Underlying Pathology of Rare Neuroimmune Disorders

WATCH TIME: 7 minutes

Rare neuroimmune disorders are immune-mediated disorders of the central nervous system in which cells become “confused” and mistakenly attack an organ within a person. Patients may have acute flaccid myelitis (AFM) or transverse myelitis (TM) when the spinal cord is affected or optic neuritis when the optic nerve is impacted. In acute disseminated encephalomyelitis (ADEM), MOG antibody disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), there are various patterns of organ involvement, and in some disorders there is the potential for recurrent events.

Over the years, the detection of these disorders, and the way they are treated, has improved significantly. For years, neuromyelitis optica was thought to be a variant of multiple sclerosis (MS), but in 2004, a circulating immunoglobulin autoantibody was reported in patients with neuromyeltis optica that was absent in those with MS. Within a year, the astrocyte water channel protein aquaporin-4 was identified as its target, leading to several advanced therapeutics more than a decade later.

In collaboration with the Siegel Rare Neuroimmune Association, NeurologyLive^® hosted a Roundtable Discussion focusing in on the major advances since the organization’s birth, nearly 30 years ago. The panel included Sanford Siegel, current president of SRNA, Benjamin Greenberg, MD, vice chair of clinical & translational research at UT Southwestern Medical Center, and Douglas Kerr, MD, chief medical officer of GeneratioBio and a key figure in the establishment of the Johns Hopkins Transverse Myelitis Center, the only such specialized center in the world. In this episode, the group provided commentary on how the definition of neuroimmune disorders has changed, citing advances in biomarker research and diagnostic criteria.

Marco Meglio: Let's delve into the mechanisms behind these disorders and what we've learned about their underlying pathology in rare neuroimmune disorders.

Benjamin Greenberg, MD: Sure, I can provide a more contemporary perspective on this topic, given that I'm younger than Doug. I'll also share some of the insights I gained from Doug's teachings, some of which have evolved over time. When I joined Doug and Sandy, I was just finishing my neurology residency and starting my fellowship. Two aspects drew me to this field: the remarkable scientific advancements within the community and the integration of science and clinical care.

From a scientific standpoint, what we've learned in the past 20 years (although it's hard to believe it's been that long) is quite remarkable. We've uncovered that there are numerous ways to inflame and damage the spinal cord. Doug touched on this earlier, including infectious, post-infectious, and systemic autoimmune triggers. Since the establishment of diagnostic criteria in 2002, we've gradually dissected the subgroups within these disorders. It's hard to fathom that we were running a myelitis center in 2002 without a blood test for neuromyelitis optica (NMO) or the aquaporin-4 antibody. We were seeing NMO patients without realizing they had neuromyelitis optica. We encountered patients with anti-MOG-associated disorder, but it wasn't until 2015 or 2016 that we identified it as a distinct condition. The understanding of transverse myelitis, previously defined as a white matter demyelinating disease, shifted when we recognized acute flaccid myelitis in 2014, primarily affecting gray matter.

The framework established in 2002 allowed us to identify these outliers and scientifically define their unique characteristics. We found autoantibodies in some cases and viral infections triggering immune responses in others. The number of people worldwide classified as having idiopathic transverse myelitis, where the cause is unknown, has been steadily decreasing since 2002. This is beneficial for patients who were previously placed in the unknown category, but it also helps us better understand idiopathic patients. As a result, the evaluation and workup for patients today are vastly different from before.

Additionally, something often overlooked is the therapeutic interventions Doug introduced when he set up the myelitis center in Baltimore. I assumed that these interventions were standard practice everywhere, but that wasn't the case when I moved to Dallas. Our early and aggressive treatment approach was met with surprise. However, over the last 20 years, this approach has become increasingly accepted as a standard of care. The American Academy of Neurology now recognizes the benefits of early intervention, and more physicians are embracing it. This shift has led to better outcomes for patients in the post-acute setting. The experience of receiving calls from new patients who haven't experienced recovery is vastly different from what was happening at your kitchen table in 2000. This is just my impression, but it aligns with the scientific progress we've seen.

Sanford Siegel: I agree. Physicians have become more aggressive in their approach, thanks to the work of Doug, Ben, and others in the field who understand the importance of early and aggressive treatment. It's worth noting that we had some quasi-clinical trials, like Brian Weinshenker's study on plasma exchange.

Benjamin Greenberg, MD: Indeed, that trial was groundbreaking, although it's something we couldn't replicate today, given the ethical constraints. However, we've found alternative ways to build evidence for interventions like plasmapheresis through tangential studies. Its acceptance has grown worldwide, allowing us to treat patients more aggressively early on and achieve better outcomes.

Sanford Siegel: To add to what Ben mentioned, correct diagnosis is crucial, especially because some of these disorders are monophasic, like ADM and idiopathic transverse myelitis, while others, such as Neuromyelitis optica and MOG antibody-related disorders, carry the risk of recurrent attacks. Identifying these patients correctly is essential for considering disease management therapy. Having biomarkers for these disorders has played a critical role in improving diagnosis and treatment.