Imagine facing a debilitating disease where every relapse could leave you permanently impaired. That's the reality for patients with neuromyelitis optica spectrum disorder (NMOSD), a condition that demands rapid, accurate diagnosis and evolving treatment strategies. But here's the challenge: NMOSD can mimic other neurological diseases, and diagnostic criteria are constantly being refined. This makes it incredibly tricky for clinicians to navigate. Elena Grebenciucova, MD, a leading expert in neuroimmunology and assistant professor of neurology at Northwestern University, sheds light on these complexities, offering practical guidance for managing NMOSD in today's dynamic medical landscape.
NMOSD presents a significant hurdle for doctors. It's a neuroimmunologic disease characterized by potentially devastating relapses. What makes it even more complicated is its tendency to overlap with other conditions, such as MOGAD (MOG antibody-associated disease) and multiple sclerosis (MS). The need for a swift and precise diagnosis is paramount to prevent irreversible damage. However, the diagnostic criteria for NMOSD are constantly evolving, and our understanding of the disease's seropositive and seronegative variations is expanding rapidly. This means the field is in a state of continuous learning and adaptation. Recent updates, including the anticipated 2025 revisions to NMOSD criteria, emphasize critical differences in the underlying biology of the disease, the reliability of diagnostic tests, and how patients respond to different treatments. This underscores the vital importance of diligent clinical observation and the use of high-quality antibody testing in patient care.
Dr. Grebenciucova, in a detailed conversation, addresses several crucial and emerging issues in NMOSD management. She provides an in-depth look at common diagnostic pitfalls, the clinical implications of cases where antibody tests come back negative (seronegative presentations), the latest strategies for long-term immunotherapy, and key considerations for specific patient populations, such as pregnant women and individuals with other autoimmune diseases. Her insights offer a practical and clinically focused perspective to neurologists grappling with the complexities of NMOSD in their daily practice. It's like having an experienced colleague share their hard-earned wisdom.
NeurologyLive®: For clinicians just starting out in neuroimmunology, what are the most important aspects of NMOSD to keep in mind for effective treatment?
Elena Grebenciucova, MD: "Clinical syndrome recognition is absolutely fundamental. If you see optic neuritis, particularly if it's severe or affects both eyes, you should immediately consider testing for both aquaporin-4 and MOG antibodies. And this is the part most people miss... don't dismiss mild cases of optic neuritis! Even mild symptoms warrant antibody testing." Dr. Grebenciucova emphasizes. "But here's where it gets controversial... many clinicians assume that because NMOSD affects the central nervous system, cerebrospinal fluid (CSF) is the best sample for testing. That's incorrect! The standard of care for both aquaporin-4 and MOG antibody testing is serum, not CSF. Make sure you're using a high-quality live cell-based assay to maximize sensitivity and specificity."
She further clarifies the nuances of cell-based assays, distinguishing between live and fixed assays. While fixed assays have slightly reduced sensitivity, they maintain excellent specificity for aquaporin-4, meaning a positive result is highly reliable. ELISA testing, on the other hand, is not recommended and should be followed by immediate retesting with a live cell–based assay. Timing is also critical. Testing should ideally be performed during the acute phase of the illness. However, prior immune therapies such as plasma exchange, high-dose steroids, or rituximab can lead to false-negative results. In such cases, retesting in three to six months is essential. If results remain negative despite a strong clinical suspicion, clinicians should remain vigilant and retest with any future relapse, ideally before initiating immunotherapy. These are crucial considerations when diagnosing NMOSD and related disorders.
NeurologyLive®: How should clinicians approach and manage patients who initially test seronegative, given the challenges of characterizing seronegative disease and the importance of retesting?
Elena Grebenciucova, MD: "The upcoming 2025 revisions to the NMOSD criteria highlight a critical distinction between seropositive aquaporin-4 NMOSD and what was previously called seronegative NMOSD. Now, we're using the term 'seronegative NMOSD clinical syndromes' for the latter. Why the change? Because aquaporin-4 positive NMOSD has a well-defined disease mechanism: it's an antibody-driven, complement-mediated disease with characteristic biopsy findings and CSF biomarkers." In contrast, Dr. Grebenciucova points out, double-seronegative cases (negative for both MOG and aquaporin-4 antibodies) are far more complex. "They don't share a uniform biology. Biopsies and postmortem data reveal diverse pathologies, CSF profiles vary, and responses to traditional NMOSD medications differ significantly."
Studies evaluating responses to therapies like anti–IL-6 agents underscore this difference. The seronegative group does not consistently respond in the same way as aquaporin-4 positive patients. Dr. Wingerchuk's presentations at ECTRIMS have emphasized that double-seronegative presentations represent a heterogeneous group of syndromes rather than a single disease. "This is crucial for treatment selection and patient counseling. Clinicians must maintain diagnostic flexibility, recognize that seronegative presentations may reflect diverse underlying processes, and understand that treatment responsiveness will vary." In essence, a one-size-fits-all approach simply won't work.
NeurologyLive®: Where does the clinical community currently stand on long-term immunotherapy and potential de-escalation strategies for NMOSD?
Elena Grebenciucova, MD: "This largely depends on whether the patient is aquaporin-4 positive. For aquaporin-4 NMOSD, most patients experience relapsing disease and require long-term therapy. Fortunately, we now have multiple FDA-approved options, including complement inhibitors, anti-CD19 therapy, and anti–IL-6 therapy. However, attempting to de-escalate therapy in aquaporin-4 disease is challenging." Dr. Grebenciucova draws a contrast with MS. "Unlike MS, where older patients may have fewer relapses, NMOSD relapses can still occur even in patients in their seventies, and they can be severe. Therefore, in my practice, we generally avoid stopping therapy altogether."
She notes that therapy may be switched instead of stopped, especially in older patients who develop recurrent infections. "In these cases, we might transition from a broadly immunosuppressive agent to one with a more favorable infection risk profile. But complete cessation of therapy is not typically recommended in aquaporin-4 positive disease."
NeurologyLive®: How should clinicians think about managing NMOSD in special populations such as pregnant patients, pediatric patients, or those with coexisting autoimmune conditions?
Elena Grebenciucova, MD: "We urgently need more data, but several studies are underway. 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. We need better guidelines to protect pregnant patients with NMOSD during this vulnerable period." She also highlights the complexities of coexisting autoimmune diseases. "AQP4-positive NMOSD often overlaps with lupus, and clinicians need more data about how NMOSD therapies interact with modern lupus medications. Safety and efficacy considerations become more complex as treatment options expand across both diseases. Continued research will help inform management strategies for these special patient groups."
What are your thoughts on the challenges of diagnosing and managing NMOSD, especially in seronegative cases and special populations? Do you agree with Dr. Grebenciucova's cautious approach to de-escalating therapy? Share your experiences and insights in the comments below!
