cultures confirmed the infecting organism to be Edwardsiella tarda which was sensitive to late-generation cephalosporins and vancomycin. He was successfully treated with a staged revision total hip arthroplasty with an antibiotic spacer and has been infection-free since. E. tarda is a gram-negative bacillus which has not been previously associated with periprosthetic infection following TJA. This organism infects both humans and fish, and is particularly associated with commercial fishing and fish farming of freshwater and marine fish, potentially putting workers in these industries at risk. Little is known about antibacterial resistance in this organism. Infection by E. tarda presents a new organism which may affect individuals undergoing TJA, particularly if they have medical comorbidities that increase their risk for infection, or work in industries which put them at a higher risk of infection by this organism. Further study on the antimicrobial resistance patterns of this organism will be required to be able to treat potentially resistant organisms.

Preserving and vouchering butterflies and moths for large-scale museum-based molecular research.

Butterflies and moths (Lepidoptera) comprise significant portions of the world's natural history collections, but a standardized tissue preservation protocol for molecular research is largely lacking. Lepidoptera have traditionally been spread on mounting boards to display wing patterns and colors, which are often important for species identification. Many molecular phylogenetic studies have used legs from pinned specimens as the primary source for DNA in order to preserve a morphological voucher, but the amount of available tissue is often limited. Preserving an entire specimen in a cryogenic freezer is ideal for DNA preservation, but without an easily accessible voucher it can make specimen identification, verification, and morphological work difficult. Here we present a procedure that creates accessible and easily visualized "wing vouchers" of individual Lepidoptera specimens, and preserves the remainder of the insect in a cryogenic freezer for molecular research. Wings are preserved in protective holders so that both dorsal and ventral patterns and colors can be easily viewed without further damage. Our wing vouchering system has been implemented at the University of Maryland (AToL Lep Collection) and the University of Florida (Florida Museum of Natural History, McGuire Center of Lepidoptera and Biodiversity), which are among two of the largest Lepidoptera molecular collections in the world.