Neuromyelitis Optica: Historically Misdiagnosed — Now Demands Prompt Treatment

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”