Frequency, characteristics, predictors and treatment of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses. OBJECTIVES: To assess the characteristics, predictors, and immunotherapy of relapsing MOGAD. METHODS: This multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies. RESULTS: The majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5-15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm3; HR 3.3 [1.18 - 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07-6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 - 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 - 0.63]; p = 0.014). CONCLUSIONS: In our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention.

Health Disparities in Multiple Sclerosis among Hispanic and Black Populations in the United States.

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS). Historically, research on MS has focused on White persons with MS. This preponderance of representation has important possible implications for minority populations with MS, from developing effective therapeutic agents to understanding the role of unique constellations of social determinants of health. A growing body of literature involving persons of historically underrepresented races and ethnicities in the field of multiple sclerosis is assembling. Our purpose in this narrative review is to highlight two populations in the United States: Black and Hispanic persons with multiple sclerosis. We will review the current understanding about the patterns of disease presentation, genetic considerations, response to treatment, roles of social determinants of health, and healthcare utilization. In addition, we explore future directions of inquiry as well as practical methods of meeting these challenges.

Immunopathogenesis, Diagnosis, and Treatment of Multiple Sclerosis: A Clinical Update.

Multiple sclerosis (MS) is the most prevalent nontraumatic disabling neurologic condition among young adults worldwide. The diagnosis and management of MS is complex. The goal of this review is to provide an updated and practical approach to the diagnosis and treatment approaches in MS, emphasizing current understanding of immunopathogenesis, recent advances, and future directions, for both MS and non-MS clinicians.

Elsberg syndrome following acute immunosuppressive treatment for multiple sclerosis relapse.

First described more than 80 years ago, Elsberg Syndrome (ES) continues to be an under-recognized cause of cauda equina syndrome (CES). ES is an infectious disorder that presents with lower thoracic and/or lumbosacral myelitis in conjunction with CES, and most often occurs in the setting of herpes simplex virus 2 (HSV-2) reactivation (Savoldi et al., 2017; Eberhardt et al., 2004; Whalen et al., 2019). Comorbid neurologic diseases like multiple sclerosis (MS) can become a detrimental confounding factor leading to delayed diagnosis and management of ES due to pre-existing diagnostic bias. We present a case of relapsing-remitting MS (RRMS) complicated by ES, likely due to reactivation of a latent HSV infection following high immunosuppression for presumed refractory MS relapses.

Clinical Reasoning: A 57-Year-Old Man With Stepwise Progressive Paraparesis, Sensory Loss, Urinary Retention, and Constipation.

We present the case of a 57-year-old man with protein S deficiency and left leg deep vein thrombosis (DVT) 5 years earlier, who developed stepwise progressive bilateral lower limb weakness, numbness/paresthesia, gait imbalance, hesitancy of micturition, and constipation in the setting of recurrent left common femoral DVT treated with apixaban. Symptoms amplified with Valsalva, corticosteroids, and postlumbar puncture, with longitudinally extensive midthoracic T2-hyperintense lesion extending to the conus associated with hazy holocord enhancement on magnetic resonance imaging (MRI), raising suspicion for spinal dural arteriovenous fistula (sDAVF). Initial digital subtraction angiography (DSA) was negative for sDAVF. However, cerebral spinal fluid (CSF) was herpes simplex virus (HSV)-2 positive, and he was treated with antiviral therapy. Unfortunately, he continued to worsen despite treatment. Repeat neuroimaging 12 months after initial presentation demonstrated persistent lower thoracic/conus lesion in addition to cauda equina enhancement and subtle dorsal T2-hypointense flow voids. We raised red flags (e.g., lack of clinical prodrome, no herpetic rash, no CSF pleocytosis, and rostral extent of the lesion) that suggested the HSV2 nucleic acid detection was perhaps unrelated to the neurologic syndrome. Given the high index of suspicion for sDAVF, we repeated spinal vascular imaging. Spinal MRA demonstrated dilated right dorsal perimedullary veins from T10 to T11. Repeat DSA revealed a right T10 sDAVF. Microsurgical treatment rather than embolization of the fistula was successful without complication, with significant improvement in motor, sphincter, and to a lesser extent sensory function, with residual gait imbalance after inpatient rehabilitation 3 weeks postoperatively.

Fingolimod-related cryptococcal meningoencephalitis and immune reconstitution inflammatory syndrome in a patient with multiple sclerosis.

Fingolimod is an oral medication for multiple sclerosis that sequesters certain subsets of lymphocytes in lymph nodes, reducing egress into blood and their subsequent CNS migration. The initial multi-site randomized Phase III controlled trials found rates of infection similar to those in control groups. However, post-marketing surveillance has revealed an association with several opportunistic infections, including cryptococcosis. We report a case of fingolimod-related cryptococcal meningoencephalitis and IRIS after drug discontinuation and suggest a surveillance and risk mitigation strategy.

Multiple Sclerosis in a Multi-Ethnic Population in Houston, Texas: A Retrospective Analysis.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe similarities and differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. While we found several similarities between the groups regarding mean age, disability severity, and degree of brain atrophy at diagnosis, we also describe a few divergences. Interestingly, we found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) > 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16-0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10-7.10, OR= 2.44, 95% CI: 1.35-6.12, p = 0.01, respectively). Additionally, we observed significant differences in treatment adherence between groups. Assessment of the degree of brain atrophy and progression over time, along with an enumeration of T1, T2, and gadolinium-enhancing brain lesions, did not reveal differences across groups.

Current Advances in Pediatric Onset Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more about pediatric MS, there has been a development of improved diagnostic criteria leading to earlier diagnosis, earlier initiation of disease-modifying therapies (DMT), and an increasing number of DMT used in the treatment of pediatric MS. Over time, treatment with DMT has trended towards the initiation of higher efficacy treatment at time of diagnosis to help prevent further disease progression and accrual of disability over time, and there is evidence in current literature that supports this change in treatment patterns. In this review, we discuss the current knowledge in diagnosis, treatment, and clinical outcomes in pediatric MS.

Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease of the central nervous system (CNS). Disease-modifying therapies (DMT) targeting inflammation have been shown to reduce disease activity in patients with relapsing⁻remitting MS (RRMS). The current therapeutic challenge is to find an effective treatment to halt disease progression and reverse established neural damage. Stem cell-based therapies have emerged to address this dilemma. Several types of stem cells have been considered for clinical use, such as autologous hematopoietic (aHSC), mesenchymal (MSC), neuronal (NSC), human embryonic (hESC), and induced pluripotent (iPSC) stem cells. There is convincing evidence that immunoablation followed by hematopoietic therapy (aHSCT) has a high efficacy for suppressing inflammatory MS activity and improving neurological disability in patients with RRMS. In addition, MSC therapy may be a safe and tolerable treatment, but its clinical value is still under evaluation. Various studies have shown early promising results with other cellular therapies for CNS repair and decreasing inflammation. In this review, we discuss the current knowledge and limitations of different stem cell-based therapies for the treatment of patients with MS.

Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury.

Macrophage-mediated axonal dieback presents an additional challenge to regenerating axons after spinal cord injury. Adult adherent stem cells are known to have immunomodulatory capabilities, but their potential to ameliorate this detrimental inflammation-related process has not been investigated. Using an in vitro model of axonal dieback as well as an adult rat dorsal column crush model of spinal cord injury, we found that multipotent adult progenitor cells (MAPCs) can affect both macrophages and dystrophic neurons simultaneously. MAPCs significantly decrease MMP-9 (matrix metalloproteinase-9) release from macrophages, effectively preventing induction of axonal dieback. MAPCs also induce a shift in macrophages from an M1, or "classically activated" proinflammatory state, to an M2, or "alternatively activated" antiinflammatory state. In addition to these effects on macrophages, MAPCs promote sensory neurite outgrowth, induce sprouting, and further enable axons to overcome the negative effects of macrophages as well as inhibitory proteoglycans in their environment by increasing their intrinsic growth capacity. Our results demonstrate that MAPCs have therapeutic benefits after spinal cord injury and provide specific evidence that adult stem cells exert positive immunomodulatory and neurotrophic influences.

Adult NG2+ cells are permissive to neurite outgrowth and stabilize sensory axons during macrophage-induced axonal dieback after spinal cord injury.

We previously demonstrated that activated ED1+ macrophages induce extensive axonal dieback of dystrophic sensory axons in vivo and in vitro. Interestingly, after spinal cord injury, the regenerating front of axons is typically found in areas rich in ED1+ cells, but devoid of reactive astrocyte processes. These observations suggested that another cell type must be present in these areas to counteract deleterious effects of macrophages. Cells expressing the purportedly inhibitory chondroitin sulfate proteoglycan NG2 proliferate in the lesion and intermingle with macrophages, but their influence on regeneration is highly controversial. Our in vivo analysis of dorsal column crush lesions confirms the close association between NG2+ cells and injured axons. We hypothesized that NG2+ cells were growth promoting and thereby served to increase axonal stability following spinal cord injury. We observed that the interactions between dystrophic adult sensory neurons and primary NG2+ cells derived from the adult spinal cord can indeed stabilize the dystrophic growth cone during macrophage attack. NG2+ cells expressed high levels of laminin and fibronectin, which promote neurite outgrowth on the surface of these cells. Our data also demonstrate that NG2+ cells, but not astrocytes, use matrix metalloproteases to extend across a region of inhibitory proteoglycan, and provide a permissive bridge for adult sensory axons. These data support the hypothesis that NG2+ cells are not inhibitory to regenerating sensory axons and, in fact, they may provide a favorable substrate that can stabilize the regenerating front of dystrophic axons in the inhibitory environment of the glial scar.

PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration.

Chondroitin sulfate proteoglycans (CSPGs) present a barrier to axon regeneration. However, no specific receptor for the inhibitory effect of CSPGs has been identified. We showed that a transmembrane protein tyrosine phosphatase, PTPsigma, binds with high affinity to neural CSPGs. Binding involves the chondroitin sulfate chains and a specific site on the first immunoglobulin-like domain of PTPsigma. In culture, PTPsigma(-/-) neurons show reduced inhibition by CSPG. A PTPsigma fusion protein probe can detect cognate ligands that are up-regulated specifically at neural lesion sites. After spinal cord injury, PTPsigma gene disruption enhanced the ability of axons to penetrate regions containing CSPG. These results indicate that PTPsigma can act as a receptor for CSPGs and may provide new therapeutic approaches to neural regeneration.

Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I.

Pain hypersensitivity is a cardinal sign of tissue damage, but how molecules from peripheral tissues affect sensory neuron physiology is incompletely understood. Previous studies have shown that activin A increases after peripheral injury and is sufficient to induce acute nociceptive behavior and increase pain peptides in sensory ganglia. This study was designed to test the possibility that the enhanced nociceptive responsiveness associated with activin involved sensitization of transient receptor potential vanilloid I (TRPV1) in primary sensory neurons. Activin receptors were found widely distributed among adult sensory neurons, including those that also express the capsaicin receptor. Whole-cell patch-clamp recording from sensory neurons showed that activin acutely sensitized capsaicin responses and depended on activin receptor kinase activity. Pharmacological studies revealed that the activin sensitization of capsaicin responses required PKCepsilon signaling, but not PI3K (phosphoinositide 3-kinase), ERK (extracellular signal-regulated protein kinase), PKA, PKCalpha/beta, or Src. Furthermore, activin administration caused acute thermal hyperalgesia in wild-type mice, but not in TRPV1-null mice. These data suggest that activin signals through its own receptor, involves PKCepsilon signaling to sensitize the TRPV1 channel, and contributes to acute thermal hyperalgesia.