BOSTON, Massachusetts—When Gabriela Romanow’s son, Max, was 20 years old, he suffered 3 frightening attacks of optic neuritis, in which any attempt to move his eyeballs left, right, up, or down caused excruciating pain. During 2 out of those 3 attacks, he temporarily lost vision.
At that time, Max was in Florida, studying at the University of Miami, and Romanow was at a loss for information.
“It was clear his optic nerves were inflamed. So I found myself researching why a healthy young man might be having a series of attacks of optic neuritis. Online, I kept seeing multiple sclerosis (MS) and neuromyelitis optica (NMO),” she said. “And since NMO looked more dangerous, I was actually hoping my son had MS.”
Diagnosed with NMO, which now falls under the broader category of neuromyelitis optica spectrum disorder (NMOSD), Max was put under the care of a trio of “excellent neurologists,” Romanow said.
“I began raising money through the Guthy-Jackson Charitable Foundation and started a program to proclaim March as NMO Awareness Month,” she said. “I joined the boards of some local foundations working on NMO, and I attended every conference I could to learn and advocate as much as possible.”
Through her activism, Romanow eventually began working for Michael Levy, MD, PhD, director of the Neuroimmunology and Neuro-Infectious Diseases Division of Massachusetts General Hospital in Boston. But on a personal level, she was in despair; none of the drugs prescribed for her son’s disease seemed to be working.
After a year at Mass General, Romanow mentioned Max’s situation to Dr. Levy, and within 3 minutes of conversation he determined that NMO wasn’t the problem. Instead, he said, Max had myelin-oligodendrocyte-glycoprotein antibody disease (MOGAD)—a rare neurological, immune-mediated disorder defined by inflammation in the optic nerve, spinal cord and/or brain.
“For most of the history of my son’s disease, we thought it was NMO because MOGAD hadn’t been diagnosable in this country until 2017,” said Romanow, adding that Max, 28, is “doing great” now that he’s been properly diagnosed. “Dr. Levy is special because he is such a kind, open, gracious professional who makes his patients feel understood. He communicates clearly and makes himself available to them in a way most doctors do not.”
Initially, 95% of NMOSD Cases Misdiagnosed as MS
Dr. Levy, 46, studied medicine at Baylor University in his native Texas, then did his residency at Johns Hopkins University in Baltimore, Maryland. That’s how he came to specialize in NMOSD, an extremely rare disease that affects only 1-2 per 100,000 people in the United States.
“Johns Hopkins is a great place to be a resident because you really make a lot of decisions, and pretty quickly, I fell into this routine of running the hospital floor for neurology,” he said. “A lot of the patients we were getting in Baltimore were coming in with a diagnosis of MS, put on treatments and having bad outcomes. Most of them were African-Americans. I’d hear the same story over and over: ‘I was taking the medicine my doctor put me on, and I’ve had 3 relapses.’”
Dr. Levy added: “We didn’t even know NMO was a thing back then. Around that time, a lot of studies were going on in MS, and these people were messing up their MS trials because they were failing the therapies. It was good timing for me.”
In 1999, he said, some 95% of all NMO cases were being misdiagnosed as MS. But 5 years later, the Mayo Clinic in Rochester, Minnesota, published a landmark paper on the disease, and in 2006, a test for the NMO aquaporin‑4 antibody became commercially available.
“We started recognizing this was a unique disease that immunologically was different from MS, and that MS medications were driving the disease in the wrong direction,” he said. “We didn’t know this at the time, but in our attempt to treat these people, we were actually making them worse.”
Dr. Levy, who’s also an associate professor of neurology at Harvard Medical School here, said he and his team created a neuromyelitis optica clinic at Johns Hopkins, “and then we started trying to identify new drugs that would be beneficial in this disease.”
NMOSD, a term which came into use in 2007 and was formalized in new criteria established in 2015, is roughly 3-4 times more likely to affect Black people than in the general population. This is why Americans of African or Caribbean origin represent 13% of the US population but 50% of the nation’s patients with NMOSD.
Similar patterns have been observed in Great Britain, where Afro-Caribbean people make up the vast majority of those with NMOSD. The world’s highest incidence of the disease is on the Caribbean island of Martinique—an overseas department of France—where it occurs at a rate of 12 per 100,000 people.
“Nobody knows why this is, and it’s not just an issue of susceptibility,” he said. “They are more likely to develop NMO, and when they get NMO attacks, they’re more likely to have severe outcomes. They’re more likely to lose vision permanently, they’re more likely to remain immobilized after an attack of transverse myelitis, and they’re much more likely to die of NMO than Caucasians.”
Likewise, women are 9 times more likely to develop NMOSD than men, compared to MS, where the ratio is 3:1.
Asked why, Dr. Levy said “there must be a hormonal component. We think that in childhood before menarche, that the rates are more equal between boys and girls. Then after menarche it almost completely skews towards women.”
Few Studies, Shortage of Testing in Africa
Given such a high prevalence of NMOSD among Black individuals, he said, it’s clear there isn’t enough testing for the disease in Africa.
“It’s hard to get accurate testing there,” he said. “I have one case in South Africa, for example, where the blood sample had to be shipped from Cape Town to London to even make the diagnosis. Not enough studies have been done.”
The 2005 publication of a study detailing the effect of rituximab on a small group of NMO patients “really changed the tide,” Dr. Levy said.
“We started putting everybody on rituximab. I remember people saying that the drug was a chemotherapy that causes lymphoma. It was still really early days, and our NMO patients were responding really well,” he said. “It became super popular.”
Since then, 3 blinded, placebo-controlled phase 3 trials have all demonstrated efficacy and safety in NMO. The first therapy, eculizumab (Soliris®)—approved by the US Food and Drug Administration (FDA) in 2020—blocks a part of the immune system called the complement system. Out of 96 patients, only 3 relapsed within the first year, compared to the placebo arm, in which 40% relapsed; that translates into a 94% reduction in relapse risk. A newer version of eculizumab, known as ravulizumab-cwvz (Ultomiris™) requires infusions every 8 weeks rather than every 2 weeks.
The second study involved inebilizumab (Uplizna®) , a CD19 monoclonal that depletes B cells like rituximab does, but across a broader set of them. In this study, patients on inebilizumab showed a 77% drop in relapse risk in the aquaporin-4 serum positive group, with many of the same safety benefits as with rituximab. This drug also won FDA approval in 2020.
Early Initiation of Treatment
The third study involved satralizumab-mwge (Enspryng™), an interleukin‑6 blocker. It was tested in 2 trials, 1 in the United States, the other overseas, where both aquaporin‑4 positive and aquaporin‑4 negative patients received a monthly subcutaneous injection. That provided about a 62% risk reduction overall, with the drop in the risk of relapse reaching 79% for the aquaporin-4 positive group. The FDA approved satralizumab in 2020 only for the aquaporin-4 positive group.
“It’s being recognized that we have to identify these patients early and put them on the right treatment. All 3 of these medications are so wonderfully effective, especially compared to the risk in the damage from each attack,” Dr. Levy said. “Each attack usually leaves behind some residual disability.”
He added: “Attacks in the optic nerve will cause vision loss, and vision loss tends to be severe. Attacks on the spinal cord cause weakness, numbness, and bowel bladder dysfunction. Although people can recover to the point that they can walk sometimes with assistance or even better, there’s usually a component of pain and spasms and immobility that persists.”
Dr. Levy praised Guthy-Jackson for having catalyzed research on NMOSD.
“They brought everybody together, made everybody talk and come up with ideas, and provided funding for research,” he said. “I don’t think it’s an exaggeration to say that their work has single‑handedly led to the science that underlies all 3 of the clinical trials.”
Early on, the organization funded Dr. Levy’s basic research, he said. “Based on their funding, I had enough research to apply for a 5-year grant through [the National Institutes of Health] to develop a mouse model for NMO.”
These days, Dr. Levy sees patients once a week, on Tuesdays. The rest of his time is split evenly between clinical trials and basic science.
“One thing we’re now doing in the lab is looking at how to turn the immune system off just to aquaporin-4,” he said. “People are born normal, then at some point the system builds an immunity to aquaporin-4. Our challenge is how to turn that off so that the rest of the immune system remains intact.”