Differences in Diagnosis and Prevention Between NMOSD and MS

Michael Levy, MD, PhD

In the diagnosis of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and related central nervous system diseases, research has shown that B cells play an important role in the pathological course. Additionally, recent research assesing B cells relating to disease activity revealed that regulatory functions of cytokines and immunoglobulins strongly impact the disease pathobiology.¹

Although there are similarities, the diagnosis of the 2 conditions differs. Symptoms for NMOSD include fatigue, pain, stiffness, bladder and bowel dysfunction, cognitive and emotional symptoms, and visual disturbances. Additionally, tests leading to diagnosis may include magnetic resonance imaging, lumbar puncture, and blood tests for autoantibodies including aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG).²

Michael Levy, MD, PhD, sat down in an interview with NeurologyLive® to discuss notable research topics in the field of NMOSD and the current understanding of the disease in relation to MS. Levy, an associate professor at Harvard Medical School, compared the diagnosis and treatment of the 2 disorders, as well as the most important aspect of cares and the next steps in NMOSD-related research.

NeurologyLive®: What is the main difference between NMO and MS in terms of their underlying immunology and pathophysiology?

Michael Levy, MD, PhD: We used to think [NMO] was a variant of multiple sclerosis as the phenotype looks the same with optic neuritis and transverse myelitis. Patients with MS get those too, but for a long time NMO was just thought to be a more severe type of multiple sclerosis. Now, we know that the immunology is completely different between these diseases. NMO involves an immune attack on the aquaporin-4 water channel in the central nervous system, preferential attacks to the optic nerve and spinal cord. In comparison in multiple sclerosis, it appears to be more of a demyelinating disease, which may be driven by Epstein Barr virus and other factors. In NMO, it is purely thought to be an autoimmune process.

How effective is AQP4 in distinguishing NMO from MS and other similar autoimmune diseases?

The way that we know NMO is mediated by immunity against the aquaporin-4 water channel is that patients with NMO have an antibody to that water channel. That's a good biomarker for diagnosis and it also helps us to understand the underlying pathogenesis. The test for the aquaporin-4 water channel, NMO-IgG, is about 85% sensitive, meaning we have about 15% who are seronegative NMO, who don't test positive. But the vast majority do test positive, we call those aquaporin-4 seropositive in NMO. Patients with MS do not test positive for this antibody. In fact, the test is almost 100% specific. If I have a patient with optic neuritis, or transverse myelitis, even a brain lesion in inflammatory brain lesion, who tests positive for the aquaporin-4 water channel, there's a nearly 100% chance that they have the disease. There were some earlier testing methods that weren't as good. We had some more false positive cases in the past, but we don't have as much of them these days using the best type of assay called the cell-based assay available at Quest [Diagnostics], Mayo [Clinic], and other places that have really reduced that risk of false positive cases. Now, I would say it’s 100% specific.

What are some key differences between MS and NMO in terms of patient recovery, prevention, and medications available to prevent attacks?

The most important aspect of care is prevention. While patients with MS may recover well from any single attack, some patients aren't even treated for individual attacks. In NMO, that's not the case. In NMO, recovery is bad, it's poor. Even when you treat aggressively and you treat early,most patients will live with some sort of residual disability from that attack. Clearly, the best way to avoid ongoing disability and MS progressive courses is to prevent attacks. Every disability in NMO is mediated by attacks that don't recover well, so that's really the key here. For that, we do have 3 good FDA-approved medications that are used now to prevent attacks. We’ve gotten a lot better at it. I would say that the number of cases in NMO who have breakthrough disease, who have recurrent attacks, who have a disease that’s not responsive to these treatments, are far fewer than we used to have.

What is the potential next wave of research in NMO for treatment, and how would it differ from current medications?

Now that we have these approved drugs that prevent future attacks, we're now retraining our focus on what is causing the disease and stopping the immune system from targeting the aquaporin-4 water channel far upstream. These drugs work to suppress the immune system, and they're very effective. But what if we could just re-educate the immune system, tell it that “aquaporin-4 is not foreign, is not bad, don't attack it, leave it alone, accept itself.” If we could restore that level of tolerance to the immune system, maybe it would stop attacking the aquaporin-4 water channel. So, there are ways to do that, and we are pursuing them, and companies are interested as well. I think this is going to be the next wave of research in NMO, a more specific targeted approach to treatment that tries to re-educate the immune system rather than just suppress it.

Transcript edited for clarity.

REFERENCES
1. Furman MJ, Meuth SG, Albrecht P, et al. B cell targeted therapies in inflammatory autoimmune disease of the central nervous system. Front Immunol. 2023;14:1129906. Published 2023 Mar 9. doi:10.3389/fimmu.2023.1129906
2. Delgado-Garcia G, Lapidus S, Talero R, Levy M. The patient journey with NMOSD: From initial diagnosis to chronic condition. Front Neurol. 2022 Sep 6;13:966428. doi: 10.3389/fneur.2022.966428. PMID: 36147040; PMCID: PMC9488131.