Dr. Elena Grebenciucova, an assistant professor of neurology at Northwestern University, sheds light on the evolving landscape of neuromyelitis optica spectrum disorder (NMOSD) diagnosis and management. This complex neuroimmunologic disease presents unique challenges for clinicians, from its severe relapse potential to its overlapping symptoms with other conditions like MOGAD and MS. The need for rapid and accurate diagnosis is critical, especially given the ongoing changes to diagnostic criteria and our expanding understanding of seropositive and seronegative phenotypes.
In a recent conversation, Dr. Grebenciucova, an expert in neuroimmunology and CNS inflammatory disorders, delved into practical and emerging issues in NMOSD management. She provided a comprehensive overview, covering diagnostic pitfalls, the clinical implications of seronegative presentations, evolving long-term immunotherapy strategies, and key considerations for special populations such as pregnant patients and those with coexisting autoimmune diseases. Her insights offer a clinically oriented perspective, guiding neurologists through the complexities of NMOSD in their daily practice.
Recognizing the Clinical Syndrome
For young clinicians entering neuroimmunology, Dr. Grebenciucova emphasizes the critical importance of recognizing the clinical syndrome associated with NMOSD. Optic neuritis, especially when severe or bilateral, should prompt testing for aquaporin-4 and MOG antibodies. Even mild cases of optic neuritis should not be overlooked, as they may still warrant antibody testing. The type of specimen used for testing is crucial; serum, not cerebrospinal fluid (CSF), is the standard for both aquaporin-4 and MOG antibody testing. This is a common pitfall, as clinicians may assume that, given the CNS involvement, CSF should be the primary source for testing. Serum testing is essential, and clinicians must ensure high-quality testing through live cell-based assays, which offer excellent sensitivity and specificity.
There are two main types of cell-based assays: live and fixed. While the fixed assay has slightly reduced sensitivity, it maintains excellent specificity for aquaporin-4, meaning a positive result does not require retesting. ELISA testing is not recommended, and patients evaluated by ELISA should be immediately retested with a live cell-based assay. Timing is also critical; testing should ideally be done in the acute phase, but results may be falsely negative if the patient has received immune therapy such as plasma exchange, high-dose steroids, or rituximab. In such cases, retesting in 3-6 months is essential. If results remain negative but clinical suspicion is high, clinicians must stay vigilant and retest with any future relapse, ideally before initiating immunotherapy.
Navigating Seronegative Presentations
The 2025 revisions to the NMOSD criteria emphasize the distinction between seropositive aquaporin-4 NMOSD and what was previously termed seronegative NMOSD. The seronegative entity is now referred to as "seronegative NMOSD clinical syndromes." This change reflects the known pathobiology of aquaporin-4 positive NMOSD, which is an antibody-driven, complement-mediated disease with recognizable biopsy patterns and typical CSF biomarkers. In contrast, double-seronegative cases (both MOG and aquaporin-4 negative) do not share a uniform biology. Biopsies and postmortem data reveal diverse pathologies, CSF profiles differ, and responses to classic NMOSD medications vary significantly.
Studies evaluating responses to therapies like anti-IL-6 agents highlight this distinction. The seronegative group does not respond uniformly, unlike aquaporin-4 positive patients. These insights, presented by Dr. Wingerchuk at ECTRIMS, emphasize that double-seronegative presentations represent a heterogeneous group of syndromes rather than a single disease. This has important implications for treatment selection and patient counseling. Clinicians must maintain diagnostic flexibility, recognizing that seronegative presentations may represent diverse underlying processes, and understand that treatment responsiveness will vary.
Long-Term Immunotherapy and De-escalation Strategies
The approach to long-term immunotherapy and potential de-escalation strategies depends largely on whether the patient is aquaporin-4 positive. For aquaporin-4 NMOSD, most patients have relapsing disease and require long-term therapy. Fortunately, there are multiple FDA-approved options, including complement inhibitors, anti-CD19 therapy, and anti-IL-6 therapy. However, de-escalation is challenging in aquaporin-4 disease. Unlike MS, where older patients may experience fewer relapses and lower inflammatory activity, relapses still occur in NMOSD, even in patients in their seventies, and these relapses can be severe. As such, Dr. Grebenciucova's practice generally does not recommend stopping therapy entirely.
There may be cases where therapy is switched rather than stopped, particularly in aging patients who develop recurrent infections. In such situations, a transition from a broadly immunosuppressive agent to one with a more favorable infection risk profile may be considered. But complete cessation of therapy is typically not recommended for aquaporin-4 positive disease.
Managing NMOSD in Special Populations
When it comes to managing NMOSD in special populations such as pregnant patients, pediatric patients, or those with coexisting autoimmune conditions, more data is needed. Unlike MS, where pregnancy often has a protective effect, NMOSD carries a risk for relapse during pregnancy. If a therapy is known to be reasonably safe during pregnancy, treatment continuation can be considered on a case-by-case basis. Better guidelines are needed to protect pregnant patients with NMOSD during this vulnerable period.
Coexisting autoimmune diseases also present unique challenges. AQP4-positive NMOSD often overlaps with lupus, and clinicians require more data on how NMOSD therapies interact with modern lupus medications. As treatment options expand across both diseases, safety and efficacy considerations become increasingly complex. Continued research will help inform management strategies for these special patient groups.
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