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The impact of COVID-19 on patients with neuromyelitis optica spectrum disorder; a pilot study

      Highlights

      • NMOSD is an immune-mediated, inflammatory degenerative condition affecting the CNS.
      • Immunomodulatory treatments put these patients at a greater risk of infection.
      • We report how the COVID-19 pandemic may affect NMOSD patients.
      • Pandemic-related stress may increase risk of disease activity in NMOSD.

      Abstract

      Neuromyelitis optica spectrum disorder (NMOSD) is a CNS neuroinflammatory disorder, mediated by the pathogenic autoantibody aquaporin-4 (AQP4-IgG). Current treatment includes long-term use of immunomodulatory therapies, leading to increased rates of infections among this population. It is of interest therefore, to study how the COVID-19 pandemic affects NMOSD patients in terms of their disease activity. A 15-point questionnaire was administered to 33 participants living in Northern California with NMOSD, MS and other related disorders. Although none of the participants were diagnosed with COVID-19, our results show that 2 participants with NMOSD experienced new onset of neurological symptoms and 2 experienced worsening of previous neurological symptoms – suggesting a possible effect of pandemic-related stress on this CNS autoimmune disorder.

      Keywords

      1. Background

      Neuromyelitis optica spectrum disorder (NMOSD) is a group of chronic, immune-mediated, inflammatory and degenerative conditions predominantly affecting the central nervous system (CNS) (Wingerchuk et al., 2015). Patients with NMOSD are often immunocompromised as a result of exposure to long-term immune modulatory therapies to prevent irreversible and progressive neurologic disabilities caused by relapses (Glück et al., 2005). In addition, patients often experience worsening of pre-existing symptoms or relapses under stressful situations (
      • Kessler R.A.
      • Mealy M.A.
      • Levy M
      Early indicators of relapses vs pseudorelapses in neuromyelitis optica spectrum disorder.
      ). This pilot study investigates the impact of the pandemic COVID-19 on patients with NMOSD in terms of clinical relapses and susceptibility to infection utilizing a clinical questionnaire.

      2. Methods

      We used a 15-point clinical questionnaire (see Appendix A) to investigate the association between NMOSD and COVID-19 infection among 33 subjects (19 NMOSD and 14 controls) living in Northern California during the months of March and April 2020. Controls consisted of patients with multiple sclerosis (MS) and transverse myelitis (TM). All NMOSD and MS patients had confirmed diagnoses using the Wingerchuck 2015 and McDonald 2010 criteria, respectively. The questionnaire consisted of questions regarding NMOSD diagnosis (2), current immunomodulatory therapies (2), seasonal flu (2), COVID-19 (3), change in neurological symptoms (5), and other (1). Participants that experienced new neurological symptoms were contacted by phone to determine the potential effect of pandemic-related stress on the development of new symptoms (see Appendix B). The study population was composed of participants followed at the Stanford Neuroimmunology Clinic, some of which were enrolled in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD (CIRCLES) study (
      • Cook L.J.
      • Rose J.W.
      • Alvey J.S.
      • et al.
      Collaborative international research in clinical and longitudinal experience study in NMOSD.
      ), and consisted of primarily Caucasians (52%, 17/33), women (64%, 21/33), and NMOSD patients (58%, 19/33). A difference in proportions z score test was used to determine whether NMOSD patients had a higher risk of experiencing worsening of symptoms or new symptoms compared to control subjects during the early COVID-19 pandemic. This study was approved by the Stanford University Institutional Review Board.

      3. Findings

      In our current study, 85% of total subjects (28/33) responded to the questionnaire – of which 89% (17/19) were NMOSD and 79% (11/14) were control subjects. Among the NMOSD patients, 18% (3/17) were diagnosed with MOG-associated disease, 59% (10/17) were NMO-IgG seropositive, and 24% (4/17) were NMO-IgG seronegative. In the control group 73% (8/11) carried the diagnosis of MS and 27% (3/11) were diagnosed with transverse myelitis (TM).
      All of the NMOSD patients included in the study were treated with preventative immune therapy – among which 88% (15/17) were treated with rituximab while the remaining 12% (2/17) were treated with azathioprine (6%) and tocilizumab (6%). Only 64% (7/11) of the controls were on preventative immunomodulatory therapies, 36% (4/11) of which were treated with ocrelizumab, 9% (1/11) with alemtuzumab, 9% (1/11) with glatiramer acetate, and 9% (1/11) with natalizumab.
      Upon investigating the incidence of COVID-19 infection, 11% (3/28) (2 NMOSD and 1 control) of the subjects experienced respiratory symptoms including fever, chills, and shortness of breath. We also observed that 71% (20/28) of the subjects received prior influenza vaccination. None of the subjects who experienced infectious symptoms were tested for seasonal influenza and/or SARS-CoV2 infection. In addition, 14% (4/28) of subjects (2 NMOSD, 2 control) experienced worsening of pre-existing neurological symptoms, which include cognitive symptoms, fatigue and spasticity. 12% (2/17) NMOSD patients developed new neurological symptoms suggestive of a clinical relapse. However, none of the patients experienced symptoms severe enough to seek medical attention (Table 1). Both of these patients reported experiencing more stress than usual prior to the onset of these new symptoms. They also experienced symptoms related to stress, including insomnia, anxiety and depression. Additionally, both of these patients remained compliant with their preventative medications – with no delays. Stress was not measured in participants who did not exhibit new neurological symptoms.
      A difference in proportions z score test found no significant difference between risk of experiencing worsening of symptoms (2/17 NMOSD vs. 2/11 controls) or new symptoms (2/17 NMOSD vs. 0/11 controls) between NMOSD and control subjects (p>0.05). Additionally, there was no significant difference in experiencing flu-like symptoms (2/17 NMOSD vs. 1/11 control) between NMOSD and control study groups (p>0.05).

      4. Discussion

      Autoimmune disorders are often debilitating conditions and generally require life-long treatment management. NMOSD is a rare neuroinflammatory autoimmune disorder, that when left untreated, can cause sever disability and even death (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). As with most autoimmune conditions, patients with NMOSD rely on immunomodulatory treatments to prevent worsening of their conditions (
      • Glück T.
      • Kiefmann B.
      • Grohmann M.
      • Falk W.
      • Straub R.H.
      • Schölmerich J
      Immune status and risk for infection in patients receiving chronic immunosuppressive therapy.
      ). Although these therapies can minimize disease progression, they also cause patients to be more susceptible to infections. Due to the severity of the COVID-19 pandemic, it is imperative to understand if these immune-compromised individuals are at a greater risk of being diagnosed with COVID-19.
      Table 1Description of the study population.
      Case (n = 17)Controls (n = 11)
      Female:Male ratio14:34:7
      Diagnosis
      AQP4-IgG (+) NMOSD100
      AQP4-IgG (-) NMOSD40
      MOG (+) NMOSD30
      MS08
      TM03
      Immunomodulatory treatment176
      Rituximab150
      Azathioprine10
      Tocilizumab10
      Ocrelizumab03
      Alemtuzumab01
      Glatiramer acetate01
      Natalizumab01
      Flu-like symptoms
      Flu-like symptoms include respiratory symptoms, fever, chills, and/or shortness of breath.
      21
      Worsening of existing symptoms
      Refers to neurological symptoms related to underlying neurological disorder.
      22
      New symptoms
      Refers to neurological symptoms related to underlying neurological disorder.
      20
      low asterisk Flu-like symptoms include respiratory symptoms, fever, chills, and/or shortness of breath.
      low asterisklow asterisk Refers to neurological symptoms related to underlying neurological disorder.
      The purpose of this pilot study was to determine whether patients with NMOSD were more likely to be diagnosed with COVID-19 and how the pandemic affected their current neurological conditions. To our knowledge, this is the first ever study investigating the association of pandemic related effects on NMOSD. We observed that although none of the participants tested positive for COVID-19, 12% of NMOSD patients and 18% of controls experienced worsening of previous neurological symptoms. 12% of NMOSD patients also experienced new neurological symptoms, suggestive of a relapse.
      NMOSD relapses occur throughout the disease course and are often triggered by stressful situations. Studies have shown that stressful events can impact the autoimmune conditions, such as MS, by inducing immunological alterations (
      • Grant. I.
      • Brown. G.W.
      • Harris. T.
      • et al.
      Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis.
      ;
      • Mohr D.C.
      • Pelletier D.
      A temporal frame work for understanding the effects of stressful life events on inflammation in patients with multiple sclerosis.
      ). Two studies looked at the effect of a stressful event -the Israel–Hezbollah war – on MS relapses and disease activity (
      • Golan D.
      • Somer E.
      • Dishon S.
      • et al.
      Impact of exposure to war stress on exacerbations of multiple sclerosis.
      ;
      • Yamout B.
      • Itani S.
      • Hourany R.
      • et al.
      The effect of war stress on multiple sclerosis exacerbations and radiological disease activity.
      ). They found that a significant number of MS patients were having relapses (18% of compared to the average of only 3% per month), (
      • Golan D.
      • Somer E.
      • Dishon S.
      • et al.
      Impact of exposure to war stress on exacerbations of multiple sclerosis.
      ) and that exposure to war-related events was associated with enhanced MRI activity (
      • Yamout B.
      • Itani S.
      • Hourany R.
      • et al.
      The effect of war stress on multiple sclerosis exacerbations and radiological disease activity.
      ). A recent study evaluated the impact of a natural disaster - the 2011 Great East Japan Earthquake – on MS and NMOSD (
      • Kanamori Y.
      • Nakashima I.
      • Takai Y.
      • et al.
      Impact of the Great East Japan Earthquake in 2011 on MS and NMOSD: a study in Sendai, Japan.
      ). Although there was no significant increase in relapse rates in the MS and NMOSD patients, 18% of NMOSD patients had a relapse within a year of the natural disaster. It is thus postulated that the stress of the uncertainty caused by a pandemic, such as the COVID19 pandemic, can create comparative levels of stress as those in natural disasters or during war – potentially leading to an increase in disease progression in patients with NMOSD. In support of these findings, our study also showed that 2 patients experienced new neurological symptoms indicative of a relapse, which corresponded to an increased perception of stress.
      As with many pilot studies, the small study size is a weakness in determining true effects of the pandemic on NMOSD patients. Additionally, stress levels were only evaluated in participants with an onset of new neurological symptoms and were not evaluated with a validated stress measure– therefore all conclusions about possible associations between stress and worsening of neurological conditions will need to be further validated. Furthermore, as these were patient-reported outcomes that were not confirmed by a physician, information bias may exist. Since the spread of the SARS-CoV2 virus began earlier than first reported, a subset of infected patients can remain asymptomatic, and confirmatory blood test has not been carried out (
      • Bai Y.
      • Yao L.
      • Wei T.
      • et al.
      Presumed asymptomatic carrier transmission of COVID-19.
      ), our findings may underestimate the true impact of the COVID19 pandemic on the NMOSD population.
      Despite these weaknesses, this is the first study that investigates COVID19 prevalence among the NMOSD population. In addition, it sheds light on the possible impact of a pandemic on the risk of relapse in NMOSD patients. Larger studies should be conducted to further determine the impact of the COVID19 pandemic on the health outcomes of patients with NMOSD.

      5. Conclusion

      Two NMOSD patients in our cohort experienced worsening of their neurological symptoms suggestive of a relapse. It is hypothesized that the uncertainty and stress caused by this pandemic may have played a role in the worsening of neurological conditions. None of the cases in our cohort were diagnosed with COVID-19.

      CRediT authorship contribution statement

      Anna Tomczak: Investigation, Writing - original draft. May H. Han: Supervision, Writing - review & editing.

      Appendix A. Dear CIRCLES study participant,

      I hope you are staying healthy during these days of COVID19 infection. We want to check in on your neurological symptoms, in order to keep the infection at bay. We have attached a questionnaire for your response, which will enhance our knowledge of how to best care for our patients with immune-compromised conditions.
      • 1
        Have you been diagnosed with NMO?
        • a
          Yes
        • b
          No
      • 2
        If yes, have you been tested positive for anti-AQP4 or anti-MOG?
        • a
          Yes, anti-AQP4
        • b
          Yes, anti-MOG
        • c
          Yes, both anti-AQP4 and anti-MOG
        • d
          No
      • 3
        Are you currently being treated with immune therapies?
        • a
          If yes, please specify which ones.
      • 4
        Have you recently suffered from fever, chills, cough and/or respiratory tract infections?
        • a
          Yes
        • b
          No
      • 5
        Have you been diagnosed with the influenza infection?
        • a
          Yes
        • b
          No
      • 6
        Have you been diagnosed with COVID19?
        • a
          Yes
        • b
          No
      • 7
        Have you received the influenza vaccine this year?
        • a
          Yes
        • b
          No
      • 8
        Have your household contacts been diagnosed with influenza or COVID19?
        • a
          Yes
        • b
          No
      • 9
        Have you recently traveled to areas of an outbreak?
        • a
          Yes
        • b
          No
      • 10
        Are you experiencing any worsening of previous neurological symptoms?
        • a
          Yes
      • 11
        If yes, please specify.
        • a
          No
      • 12
        Are you experiencing any new neurological symptoms?
        • a
          Yes
      • 13
        If yes, please specify.
        • a
          No
      • 14
        Any other comments you would like to share with us?

      Appendix B

      • 1
        Have you been under more stress than usual because of the pandemic?
      • 2
        Did the onset of these new symptoms correspond to a time of increased stress?
      • 3
        Have you been taking your preventative treatments on time?
      • 4
        Have you experienced any other symptoms of stress (ex. depression symptoms, anxiety, insomnia, apathy etc.)?

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