Neurol Ther (2022) 11:1101–1116 https://doi.org/10.1007/s40120-022-00356-6 ORIGINAL RESEARCH Impact of Neuromyelitis Optica Spectrum Disorder on Quality of Life from the Patients’ Perspective: An Observational Cross-Sectional Study José E. Meca-Lallana . Rocı́o Gómez-Ballesteros . Francisco Pérez-Miralles . Lucı́a Forero . Marı́a Sepúlveda . Carmen Calles . Marı́a L. Martı́nez-Ginés . Inés González-Suárez . Sabas Boyero . Lucı́a Romero-Pinel . Ángel P. Sempere . Virginia Meca-Lallana . Luis Querol . Lucienne Costa-Frossard . Daniel Prefasi . Jorge Maurino Received: March 18, 2022 / Accepted: April 8, 2022 / Published online: May 6, 2022 Ó The Author(s) 2022 ABSTRACT perspective and its relationship with other dis- ease factors. Introduction: Neuromyelitis optica spectrum Methods: An observational, cross-sectional disorder (NMOSD) is associated with a reduced study was conducted at 13 neuroimmunology health-related quality of life (HRQoL). The clinics in Spain. Patients with NMOSD diagnosis purpose of this study was to describe the impact (2015 Wingerchuk criteria) were included. The of NMOSD on HRQoL from the patients’ 29-item Multiple Sclerosis Impact Scale (MSIS- 29) was used to assess the HRQoL. Different questionnaires were used to measure symptom severity, stigma, mood disorders, pain, fatigue, José E. Meca-Lallana and Rocı́o Gómez-Ballesteros contributed equally to this work (co-first authors). and difficulties in the workplace. Factors that J. E. Meca-Lallana C. Calles Clinical Neuroimmunology Unit and Multiple Department of Neurology, Hospital Universitari Son Sclerosis CSUR, Department of Neurology, Hospital Espases, Palma de Mallorca, Spain Universitario ‘‘Virgen de la Arrixaca’’, IMIB-Arrixaca, Murcia, Spain M. L. Martı́nez-Ginés Department of Neurology, Hospital Universitario R. Gómez-Ballesteros (&)  D. Prefasi  J. Maurino Gregorio Marañón, Madrid, Spain Medical Department, Roche Farma, Madrid, Spain e-mail: rocio.gomez@roche.com I. González-Suárez Department of Neurology, Hospital Universitario F. Pérez-Miralles Álvaro Cunqueiro, Vigo, Spain Unit of Neuroimmunology, Department of Neurology, Hospital Universitari i Politècnic La Fe, S. Boyero Valencia, Spain Department of Neurology, Hospital Universitario Cruces, Bilbao, Spain L. Forero Department of Neurology, Hospital Universitario L. Romero-Pinel Puerta del Mar, Cádiz, Spain Department of Neurology, Hospital Universitari de Bellvitge, Barcelona, Spain M. Sepúlveda Department of Neurology, Hospital Clı́nic i Á. P. Sempere Provincial de Barcelona, Barcelona, Spain Department of Neurology, Hospital General Universitario de Alicante, Alicante, Spain 1102 Neurol Ther (2022) 11:1101–1116 impact HRQoL were identified by Spearman’s correlation and multivariate linear regression Key Summary Points analysis. Results: Seventy-one patients were included In addition to relapses, neuromyelitis (mean age 47.4 ± 14.9 years, 80.3% female, optica spectrum disorder (NMOSD) has a mean time since disease onset 9.9 ± 8.1 years). variety of symptoms that can accumulate The median Expanded Disability Status Scale and increase the burden on patients’ lives, score was 3.0 (1.5–4.5). The mean (± SD) phys- but few studies have evaluated this issue ical and psychological MSIS-29 sub-scores were and its associated factors. 41.9 ± 16.8 and 20.9 ± 8.3, respectively. Fati- gue and body pain were the most prevalent This is the first study in Spain describing symptoms. Depressive symptoms were found in NMOSD’s impact on health-related 44.3% (n = 31) of patients. The physical MSIS- quality of life using a comprehensive 29 dimension showed the highest correlation battery of patient-reported measurements. with symptom severity (q = 0.85584, Our results show that NMOSD negatively p \ 0.0001), whereas the highest correlations impacts patients’ physical and for psychological MSIS-29 dimension were pain, psychological health-related quality of life MSIS-29 physical dimension, and depression even in a clinically stable population with (q = 0.76487, 0.72779, 0.71380; p \ 0.0001, low physical disability. respectively). Pain was a predictor of both dimensions of MSIS-29. Symptom severity, depression, pain, Conclusion: Fatigue, pain, and depressive fatigue, and workplace difficulties are symptoms are frequent problems among common features affecting patients’ patients with NMOSD, impacting on their quality of life. quality of life. Assessment of patient-oriented Awareness of these patient-reported outcomes may be useful to achieve a holistic symptoms is crucial for implementing approach, allowing early specific interventions. appropriate early interventions. Keywords: Depression; Fatigue; Health-related quality of life; Neuromyelitis optica spectrum disorder; Patient-reported outcomes INTRODUCTION Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system targeting the optic nerve, spinal cord, and brain [1, 2]. The estimated prevalence of NMOSD in Europe is between 1 and 5 cases/100,000 inhabitants, with women up to 10 times more likely to be affected than men, and antibodies to the V. Meca-Lallana astrocytic water channel aquaporin-4 (AQP4) Department of Neurology, Hospital Universitario La Princesa, Madrid, Spain found in 73% of cases [3–5]. The main charac- teristics of NMOSD include acute episodes of L. Querol optic neuritis or transverse myelitis, along with Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain other symptomatology such as pain, fatigue, anxiety, depression, sleep disorders, and cogni- L. Costa-Frossard tive impairment [6–8]. Department of Neurology, Hospital Universitario Ramón y Cajal, Madrid, Spain Neurol Ther (2022) 11:1101–1116 1103 The number of attacks, their unpredictabil- moderately, and extremely. Scores on the ity, severity, increasing disability, cognitive physical and the psychological impact subscales impairment, psychiatric symptoms, and finan- can range from 20 to 80 and from 9 to 36, cial burden have a strong negative impact on respectively. Lower scores indicate a higher health-related quality of life (HRQoL) of HRQoL. patients with NMOSD and result in high costs The SymptoMScreen questionnaire (SyMS) for the healthcare system [6, 9–15]. [21] is used to rapidly assess symptom severity As disease symptoms pose a major risk for in 12 neurologic domains commonly affected patients’ HRQoL, further research may be by MS: mobility, dexterity, spasticity, body essential to improve knowledge of the different pain, sensation, bladder function, fatigue, dimensions affected by NMOSD and develop a vision, dizziness, cognition, depression, and holistic approach for early interventions. anxiety. Each item is assessed on a seven-point Therefore, in this study, we used a comprehen- Likert scale ranging from 0 (not affected at all) sive battery of different patient-reported mea- to 6 (total limitation). The total score is calcu- surements to describe NMOSD’s impact on lated as the sum of individual items, ranging HRQoL from the patients’ perspective. from 0 to 72, with higher scores indicating more severe symptom endorsement. The 8-item Stigma Scale for Chronic Illness METHODS (SSCI-8) [22, 23] is an eight-item scale devel- oped to assess internalized and experienced We conducted an observational, cross-sectional stigma across neurological conditions. It uses a study at 13 hospital-based neuroimmunology five-point Likert scale ranging from 1 (never) to clinics in Spain as part of the PERSPECTIVES- 5 (always). Total scores range from 8 to 40, with NMO study, which aimed to evaluate the higher scores indicating higher levels of per- stigmatization among patients with NMOSD ceived stigma. A cutoff score greater than 8 [16]. The present analysis aimed to assess the indicates the presence of stigmatization. impact of NMOSD on HRQoL from the patients’ The Beck Depression Inventory-Fast Screen perspective. Eligibility criteria included age at (BDI-FS) [24] is a seven-item questionnaire least 18 years old and a diagnosis of NMOSD assessing the level of depressive symptoms. according to Wingerchuk 2015 criteria [17]. Responses to the items are provided on a four- point scale (no symptoms to severe symptoms). Outcome Measures and Procedures Total scores range from 0 to 21, with higher scores reflecting greater severity of depressive Participating neurologists collected sociodemo- symptoms. Depressive disorders are considered graphic and clinical characteristics from indi- in individuals scoring at least 4. Cutoff scores of viduals with NMOSD and assessed participants’ at least 4, at least 9, and greater than 12 are used disability, hand function, and gait using the to define the presence of mild, moderate, and Expanded Disability Status Scale (EDSS) [18], the severe depression, respectively. 9-Hole Peg Test (9-HPT) [19], and the Timed The Fatigue Impact Scale for Daily Use (D- 25-Foot Walk (T25-FW), respectively. FIS) [25] is an eight-item instrument designed to Each participant completed the following measure the subjective daily experience of fati- assessment instruments. gue. Items are rated using a five-point Likert The 29-item Multiple Sclerosis Impact Scale scale from 0 (no problem) to 4 (extreme prob- (MSIS-29) [20] is a self-reported questionnaire lem), with total scores ranging from 0 to 32 and used to determine the impact of multiple scle- higher scores indicating a greater impact of rosis (MS) on HRQoL. It consists of two com- fatigue on daily quality of life. posite impact domains/subscales, physical The MOS Pain Effects Scale (PES) [26] is a six- impact (20 items) and psychological impact (9 item questionnaire that assesses how pain and items). Items are rated using four-point unpleasant sensations interfere with mood, response categories: not at all, a little, ability to walk or move, sleep, work, recreation, 1104 Neurol Ther (2022) 11:1101–1116 and enjoyment of life. PES scores can range chi-square test and Mann–Whitney U test. from 6 to 30, with higher scores indicating Patients were classified according to employ- greater impact of pain on a patient’s mood and ment status as employed vs. other. The other behavior. employment status category included all The Multiple Sclerosis Work Difficulties patients not fulfilling the active employment Questionnaire (MSWDQ-23) [27, 28] measures category (temporary sick leave, permanent dis- difficulties experienced in the workplace across ability, students, unemployment, retirement, three broad domains, including physical barri- others, unknown). Sociodemographic and clin- ers (11 items), psychological/cognitive barriers ical characteristics (including the EDSS, the (8 items), and external barriers (4 items). Par- 9-HPT, the T25-FW), and patient-reported ticipants provide ratings on 23 statements measurements scores (SyMS, SSCI-8, BDI-FS, concerning various work difficulties experi- D-FIS, and PES) were described and related to enced over the past 4 weeks in their current or the MSIS-29 scores and the MSWDQ-23 scores most recent job using a five-point Likert scale using Spearman’s correlation. Two multiple (never, rarely, sometimes, often, and almost linear regression models were constructed using always). The three subscales and the total each domain of the MSIS-29 scores as the MSWDQ-23 scale are scored as percentages by dependent variable and sociodemographic, summing the observed item scores divided by clinical, and neuroimaging characteristics as the total possible item scores in each subscale. independent variables. The final multivariate Each value is then multiplied by 100 to give a model included all variables with a p value of maximum score of 100. Higher scores indicate less than 0.1. A p value lower than 0.05 was more work difficulties. considered significant. All analyses were con- ducted using SAS Enterprise Guide 7.15. Statistical Analysis The study was approved by the investiga- tional review board of Galicia (CEIm-G), Santi- As a result of the lack of previous data about ago de Compostela, Spain [Registration Number MSIS-29 in patients with NMOSD, the sample 2019/406, Sponsor Number ROC-NEU-2019-01 size was calculated on the basis of statistical (ML41397)], and performed in accordance with criteria. To estimate MSIS-29 scores with a pre- the 1964 Helsinki Declaration and its later cision of 0.25 standard deviations and a 95% amendments. According to Spanish legislation confidence interval, assuming 10% of non- (Orden SAS/3470/2009), observational studies evaluable patients because of non-available require approval by a single ethics committee information, a sample of 70 patients was and this approval applies to all participating required. For the primary objective, imputation centers. Participants were recruited consecu- was used to address questionnaires returned tively between November 2019 and July 2020. with missing data using the following rule: if at Written informed consent was obtained from least 50% of the items in a scale had been all subjects. completed, a respondent-specific mean score computed from the completed items was used RESULTS [29], also known as the half rule. For the descriptive and univariate analysis, Demographic and Clinical Characteristics categorical variables were described as the total number of available values and relative per- A total of 71 patients were included in the centage per subgroup of interest. Continuous study. The mean (± SD) age was variables were described by the number of 47.4 ± 14.9 years (range 18–81 years), and available values, mean, standard deviation, and 80.3% were female. The mean time since disease median, Q1, Q3, minimum and maximum. onset was 9.9 ± 8.1 years, with a mean time When appropriate, patient characteristics were since diagnosis of 6.2 ± 3.9 years, and the compared according to AQP4 status using the median EDSS score was 3.0 (interquartile range Neurol Ther (2022) 11:1101–1116 1105 Table 1 Demographic and clinical characteristics according to AQP4 antibody status Totala AQP4 positive AQP4 negative p value n = 71 n = 54 n = 16 Age, mean ± SD, years 47.4 ± 14.9 49.3 ± 14.6 41.4 ± 15.1 0.0570 Sex (female), n (%) 57 (80.3) 47 (87.0) 9 (56.3) 0.0068 Educationb, n (%) 0.4624 Primary 17 (24.6) 14 (26.4) 3 (20.0) Secondary 21 (30.4) 18 (34.0) 3 (20.0) Tertiary 30 (43.5) 30 (37.7) 9 (60.0) Living with family members or a partner, n (%) 63 (90.0) 49 (90.7) 13 (86.7) 0.6438 c Employment status , n (%) 0.9262 Employed (part or full-time) 21 (30.0) 15 (27.8) 6 (40.0) Temporary sick leave due to NMOSD 2 (2.9) 1 (1.9) 0 Permanent disability due to NMOSD 17 (24.3) 14 (25.9) 3 (20.0) Permanent disability due to other reasons 3 (4.3) 3 (5.6) 0 Student 3 (4.3) 2 (3.7) 1 (6.7) Unemployed 9 (12.9) 7 (13.0) 2 (13.3) Retired 12 (17.1) 10 (18.5) 2 (13.3) Housework 3 (4.3) 2 (3.7) 1 (6.7) Other 0 Age at onset, mean ± SD, years 41.1 ± 14.8 42.4 ± 14.9 37.1 ± 14.5 0.2750 Time since diagnosis, mean ± SD 6.2 ± 3.9 6.7 ± 3.8 4.2 ± 3.8 0.0171 Time since disease onset, mean ± SD 9.9 ± 8.1 10.7 ± 8.7 6.6 ± 4.8 0.1062 Onset attack type, n (%) 0.1762 Myelitis 34 (47.8) 29 (53.7) 5 (31.3) Optic neuritis 27 (38.0) 19 (35.2) 8 (50.0) Myelitis ? optic neuritis 3 (4.2) 1 (1.9) 2 (12.5) Relapsing form, n (%) 59 (83.1) 44 (81.5) 14 (87.5) 0.5748 d Number of relapses since diagnosis , 3.0 ± 2.3 3.2 ± 2.5 2.3 ± 1.4 0.3648 mean ± SD Number of relapses in the last yeare, 0.5 ± 0.9 0.4 ± 1.0 0.8 ± 1.0 0.2311 mean ± SD Coexisting autoimmune disease, n (%) 21 (29.6) 19 (35.2) 2 (12.5) 0.0820 c EDSS score , median (IQR) 3.0 (1.5–4.5) 3.0 (2.0–4.5) 2.3 (1.5–3.5) 0.2497 9-HPT, mean ± SD, s 1106 Neurol Ther (2022) 11:1101–1116 Table 1 continued Totala AQP4 positive AQP4 negative p value n = 71 n = 54 n = 16 Dominant handf 23.9 ± 10.7 24.7 ± 12.0 21.7 ± 5.3 0.3791 g Non-dominant hand 25.1 ± 10.4 24.3 ± 7.1 28.1 ± 17.2 0.5268 h T25FW , mean ± SD, s 7.6 ± 6.3 8.2 ± 7.0 6.0 ± 2.6 0.1866 Visual acuity (\ 20/100), n (%) 18 (27.7) 12 (25.0) 5 (31.3) 0.6240 MSIS-29, mean ± SD Physical impact score (20–80) 41.9 ± 16.8 42.6 ± 16.8 40.9 ± 16.8 0.6745 Psychological impact score (9–36) 20.9 ± 8.3 20.3 ± 8.0 23.4 ± 9.2 0.1677 PES score, mean ± SD (6–30) 14.0 ± 6.3 13.8 ± 6.4 14.9 ± 6.0 0.4740 c D-FIS score , mean ± SD (0–32) 9.0 ± 8.3 8.9 ± 8.6 10.1 ± 7.4 0.3532 BDI-FS scorec, mean ± SD (0–21) 3.6 ± 3.4 3.5 ± 3.4 4.3 ± 3.3 0.2534 b SyMS score , mean ± SD (0–72) 22.0 ± 14.5 22.7 ± 14.1 20.5 ± 16.0 0.5105 SSCI-8 scorec, mean ± SD (8–40) 11.9 ± 5.1 11.7 ± 4.8 13.0 ± 5.9 0.5447 i MSWDQ-23 total score , mean ± SD (0–100) 23.3 ± 20.3 21.0 ± 17.8 29.4 ± 25.7 0.4081 AQP4 aquaporin-4, EDSS Expanded Disability Status Scale, 9-HPT 9-Hole Peg Test, T25-FW Timed 25-Foot Walk, MSIS-29 29-item Multiple Sclerosis Impact Scale, PES MOS Pain Effects Scale, D-FIS Fatigue Impact Scale for Daily Use, BDI-FS Beck Depression Inventory-Fast Screen, SyMS SymptoMScreen, SSCI-8 Stigma Scale for Chronic Illness 8-item version, MSWDQ-23 Multiple Sclerosis Work Difficulties Questionnaire, IQR interquartile range, SD standard deviation a 1 patient with missing data for AQP4 antibodies b n = 69 c n = 70 d n = 55 (4 missing values) e n = 56 (3 missing values) f n = 64 g n = 63 h n = 62 i n = 41 1.5, 4.5). At the time of the study visit, 30.0% (77.1%). In the subgroup without AQP4 anti- were employed, and 24.3% had a permanent bodies, five patients had antibodies against the disability due to NMOSD. Concomitant myelin oligodendrocyte glycoprotein (MOG). autoimmune diseases were present in 29.6% of Patients’ characteristics in the AQP4-positive patients, with systemic lupus erythematosus and AQP4-negative groups were similar, except (7.0%) being the most prevalent, followed by for a shorter time since diagnosis and a lower Sjögren’s syndrome (5.6%). The majority of proportion of women among AQP4-negative patients (93.9%) were receiving a disease-mod- patients. In addition, an upwards trend in the ifying treatment at the time of the study visit. presence of concomitant autoimmune diseases AQP4 antibodies were positive in 54 patients in the AQP4-positive subgroup was observed. Neurol Ther (2022) 11:1101–1116 1107 Table 1 shows the demographic and clinical Table 2 Description of MSWDQ-23 scores according to characteristics of the sample in further detail. employment status Overall Employed Other employment Patient-Reported Outcome Results n = 41 n = 21 status n = 20 Psychological/cognitive barriers Results from the MSIS-29, SyMS, SSCI-8, BDI-FS, D-FIS, PES, and MSWDQ-23 are shown in Mean 19.1 9.5 (11.5) 29.2 (21.5) Table 1. No significant differences were (SD) (19.6) observed between AQP4-positive and AQP4- Median 15.9 4.5 (0.0; 27.3 (8.0; 46.6) negative patient subgroups. Symptom severity was low in the studied (IQR) (2.3; 15.9) population. Individual domain SyMS scores 29.5) were highest for fatigue and body pain, and Physical barriers lowest for dizziness and hand dexterity. In comparison, vision and bladder control stood Mean 25.8 11.9 (12.3) 40.3 (23.9) out as the domains with the highest levels of (SD) (23.5) perceived severity. Only one patient had a Median 18.8 9.4 (0.0; 37.5 (21.9; 57.8) composite score of 0, meaning that the vast (IQR) (9.4; 18.8) majority of patients [98.6% (n = 69)] had at 40.6) least one of the 12 domains affected, leading to minor adjustments in their lives. External barriers Both dimensions of the MSIS-29 question- Mean 29.9 22.3 (26.5) 37.8 (28.2) naire were modestly affected by NMOSD, (SD) (28.1) decreasing health perception with a slightly greater impact in the psychological dimension. Median 25.0 12.5 (0.0; 34.4 (15.6; 62.5) Overall, 23.9% (n = 17) of patients suffered a (IQR) (0.0; 43.8) moderate/extreme physical impact (mean score 56.3) at least 3), whereas 28.2% (n = 20) experienced a moderate/extreme psychological impact from MSWDQ-23 total scorea NMOSD. Of note, 28.2% of participants repor- Mean 23.3 12.6 (12.5) 34.6 (21.1) ted having an urgent need to go to the toilet, (SD) (20.3) which extremely impacted their HRQoL. The majority of patients (81.4%, n = 57) Median 18.5 8.7 (2.2; 32.6 (14.1; 48.4) reported fatigue impacting their life in at least (IQR) (5.4; 20.7) one of the statements studied in the question- 33.7) naire. The presence of pain was reported in MSWDQ-23 Multiple Sclerosis Work Difficulties Ques- 83.1% (n = 59) of patients (score greater than 6), tionnaire, SD standard deviation, IQR interquartile range as assessed by the PES scale. The PES question- a MSWDQ-23 scores range from 0 to 100, with higher naire revealed that in 29.6% (n = 21) of values indicating greater workplace problems. Values were patients, pain interferes with their sleep quite a missing for 30 patients. 41 patients completed the bit or to an extreme degree, and the same effect MSWDQ-23 questionnaire (21 employed, other employ- was reported by 23.9% (n = 17) of patients ment status = 2 temporary sick leave due to study disease, regarding recreational activities. 7 permanent disability due to study disease, 1 student, 4 A total of 41 patients completed the unemployed, 5 retired, and 1 missing at study visit) MSWDQ-23 questionnaire (Table 2). The mean MSWDQ-23 total score was 23.3 ± 20.3, with external barriers being the dimension most the psychological/cognitive dimension, 85.4% affected among patients. In addition, 75.6% (n = 35) in the physical dimension, and 70.7% (n = 31) of patients experienced some barriers in (n = 29) in the external barriers dimension. 1108 Neurol Ther (2022) 11:1101–1116 Patients employed at the time of the study but low or moderate correlation with EDSS, obtained lower scores (fewer workplace diffi- while fatigue was not significantly correlated culties) than those not actively employed. with disability. The stepwise linear regression analysis Correlation Between HRQoL revealed that some employment status cate- and Disability, Symptom Severity, Mood gories were the best predictors of a poor score Disorders, Fatigue, and Pain for the physical dimension of MSIS-29, followed by pain (PES score), stigma (SSCI-8 raw score), The physical and psychological dimensions of overall symptom severity (SyMS composite the MSIS-29 showed significant correlation score), and hand impairment (dominant hand between them (Table 3). The physical dimen- 9-HPT) (adjusted r2 = 0.89, p \ 0.0001) sion of the MSIS-29 significantly correlated with (Table 4). A higher number of years since the disability, symptom severity, depressive symp- NMOSD diagnosis predicted a better physical toms, fatigue, and pain, although the strongest health score. The major predictors of lower correlation was seen with symptom severity psychological quality of life were higher levels (q = 0.85584, p \ 0.0001). The psychological of pain and stigma. dimension showed a significantly strong corre- lation with symptom severity, depressive Correlation Between Work Difficulties symptoms, fatigue, and pain (q = 0.69589, and Disability, Symptom Severity, Stigma, 0.71380, 0.64005 and 0.76487, p \ 0.0001, Mood Disorders, Fatigue, and Pain respectively), and a weak correlation with EDSS. Overall, symptom severity exhibited the highest Employment status and other work-related correlation with MSIS-29 for both dimensions. characteristics were predictors of HRQoL We found that pain, fatigue, and depressive dimensions; we therefore assessed the relation- symptoms displayed a high correlation between ship between work difficulties and disability, them. Symptom severity showed a high corre- symptom severity, stigma, mood disorders, lation with pain and mood disorders and a fatigue, and pain (Table 5). The psychological/ moderate correlation with EDSS and fatigue. cognitive barriers dimension of the MSWDQ-23 Mood disorders and pain displayed a significant questionnaire showed the highest correlation Table 3 Correlation coefficients across questionnaires and disability, n = 70 EDSS D-FIS PES BDI-FS SyMS MSIS-29 psychological MSIS-29 physical 0.67539 0.52165 0.62515a 0.51243 0.85584b 0.72779a MSIS-29 psychological 0.36858** 0.64005 0.76487a 0.71380 0.69589b SyMS 0.58643c 0.56130b 0.66387b 0.62122b BDI-FS 0.29437*b 0.66302 0.66393 PES 0.34529** 0.66725 NS,b D-FIS 0.17458 All values have p \ 0.0001 except for NS = non-significant MSIS-29 29-item Multiple Sclerosis Impact Scale, SyMS SymptoMScreen, BDI-FS Beck Depression Inventory-Fast Screen, PES Pain Effects Scale, D-FIS Fatigue Impact Scale for Daily Use, EDSS Expanded Disability Status Scale *p \ 0.05; **p \ 0.01 a n = 71 b n = 69 c n = 68 Neurol Ther (2022) 11:1101–1116 1109 Table 4 Multivariate linear regression analysis of sociodemographic, clinical, and neuroimaging characteristics related to the physical and psychological dimensions of health-related quality of life (MSIS-29) Estimate SE t value p value MSIS-29 physical dimension Employment status Employed Ref. NA NA NA Employed-sick leave due to NMOSD 7.154380 4.019832 1.78 0.0822 Permanent disability due to NMOSD 7.241089 2.637959 2.74 0.0088 Permanent disability not due to NMOSD 4.924847 4.286278 1.15 0.2569 Student 3.149009 3.394496 0.93 0.3588 Unemployed - 1.824505 3.046121 - 0.60 0.5523 Retired 6.002214 2.487172 2.41 0.0201 Housework 19.450953 3.679419 5.29 \ 0.0001 Years since NMO diagnosis - 0.610604 0.214308 - 2.85 0.0067 Dominant hand 9-HPT (s) 0.251258 0.073172 3.43 0.0013 SyMS composite score 0.377865 0.097077 3.89 0.0003 SSCI-8 raw score 0.642608 0.231835 2.77 0.0082 PES score 0.940046 0.201495 4.67 \ 0.0001 MSIS-29 psychological dimension SSCI-8 raw score 0.316583 0.144719 2.19 0.0329 PES score 0.698613 0.125454 5.57 \ 0.0001 Independent models were used for each dimension. The final regression model was constructed using a stepwise regression analysis for variable selection. All variables with a p value of less than 0.1 in univariate analyses were included in the model, and the final model only included those that remained below this threshold when combined. The final model for each dimension includes only shown variables. MSWDQ-23 was not included in the multivariate analysis because of the high level of missing values NA not applicable, 9-HPT 9-Hole Peg Test, MSIS-29 29-item Multiple Sclerosis Impact Scale, NMO Neuromyelitis Optica, PES MOS Pain Effects Scale, SyMS SymptoMScreen, SSCI-8 Stigma Scale for Chronic Illness 8-item version with the physical dimension of the question- significant correlations were present with naire. Significantly, high correlations were stigma, EDSS, and hand dexterity. found with fatigue, followed by mood disorders, symptom severity, and pain, and a moderate correlation was found with stigma. Non-signif- DISCUSSION icant low correlations were present for disabil- ity. The physical barriers dimension displayed Understanding HRQoL and well-being in the highest correlation with pain (q = 0.82712, patients suffering from NMOSD is relevant for p \ 0.0001), followed by symptom severity, improving patient care. Evaluations of HRQoL mood disorders, and fatigue. Moderate to low are being used as outcome measures in clinical trials on NMOSD [30–32], and new studies are 1110 Neurol Ther (2022) 11:1101–1116 emerging worldwide. However, there is still a MSWDQ-23 Multiple Sclerosis Work Difficulties Questionnaire, EDSS Expanded Disability Status Scale, T25FW Timed 25-Foot Walk, 9-HPT 9-Hole Peg Test, D-FIS Fatigue Impact Scale for Daily Use, PES Pain Effects Scale, BDI-FS Beck Depression Inventory-Fast Screen, SyMS SymptoMScreen, SSCI-8 Stigma Scale for lack of research that focuses on HRQoL in (Physical barriers) patients diagnosed with this disorder [6, 9, 11, 14, 33]. Furthermore, patients with MSWDQ-23 NMOSD also suffer from various symptoms like 0.71177a 0.62733 0.68408a 0.54532**a 0.68067b 0.81117 pain, fatigue, and depression, all of which can affect their quality of life and should be addressed. Additionally, most patients present a 0.65436a 0.82712 0.71901a 0.52392**a 0.79879b recurrent relapsing course, and AQP4-positive SyMS patients tend to have a higher prevalence of concomitant diseases, making these symptoms accumulate and increase the burden on their quality of life. Thus, the primary goal of this SSCI-8 study was to assess the HRQoL of patients with NMOSD using the MSIS-29 and explore how it is Table 5 Correlation coefficients across MSWDQ-23, patient-reported outcomes (PROs), and disability, n = 41 impacted by different disease factors. BDI-FS Overall, this study has shed light on the perspective of patients with NMOSD, who suffer a marked psychological and physical impact that is mainly affected by symptom severity. PES According to our results based on different PROs, depression, fatigue, pain interference with daily activities, and work-related difficul- D-FIS ties are common features even in a clinically stable population with low physical disability. Similar to results reported by Yalachkov et al. Dominant hand in a population with low physical disability [15], our study showed that NMOSD has a 0.25477NS 0.29207NS,d 0.28362NS,c 0.21524NS,d 0.39924*c marked psychological impact on patients’ life 9-HPT [mean (SD) 20.9 (8.3)], while the physical impact was more modest [mean (SD) 41.9 (16.8)]. However, these results differ from pre- All values have p \ 0.0001 except for NS = non-significant vious reports by Beekman et al. and Huang et al. T25FW that evaluated HRQoL in patients with NMOSD in North America and China, which reported that emotional health remained generally 0.48870** unimpaired or less impaired compared to poor EDSS physical health results [9, 11]. The discrepancies observed could be due to the different ethnicity, questionnaires used in the studies, and disease MSWDQ-23 (Physical barriers) activity in the cohorts, as Chinese and North Chronic Illness 8-item version MSWDQ-23 (Psychological/ American populations included a higher per- centage of patients who had relapsed within the previous year (52.5% and 38.0%, respectively), *p \ 0.05; **p \ 0.01 cognitive barriers) in comparison to our cohort (28.6%). In addi- tion, the presence of pain—although measured on a different scale—seemed to be higher in these cohorts, and pain severity and walking n = 37 n = 39 n = 40 n = 38 impairment have been reported as two inde- pendent predictors explaining 53.9% of the d b a c Neurol Ther (2022) 11:1101–1116 1111 physical quality of life composite variability as used in our sample [15]. Nonetheless, we should measured with the Short Form 36 Health Survey note that our study did not record depression (SF-36) [34]. Furthermore, our study included treatment or psychotherapy. Consistent with patients with a longer disease duration since the findings in these cohorts, depression sig- diagnosis (6.2 years in our study, compared to nificantly correlated with fatigue and pain. We 3.7 and 5.0 years in China and North America also found a high correlation between depres- patients, respectively). Although Beekman et al. sion and the psychological and physical found a correlation between seronegative or dimensions of the MSIS-29, while a more mod- unknown AQP4 status and a lower impact on est correlation was found with disability. These quality of life, we could not find differences results highlight the need for active screening between positive or negative serostatus and for psychologic disorders in this population MSIS-29 results [9]. group, offering early treatment and rehabilita- Despite being a population with low dis- tion and thus improving HRQoL [14]. ability and symptom burden, symptom severity Several studies have identified fatigue as a was one of the predictors of HRQoL and common complaint among patients with exhibited the highest correlation with MSIS-29 NMOSD [6, 38, 39]. Furthermore, this symptom for both dimensions. Bladder control and vision is most commonly rated as moderate/severe were the domains with the highest levels of [40]. However, fatigue was rated as having a low perceived severity and having an urgent need to impact on daily quality of life within our pop- go to the toilet was reported as having an ulation when assessed by the D-FIS scale, extreme impact on the HRQoL of almost one- although it affected more than 80% of individ- third of the patients. Similarly, previous studies uals. These observations are in marked contrast have reported bodily pain, bowel and bladder with a retrospective observational study dysfunction, and visual impairment as the pre- including 522 patients with NMOSD by Eaneff dominant physical issues affecting quality of et al. [40], which reported that 53% of patients life [9, 11]. Moreover, previous reports have experienced moderate-severe fatigue symptom shown a correlation between bladder and bowel severity. These differences are likely explained dysfunction and a significant physical, psycho- by the different questionnaires and patient logical, and social impact in 87% of patients selection methods. While the impact of fatigue with transverse myelitis, thus lowering their was relatively low within our cohort, higher HRQoL [35]. These results highlight the need to fatigue scores were correlated with a worse address bladder and bowel symptoms with psychological and physical quality of life. This nutrition advice and appropriate treatment to is in line with results observed by Shi et al. [6], improve urinary symptoms in patients with in which chronic fatigue [measured using the NMOSD and, consequently, improve their Fatigue Impact Scale (FIS)] showed a significant quality of life. negative correlation with HRQoL, although the More than 44% of patients experienced correlation was not as strong as the one found depression, although most cases were mild, and by Barzegar et al. [41]. Barzegar et al. [41] found remarkably no patients scored within the severe that fatigue was the most important variable to category. Our prevalence and severity were predict the variance of physical and mental lower than in studies measuring depression components of HRQoL, and depression was also prevalence among NMOSD in Argentina, the a predictive factor of mental HRQoL. USA, and Germany [34, 36, 37]; however, pain Previous studies have reported the presence and disability were higher in these cohorts, and of pain in 62–86% of patients [7, 8, 34, 42]. In ethnicity also differed. It should be noted that our study, the pain was markedly prevalent as our results on depression were similar to those well, impacting mood, walking ability, sleep, reported by Yalachkov et al., as both popula- work, recreation, and enjoyment of life. How- tions had similar disease duration, low physical ever, pain in our population was not as severe as disability, and the same questionnaire was used, that reported by Ayzenberg et al. in a cohort of although the fast screen BDI questionnaire was 166 patients from 13 tertiary referral centers 1112 Neurol Ther (2022) 11:1101–1116 [34], with moderate to severe NMOSD-associ- Several limitations should be noted regard- ated chronic pain in 55.2% of patients even ing our study. First, the cross-sectional design when receiving with symptomatic treatment. did not allow us to assess changes or causal Similar to our results, they found that pain relationships in HRQoL of patients over time as severity but not physical impairment was asso- the study consisted of a single visit. Likewise, ciated with depression, and that pain, depres- causal inferences were not possible. Second, as sion, and walking impairment were three main patients with NMOSD present several symp- HRQoL predictors. As in previous studies, the toms which could act as barriers and prevent psychological and physical dimensions of them from completing questionnaires (such as quality of life were correlated with pain in our motor limitations, fatigue, etc.), this could cohort [10, 42]. Furthermore, the pain was a cause our results to be underestimated. An predictor for the physical and psychological adjusted analysis based on patients’ medication dimensions of HRQoL. should have been performed [34]. However, we Eaneff et al. [40] reported that almost all did not collect medication details, which is an patients with NMOSD claimed at least some important limitation of the study. Furthermore, impairment in their ability to fulfill their goals although recruitment was consecutive, visits or participate in work or other activities, sug- were performed during the coronavirus pan- gesting that impairment in the ability to work demic, and this could potentially have affected may be a significant concern for these patients. patients’ willingness to participate in those In our study, more than 70% of patients repor- more severely impaired. Third, although the ted work difficulties in at least one dimension majority of people in Spain are Caucasian, we (psychological/cognitive, physical, external did not collect ethnicity data, thereby underes- barriers). Work difficulties were most prevalent timating its influence on the results. Fourth, a in the physical dimension (85.4%), and the more extended and detailed psychological dimension of the external barriers was the most evaluation instead of a 9-item questionnaire affected. More workplace problems were noted would have been better to achieve a clearer among patients not actively employed. In understanding on how NMOSD impact addition, several categories within patients not patients’ lives. Further longitudinal studies actively employed and hand impairment were including patients with different age ranges significant predictors of a low score for the may help to confirm our results and to deter- physical dimension of HRQoL. Physical and mine whether the disease duration might have psychological work difficulties exhibited a sig- impact on the patients’ perspectives. Neverthe- nificantly high correlation with symptom less, we describe the perception of HRQoL and severity, mood, fatigue, and pain. In compar- the prevalence of different key symptom ison, only physical difficulties exhibited a sig- domains among a sample of patients treated in nificantly moderate to low correlation with 13 different hospitals throughout Spain, allow- stigma, disability, and hand impairment. These ing results to be generalized to community findings are likely related to the marked psy- practice. To the best of our knowledge, this is chological burden of our study population. the first study on HRQoL and related factors Our results underscore that NMOSD mani- among patients with NMOSD in Spain. festations interfere with the ability to work, which in turn negatively impacts HRQoL. These findings are in line with previous reports. CONCLUSION Moreover, they stress the need for further research and interventions in this field, with Evaluating the impact of NMOSD on HRQoL patients experiencing high unemployment from the patients’ perspective is essential to rates, which are often related to worsening of allow early effective interventions that may symptoms, greater disability, lessened mobility, help improve patients’ well-being. Our findings impaired hand function, fatigue, and cognitive clearly confirm the negative impact and signif- dysfunction [9–11, 40, 43]. icant burden of NMOSD on the psychological Neurol Ther (2022) 11:1101–1116 1113 and physical dimensions of HRQoL, even in a Author Contributions. All authors made a clinically stable population with low physical significant contribution to the work reported, disability. Symptom severity, stigma, depres- whether in study conception, design, execu- sion, pain, fatigue, and work-related problems tion, acquisition of data, analysis and interpre- are common features affecting patients’ quality tation, or in all these areas; all took part in of life. There is a need for healthcare providers drafting, revising or critically reviewing the to be aware of these symptoms and to adopt article; all gave final approval of the version to appropriate interventions to improve overall be published; all have agreed on the journal to HRQoL in patients with NMOSD. Future studies which the article has been submitted; and all should investigate HRQoL longitudinally and agree to be accountable for all aspects of the consider developing specific PROs for NMOSD work. to improve understanding of this disease. Prior Presentation. The abstract of this paper was presented at the 25th World Congress of Neurology (WCN) as a poster presentation ACKNOWLEDGEMENTS with interim findings (Poster 867; Virtual, October 3–7, 2021). The authors are most grateful to all patients and their families for making the PERSPECTIVES- Disclosures. This study was funded by the NMO study possible. We would like to recog- Medical Department of Roche Farma Spain nize the work done by Cristina Garcı́a, Elisa (ML41397). The funder was not involved in the Guillen, and Carmen Álvarez, and the clinical study design, collection, analysis, interpretation research monitors Verónica Fernández and of data, the writing of this article or the decision Úrsula Vilardosa. We thank the support to submit it for publication. Jorge Maurino and received from IQVIA, especially Julieta Politi, Rocı́o Gómez-Ballesteros are employees of Anna de Prado, and Neus Canal. Roche Farma Spain. Daniel Prefasi was an employee of Roche Farma Spain when the study Funding. This study was funded by the was designed, the data were collected, and the Medical Department of Roche Farma Spain statistical analysis was carried out, and now is (ML41397). The sponsor also funded the jour- an employee of ICON plc. José E. Meca-Lallana nal’s Rapid Service fee. has received grants and consulting or speaking fees from Almirall, Biogen, Bristol-Myers- Medical Writing and Editorial Assis- Squibb, Genzyme, Merck, Novartis, Roche and tance. Medical writing assistance of this article Teva. Francisco Pérez-Miralles has received was provided by Julieta Politi at IQVIA during compensation for serving on scientific advisory the preparation of the manuscript. Editorial boards or speaking honoraria from Almirall, assistance of this article was provided by Car- Biogen Idec, Genzyme, Merck-Serono, Mylan, mela Garcı́a Doval at Dynamic S.L.U. during the Novartis, Roche, Sanofi Aventis, and Teva, out- preparation of the manuscript. The sponsor side the submitted work. Marı́a Sepúlveda funded both the medical writing and editorial reports speaking honoraria from Roche and assistance for the article. UCB Pharma, and travel reimbursement from Sanofi and Zambon. Carmen Calles reports Authorship. All named authors meet the personal fees from Biogen, Sanofi, Merck, International Committee of Medical Journal Novartis, Teva, and Roche, outside the submit- Editors (ICMJE) criteria for authorship for this ted work. Inés González-Suárez has received article, take responsibility for the integrity of funding for research projects or in the form of the work as a whole, and have given their conference fees, mentoring, and assistance for approval for this version to be published. conference attendance from Biogen-Idec, Roche, Merck, Novartis, and Sanofi-Genzyme. Sabas Boyero has received conference fees, 1114 Neurol Ther (2022) 11:1101–1116 mentoring, and assistance for conference consecutively between November 2019 and July attendance from Bayer, Biogen-Idec, Bristol- 2020. Written informed consent was obtained Myers Squibb, Roche, Merck, Novartis, Almirall, from all subjects. and Sanofi-Genzyme. Lucı́a Romero-Pinel received honoraria compensation to participate Data Availability. Qualified researchers in advisory boards, collaborations as a consul- may request access to individual patient-level tant and scientific communications and data through the corresponding author. The received research support, funding for travel datasets generated during the analysis of the and congress expenses from Roche, Biogen Idec, study are available from the corresponding Novartis, TEVA, Merck, Genzyme, Sanofi, Bayer, author on reasonable request. Almirall and Celgene. Ángel P. Sempere has received personal compensation for consulting, Open Access. This article is licensed under a serving on a scientific advisory board or speak- Creative Commons Attribution-NonCommer- ing with Almirall, Biogen, Bayer Schering cial 4.0 International License, which permits Pharma, Merck Serono, Novartis, Roche, Sanofi- any non-commercial use, sharing, adaptation, Aventis, and Teva. Luis Querol reports research distribution and reproduction in any medium grants from Instituto de Salud Carlos III—of or format, as long as you give appropriate credit Economy and Innovation (Spain), CIBERER, to the original author(s) and the source, provide GBS-CIDP Foundation International, Roche, a link to the Creative Commons licence, and UCB and Grifols. He provided expert testimony indicate if changes were made. The images or to CSL Behring, Novartis, Sanofi-Genzyme, other third party material in this article are Merck, Annexon, Johnson and Johnson, Alex- included in the article’s Creative Commons ion, UCB, Takeda and Roche. He serves in the licence, unless indicated otherwise in a credit Clinical Trial Steering Committee for Sanofi line to the material. If material is not included Genzyme and is Principal Investigator for UCB’s in the article’s Creative Commons licence and CIDP01 trial. Lucienne Costa-Frossard has your intended use is not permitted by statutory received funding for research projects or in the regulation or exceeds the permitted use, you form of conference fees, mentoring, and assis- will need to obtain permission directly from the tance for conference attendance from Bayer, copyright holder. To view a copy of this licence, Biogen-Idec, Bristol-Myers Squibb, Biopas, visithttp://creativecommons.org/licenses/by- Roche, Merck, Novartis, Almirall, Celgene, nc/4.0/. Ipsen, and Sanofi-Genzyme. Lucı́a Forero, Marı́a L. Martı́nez Ginés, and Virginica Meca-Lallana declared no potential conflicts of interest with respect to the research, authorship, and/or REFERENCES publication of this article. 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