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A new study revealed stark racial and socioeconomic disparities in pediatric neuromyelitis optica spectrum disorder outcomes, underscoring the need for targeted interventions.

Race, Socioeconomic Status Play Major Role in Disparities Seen in Pediatric NMOSD Outcomes

Over the 6-month treatment period, patients saw improvements in cataplexy frequency, excessive daytime sleepiness, cognition, and work productivity with AXS-12.

Axsome to File NDA Following Positive Phase 3 Results of AXS-12 in Narcolepsy

Videos

The pediatric neurologist at Duke Health and chief executive officer at Theranica talked about a remote electrical neuromodulation wearable that showed promising results for the treatment and prevention of migraine in pediatric patients. [WATCH TIME: 5 minutes]

Advancing the Treatment of Pediatric Migraine With Nerivio REN Wearable: Klaus Werner, MD & Alon Ironi

The vice president of scientific engagement at the Alzheimer's Association discussed advancements in blood biomarker tests, their use in specialty care, and the development of clinical guidelines for broader integration.

NeuroVoices: Rebecca M. Edelmayer, PhD, on Advancing Blood Biomarkers in Alzheimer Disease for Earlier Diagnosis and Treatment Intervention

Here's the latest multidisciplinary multiple sclerosis (MS) research from the International Journal of MS Care.

Research from IJMSC October 2024

The neurologist in the Headache Center at Cleveland Clinic shared her post perspective on the 2024 AHS Scottsdale meeting which highlighted advancements in headache medicine and the growing impact of the field on patient care. [WATCH TIME: 5 minutes]

Highlights on Exploring Advances in Headache Medicine from AHS Scottsdale 2024: MaryAnn Mays, MD

The epilepsy specialist and Cleveland Clinic’s Chief Research and Information Officer discussed the wide-spread applicability of scalp EEG and the potential for machine learning models to help predict epilepsy surgery outcomes. [WATCH TIME: 4 minutes]

Scalability of Scalp EEG as a Tool for Epilepsy Surgery Outcomes: Lara Jehi, MD, MHCDS

Dean and chief academic officer at the University of Miami Miller School of Medicine.

The dean and chief academic officer at the University of Miami Miller School of Medicine discussed the university’s investment in computational biology to advance aging and neuroscience research. [WATCH TIME: 5 minutes]

Driving Innovation in Aging and Neurodegenerative Research: Henri Ford, MD, MHA 

NeurologyLive is your direct connection to the latest neurology news and interviews with expert neurologists in multimedia formats.

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Clinical

 MS Disease Spotlight page offers specific updates and coverage on the latest expert conversations and data readouts related to the treatment and management of patients with multiple sclerosis and demyelinating disorders.

The findings were consistent with the established safety profile for eculizumab in other non-neurologic indications, according to study authors.

Eculizumab Demonstrates Safety, No Increased Infection Rates in NMOSD or Myasthenia Gravis

In a longitudinal study lasting 2 years, impaired test performance in semantic fluency and congruent speed were observed in patients with MOGAD relative to healthy controls.

Cerebral Lesions Considered Important Predictor of Cognitive Deficits in MOGAD

The phase 1 study, which is currently recruiting, includes a 4-week screening period, a 52-week treatment period, and a 4-year long-term extension to continue to test the effects of HG202.

First-Ever CRISPR/Cas13-RNA Editing Therapy to be Tested in Phase 1 Study of Age-Related Macular Degeneration

HNSA-5487 exhibited lower pre-treatment anti-drug antibody levels and reduced ADA responses compared to imlifidase, indicating a favorable immunogenicity profile and strong potential for redosing, with no serious adverse events observed.

Hansa to Advance HSNA-5487 in Chronic Autoimmune Diseases Following Robust IgG Reduction in First-in-Human Trial

For the majority of patients who were either aquaporin-4-antibody seropositive or seronegative, rituximab was the first disease-modifying therapy administered for neuromyelitis optica spectrum disorder.

Lower-Dose Rituximab Demonstrates Long-Term Efficacy in Neuromyelitis Optica Spectrum Disorder

Shamik Bhattacharyya, MD, discussed a study presented at ECTRIMS 2024 that compared the effectiveness and safety profiles of FDA-approved NMOSD therapies with other commonly used treatments.

Comparative Analysis Insights on Neuromyelitis Optica Spectrum Disorder Treatments: Shamik Bhattacharyya, MD

"We are very often as a field focused on relapses, and perhaps not enough on infection hospitalizations or other serious complications of therapy."

Currently, there are 4 FDA-approved treatments for aquaporin-4-antibody seropositive neuromyelitis optica spectrum disorder (NMOSD): satralizumab (Enspryng; Genentech), eculizumab eculizumab (Soliris; Alexion), ravulizumab (Ultomiris; Alexion), and inebilizumab (Uplizna; Amgen). Besides these therapies, rituximab (RTX), mycophenolate mofetil (MMF) and azathioprine (AZA) are also commonly used to treat the disease. At the 

2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress

, September 18-20, in Copenhagen, Denmark, a new study presented assessed the efficacy and safety of both off- and on-label therapies in the treatment of patients with NMOSD.

In this analysis of patients with NMOSD (n = 107), investigators collected data from the Mass General Brigham system (mean age at diagnosis, 45.3 years [SD, 15.9]; AQP4 positive, 93.4%, women, 82.2%; White 63.6%) as well as defined relapses as new signs and symptoms consistent with a core NMOSD phenotype. Authors also included all non-relapse hospitalizations and noted that the median follow-up was 9.8 years (IQR 8.1). Among the total 280 relapses analyzed by researchers, 65.3% of them were reported as requiring hospitalization and 83.5% of the relapses with available MRI had a new T2 lesion.

Conducted senior author Shamik Bhattacharyya, MD, and colleagues, 85 patients were given rituximab, compared with 27 patients for MMF, 12 patients for AZA, 4 patients for satralizumab, 5 patients for inebilizumab, and 9 patients for eculizumab. The median treatment duration was 6.5 years (IQR 7.5) for MMF, 5.8 years (IQR 6.4) for rituximab, 1.05 years (IQR 3.69) for AZA, 2.1 years (IQR 2.74) for eculizumab, 3.0 years (IQR 0.13) for inebilizumab and 1.2 years (IQR 2.3) for satralizumab. The failure rate, which was defined as at least 1 relapse on treatment, was reported by investigators as 40% for rituximab, 59% for MMF and 75% for AZA.

In the analysis, the most common treatments at relapse were rituximab (30.6%), MMF (23.2%) and AZA (11.0%). Researchers also reported no relapses observed with patients on satralizumab, 1 relapse reported on eculizumab 1 week after starting treatment, and 1 relapse reported on inebilizumab prior to completing the initial load. In 183 non-relapse hospitalizations recorded, 55.7% were because of infections and 57.9% were reported while on rituximab treatment, compared with 23.2% for MMF and less than 1% for satralizumab, inebilizumab, and eculizumab.

During the Congress, Bhattacharyya, a neurologist at Brigham and Women's Hospital, sat down with 

 in an interview to discuss how relapse rates in NMOSD differed between rituximab and the newer FDA-approved therapies. He also talked about the factors that may contribute to the 30% failure rate of rituximab in preventing NMOSD relapses. Furthermore, Bhattacharyya, who also serves as an associate professor of neurology at Harvard Medical School, spoke about the barriers that might exist for patients who would switch from rituximab to newer NMOSD therapies.

Click here for more coverage of ECTRIMS 2024.

REFERENCES
1. Bilodeau PA, Narasimhan S, Pua DK, et al. Comparative Effectiveness and Safety of Disease-modifying Treatments (DMTs) in a Real-World Neuromyelitis Optica Spectrum Disorder Cohort (NMOSD). Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract P022.

The associate professor of neurology at Harvard Medical School discussed a study presented at ECTRIMS 2024 that compared the effectiveness and safety profiles of FDA-approved NMOSD therapies with other commonly used treatments. [WATCH TIME: 4 minutes]

MOGAD diagnosis pearls

Over the last 2 decades, the understanding of inflammatory demyelinating disorders of the central nervous system has radically changed with the identification of specific autoantibody-associated conditions distinct from multiple sclerosis (MS), namely aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. In the most recently published diagnostic criteria of MOGAD, the identification of MOG-IgG was considered a core criterion, marking a major step in improving care and diagnosis rates.

, and others, noted that MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. In collaboration with the 

Siegel Rare Neuroimmune Association (SRNA)

® gathered Bennett and autoimmune expert 

, for a Roundtable Discussion highlighting the latest updates in the diagnosis, treatment, and research of MOGAD.

In episode 6, Bennett and Greenberg close the panel discussion with thoughts on the future directions of research for MOGAD. Bennett, a professor of neurology at the University of Colorado School of Medicine, and Greenberg, a pediatric neurologist at the University of Texas Southwestern Medical Center, discussed ongoing efforts to identify immunological markers that could help predict which patients will lose their antibody status and avoid relapses. Furtheremore, the discussion harped on refining diagnostic criteria to improve accuracy in MOGAD detection, as well as understanding the unique recovery mechanisms in patients with MOGAD, which could be applied to other neuroimmune disorders.

SRNA is also hosting the 2024 Rare Neuroimmune Disorders Symposium (RNDS) on October 18-20th. The RNDS was created to bring together individuals diagnosed with acute disseminated encephalomyelitis (ADEM), acute flaccid myelitis (AFM), MOG antibody disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), optic neuritis (ON), and transverse myelitis (TM) and clinicians and researchers that focus on these disorders. Invite your patients who may benefit from attending either virtually or in person in Dallas, TX. Healthcare professionals are also welcome to join! Learn more 

: Let’s talk a little about the research going forward for MOGAD. Are there any emerging research initiatives or areas of focus regarding MOGAD that are gaining ground, or that you feel should gain more attention? Let’s dive into the research side of things over the next couple of years.

: So I'll take the opportunity to highlight a colleague of mine at UT Southwestern, who's embarked on some research relative to anti-MOG associated disorder that I think is critical. That’s Linda Wynn, who was a fellow with us and has joined the faculty. She’s looking at immunologic markers at onset that could predict who is going to lose their antibody status over time. If, from the very first event where someone is antibody-positive, we could better counsel them—whether they need secondary prevention from that moment, versus waiting for a second attack to occur—I think that would not only make a big clinical difference but also open the door for fascinating clinical trials around immune remodeling.

Can we take someone from their first event and actually wipe out the autoimmune characteristics inherent in their immune system, whether it’s through things like CAR T-cell therapy or other interventions? Over the next 10 years, Linda’s not the only one—we’ll see a plethora of studies trying to better understand this fascinating aspect of anti-MOG associated disorder, where some patients sero-revert and others do not.

: I think I see highlights for the future not only in what Ben just discussed, which is the important issue of trying to predict who will relapse, and whether we can get them started on therapy before waiting for that next relapse to happen. Another focus is refining our diagnostic criteria. Right now, we know there are specific caveats for cerebrospinal fluid, as well as for serum based on the level of antibody titer that’s recorded. We’ve found clinical and MRI criteria that appear specific for MOGAD, but we need to understand how these criteria are performing. Are we selecting—or perhaps self-selecting—groups of patients by using these criteria? Do patients who meet MOGAD diagnostic criteria with high titers really look exactly the same as those who meet criteria with what we would call "not clearly definite" titers?

Moving forward, this will help refine not only who we diagnose but how we diagnose them, and which assays are optimal to use. We also need to think about our treatment of acute MOGAD, and understand in the laboratory why MOGAD patients seem to recover better, on average. We know that in MOGAD patients, we sometimes see lesions disappear, something we don’t often observe in other disorders. What’s driving that ability for recovery? How can we harness that to better treat not only MOGAD but also other neuroimmune disorders? By modifying the local environment, we might be able to extend that recovery ability to other neuroinflammatory conditions.

In this episode, a pair of neuroimmune experts discussed some of the emerging research for patients with MOGAD, highlighting the need for immunological markers, remodeling therapies, and enhancements to diagnostic criteria. [WATCH TIME: 5 minutes]

SAP Partners

Advancing MOGAD Research: Predictive Markers, Immune Remodeling, and Future Therapies

In episode 5, the duo dove into the challenges faced by patients with MOGAD, especially in pediatric and adult populations. Greenberg, a pediatric neurologist at the University of Texas Southwestern Medical Center, emphasized the need for better support systems, including academic interventions for children and psychological care for adults. Bennett, a professor of neurology at the University of Colorado School of Medicine, discussed the difficulty in determining who needs treatment and highlighted the cognitive, academic, psychological, and functional struggles patients with MOGAD face after initial attacks. Overall, the two neurologists touched upon the lesser reported complications such as sleep disturbances and genitourinary issues in adults.

: What are some of the greatest unmet needs outside of treatments? Obviously, we know we need approved therapies, but just from a physician's standpoint, seeing patients on a daily basis, what are certain things that you guys feel maybe need a little more attention? What are things our patients might need more help with in terms of their day-to-day lives? Can you talk a little about some of the unmet needs that patients still face?

: Yeah, so I would have two, and one of them overlaps with the treatment side. I think one of the biggest challenges in the long term is deciding who to treat and who not to. If we could identify better prognostic markers for who's at risk, not just for relapses but for relapses that might leave a significant impact—because some relapses are mild—we could avoid treating some patients who may not need it. That’s a global scientific issue. But more to your point about quality of life and function: one thing we haven't touched on yet in relation to anti-MOG associated disorder is the high prevalence in the pediatric population compared to the adult population.

For aquaporin-4 mediated disease, it's exceedingly rare in prepubescent children. It happens, but it's very rare. Multiple sclerosis is also very rare in prepubescent children, and both of those disorders increase as you move into adolescence and adulthood. However, anti-MOG associated disorder has a much higher incidence of onset during childhood, especially in prepubescent children, and it often presents as acute disseminated encephalomyelitis (ADEM). When I was training, we were taught that ADEM was a “one and done” event. The issue was that many kids grew up, had their second event later, and no one connected the two.

In our pediatric practice, one of the biggest issues we’re seeing in this unique population is cognitive and academic. We refer to it as "growing into the deficit." A 3, 4, 5, or 6-year-old who has ADEM recovers and looks great, goes off to kindergarten and first grade, and everyone is thankful that their child is doing well after being so sick. But then, in third, fourth, or fifth grade, as academics get harder, people forget the medical event that happened years ago. These kids get diagnosed with ADHD, need to repeat a grade, or struggle in school, but it's actually a neuropsychological issue related to the insult they suffered years earlier.

So one of the main things we try to do in our pediatric practice is make sure these kids get the academic and social support they need after the acute insult, to ensure they succeed not just academically, but in life. We really focus on the cognitive aspects of this condition, finding ways to support any deficits our patients may have.

: I agree that's a critical issue—MOGAD’s involvement in the pediatric population and the special needs that arise from it. We see some of those same needs in the adult population as well. Psychologically, there’s depression, anxiety, fear, all of which need to be addressed with symptomatic medicine. Cognitively, we see difficulty concentrating, memory problems, sometimes confusion, whether or not ADEM or another attack was involved.

In the adult population, issues like inability to work and impaired relationships often stem from this. Additionally, something that's not often reported but is significant is poor sleep, which can be addressed medically, as well as genitourinary complications after spinal cord involvement in MOGAD. We don't see this as often with spinal cord injuries in MS or NMOSD, but it’s prominent in MOGAD, and addressing these issues early is crucial to helping patients function and return to work because they can be quite debilitating.

So as we continue focusing on MOGAD and its symptomatology, we’ll get better not only at dealing with attacks and preventing future ones, but also at helping people return to their highest possible level of functioning.

The pair of neurologists provided clinical insight on a number of lingering non-treatment unmet needs for patients with MOGAD, including improved care for pediatric patients and underreported complications like sleep disturbances and genitourinary issues in adults. [WATCH TIME: 5 minutes]

Unmet Needs and Challenges Across Pediatric and Adult MOGAD Populations

In episode 4, Bennett, a professor of neurology at the University of Colorado School of Medicine, and Greenberg, a pediatric neurologist at the University of Texas Southwestern Medical Center, discussed the current landscape of treatment options for MOGAD. The duo highlighted 2 promising studies: the COSMOG trial investigating rozanolixizumab, and the METEROID trial testing satralizumab, both with differing mechanisms of action. In the discussion, Bennett and Greenberg emphasize the importance of exploring diverse treatment options for this rare condition, noting that the trials not only provide potential therapies but also deepen the understanding of the disease’s biology. Furthermore, they touch on the evolving role of immune-modulating drugs, like anti-IL-6 inhibitors, and discuss how the availability of varied administration methods can address the individual needs of patients.

: We're still kind of missing that elusive, first approved therapy. Where do we stand on drug development right now? And could you talk a little bit about some of the ongoing studies or agents in the pipeline that you're paying attention to? Hopefully, we might see a little more success.

: So there are multiple industry-sponsored and investigator-initiated trials for different drugs and interventions for anti-MOG associated disorder. Two of them, in particular, are being conducted nationally, and even internationally to a degree, looking at drugs that have been studied in other conditions. One of the studies, called COSMOG—C-O-S-M-O-G—is investigating rozanolixizumab. Try saying that five times fast! It’s being studied in the setting of anti-MOG associated disorder. The second trial, called METEOROID, is looking at satralizumab for the same condition.

What’s exciting about these trials is that these are very different drugs with very different mechanisms of action. And I highlight that because it's great to have variety—options are critical if both drugs work. No drug ever works for 100% of patients, so having multiple options is extremely important. Through the success or failure of these drugs, we'll also learn a lot about the disease itself, particularly about the underlying biology and which parts of the biology we can intervene on to make a difference.

For example, satralizumab, which is FDA-approved for aquaporin-4 antibody-positive NMO, is an anti-IL-6 receptor monoclonal antibody. It blocks IL-6 signaling within the body, and ideally, reduces B-cell activation and antibody production in these disorders. We don’t know yet if this strategy will be effective for anti-MOG associated disorder, but there’s reason to believe it might be, hence the clinical trial. Either way, the outcome will teach us more about the disease. It’s an exciting time for us, especially since anti-MOG associated disorder was only really differentiated as its own condition about eight or nine years ago.

: I think we’re going to move forward with many of these new therapies, driven in part by agents crossing over from other diseases, as you mentioned with the COSMOG trial and the anti-neonatal receptor-inhibiting antibody, which may help modulate MOG IgG levels and perhaps alter the immune response. This could happen independently of its ability to deplete the MOG antibody.

We also have the anti-IL-6 receptor inhibitors, and we may even explore anti-microglial-targeted agents that have been studied in multiple sclerosis. On top of that, we’ll likely revisit anti-B cell therapy to see how it performs with MOGAD. Retrospective studies have shown it’s about 50/50 in efficacy for MOGAD compared to NMOSD and MS.

There are also Bruton tyrosine kinase inhibitors, anti-neonatal Fc receptor inhibitors, and anti-IL-6 receptor inhibitors, all of which will likely see more interest as we try different approaches to treating patients. Beyond the variety of mechanisms, we’re also seeing variety in how treatments are administered. We have a subcutaneous injection with satralizumab, subcutaneous infusions with the anti-neonatal receptor antibody inhibitors, and oral options with the Bruton tyrosine kinase inhibitors. This variety gives patients options based on their individual needs, including baseline deficits, social factors, and financial considerations around prescription costs.

In this discussion, the pair of neurologists explore the latest drug development and ongoing clinical trials for MOGAD, a rare neuroimmune disorder. [WATCH TIME: 4 minutes]

Evaluating the Treatment Pipeline for MOGAD

In episode 3, the duo discuss the treatment and management of MOGAD, including acute options such as high-dose intravenous steroids and plasma exchange, and the importance of rapid treatment to improve recovery outcomes. Bennett, currently a professor of neurology at the University of Colorado School of Medicine, highlighted the differences in MOGAD’s response to therapies compared with other neurological disorders like MS and neuromyelitis optica. Greenberg, who serves as a pediatric neurologist at the University of Texas Southwestern Medical Center, added that while prevention strategies for MS and neuromyelitis optica are more established, MOGAD is at an early stage of understanding, and long-term treatments like IVIG and rituximab are being used off-label. Furthermore, the two discussed ongoing clinical trials and the unique challenges of treating MOGAD, including the need for longer steroid tapers to prevent relapse.

: Let's talk a little bit about the treatment course for patients with MOGAD. Can you discuss some of the main treatment options for this disease, as well as some of the non-pharmacologic approaches that can help alleviate symptoms or improve the disease course in general?

: When it comes to acute attacks of MOGAD, we tend to rely on what we do for many other autoimmune inflammatory disorders of the central nervous system that we’ve discussed. We typically use high-dose intravenous steroids, like Solu-Medrol or dexamethasone. We also think about short-term immune modulation therapies, such as intravenous immunoglobulin (IVIG) or plasma exchange, especially for patients with severe attacks.

Right now, it seems that MOGAD responds more vigorously to high-dose corticosteroids than other similar disorders, like multiple sclerosis (MS) or neuromyelitis optica (NMO). There's some recent research suggesting that in MOGAD, rapid treatment with steroids can have a significant impact on recovery, especially in cases like optic neuritis. So, treating these acute attacks quickly is critical.

We know that in NMO, alternative treatments like plasma exchange can be more effective in enhancing recovery from attacks. But with MOGAD, we don’t have as much data to support that yet. For MS, plasma exchange seems to work better for severe attacks, but again, we don’t have strong data for MOGAD. So, we rely on our standard acute therapies for now.

I’ll let Dr. Greenberg talk more about the long-term treatment strategies and how we manage patients once they’re off steroids, which may differ from how we treat other disorders.

: On the prevention side, we're at a point with MOGAD that's similar to where we were with NMO about 20 years ago. Back then, NMO wasn’t fully recognized as its own category and was often misdiagnosed as MS. But now, with molecular diagnostics like antibodies, we can better differentiate these disorders.

As for long-term treatment, we’re still learning which patients need preventative therapy and what that therapy should be. Right now, we use some of the same tools that we’ve used for other CNS autoimmune disorders, like mycophenolate mofetil, rituximab, and, uniquely for MOGAD, intravenous immunoglobulin (IVIG). IVIG is something we don’t typically use for MS or NMO, so there are some clear differences in the way we treat MOGAD in the long term.

One key point for listeners is that while I always recommend secondary prevention for patients with MS or NMO right from their first event, that’s not necessarily the case for MOGAD. Some patients may not need secondary prevention at all because their relapse rate is lower, and their relapses tend to be more treatable. We might wait until a patient has a second clinical event before recommending long-term treatment with mycophenolate, rituximab, or IVIG, which is all off-label for now.

The exciting part is that just like with NMO, where we saw rapid investment in clinical trials after the disorder was better defined, we’re seeing the same thing with MOGAD. There are multiple clinical trials underway, which is pretty remarkable for a rare disease. It shows how organized the clinical and research communities are in rapidly deploying interventions and determining what works.

One last point about steroids: In the past, there was a lot of debate about how long to taper steroids after an acute attack. We didn’t have much data, and many clinicians based their decisions on personal experiences. However, we now know that patients with MOGAD often experience a “bounce-back” effect if steroids are tapered too quickly. That’s why at my center, we use a longer steroid taper for MOGAD than we would for other autoimmune disorders like MS or NMO.

So, it’s clear that MOGAD is its own unique disease, with its own specific treatment needs, and we’re making progress in understanding it better.

In this segment, Bennett and Greenberg explore the diagnosis, acute treatment, and long-term management of MOGAD, highlighting current therapies and ongoing research. [WATCH TIME: 8 minutes]

Understanding the Treatments and Tools for MOGAD Management

Over the last 2 decades, the understanding of inflammatory demyelinating disorders of the central nervous system has radically changed with the identification of specific autoantibody-associated conditions distinct from multiple sclerosis, namely aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. In the most recently published diagnostic criteria of MOGAD, the identification of MOG-IgG was considered a core criterion, marking a major step in improving care and diagnosis rates.

That criterion, which was authored by Jeffrey Bennett, MD, PhD, and others, noted that MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. In collaboration with the Siegel Rare Neuroimmune Association (SRNA), 

 gathered Bennett and autoimmune expert Benjamin Greenberg, MD, for a Roundtable Discussion highlighting the latest updates in the diagnosis, treatment, and research of MOGAD.

In episode 2, Greenberg, who serves as a pediatric neurologist at the University of Texas Southwestern Medical Center provided commentary on the changes in how MOGAD is diagnosed, the positives with established criteria, and the questions surrounding titers and timing of the testing. Bennett, currently a professor of neurology at the University of Colorado School of Medicine, mentioned the fluidity of the diagnostic criteria, the importance of timely testing and eliminating delays, as well as the potential impact of the upcoming McDonald criteria.

My next question for you both—obviously, MOGAD is a relatively newer disorder. We're still learning a lot about MOGAD in relation to other similarly presenting disorders like MS and NMOSD, as you alluded to earlier. So, how will the diagnosis evolve, or not evolve, over the coming years? Can you discuss how we're going to diagnose MOGAD as we incorporate more technology, assays, imaging, and things like that?

 I think it's important to note that there is now a published diagnostic criteria for anti-MOG-associated disorder. It really starts, as Jeff mentioned, with the clinical history and imaging, meaning you have a patient that fits a known phenotype associated with this antibody. Then, you do reliable testing, getting an appropriately high titer of the antibody to correlate with what you're seeing clinically and on the MRI. The gray area, I think, comes around the titers and timing of the testing.

What we’ll likely see in the next few years are more studies fleshing this out. The gray area includes, for instance, if you get back a titer of 1:40, how is that different from 1:100? In the right clinical scenario, we struggle with what to do with individuals who look like they have anti-MOG-associated disorder but either have a low titer or the testing wasn’t done acutely. By the time a person is tested, the event is in the past, and their results come back negative. You look back and think, "Geez, the event they had a year ago really looks and sounds like an anti-MOG event, but now their titers are negative." Could they have been positive and then reverted to negative? A lot of work is going to be done around these scenarios to give more guidance to clinicians.

In general, if you take the revised McDonald criteria for multiple sclerosis, the international diagnostic group for neuromyelitis optica, and the anti-MOG-associated diagnostic criteria, each of them references the others. They point out red flags and when testing should be done, or when to be wary of a diagnosis. I find that if you take all three together, they are consistent with each other and give clinicians good guidance on when to test and how to interpret a clinical scenario.

 Ben brings up a great point. Our diagnostic criteria are very fluid, and they're becoming more specific and sensitive as we learn more about these disorders. We’re understanding how we, as clinicians, can sometimes fall through the cracks in mistaking one for the other. MOGAD holds an interesting status—it’s the only disorder among these that requires a serologic test for its diagnosis.

As Ben mentioned, the delay between testing and disease onset can affect the results of that assay. Treatment may also affect results, and our knowledge is still evolving. There may be groups of patients who essentially have MOGAD but don’t test positive for the antibody. We've known this from the beginning—some patients who were seropositive for MOG antibodies had an attack, then lost the antibody, yet still had another attack and remained antibody-negative. That tells us right there that some MOGAD patients may be negative for our antibody tests.

Going forward, we’re going to get more sophisticated in testing for MOGAD, as Ben said. We’ll need to understand how the assays are done and how they impact diagnostic sensitivity. We’re also going to appreciate clinical clues that might be more specific for one disease or another. You mentioned the revised McDonald criteria for MS, which will be previewed at an upcoming meeting at ECTRIMS this month. That’s going to incorporate new domains into MS diagnosis, new tests that aren’t necessarily specific for MS.

We’ll have to be careful as we move forward because NMOSD and MOGAD might overlap with these diagnostic criteria, and that could make it harder to make a clean diagnosis. So, assays will be critical, and we might even need different assays that look for non-antibody-dependent diagnostic abilities. Also, whether we get the antibodies from the spinal fluid or the serum may affect our ability to refine diagnoses moving forward.

In this episode, Greenberg and Bennett provide some perspective on the fluidity of MOGAD diagnosis and how it could potentially change over time as more is understood about neuroimmune disorders. [WATCH TIME: 5 minutes]

Continuing Evolution of MOGAD Diagnosis, Remaining Questions in Antibody Titer Testing

® gathered Bennett and autoimmune expert Benjamin Greenberg, MD, for a Roundtable Discussion highlighting the latest updates in the diagnosis, treatment, and research of MOGAD.

In episode 1, the duo provide an overview of how MOGAD is currently diagnosed, including the neurological symptoms that clinicians should be aware of, and the presence of MOG-IgG antibody in either serum of cerebrospinal fluid. Bennett, who serves as a professor of neurology at the University of Colorado School of Medicine, and Greenberg, a pediatric neurologist at the University of Texas Southwestern Medical Center, describe the conditions to rule out during diagnosis, considerations for testing, and the need to be aware of false positives.

The first topic we're going to talk about is the diagnosis of MOGAD. So, how is MOGAD diagnosed these days? And from a clinician’s perspective, what are the clinical pearls that treating physicians should understand about this process?

 MOGAD is diagnosed through a combination of a new clinical neurologic symptom—something that, upon evaluation, is consistent with an inflammatory attack on the central nervous system—and the presence of the MOG-IgG antibody. We’ve now published compendium criteria for this diagnosis, which can be found in 

. Essentially, the first step is identifying such an event in a domain of the nervous system, which could be the optic nerve, brain, brainstem, or spinal cord. There’s also a caveat for more diffuse presentations like acute disseminated encephalomyelitis (ADEM), which can involve multiple areas of the nervous system at once, often with altered consciousness or behavior.

Once that’s identified, testing for the MOG-IgG antibody is prompted, and this can be done in the serum or cerebrospinal fluid (CSF), though there are some caveats. For instance, if the antibody is only present in the CSF, you need to see a definitively high positive titer for the MOG antibody to make the diagnosis, after ruling out neuromyelitis optica spectrum disorder (NMOSD). If the titer is equivocal, then additional MRI and clinical criteria are considered. The criteria vary slightly depending on whether the antibody is found in the CSF or serum. So, that’s the basic rundown for diagnosing MOGAD.

 Yeah, I agree with Jeff. The only thing I’d add, just to raise awareness, is about when clinicians should consider sending the test. Basically, anytime you’re thinking about diagnosing multiple sclerosis (MS) or NMOSD, it should at least prompt you to consider the MOG test. There are different practice patterns out there—some clinicians say, “Before I make an MS or NMOSD diagnosis, I send the anti-MOG antibody test to rule it out as a mimic.” Others limit testing to certain presentations. I’m in the former camp—I tend to send it for everyone and then interpret the data. But it should definitely be on your radar if a patient has symptoms like loss of vision, numbness, or weakness, and you’re working them up for a demyelinating disease. At some point, testing for the anti-MOG antibody should come into consideration.

 On the flip side, I would caution physicians to have a strong indication that the condition is inflammatory—whether it’s vision loss, weakness, or altered consciousness—before sending off the test. Most of the false positives I’ve seen happen when the test is sent without a firm belief that the condition in front of them is inflammatory, either based on MRI findings or spinal fluid criteria.

In this segment, the duo of neurologists provided a number of informative considerations treating clinicians should take when diagnosing MOGAD, emphasizing careful testing and interpretation of data in this complex process. [WATCH TIME: 4 minutes]

Navigating MOGAD Diagnosis: Clinical Insights and Key Considerations

Bruce Cree, MD, PhD, MAS, FAAN, discussed findings from the end-of-study analysis assessing inebilizumab over time in NMOSD.

Analyzing Long-Term, End-Of-Study Results for Inebilizumab Treatment in NMOSD: Bruce Cree, MD, PhD, MAS, FAAN

"It’s very interesting observation because it speaks to a biological impact of long-term B cell depletion in NMO (neuromyelitis optica) and resonates with the clinical experience that many of us have had when we have treated patients with other B-cell depleting therapies such as rituximab: once patients stabilized on treatment they tend to stay stable on treatment over the long term."

Inebilizumab (Uplizna; Amgen), an FDA-approved anti-CD19 B-cell-depleting antibody, has shown sustained efficacy and safety in patients with neuromyelitis optica spectrum disorder (NMOSD) according to newly published end-of-study results from the phase 2/3 N-MOmentum trial (NCT02200770). The end-of-study analysis of N-MOmentum, which included both the randomized controlled period and the open-label extension period, confirmed the long-term clinical benefits of inebilizumab treatment in patients with NMOSD.

The clinical research director of the UCSF Multiple Sclerosis Center discussed findings from the end-of-study analysis assessing inebilizumab which revealed a significant reduction in attack rates among patients with NMOSD over time. [WATCH TIME: 3 minutes]

NMOSD

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