In the management of any disease in which relapses are known to occur, it is important to identify the risk factors for their occurrence, as well as any other factors that might influence their severity.

In this article, we will be assessing the risk factors for relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) based on a paper written by Ma et al. 

Interestingly, there is still debate about what constitutes a relapse in the context of NMOSD. Ma and colleagues wrote, “Currently, the definitions of relapse and severe relapse in NMOSD remain vague. The most widely used definition of relapse is the onset of patient-reported or objectively observed events related to new symptoms or worsening original symptoms, with a duration of more than 24 hours, in the absence of other recognized causes such as fever and infection.” 

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Read more about NMOSD etiology 

The problem, of course, is that not all clinicians agree with this definition of NMOSD relapse. Some definitions are highly specific: for example, one definition limits the scope of relapse to an increase of at least 0.5 on the Expanded Disability Status Scale (EDSS); another states that the symptoms of area postrema should last for more than 48 hours. 

The lack of uniformity when it comes to defining NMOSD relapse hampers international cooperation and the sharing of data. Ma et al wrote, “Uniform and clear definitions of relapse will help to compare different cohorts and clinical trials, recognize poor responses and evaluate the efficacy of drugs on preventing relapse.” 

Gender, Age and More 

For the purpose of this article, we will adopt the broadest possible definition of NMOSD relapse, namely the worsening of original symptoms for more than 24 hours.

Females constitute the main population of NMOSD patients. When the diagnostic criteria for NMO was proposed in 1999, it was divided into 2 categories: monophasic NMO and relapsing NMO. The ratio of women to men under the “relapsing NMO” category was 40:8. Recent studies have validated the results that women are at a greater risk of developing NMOSD—and NMOSD relapse—compared to men.

“In the predictive models of relapsing course and survival, female sex was the most predominant factor that predicted relapse,” Ma et al wrote. 

Age also influences the risk of NMOSD relapse. “Increasing age is associated with a lower risk of relapse, as well as a higher frequency of myelitis attacks,” the researchers wrote.

However, studies have produced seemingly contradictory results on the exact age bracket in which patients are most susceptible to NMOSD relapse. One suggests that NMOSD patients aged between 30 and 40 years are at the highest risk of relapse, with relapses occurring less frequently in younger or older patients. However, it should be noted that patients with an older onset age also tend to have more comorbidities and disabilities which may increase the severity of each relapse episode, regardless of the number of relapses. 

Read more about NMOSD epidemiology

A patient’s medical history has also been recognized as a potential risk factor for NMOSD relapse. “Compared to multiple sclerosis patients, patients with NMOSD are more likely to relapse and have autoimmune comorbidities, such as Sjögren’s syndrome, systemic lupus erythematosus and thyroiditis,” Ma et al wrote.

In addition, infection may also make a patient more susceptible to NMOSD relapse by compromising the blood-brain barrier. Studies have shown that about 15% to 35% of patients present with clinical symptoms of acute infection before the occurrence of an NMOSD relapse. 

Related to the topic of infection, Fragoso and colleagues have written a paper that hypothesizes that the AstraZeneca AZD1222 COVID-19 vaccine triggers relapses of multiple sclerosis and NMOSD. 

There is a near-unanimous medical consensus that vaccines are a crucial piece of ending the COVID-19 pandemic. However, scientists are also very sensitive to reports of adverse effects following the receiving of a COVID-19 vaccine dose. Fragoso and colleagues reported on 9 patients (1 case of NMOSD and 8 of multiple sclerosis) who developed a disease relapse in close proximity to their first AZD1222 dose. 

As for the single NMOSD relapse case reported, the patient was a 62-year-old female. She previously had 8 years of controlled disease. A total of 7 days passed after her first AZD1222 dose when she began to experience loss of vision in her left eye. Magnetic resonance demonstrated new gadolinium-enhancing lesions in her left optic nerve. 

What could explain this association between COVID-19 and NMOSD relapse, if there indeed was one? (As the saying goes, correlation does not imply causation). Fragoso et al wrote, “Recent reports have also shown that COVID-19 severity correlates with a broad spectrum of self-reacting antibodies, including against central nervous system antigens. Unexpectedly, these responses were found to be compartmentalized to the central nervous system.” 

However, they stressed that their aim was simply to bring this subject to light, and not to discourage vaccination. “We strongly support vaccination, and we believe in its importance for controlling the pandemic,” they emphasized.

We can conclude from both of these studies that our understanding of the risk factors of NMOSD relapse is still in its infancy. In fact, we still know very little about what causes NMOSD in the first place.

“Taken together, these findings indicate that a well-defined, multicenter and prospective study with a larger population and longer follow-up in NMOSD patients is needed to further investigate the clinical, laboratory and radiographic biomarkers that are correlated with the risk of relapse, in order to develop a more precise therapy for patients in the future,” Ma and colleagues concluded. 


Ma X, Kermode AG, Hu X, Qiu W. Risk of relapse in patients with neuromyelitis optica spectrum disorder: recognition and preventive strategyMult Scler Relat Disord. 2020;46:102522. doi:10.1016/j.msard.2020.102522

Fragoso YD, Gomes S, Gonçalves MVM, et al. New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19Mult Scler Relat Disord. Published online October 13, 2021. doi:10.1016/j.msard.2021.103321