Disease risk factors and the underlying etiology for neuromyelitis optica spectrum disorder (NMOSD) are not known. Using controls and the validated questionnaire from the Environmental Risk Factors in MS Study (EnvIMS) study [1] to query a Canadian cohort of well-defined NMOSD patients, researchers sought to determine what factors might play a role in the development of this disease. Physician’s Weekly spoke with Dalia Rotstein, MD, MPH, Assistant Professor of medicine at the University of Toronto and neurologist specialized in multiple sclerosis, who presented the findings at the virtual European Committee for Treatment and Research In Multiple Sclerosis Virtual Congress  (ECTRIMS 2021, the Digital Experience)[2].


The validated EnvIMS questionnaire, previously used to study risk factors for MS, was returned by adults with confirmed aquaporin-4 antibody positive (AQP4+) NMOSD at 6 large Canadian MS clinics (n=122), of which 109 were matched to controls. Controls without a diagnosis of demyelinating disease from the Canadian arm of the EnvIMS study were frequency-matched at a 3:1 ratio to NMOSD participants by age and gender (n=319). In both cohorts, 89% were women, with a mean age of 50.1 years. With regard to ethnicity, 19.4% of NMOSD participants reported that both parents were East Asian, 13.9% reported that both parents were Black, 35.2% reported that both parents were White, 23.2% reported that both parents had another ethnicity, and 8.3% reported mixed ethnic parentage. Comorbid autoimmune disease (lupus, rheumatoid arthritis, psoriasis, or Celiac disease) was reported by 15.8% of the respondents. Although non-White ethnicity and comorbid immune disease were associated with increased odds of NMOSD compared with individuals with 2 White parents (odd ratios for East Asians were 55.0-fold higher; Blacks 12.5-fold higher, and for other ethnicities 10.0-fold higher), no association with infectious mononucleosis was observed. NMOSD was also positively associated with comorbid autoimmune disease (odds ratio 13.3). The unexpected findings of lower odds of NMOSD in smokers may be attributable to lower rates of smoking in East Asian women, who are disproportionally represented among AQP4+ NMOSD cases. The authors conclude that considering immigrant status and ethnicity in epidemiological studies is important. Furthermore, their study supports findings from other regions that non-White ethnicity and comorbid immune diseases are primary risk factors for AQP4+ NMOSD.

Physician’s Weekly spoke with Dr. Dalia Rotstein, presenter of this study, to find out more:


Physician’s Weekly: What was the rationale of this study?

“We wanted to learn more about the causes and risk factors for AQP4+ NMOSD in Canada, including demographic and environmental risk factors. To this end, we administered the EnvIMS validated questionnaire to AQP4+ NMOSD patients and compared their responses to the unaffected control population from the original EnvIMS study. In this manner, we were able to tap into a large group of controls [1].’’


Physician’s Weekly: Did you also distribute the questionnaire to sero-negative (AQP4-) individuals?

“We separately distributed the questionnaire to patients with myelin oligodendrocyte glycoprotein (MOG-IgG)-antibody positive disease as well. We currently appreciate that people with the clinical phenotype of NMOSD can belong to several different serotypes and have different underlying pathophysiology as a result. Around 70% of NMOSD cases are AQP4+, with perhaps an additional 10-15% are MOG-positive. The remaining 15% are double seronegative NMOSD individuals. So, the reason for evaluating them separately is because it does seem that the underlying pathophysiology differs depending on serologic subtype. For example, AQP4+ disease is primarily an astrocytopathy, where demyelination happens secondary to the loss of astrocytes. We think that the etiology and the triggers of these conditions may be different.”


Physician’s Weekly: What were the main findings?

“One of our main findings was that risk of NMOSD did seem to differ across ethnic groups, which has been reported in other cohorts before, but it was nice to be able to investigate that in a controlled fashion. We found the highest risk in people of East Asian background, whereas the second highest was in people of Black background, with the lowest risk being in the White population.

‘’One unique angle we were able to take was to investigate age of onset of NMOSD by ethnic group. And we found youngest age of onset was in Black individuals, which was only slightly older in Asian individuals. The oldest age of onset was in White individuals with NMOSD. I think this is an important finding in terms of being alert in the clinical setting to people who are at higher risk and it may lead to additional research around the etiology of the condition in different groups.

‘’Interestingly a large portion of our cohort was immigrants, but age of onset did not seem to differ by immigrant status. Although not a definitive finding, this observation could suggest that it is not something unique about the Canadian environment that is predisposing to NMOSD in these different groups.”


Physician’s Weekly: Will your study change practice with regard to how the ethnic background of individual patients may be taken into account and that the ability to intervene or recognize the disease sooner?

“Facilitating early diagnosis is essential. Knowing which people are at higher risk for NMOSD is important to facilitating earlier diagnosis of this condition. NMOSD can present in the same way as multiple sclerosis, which is much more common, with, for example, optic neuritis or transverse myelitis. My hope would be that generation of this kind of data will increase the index of suspicion in the right individuals to help direct when to order NMO/AQP4 antibody testing. The other question these data raise is regarding prognostication in NMOSD.  For example, we have seen in several studies that Black individuals seem to have worse outcomes. Now we have to ask: is that related to the observed earlier onset of the disease and/or more severe relapses?

“When we have a better understanding of some of these basic issues, we will be able to better tailor therapy accordingly. Treatment options have exploded in NMOSD over the last few years, including higher efficacy therapies but they do have higher costs. We want to be able to choose the right therapy for the right person.”


Physician’s Weekly: What are the next steps?

“It is very important to validate these findings in a prospective manner. In Canada, right now, I am leading a national prospective longitudinal study in NMOSD that was launched earlier this year, collecting data about ethnicity. Not only is it important to understand how ethnicity affects risk of NMOSD, but also the age of onset, and the course of the disease.

“Another finding from this study was that there was an increased risk of NMOSD in people with other auto-immune diseases. That is very interesting to explore further; we do not understand much about the etiology of NMOSD, but we do think that there probably is some dysfunction of systemic immune control before the pathogenic antibodies breach the blood-brain barrier. Some of my other research is focused on that, trying to understand other comorbidities that may crop up in advance of NMOSD, that may provide us further clues to the etiology of the condition.”


Additional reading

  1. Magalhaes S, et al. The EnvIMS Study: Design and Methodology of an International Case-Control Study of Environmental Risk Factors in Multiple Sclerosis. Neuroepidemiology. 2015;44(3):173-81.
  2. Rotstein D, et al, A Canadian national case control study into demographic and environmental risk factors for NMOSD. ECTRIMS 2021, abstract P043.