Risk Factors Associated with Relapse in Double Seronegative Neuromyelitis Optica Spectrum Disorder and the Role of Platelet to Lymphocyte Ratio in Monophasic Idiopathic Transverse Myelitis

Abstract

Autoimmune diseases of the central nervous system encompass a number of different conditions including Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), and Myelin Oligodendrocyte Glycoprotein Antibody Disease (MOGAD). MS is a demyelinating disease of the brain and spinal cord associated with Epstein Barr virus, while NMOSD is an antigen-specific disorder characterized by the presence of anti-aquaporin 4 (AQP4) antibodies and typically presents with optic neuritis and transverse myelitis(1). MOGAD, another demyelinating condition that clinically overlaps both MS and NMOSD, is associated with antibodies against MOG, a component of the myelin sheath. The development of cell-based assays for NMO and MOG led to revisions of the NMOSD diagnostic criteria established in 2006 and MOGAD diagnostic criteria in 2023. Beyond MS, AQP4 seropositive NMOSD and MOGAD, there is a population of people with similar clinical features – but who test negative for MS, NMOSD and MOGAD. These people carry a diagnosis of double seronegative NMOSD (DSN-NMOSD). Studies have been conducted to differentiate DSN-NMOSD from seropositive NMOSD, MOGAD, and MS. However, the lack of sufficient sample sizes remains a significant obstacle. Additionally, the challenges of proper testing in poorly resourced countries exacerbate the situation. Although a definitive cure remains elusive, early diagnosis, treatment, and efforts to slow disability progression are critical in managing these debilitating conditions. But the absence of established treatment strategies makes these subsets more susceptible to relapse compared to AQP4-IgG+ NMOSD, where four new approved immunotherapies is typically initiated at the time of diagnosis. Our first manuscript addresses the risk factors associated with relapse rates in DSN-NMOSD. With the advent of the MOG antibody test and clinical criteria in 2023, the category of double seronegative NMOSD is relatively new. We explored various clinical and paraclinical factors that might influence disease progression and utilized a multicenter dataset, to increase the generalizability of our results. To our knowledge this the first and largest cohort to not only study the relapse rate of DSN-NMOSD but also establish a demographic, clinical and paraclinical landscape of the disease. Another subset of seronegative autoimmune disease experience only a monophasic transverse myelitis (TM) attack of unknown etiology despite thorough diagnostic investigations and they are called Idiopathic Transverse Myelitis (ITM). Some cases of ITM eventually convert to either MS, MOGAD or NMOSD; however, a subset does not convert and are called monophasic ITM. Several studies have investigated various biomarkers, such as serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP), along with predictors of recurrence, to differentiate between ITM, MS, and NMOSD (2–5). Current research on the Platelet to Lymphocyte ratio (PLR) and Neutrophil to Lymphocyte ratio (NLR) in these conditions shows promising results regarding their roles in disease activity and disability progression (6,7). Our second manuscript focuses on PLR and its role in monophasic ITM. We determined whether PLR is associated with severe neurologic outcomes as defined by Expanded Disability Status Scale (EDSS). These two clinical research studies not only established a foundational understanding in DSN-NMOSD and monophasic ITM but also provided researchers with opportunities to explore its underlying causes. This groundwork is crucial for developing more effective therapeutic frameworks aimed at preventing further damage and disability.