Neuromyelitis optica spectrum disorders

The landscape of neuromyelitis optica spectrum disorder (NMOSD) has undergone a profound transformation over the past two decades, evolving from a severe variant of multiple sclerosis or a disease with a monophasic course restricted to optic nerves and spinal cord into a distinct antibody-mediated relapsing disease with involvement of various parts of the central nervous system.

Following the discovery of aquaporin-4 antibodies (AQP4-IgG) by Lennon et al. ¹ in 2004, thousands of investigations and studies have shed more lights on pathophysiology, diagnosis, and treatment of NMOSD.

Six articles in this Special Collection collectively capture this transformation, addressing structural neuroimaging changes, pregnancy management, environmental risk factors, biomarkers of tissue injury, immune tolerance-based strategies, and therapeutic advances. Together, they collectively highlight how NMOSD research is in transitioning from descriptive pathology and etiology toward mechanism-driven precision medicine.

In the first article, Heine and Chien ² performed a systematic review and meta-analysis on brain volumetry and spinal cord imaging in AQP4-IgG-positive NMOSD patients. The authors demonstrated that the neurostructural damage is beyond the focal inflammatory lesions which were previously or historically regarded. Changes in the whole-brain volume, deep gray matter structures, and spinal cord cross-sectional area suggest that NMOSD is associated with more diffuse involvement of the central nervous system. Spinal cord atrophy, especially that in the cervical part may correlate strongly with long-term disability, and serve as a potential surrogate marker for future studies on therapeutic efficacy. This study also raises an important clinical question whether current medications can halt or reverse these changes? ²

The second article by Shimizu et al. ³ outlines the family planning and pregnancy management in patients with NMOSD and MOGAD. They nicely elaborated preconception strategy and then treatment considerations during pregnancy and lactation. In their article, the clinicians can learn about delivery management as well as treatment of relapse during pregnancy. In addition, safety of the monoclonal antibodies that may be used in NMOSD during pregnancy and lactation are addressed and the answers to the principal questions on assisted reproductive technology are provided. ³

Alongside with other immune-mediated diseases, NMOSD may result from gene-environment interaction. Mohammadi Lapevandani et al. ⁴ have reviewed the previous studies on different risk factors for developing NMOSD and introduced a broader etiological perspective on the disease development. In this review they have focused on infections, vitamin D deficiency, smoking, hormonal factors, and geographic influences as potential risk factors for disease onset or relapse risk. Heterogeneity of available evidences limits definitive conclusions, but they managed to frame NMOSD as a disorder arising from the interaction between immune vulnerability and environmental triggers. They also tried to seek more attention on this subject for future studies to see weather environmental modifications can eventually decrease the incidence or enhance preventive strategies. ⁴

The comprehensive review by Correale and Carnero Contentti ⁵ addresses one of the most exciting and growing methods for treatment of autoimmune diseases such as NMOSD and MOGAD. The induction of immune tolerance instead of chronic immunosuppression may regulate the dysregulated immune system with less adverse events such as infections or malignancies. The authors first gave an overview of central and peripheral tolerance mechanisms and how their dysregulation contributes to disease pathogenesis and then they continued with antigen-specific tolerance strategies, including peptide-based vaccines, nanoparticle delivery systems, tolerogenic dendritic cells, and cell-based therapies using regulatory T and B cells. They also highlighted the promise and the translational challenges of these approaches and also tried to open research topics with immune reprogramming rather than immune suppression in controlling both diseases. ⁵

The original research article by Schindler et al. ⁶ clarified the relationship between serum glial fibrillary acidic protein (sGFAP) and structural brain damage in NMOSD. By integrating serial serum measurements with detailed brain and cervical cord MRI volumetry, the authors demonstrated that elevated sGFAP levels are specifically associated with reduced thalamic and hippocampal volumes, increased cerebrospinal fluid volume, and greater brain atrophy in AQP4-IgG-positive NMOSD. Notably, these associations were not observed in MOGAD or healthy controls, reinforcing the disease-specific relevance of astrocytic damage in NMOSD. These findings help in depicting subclinical disease activity and possibly evaluating treatment response in future studies. ⁶

The approval of eculizumab/ravulizumab, inebilizumab, and satralizumab, and has revolutionized treatment options, shifting expectations from partial relapse reduction to near-complete relapse suppression in seropositive patients. Yang et al. ⁷ reviewed different preparations for relapse prevention and their adverse events, monitoring, vaccination-related issues, cost, and their access. The article also highlights monitoring before and during treatments and also reviews the pivotal studies leading their approvals. ⁷

Taken all together, this Special Collection tries to show despite the complexity of NMOSD, the field has progressed a lot from recognizing AQP4-IgG as a diagnostic marker to specific therapeutic targets. Still there is a long way in integrating clinical manifestations, imaging findings, and biomarkers. The exciting opportunities with immune tolerance and other targeted treatments should not be underscored for achieving durable relapse and disability prevention.