MOG Antibody-Associated Disease in the Setting of Metastatic Melanoma Complicated by Immune Checkpoint Inhibitor Use.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.

Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis.

Objective: To evaluate and characterize cardiac arrythmias associated with LGI1-IgG (Leucine-rich glioma inactivated 1-IgG) autoimmune encephalitis (AE). Patients and methods: In this retrospective descriptive study, we identified Mayo Clinic patients (May 1, 2008 - December 31, 2020) with LGI1-IgG AE who had electrocardiogram proven bradyarrhythmias during the initial presentation. Inclusion criteria were 1) LGI1-IgG positivity with a consistent clinical syndrome; 2) electrocardiographic evidence of bradyarrhythmia; and 3) sufficient clinical details. We excluded patients who were taking negative ionotropic agents at the time of their bradyarrhythmias. We collected demographic/clinical data including details of bradyarrhythmia (severity, duration, treatments), and neurologic and cardiac outcomes. Results: We found that patients with LGI1-IgG AE had bradyarrhythmia at a frequency of 8% during the initial presentation. The bradyarrhythmia was often asymptomatic (6/11, 55%); however, the episode was severe with one patient requiring a pacemaker. Outcome was also generally favorable with the majority (8/11, 73%) having full resolution without further cardiac intervention. Lastly, we found that mouse and human cardiac tissues express LGI1 (mRNA and protein). Conclusion: LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.

Meta-analysis of effectiveness of steroid-sparing attack prevention in MOG-IgG-associated disorder.

OBJECTIVE: To estimate the efficacy of the commonly used long-term immunotherapies in myelin oligodendrocyte glycoprotein IgG associated disorder (MOGAD) METHOD: A comprehensive search of the databases including PubMed/MEDLINE, EMBASE, and Cochrane database was performed for all studies that assessed the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), and maintenance intravenous immunoglobulin (mIVIG) in MOGAD. The random-effect model is used to estimate the standard mean difference (SMD) of annualized relapse rate (ARR) and expanded disability status scale (EDSS), mean ARR, probabilities of relapse and worsening EDSS during treatment. RESULTS: The initial search identified 714 articles, and 21 satisfied eligibility criteria. All immunotherapies significantly reduced ARR in both pediatric and adult populations. Relapse probabilities and pooled mean ARR (SE: standard error) during therapies were as follow: AZA 53.1% [95%CI 37.4% to 68.2%; ARR 0.291 (0.134)], MMF 38.5% [95%CI 19.4% to 62.0%; ARR 0.836 (0.176)], RTX 48.9% [95%CI 37.8% to 60.2%; ARR 0.629(0.162)], and mIVIG 25.3% [95%CI 14.0% to 41.3%; ARR 0.081 (0.058)]. Only RTX significantly improved EDSS, SMD -0.499 (95%CI -0.996 to -0.003). The proportion of worsening EDSS with immunotherapies were 20.7% (95%CI 8.8% to 41.6%), 8.1% (95%CI 1.1% to 41.2%), and 10.8% (95%CI 3.8% to 26.8%) for AZA, MMF, and RTX, respectively. CONCLUSION: These commonly used immunotherapies significantly reduced ARR in MOGAD. Only RTX had a significant benefit in EDSS improvement. However, a substantial portion of patients continued to relapse with treatment. Randomized controlled studies are needed to verify these findings and perform head-to-head comparisons among these treatment options.

CNS Demyelinating Attacks Requiring Ventilatory Support With Myelin Oligodendrocyte Glycoprotein or Aquaporin-4 Antibodies.

BACKGROUND AND OBJECTIVE: Severe attacks of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) may require ventilatory support, but data on episodes are limited, particularly for MOGAD. We sought to compare the frequency, characteristics, and outcomes of MOGAD and AQP4-NMOSD attacks requiring ventilatory support. METHODS: This retrospective descriptive study identified Mayo Clinic patients (January 1, 1996-December 1, 2020) with MOGAD or AQP4-NMOSD and an attack requiring noninvasive or invasive ventilation at Mayo Clinic or an outside facility by searching for relevant terms in their electronic medical record. Inclusion criteria were (1) attack-related requirement for noninvasive (bilevel positive airway pressure or continuous positive airway pressure) or invasive respiratory support (mechanical ventilation); (2) MOG or AQP4 antibody positivity with fulfillment of MOGAD and AQP4-NMOSD clinical diagnostic criteria, respectively; and (3) sufficient clinical details. We collected data on demographics, comorbid conditions, indication for and duration of respiratory support, MRI findings, treatments, and outcomes. The races of those with attacks requiring respiratory support were compared to those without such attacks in MOGAD and AQP4-NMOSD. RESULTS: Attacks requiring ventilatory support were similarly rare in patients with MOGAD (8 of 279, 2.9%) and AQP4-NMOSD (11 of 503 [2.2%]) (p = 0.63). The age at attack (median years [range]) (MOGAD 31.5 [5-47] vs AQP4-NMOSD 43 [14-65]; p = 0.01) and percentage of female sex (MOGAD 3 of 8 [38%] vs AQP4-NMOSD 10 of 11 [91%]; p = 0.04) differed. The reasons for ventilation differed between MOGAD (inability to protect airway from seizure, encephalitis or encephalomyelitis with attacks of acute disseminated encephalomyelitis 5 [62.5%] or unilateral cortical encephalitis 3 [37.5%]) and AQP4-NMOSD (inability to protect airway from cervical myelitis 9 [82%], rhombencephalitis 1 [9%], or combinations of both 1 [9%]). Median ventilation duration for MOGAD was 2 days (range 1-7 days) vs 19 days (range 6-330 days) for AQP4-NMOSD (p = 0.01). All patients with MOGAD recovered, but 2 of 11 (18%) patients with AQP4-NMOSD died of the attack. For AQP4-NMOSD, Black race was overrepresented for attacks requiring ventilatory support vs those without these episodes (5 of 11 [45%] vs 88 of 457 [19%]; p = 0.045). DISCUSSION: Ventilatory support is rarely required for MOGAD and AQP4-NMOSD attacks, and the indications differ. Compared to MOGAD, these attacks in AQP4-NMOSD may have higher morbidity and mortality, and those of Black race were more predisposed, which we suspect may relate to socially mediated health inequality.

Obesity Is Not an Independent Predictor of Necrotizing Soft Tissue Infection Outcomes.

Background: Necrotizing soft tissue infections (NSTIs) are a group of rapidly progressive infections of the skin and its underlying tissue. These infections result in substantial morbidity and mortality. The focus of this study was to determine if obesity is associated with a worsened clinical outcome or prolonged hospital course for patients with NSTIs. Patients and Methods: We conducted a retrospective chart review of patients with NSTI presenting to a single tertiary hospital. Fat content, measured with body mass index (BMI) and abdominal fat thicknesses, including subcutaneous and visceral fat, were compared against primary and secondary outcomes of NSTIs. Results: We found that women had a higher mortality rate compared with men (27% vs. 15% mortality). Women also had an increased subcutaneous abdominal fat thickness (55.7 vs. 36.9 mm, p = 0.028). However, no measurements of fat, BMI, subcutaneous fat, or visceral fat differed between survivors and mortalities of NSTIs. In fact, with the exception of a higher BMI in those who developed acute kidney injury (AKI, p = 0.034), we found no correlation between increases in fat measurement and secondary outcome, including propensity to develop sepsis during hospitalization, length of hospital stay, length of intensive care stay, or antibiotic usage. Multivariable logistic regression analysis was conducted, and we found no statistically significant differences in primary or secondary outcomes. Conclusion: Women appear to have a higher mortality in NSTI, although the reasons for this are unclear. Obesity, as measured by BMI, subcutaneous, and visceral fat thicknesses, does not appear to be an independent risk factor.

Disease-Modifying Therapies During the COVID-19 Outbreak: A Narrative Review of International and National Recommendations.

BACKGROUND: Managing multiple sclerosis (MS) during the novel coronavirus disease 2019 (COVID-19) pandemic is a challenge due to the lack of evidence from clinical studies. Disease-modifying therapies (DMTs) may affect the immune response and subsequently alter the risk of COVID-19 infections. METHODS: A literature search was conducted on the MEDLINE, Embase, and Cochrane databases. A focused Google search was also performed. Recommendations regarding the use of DMTs during the COVID-19 outbreak from national and international MS/neurology societies were identified and reviewed. RESULTS: The review included 16 recommendations from international and national MS organizations. All recommendations are based on expert opinions. The recommendations regarding DMT initiation and management during this outbreak are summarized. Moreover, the experts' views about the risk of COVID-19 infection with each DMT are discussed. CONCLUSIONS: There is significant agreement among most experts' recommendations from a variety of sources based on collective clinical experience. However, the recommendations will likely evolve because sufficient clinical data are limited. Several ongoing registries will help provide information for future recommendations.

Regional differences in the association of cytomegalovirus seropositivity and multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Despite of a few decades of investigations, the association and role of cytomegalovirus (CMV) and multiple sclerosis (MS) remain inconclusive. Herein, we performed a meta-analysis to investigate the association between CMV IgG serostatus and MS. METHODS: A literature search was conducted on MEDLINE, EMBASE, and Cochrane databases. Eligibility criteria included observational studies assessing the seroprevalence of CMV immunoglobulin G (IgG) in adults with MS and non-MS control. Two authors screened all resulting studies and evaluated the quality of the included studies. Pooled odd ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effect model. RESULTS: The search identified 771 unique citations, and 15 (3,591 MS patients and 4,241 controls) satisfied eligibility criteria. The meta-analysis of all included studies showed no significant association between CMV IgG seropositivity and MS with a substantial heterogeneity (OR 1.190; 95%CI 0.780-1.813; I2 32.7%). Subgroup analysis, stratified by geographic area, showed different associations and less heterogeneity in each geographical area. In Europe, CMV IgG seroprevalence was lower among people with MS than controls (OR 0.750; 95%CI 0.599-0.940; I213.9%). In contrast, CMV IgG seropositivity was more common among MS patients compared to controls in the Middle East region (OR 5.089; 95%CI 01.067-24.263; I2 5.6%). There was no significant association in North America. CONCLUSIONS: There is evidence of the regional differences in the association between CMV IgG seropositivity and MS. Further biological and epidemiological studies are needed to identify the genetic or environmental factors which are potentially the effect modifiers of this association.

Obligate anaerobes are abundant in human necrotizing soft tissue infection samples - a metagenomics analysis.

Necrotizing soft tissue infections (NSTIs) are associated with high morbidity and mortality and are increasing in incidence. Proper identification of the microbial causes of NSTIs is a crucial step in diagnosis and treatment, but the majority of data collected are culture based, which is biased against fastidious organisms, including obligate anaerobes. The goal of this study was to address this gap in knowledge by characterizing NSTI microbial communities through molecular diagnostics. We performed 16S rRNA sequencing on human NSTI samples and identified five genera most commonly found in NSTIs (Prevotella, Bacteroides, Peptoniphilus, Porphyromonas, and Enterococcus). We found that a >70% contribution of obligate anaerobes to the bacterial population distribution was associated with NSTI mortality, and that NSTI samples, from both survivors and non-survivors, had an increased relative abundance of gram negative bacteria compared to those of abscess patients. Based on our data, we conclude that obligate anaerobes are abundant in NSTIs and a high relative abundance of anaerobes is associated with a worse outcome. We recommend increasing anaerobe antibiotic coverage during the treatment of NSTIs even when anaerobes are not found by traditional clinical microbiology methods, and especially when there is a clinical suspicion for anaerobe involvement.

Effect of non-steroidal anti-inflammatory drugs on post-surgical complications against the backdrop of the opioid crisis.

The USA is currently going through an opioid crisis, associated with tremendous economic and societal impacts. In response to this crisis, healthcare professionals are looking for alternative pain management methods, and non-steroidal anti-inflammatory drugs (NSAIDs) are a sensible choice because of their effectiveness after surgical procedures. However, before surgeons start prescribing NSAIDs in place of opioids, it is crucial to first understand their potential post-surgical complications. The goal of this review is to summarize the data obtained through both animal and human studies, which suggest how a dramatic increase in NSAID use may affect these post-surgical complications. We first provide a short review outlining the mechanisms of action of NSAIDs, followed by a summary of animal studies, which show a trend towards the negative effects of NSAIDs on wound healing and an association between NSAID use and wound infections. Lastly, we present evidence from human studies on the association of NSAIDs with the following complications: anastomotic leaks, necrotizing soft tissue infections, bleeding complications, orthopedic injuries, wound healing, and cancer care. The human studies are much more variable in their conclusions as to whether NSAIDs are beneficial or not, with the only strong evidence showing that NSAIDs inhibit bone healing. This may partially be explained by male and female differences in response to NSAIDs as many animal studies showing the inhibitory effects of NSAIDs were performed on females, while all the human studies were performed with both sexes. We conclude that strong caution should be used in the prescription of NSAIDs, especially in female patients, but larger scale studies are warranted before solid recommendations can be made.

Traditional culture methods fail to detect principle pathogens in necrotising soft tissue infection: a case report.

OBJECTIVE: Necrotising soft tissue infections (NSTIs) progress rapidly and mortality remains high, ranging from 10% to 30%, representing a significant challenge for health professionals. Early accurate diagnosis is crucial because timely and aggressive surgical intervention remains the number one indicator for a better clinical outcome. Understanding the microbial background of NSTIs would aid early diagnosis. PRESENTATION: We present a case of NSTI, in a seemingly healthy adult male, originating from a tooth abscess. The NSTI progressed rapidly, and eventually covered the patient's chest and abdominal skin and underlying soft tissue. RESULTS: Traditional blood and tissue culture only found Group C Streptococcus where 16S sequencing detected abundant Prevotella spp., a more likely causal organisms of the NSTI. The use of antibiotics with the approriate anaerobe coverage, in combination with timely surgical intervention, contributed to the ultimate successful clinical outcome. Complete wound healing and successful graft was achieved within one month of diagnosis of the microbes present. CONCLUSION: While surgical intervention remains the most important consideration in treatment of NSTI, correct identifcation of the microbial flora could also contribute to successful treatment.

Are anaerobes a major, underappreciated cause of necrotizing infections?

Necrotizing soft tissue infections (NSTIs) are the most severe and rapidly progressing class of skin and soft tissue infections (SSTIs). They are a surgical emergency and are associated with high mortality and morbidity. While NSTIs remain relatively rare, their incidence is steadily rising. Earlier diagnosis and more focused antibiotic treatments can potentially improve patient outcome, but both of these solutions require a more accurate understanding of the microbial component of these infections. While molecular detection methods, namely 16S sequencing, have not been traditionally used to identify the causative microorganisms in NSTIs, they are becoming more commonplace for other types of SSTIs, especially for chronic wound infections. In chronic wound infections, 16S sequencing has revealed a higher than previously detected prevalence of obligate anaerobes. Therefore, it is possible that 16S sequencing may also detect a higher than expected proportion of obligate anaerobes in NSTIs. In this review, we discuss the current state of knowledge concerning the diagnosis and treatment of NSTIs and present reasons why the role of anaerobes may be significantly underestimated.

Disabled-1 dorsal horn spinal cord neurons co-express Lmx1b and function in nociceptive circuits.

The Reelin-signaling pathway is essential for correct neuronal positioning within the central nervous system. Mutant mice with a deletion of Reelin, its lipoprotein receptors, or its intracellular adaptor protein Disabled-1 (Dab1), exhibit nociceptive abnormalities: thermal (heat) hyperalgesia and reduced mechanical sensitivity. To determine dorsal horn alterations associated with these nociceptive abnormalities, we first characterized the correctly positioned Dab1 neurons in wild-type and mispositioned neurons in Reelin-signaling pathway mutant lumbar spinal cord. Using immunofluorescence, we found that 70% of the numerous Dab1 neurons in Reln+/+ laminae I-II and 67% of those in the lateral reticulated area and lateral spinal nucleus (LSN) co-express the LIM-homeobox transcription factor 1 beta (Lmx1b), an excitatory glutamatergic neuron marker. Evidence of Dab1- and Dab1-Lmx1b neuronal positioning errors was found within the isolectin B4 terminal region of Reln-/- lamina IIinner and in the lateral reticulated area and LSN, where about 50% of the Dab1-Lmx1b neurons are missing. Importantly, Dab1-Lmx1b neurons in laminae I-II and the lateral reticulated area express Fos after noxious thermal or mechanical stimulation and thus participate in these circuits. In another pain relevant locus - the lateral cervical nucleus (LCN), we also found about a 50% loss of Dab1-Lmx1b neurons in Reln-/- mice. We suggest that extensively mispositioned Dab1 projection neurons in the lateral reticulated area, LSN, and LCN and the more subtle positioning errors of Dab1 interneurons in laminae I-II contribute to the abnormalities in pain responses found in Reelin-signaling pathway mutants.