Although research shows that a subset of patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) typically present with co-occurring clinical symptoms and T2-hyperintense MRI lesions suggestive of multiple sclerosis (MS), there is limited evidence about the MRI characteristics of this overlap syndrome. Recently presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark, a new study showed that overlap with MS frequently occurred in patients with NMDARE.1
In this study, investigators compared neuroimaging data of patients with the overlapping conditions and “stand-alone” patients who had NMDARE, both from centers in the nation-wide GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) network. Conducted by lead author Joseph Kuchling, MD, and colleagues, additional findings from the presented study revealed that patients with overlap NMDARE-MS experienced more NMDARE-atypical symptoms and were characterized by an MS-typical conventional MRI lesion pattern, rapid lesion accumulation, and an MS-specific 7T-MRI lesion morphology with central vein sign (CVS).
These results suggest a potential pathophysiological connection between both entities implicating particular diagnostic and therapeutic awareness in the management of MS and NMDARE. In a new iteration of NeuroVoices, Kuchling, a postdoctoral research assistant at Charité University Berlin, talked about how the new diagnostic criteria may improve the differentiation between NMDARE and MS. He also talked about the role of imaging markers like the CVS and paramagnetic rim lesions (PRL) in the updated criteria for diagnosing MS. Furthermore, Kuchling spoke about how early MS diagnosis and treatment might impact the long-term outcomes of patients with overlapping autoimmune conditions.
NeurologyLive: Could you summarize the key findings from your presentation that related to these MRI characteristics in patients who had overlapping conditions?
Top Clinical Takeaways
- New diagnostic criteria will help with earlier MS detection by incorporating advanced imaging markers, which may help differentiate MS from other neurological conditions.
- Patients previously diagnosed solely with NMDARE might also have underlying MS, which could be diagnosed earlier, preventing delayed treatment.
- Early and accurate diagnosis, supported by the new criteria, could lead to more timely interventions and improved outcomes, particularly in patients who were previously in diagnostic gray areas.
Joseph Kuchling, MD: The interesting thing we observed was several cases initially diagnosed with NMDARE, which later, over the course of the disease, also showed MRI findings consistent with MS. These patients are often presented with MS-related symptoms. Upon reviewing their routine clinical MRIs, we found that both the dissemination in space and dissemination in time criteria, as per the 2017 McDonald criteria, were met.
We were fortunate to have the opportunity, provided by Friedemann Paul, MD, PhD, at Charité, to study these patients using a 7-tesla MRI. This was especially important because we didn’t initially know if the lesions were from MS or another neurological condition. We examined the lesions using advanced imaging techniques. What we found was the CVS, which we commonly see in patients with MS but not in other diseases. This sign, along with paramagnetic rim lesions (hypointense rims around lesions detected through T2*-weighted imaging at 7 Tesla), helped us conclude that these lesions originated from MS. Based on these findings and the clinical evidence, we are now confident that what we are seeing is an overlap between NMDARE and MS.
How significant is it to have diagnostic criteria that help better differentiate between these overlapping conditions?
In the cohort we studied, one major issue was that patients presented with encephalitis, but we also suspected MS lesions. However, they didn’t meet the 2017 McDonald criteria at the time. According to those criteria, a patient needed at least one MS symptom or a clinical finding suggestive of MS-related damage. These patients, though, had neuropsychiatric symptoms from NMDARE, making it hard to detect whether MS was also present. As a result, they were often labeled only as having NMDARE, and the potential MS was overlooked.
Initially, these patients received immunosuppressive therapy for their encephalitis, possibly CD20-depleting therapy for one or two years. However, since encephalitis is generally considered a monophasic disease, immunotherapy was discontinued after that. Then, a few years later, some of these patients developed new symptoms or new lesions. This could have been prevented if we had been able to diagnose MS from the start using updated diagnostic criteria. Now, with these new criteria, we might be able to give an MS diagnosis earlier, allowing us to begin treatment sooner—even if they wouldn’t have received a definitive MS diagnosis under the old criteria. This could make a big difference for patients currently diagnosed with NMDARE plus radiologically isolated syndrome (RIS).
Unfortunately, as Xavier Montalban, MD, PhD, pointed out during the session, we can’t apply the 2023 McDonald criteria until the paper is officially published. But once it is, applying these criteria could be a real benefit for our patients. We’d be able to diagnose MS based on RIS criteria and start treatment sooner, instead of waiting for additional clinical signs.
Another important change in the criteria, as I understood from the presentation, is the introduction of specific markers such as the CVS and PRL. These additions could help improve the specificity of diagnoses. The 2017 McDonald criteria were sensitive, but not as specific in real-world settings. With these new criteria, we hope to be more confident in diagnosing MS and start treatment earlier in patients showing strong signs of MS, such as CVS, without needing to consider other differential diagnoses like sarcoidosis or neuromyelitis optica spectrum disorder (NMOSD). But of course, we need to see how these criteria work once they’re applied in real clinical settings.
What happens to patients who go undiagnosed and untreated for long periods?
This could be a significant benefit for patients who, under the 2017 McDonald criteria, were either left untreated or followed a “watch and wait” approach. If we can treat them earlier, we could prevent disease progression in terms of new lesions, symptoms, or relapses. There’s also an issue with healthcare systems, which is dependent on location, but here in Germany, for example, we have an insurance system that covers treatments based on diagnosis. If we can’t establish a diagnosis according to the criteria, even if we strongly suspect a disease, the treatment won’t be covered. This creates a real challenge for patients who are in this diagnostic gray area, such as those with overlapping autoimmune encephalitis and MS. Hopefully, these new criteria will help us secure earlier diagnoses and treatments for these patients.
Was there anything else from the presentation that stood out to you as particularly important?
The key message from our findings is the need to closely monitor patients with encephalitis, even after their acute attack has been treated. We found a subset of patients NMDARE and with undiagnosed MS lesions. I believe it’s crucial to follow these patients regularly, perhaps with an MRI after one or two years, to check for other underlying neurological diseases. We’ve also seen overlaps with conditions like NMOSD or myelin oligodendrocyte glycoprotein antibody disease in these patients.
I’m really looking forward to the publication of the new criteria. There are many patients in our outpatient clinics who might have MS but don’t meet the current criteria, leaving them without appropriate treatment. Hopefully, the new criteria will make it easier to diagnose and treat these patients. Although the criteria looked somewhat complicated at first, we’re excited to delve deeper when the paper is released, and we hope it will provide the clarity needed to help these patients who are often caught between diagnoses.
Transcript edited for clarity. Click here for more coverage of ECTRIMS 2024.
REFERENCES
1. Kuchling J, Penner L, Fernandez Ceballos R, et al. NMDA Receptor Encephalitis and Multiple Sclerosis Overlap Syndrome - Part I: Clinical Findings and MRI Characteristics. Presented at ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Scientific Session 1: New diagnostic criteria. Abstract 2310.
