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Psychological impacts of COVID-19 pandemic on individuals living with multiple sclerosis: A rapid systematic review

Published:January 24, 2022DOI:https://doi.org/10.1016/j.msard.2022.103562

      Highlights

      • Mental health issues are common among people living with multiple sclerosis (PwMS) during the COVID-19 pandemic.
      • PwMS experienced more severe symptoms of depression and stress compared to general populations during the pandemic.
      • Evidence from longitudinal studies suggests that anxiety, depression and mental health dimensions of quality of life among PwMS were not considerably affected by pandemic-related restrictive measures.

      Abstract

      Introduction

      The global spread of COVID-19 has raised concerns about its possible impact on mental health. People living with multiple sclerosis (PwMS) are considered potentially vulnerable to the mental health effects of the pandemic, as they may be subject to increased social isolation.

      Aim

      To systematically review the current evidence on the impact of the COVID-19 pandemic on mental health outcomes among PwMS.

      Method

      We searched four major databases (Medline, EMBASE, PsychInfo and Scopus) and the WHO Global Health COVID-19 research database. We included peer-reviewed primary research studies using validated health-related quality of life (HRQOL) and psychometric screening tools to evaluate mental health outcomes among PwMS during the COVID-19 pandemic. Studies reporting data on the prevalence of mental health disorders, severity of psychological symptoms and contributing demographic and clinical factors for PwMS during the COVID-19 pandemic were included.

      Results

      Our initial search yielded 268 records; 19 studies (13 cross-sectional, 6 longitudinal) were included. Most were conducted during a peak in the pandemic in the host country via an online platform. The main mental health outcomes were depression, anxiety, stress, sleep quality and HRQOL. The included studies used a variety of outcome assessment tools and study designs. The prevalence of mental health issues such as depression, anxiety and stress were high among PwMS during the pandemic. In addition, compared to control populations, PwMS experienced more severe symptoms of depression and stress during the COVID-19 outbreak. However, results from longitudinal studies demonstrate that the severity of mental health symptoms among PwMS during the pandemic were not significantly different compared with the pre-pandemic period.

      Conclusion

      Although mental health issues such as anxiety and depression were common among PwMS during the pandemic, current evidence suggests that mental health among PwMS has not been significantly affected by pandemic-related restrictive measures. Instead, the observed differences may be the result of pre-pandemic differences in prevalence and severity. Where possible, future studies should seek to address the methodological issues identified in the included studies to ensure that data collected during the pandemic can be synthesized into recommendations for policy and practice.

      Keywords

      1. Introduction

      On March 11, 2020, the World Health organization (WHO) officially declared a COVID-19 pandemic (

      WHO Director-General's opening remarks at the media briefing on COVID-19. 2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19-11-march-2020. (Accessed 11/03/2020 2020).

      ). To date, the pandemic has affected 223 countries, areas or territories, and has caused > 113 million known cases and almost 2.5 million confirmed deaths (

      WHO Coronavirus disease (COVID-19) dashboard. 2021. https://covid19.who.int/. (Accessed 1/03/2020 2021).

      ). In response to this global health threat and the unprecedented pressures placed on healthcare systems, nearly every country has initiated social distancing measures, gradual or immediate lockdowns, border closures, and/or travel bans. However, these methods, which are aimed at stemming the spread of the virus, have also affected the lives of billions of people, directly and indirectly, by restricting social gatherings, travel, employment, and education. In addition to the social and economic impact of COVID-19, the unpredictability of the situation, unavailability of vaccination, overflow of information, and the dissemination of myths and inaccurate information via social media have led to an increase in concern and confusion for the public (
      • Bao Y.
      • Sun Y.
      • Meng S.
      • Shi J.
      • Lu L.
      2019-nCoV epidemic: address mental health care to empower society.
      ;
      • Krishnamoorthy Y.
      • Nagarajan R.
      • Saya G.K.
      • Menon V.
      Prevalence of psychological morbidities among general population, healthcare workers and COVID-19 patients amidst the COVID-19 pandemic: a systematic review and meta-analysis.
      ).
      Research from previous and ongoing outbreaks, such as severe acute respiratory syndrome (SARS) (
      • De Brier N.
      • Stroobants S.
      • Vandekerckhove P.
      • De Buck E.
      Factors affecting mental health of health care workers during coronavirus disease outbreaks (SARS, MERS & COVID-19): a rapid systematic review.
      ;
      • Rogers J.P.
      • Chesney E.
      • Oliver D.
      • Pollak T.A.
      • McGuire P.
      • Fusar-Poli P.
      • Zandi M.S.
      • Lewis G.
      • David A.S.
      Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.
      ), Middle East respiratory syndrome (MERS) (
      • De Brier N.
      • Stroobants S.
      • Vandekerckhove P.
      • De Buck E.
      Factors affecting mental health of health care workers during coronavirus disease outbreaks (SARS, MERS & COVID-19): a rapid systematic review.
      ;
      • Rogers J.P.
      • Chesney E.
      • Oliver D.
      • Pollak T.A.
      • McGuire P.
      • Fusar-Poli P.
      • Zandi M.S.
      • Lewis G.
      • David A.S.
      Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.
      ), H1N1 influenza (H1N1) (
      • Han R.H.
      • Schmidt M.N.
      • Waits W.M.
      • Bell A.K.C.
      • Miller T.L.
      Planning for mental health needs during COVID-19.
      ), Ebola virus (
      • Cenat J.M.
      • Felix N.
      • Blais-Rochette C.
      • Rousseau C.
      • Bukaka J.
      • Derivois D.
      • Noorishad P.G.
      • Birangui J.P.
      Prevalence of mental health problems in populations affected by the Ebola virus disease: a systematic review and meta-analysis.
      ), and the current COVID-19 pandemic (
      • Krishnamoorthy Y.
      • Nagarajan R.
      • Saya G.K.
      • Menon V.
      Prevalence of psychological morbidities among general population, healthcare workers and COVID-19 patients amidst the COVID-19 pandemic: a systematic review and meta-analysis.
      ;
      • Rogers J.P.
      • Chesney E.
      • Oliver D.
      • Pollak T.A.
      • McGuire P.
      • Fusar-Poli P.
      • Zandi M.S.
      • Lewis G.
      • David A.S.
      Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.
      ), demonstrate that outbreaks increase the risk of mental health issues among patients and healthcare providers, and amongst various subpopulations, including people with chronic health conditions (
      • Wu T.
      • Jia X.
      • Shi H.
      • Niu J.
      • Yin X.
      • Xie J.
      • Wang X.
      Prevalence of mental health problems during the COVID-19 pandemic: a systematic review and meta-analysis.
      ), quarantined people (
      • Hossain M.M.
      • Sultana A.
      • Purohit N.
      Mental health outcomes of quarantine and isolation for infection prevention: a systematic umbrella review of the global evidence.
      ), older people (
      • Sepulveda-Loyola W.
      • Rodriguez-Sanchez I.
      • Perez-Rodriguez P.
      • Ganz F.
      • Torralba R.
      • Oliveira D.V.
      • Rodriguez-Manas L.
      Impact of social isolation due to COVID-19 on health in older people: mental and physical effects and recommendations.
      ), children and adolescents (
      • Nearchou F.
      • Flinn C.
      • Niland R.
      • Subramaniam S.S.
      • Hennessy E.
      Exploring the impact of COVID-19 on mental health outcomes in children and adolescents: a systematic review.
      ), and pregnant and post-partum women (
      • Yan H.
      • Ding Y.
      • Guo W.
      Mental health of pregnant and postpartum women during the coronavirus disease 2019 pandemic: a systematic review and meta-analysis.
      ). A recent meta-analysis reported that the global prevalence of depression, anxiety, and distress during the COVID-19 pandemic was 31.4%, 31.9%, and 41.1%, respectively. Notably, the risk of depression and anxiety were found to be substantially higher among non-infectious chronic disease patients, quarantined people and COVID-19 patients than in other subpopulations (
      • Wu T.
      • Jia X.
      • Shi H.
      • Niu J.
      • Yin X.
      • Xie J.
      • Wang X.
      Prevalence of mental health problems during the COVID-19 pandemic: a systematic review and meta-analysis.
      ). Similarly, results from a national cohort study in UK demonstrated that the prevalence of clinically significant levels of mental health distress increased from 18.9% in 2018–19 to 27.3% by late April 2020, one month into the UK's lockdown (
      • Pierce M.
      • McManus S.
      • Hope H.
      • Hotopf M.
      • Ford T.
      • Hatch S.L.
      • John A.
      • Kontopantelis E.
      • Webb R.T.
      • Wessely S.
      • Abel K.M.
      Mental health responses to the COVID-19 pandemic: a latent class trajectory analysis using longitudinal UK data.
      ).
      People with multiple sclerosis (PwMS) may be more vulnerable to the neuropsychiatric impacts of the COVID-19 pandemic than the general population (
      • Haji Akhoundi F.
      • Sahraian M.A.
      • Naser Moghadasi A.
      Neuropsychiatric and cognitive effects of the COVID-19 outbreak on multiple sclerosis patients.
      ). Psychiatric comorbidities such as depression and anxiety are more common in PwMS compared to the general population, and these conditions are often considered to be part of the spectrum of MS symptoms (
      • Marrie R.A.
      • Reingold S.
      • Cohen J.
      • Stuve O.
      • Trojano M.
      • Sorensen P.S.
      • Cutter G.
      • Reider N.
      The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review.
      ). A recent meta-analysis of pre-pandemic studies reported that in the early phase of MS, the prevalence of anxiety and depression (as measured by HADS) was 35% (95%CI: 28–41%) and 17% (95%CI: 9–25%), respectively (
      • Rintala A.
      • Matcham F.
      • Radaelli M.
      • Locafaro G.
      • Simblett S.
      • Barattieri di San Pietro C.
      • Bulgari V.
      • Burke P.
      • Devonshire J.
      • Weyer J.
      • Wykes T.
      • Comi G.
      • Hotopf M.
      • Myin-Germeys I.
      on the behalf of the RADAR-CNS Consortium
      Emotional outcomes in clinically isolated syndrome and early phase multiple sclerosis: a systematic review and meta-analysis.
      ). Psychiatric comorbidities are major contributors to psychological distress and can influence the disease course, level of fatigue, disability progression and quality of life (QoL) in affected PwMS (
      • Berrigan L.I.
      • Fisk J.D.
      • Patten S.B.
      • Tremlett H.
      • Wolfson C.
      • Warren S.
      • Fiest K.M.
      • McKay K.A.
      • Marrie R.A.
      CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis (ECoMS)
      Health-related quality of life in multiple sclerosis: direct and indirect effects of comorbidity.
      ;
      • McKay K.A.
      • Tremlett H.
      • Fisk J.D.
      • Zhang T.
      • Patten S.B.
      • Kastrukoff L.
      • Campbell T.
      • Marrie R.A.
      CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis
      Psychiatric comorbidity is associated with disability progression in multiple sclerosis.
      ).
      As described above, restrictive measures that curtail personal freedoms such as quarantine, social isolation, and social distancing have been imposed to protect society from the rapid spread of COVID-19. However, such laudable preventative measures may impact both the physical and psychosocial well-being of PwMS. PwMS may face disruptions in lifestyle and increased stress as a result of COVID-19 containment measures, such as increased social isolation and delays in medical appointments. This could ultimately lead to adverse effects on their neuropsychological state, adherence to treatment and overall QoL (
      • Motl R.
      • Ehde D.
      • Shinto L.
      • Fernhall B.
      • LaRocca N.
      • Zackowski K.
      Health behaviors, wellness, and multiple sclerosis amid COVID-19.
      ;
      • Pedrosa A.L.
      • Bitencourt L.
      • Froes A.C.F.
      • Cazumba M.L.B.
      • Campos R.G.B.
      • de Brito S.
      • Simoes E.S.A.C.
      Emotional, behavioral, and psychological impact of the COVID-19 pandemic.
      ). Results from a large online survey among PwMS in the United States showed considerable disruptions in multiple health behaviours and access to MS-related health care during the COVID-19 pandemic. More than two-thirds of respondents reported that they had to cancel a clinical appointment during this period and almost 20% missed an MRI or laboratory test. Furthermore, about 10% reported some level of disease-modifying therapy treatment (DMT) change, including delayed dosage. Importantly, the same cohort reported that COVID-19 has had a significant economic impact on their lives, causing them to change employment, reduce work hours, or even lose their job (
      • Vogel A.C.
      • Schmidt H.
      • Loud S.
      • McBurney R.
      • Mateen F.J.
      Impact of the COVID-19 pandemic on the health care of >1,000 people living with multiple sclerosis: a cross-sectional study.
      ). Similar findings on the economic consequences of COVID-19 for PwMS have also been found in surveys from Spain and China (
      • Zhang G.X.
      • Sanabria C.
      • Martinez D.
      • Zhang W.T.
      • Gao S.S.
      • Aleman A.
      • Granja A.
      • Paramo C.
      • Borges M.
      • Izquierdo G.
      Social and professional consequences of COVID-19 lockdown in patients with multiple sclerosis from two very different populations.
      ). Notably, previous studies have demonstrated the adverse impact of unemployment on mental health (
      • Dorstyn D.S.
      • Roberts R.M.
      • Murphy G.
      • Haub R.
      Employment and multiple sclerosis: a meta-analytic review of psychological correlates.
      ), and the negative effect of DMT non-adherence on disease activity and health resource utilization (
      • Burks J.
      • Marshall T.S.
      • Ye X.
      Adherence to disease-modifying therapies and its impact on relapse, health resource utilization, and costs among patients with multiple sclerosis.
      ) among PwMS.
      Several systematic reviews and meta-analyses have reported the prevalence of common mental health conditions among the general population and various subpopulations during previous outbreaks such as SARS, MERS, H1N1, as well as the COVID-19 pandemic (
      • Cabarkapa S.
      • Nadjidai S.E.
      • Murgier J.
      • Ng C.H.
      The psychological impact of COVID-19 and other viral epidemics on frontline healthcare workers and ways to address it: a rapid systematic review.
      ;
      • Hossain M.M.
      • Sultana A.
      • Purohit N.
      Mental health outcomes of quarantine and isolation for infection prevention: a systematic umbrella review of the global evidence.
      ;
      • Xiong J.
      • Lipsitz O.
      • Nasri F.
      • Lui L.M.W.
      • Gill H.
      • Phan L.
      • Chen-Li D.
      • Iacobucci M.
      • Ho R.
      • Majeed A.
      • McIntyre R.S.
      Impact of COVID-19 pandemic on mental health in the general population: a systematic review.
      ). However, no review has evaluated the current evidence in PwMS. Therefore, the aim of this study is to conduct a rapid systematic review of the existing evidence on impact of the COVID-19 pandemic on mental health outcomes among PwMS.

      2. Methods

      2.1 Search methodology and study design

      We conducted a systematic literature search in four biomedical databases (MEDLINE, PsycInfo, EMBASE and Scopus) for studies published prior to 25 June 2021. The full list of search strategies and the retrieved records are described in Supplementary Table 1. We utilized a combination of terms relating to COVID-19 (e.g., “SARS-CoV-2″ and “coronavirus”), mental health outcomes (e.g., “psychiatric” and “mental health”) and MS-related disease and disease course. We used several keywords for each of the main concepts. We did not limit our search to specific psychiatric disorders; by selecting more general Medical Subject Headings (MeSH) or Map terms, we considered broader outcomes and determinants of mental health and wellbeing. We also conducted a search in the WHO Global Health research database on COVID-19 for additional articles. Duplicate records were removed, and titles and abstracts were reviewed by one reviewer (AZ). The full text of the remaining records was then reviewed by one reviewer (AZ). Study selection was conducted based on the inclusion and exclusion criteria summarized in Table 1, which follows the PICOS convention (population; intervention/exposure; comparison; outcome; study design) (
      • Methley A.M.
      • Campbell S.
      • Chew-Graham C.
      • McNally R.
      • Cheraghi-Sohi S.
      PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews.
      ).
      Table 1Summary of inclusion and exclusion criteria according to PICOS acronym.
      Inclusion criteriaExclusion criteria
      PopulationPeople living with MS including pediatric and adult-onset types
      Intervention/exposureCOVID-19 pandemic and related social distancing and lockdown measuresConducted prior to the COVID-19 pandemic
      ComparisonAny control population was acceptable. Having no control group was also acceptable
      OutcomePrevalence of psychiatric disorders, or the level of psychological symptoms or wellbeing measured by a valid psychometric assessment tool, or measurement determinants of mental health outcomesUsed questionnaires that have not been validated to assess mental health-related outcomes
      Study designObservational studies, including cross-sectional studiesReported the effect of any therapeutic or behavioural intervention; expert opinion; or case report
      LanguageEnglish languageNot written in English
      SettingAll

      2.2 Data extraction

      The following items were extracted from the included studies using a standardized spreadsheet: author name, year of publication, country, study design, sample size, recruitment location, study participants, type of MS, sex, average age, average disease duration, average Expanded Disability Status Scale (EDSS) score, history of psychiatric comorbidity and results of psychometric screening tools. We also recorded the timeframe of the study with respect to the COVID-19 pandemic and related lockdowns (early/during/at the peak), as stated in the included articles. The WHO defines a pandemic peak as the number of new cases rising to the highest observed levels and the peak of the epidemic curve beginning to drop following implementation of adequate surveillance (). It is noteworthy that the working definition of a pandemic peak and the severity of social and health-related containment and prevention measures depend on country/territory policies and may vary from each other.

      2.3 Quality assessment

      Two reviewers (AZ and CE) conducted the risk of bias assessment independently, and any conflicts were resolved by a third reviewer (SC). Methodological quality assessment was carried out using the Newcastle-Ottawa Scale (NOS), which contains separate quality assessment instruments for cohort studies (

      Wells, G.A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P., The newcastle-ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.2022.

      ), and an adapted form of the NOS for cross-sectional studies (
      • Herzog R.
      • Alvarez-Pasquin M.J.
      • Diaz C.
      • Del Barrio J.L.
      • Estrada J.M.
      • Gil A.
      Are healthcare workers' intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review.
      ). The quality of each study was determined for three main domains (selection, comparability, and outcome) according to the tool's assessment criteria (Supplementary Tables 2 and 3). A cohort study could be awarded a maximum of one star for each numbered item within the “Selection” and “Outcome” domains. A maximum of two stars can be awarded for the “Comparability” domain. The final score for each study was calculated as the total number of awarded stars. The higher total number stars indicate better research quality (

      Wells, G.A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P., The newcastle-ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.2022.

      ). The maximum number of stars for cohort and cross-sectional studies is 9 and 10, respectively. In addition, we used the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement for reporting this study (Supplementary Table 4).

      2.4 Data synthesis

      The included studies were too heterogeneous for a meta-analysis; a small number of studies assessed each outcome, and a wide range of psychometric screening tools were used. Consequently, we conducted a narrative synthesis focused on five major mental health-related outcomes as common themes: anxiety, depression, HRQOL, stress and sleep quality. For each outcome, we discuss the prevalence or frequency of the outcome, the severity of symptoms as measured by psychometric scales, comparisons between PwMS and controls and the comparison over time.

      3. Results

      Fig. 1 illustrates the flow of studies into this review. In summary, a total of 268 records were returned from the initial searches. After removing duplicate articles, the titles and abstract of 197 records were screened. Of these, 37 articles (18.8%) were deemed eligible for full-text review. Of these, 19 articles (51.3%) were included.
      Fig 1
      Fig. 1PRISMA Flowchart of citations selection.

      3.1 Characteristics of included studies

      Table 2 presents the characteristics of the included studies. Of the 19 included studies, 13 were cross-sectional, four were longitudinal, and two included both longitudinal and cross-sectional analyses. The included studies assessed a total of 5816 adult MS cases and 30 pediatric (aged ≤ 18 years) MS cases. Eleven studies were conducted in European countries and the remainder were based in Iran (n = 4), the USA (n = 1) and Egypt (n = 1). There were two multicentre studies; one recruited participant from six countries across North America and Europe (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ) and the other recruited participants from five Central and South American countries and Spain (
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ). All were conducted during the COVID-19 outbreak but a subset was done during a period of lockdown in the host country. About half of the studies (n = 9) described concurrent public health attempts to limit COVID-19 spread, with governments enforcing a regional or nationwide lockdown/quarantine in the state or country (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). However, the level or severity of concurrent quarantine or lockdown measures was not clearly described.
      Table 2Characteristics of the articles included in this review.
      AuthorsDateCountryStudy designCOVID-19 pandemic Time frameState of lockdown#Sample size and participant typeRecruitment sourceAge*(years)Female casesn(%)MS duration*(years)Psychiatric comorbiditiesData collectionOutcomesPsychometric scaleOverall quality score
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      SpainLongitudinalDuringBefore/

      after
      18 PwMS1NA43.5(11.2)10(55.5)NANAOnline surveyAnxietyState-Trait Anxiety Inventory (STAI)4
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.


      ItalyLongitudinalBefore/

      during
      Yes

      67 RRMS2MS center37.5(11.1)37(55.2)7.6(8.1)NAOnline surveyAnxiety, depression, quality of lifeState-Trait Anxiety Inventory (STAI), Beck Depression Inventory second edition (BDI-II), Multiple Sclerosis Quality of Life-54 (MSQoL-54)4
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      )
      Belgium, Canada, Denmark, Italy, UK, USALongitudinalBefore/

      during
      Yes131 PMS3Ongoing clinical trial (sourced from in and outpatient MS clinics)

      52.1(6.9)83(63.4)14.4(9.1)Exclusion criterionTelephonic/online, in-person surveyAnxiety, depression, impact of MS on psychological scale, quality of lifeThe Hospital Anxiety Depression Scale (HADS), The Beck Depression Inventory-II (BDI-II), Multiple Sclerosis Impact Scale (MSIS-29), EuroQol (EQ-5D-5 L)5
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.


      TurkeyLongitudinalEarly/

      during
      No50 PwMS1Web-based30.0(7.0)42(84.0)NAExclusion criterionOnline surveyAnxiety, depression, sleep quality, quality of lifeBeck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), Multiple Sclerosis Quality of Life-54 (MSQoL-54)5
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      UKLongitudinal/ cross-sectionalBefore/

      during
      Before/ during2010 PwMS1, 380 controlsUK MS Register cohortmedian: 56 (48–63)1488 (74.3)median: 12 (6–20)Baseline anxiety and depression were reported.Online surveyAnxiety, depression, post-traumatic stress disorder (PTSD)The Hospital Anxiety Depression Scale (HADS), General Anxiety Disorder 7-item (GAD-7), Patient Health Questionnaire 9-question (PHQ-9), Impact of Event Scale–Revised (IES-R)Longitudinal (6)
      Cross-sectional(8)
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      SerbiaLongitudinal/ cross-sectionalBefore/ duringYes95 RRMS2, 99 HC4MS clinic43.4(9.7)89(67.6)median: 8.2Exclusion criterionIn-person surveyAnxiety, depression, quality of lifeHamilton scales for anxiety (HAM-A), and depression (HAM-D), Multiple Sclerosis Quality of Life-54 Instrument (MSQOL-54),Longitudinal (5)
      Cross-sectional(6)
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.


      USACross-sectionalDuringNo491 PwMS1Online55.8(12.6)399(81.3)16.7(11.2)NAOnline surveyAnxiety, depression, positive affect and well-beingPROMIS Short Form v1.0 – Depression 6a and Anxiety 6a, Quality of Life in Neurological Disorders (Neuro-QoL) Short Form v1.07
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      TurkeyCross-sectionalDuringNo205 PwMS1Outpatient clinic37.7(10.0)152(74.1)7.4(6.5)Exclusion criterionOnline surveyStress, quality of lifePerceived Stress Scale (PSS),SF-124
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ItalyCross-sectionalDuringNo612 PwMS1, 674 controlsOnline43(10)465(76.0)median: 10NAOnline surveyStress, depressionPerceived Stress Scale (PSS), Patient Health Questionnaire 2(PHQ-2)5
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      Argentina, Mexico, Spain, Dominican Republic, Venezuela, CubaCross-sectionalDuringNA202 PwMS1Online and medical record42,8(12,7)154(76.2)9.6(8.5)NAOnline survey

      Anxiety, depressionBeck Depression Inventory-II (BDI-II), Generalized Anxiety Disorder Scale (GAD-7)5
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.


      ItalyCross-sectionalDuringYes497 PwMS1, 348 controls+Web-based42.4(10.7)351(70.6)NAReported and controlled for comparisonsOnline surveyMental distressQuality of Life in Neurological Disorders (Neuro-QoL),7
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.


      TurkeyCross-sectionalDuringNA

      30 children with MS, 49 age-sex matched HC4University hospital15.6(2.1)19(63.3)2.5(1.3)NAOnline surveyAnxietyState-Trait Anxiety Inventory (STAI)7
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      )
      ItalyCross-sectionalDuringYes60 PwMS1, 50 HC4Outpatient clinicNA41(68.3)5.1(5.9)ReportedOnline surveyAnxiety, depression, sleep qualityBeck Depression Inventory II (BDI-II) and the Generalized Anxiety Disease 7 (GAD-7), the Pittsburgh Sleep Quality Index (PSQI)5
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      )
      IranCross-sectionalDuringNA33 PwMS1MS clinic33.5(5.2)27(81.8)6.1(4.2)NAIn-person surveyAnxietyBeck Anxiety Inventory (BAI)4
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      IranCross-sectionalDuringNA410 PwMS1MS clinic38.6(10.3)326 (79.5)NAReportedIn-person surveyAnxiety, depressionHospital Anxiety and Depression Scale (HADS)4
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      )
      IranCross-sectionalDuringNA165 PwMS1MS clinic35.3(8.6)136 (82.4)7.1(5)NAIn-person surveyAnxiety, depression, stressDepression Anxiety Stress Scales-21 (DASS-21)4
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      )
      IranCross-sectionalDuringYes223 PwMS1, 245 HC4MS clinic35.9(7.5)183(82.1)6.4(5.2)ReportedOnline surveyAnxiety, depression, stressDepression Anxiety Stress Scales-21 (DASS-21)5
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      EgyptCross-sectionalDuringNA115 PwMS1, 129 HC4University hospital34.4(8.5)89(77.4)6.8(5.5)NAOnline surveyAnxiety, depression, stressDepression Anxiety Stress Scales-21 (DASS-21)5
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ItalyCross-sectionalDuringAfter ease of lockdown432 RRMS2MS center40.4(12.4)277(64.1)5.3(3.2)

      Reported

      Telephonic interviewAnxiety, depression, stress, Post-Traumatic Stress Disorder (PTSD), Sleep qualityDepression Anxiety Stress Scales-21 (DASS-21), Short Screening Scale for DSM-IV (SSS DSM-IV), Insomnia Severity Index (ISI).6
      *Data are mean(SD) unless otherwise stated. 1.PwMS: People Living with Multiple Sclerosis, 2. RRMS: Relapsing Remitting MS, 3.PMS: Progressive MS, 4. HC: Healthy controls, NA: Not available. # Study conducted during the local or national state of lockdown + Control group in this study was selected from family members and/or friends not affected by MS.
      Nine studies (47.4%) reported the prevalence of mental health outcomes during the COVID-19 pandemic as determined by psychometric scales (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ;
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). However, only two studies (10.5%) reported a prospective comparison before and during the pandemic (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). All 15 cross-sectional studies reported the severity of mental health symptoms during the COVID-19 pandemic. Of these, eight (53.3%) sampled a control population to compare with PwMS (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ). Two cross-sectional studies examined the mental health status of parents and caregivers of PwMS as well as PwMS (
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ).All six longitudinal studies reported the severity of mental health symptoms among PwMS prior to or early in the COVID-19 pandemic along with follow-up measures in a lockdown period (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). However, none of the longitudinal studies recruited a control group for prospective comparison.
      Most studies did not limit their study population by MS phenotype. However, one study only included participants with primary or secondary progressive MS (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ). Most of the studies (n = 14) used online surveys for data collection. Four studies excluded participants with comorbid psychiatric conditions (
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ), nine studies did not mention pre-existing psychiatric comorbidities prior to the onset of the COVID-19 outbreak (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ;
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ;
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ), and the remaining six articles reported baseline psychiatric comorbidity status (
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ).

      3.2 Risk of bias assessment

      Tables 3 and 4 provide the details of quality assessment, including rationale. Among the longitudinal studies (n = 6), two items (comparability domain and selection of the non-exposed cohort sub-domain) were not applicable and were not considered in the overall score. Thus, the maximum achievable number of stars for longitudinal studies was 6. The domain that was best addressed by all longitudinal studies was “outcome” and all the six studies were rated full points in this domain. Conversely, the selection domain was poorly addressed by five of the six studies in this group, due to the use of convenience sampling methods and the study cohort not being representative of PwMS in the community. A total of four studies had ≥ 5 points (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ), indicating satisfactory quality.
      Table 3Results of the critical appraisal of the included longitudinal studies #.
      Table 4Results of the critical appraisal of the included cross-sectional studies #.
      All cross-sectional studies (n = 15) had a possible risk of selection bias. All but one study in this group had a high risk of bias related to the representativeness of the sample as their sampling was not random. The sample size was justified and satisfactory (including sample size calculation) in only four (26.7%) cross-sectional studies. Seven (46.7%) studies had a satisfactory recruitment rate or summarized the characteristics of non-respondents. All cross-sectional studies utilized a validated psychometric tool to measure mental health outcomes and clearly described their statistical analyses. In total, only four studies in this group were rated ≥ 7 out of 10 (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ), indicating satisfactory quality.
      A wide range of assessment tools were used in the included studies. Detailed descriptions of the HRQOL and psychometric scales used are presented in the Supplementary Table 2.

      3.3 Anxiety

      Anxiety was the primary outcome variable in 16 (84.2%) of the included studies (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ,
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). Measurement scales used to assess anxiety included the Depression Anxiety Stress Scales-21 (DASS-21) (n = 4) (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ,
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ); the State-Trait Anxiety Inventory (STAI) (n = 3) (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ); the Hospital Anxiety and Depression Scale (HADS) (n = 3) (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ); the Generalized Anxiety Disorder-7(GAD-7) (n = 3) (
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ); the Beck Anxiety Inventory (BAI) (n = 2) (
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ); the Hamilton scales for anxiety (HAM-A) (n = 1) (
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ); and the PROMIS Short Form v1.0 – Anxiety 6a (n = 1) (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ). One study used two scales to assess anxiety in their participants (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ).
      Four studies reported the prevalence of clinically significant anxiety, which ranged from 16% (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ) to 31% (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ) during the COVID-19 pandemic. Additionally, three studies reported severe to extremely severe anxiety in 13.9% (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ), 37.4% (
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ) and 45.4% (
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ) of their sample populations. A Turkish study of pediatric MS (n = 30) found that 100% of the sample reported clinically meaningful anxiety during lockdown (
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ). It is noteworthy that two studies only reported the average severity of anxiety symptoms in their samples rather than the frequency of different severity groups or categories (
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ).
      Anxiety was measured prospectively in six studies (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). Two studies found a significant increase in anxiety. A Serbian study reported increased levels of anxiety during a COVID-19 lockdown compared to the pre-pandemic period (HAM-A: 18.9 ± 5.1 vs. 15.8 ± 4.7; p < 0.05) (
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). Similarly, a Spanish study found a significant increase in state anxiety (i.e., anxiety about an event) (STAI: 22.1 ± 11.8 vs. 17.40 ± 12.8; p = 0.01) but not in trait anxiety (i.e., anxiety level as a personal characteristic) (STAI: 21.8 ± 9.8 vs. 20.6 ± 11.1; p = 0.19) among PwMS after ease of the lockdown compared with the pre-lockdown period (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Manonelles P.
      • Abellan-Aynes O.
      • Rubio-Arias J.A.
      The impact of COVID-19 home confinement on neuromuscular performance, functional capacity, and psychological state in Spanish people with multiple sclerosis.
      ). Conversely, the remaining four studies found no significant difference (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). A large longitudinal study in the UK (n = 2226) did not show a significant increase in the severity of anxiety symptoms (HADS-A(IQR): 6 (3–10) vs. 6 (3–10); p = 0.87) or the proportion of sample with a clinically significant anxiety (470 (21.1%) vs. 463 (20.8%);p = 0.72) during the outbreak compared to the year before (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ).
      Two studies found that PwMS had significantly higher levels of anxiety during lockdown compared to controls: one in Egypt (12.7 ± 10.0 vs. 9.3 ± 6.7; p < 0.001) (
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ) and one in Serbia (18.9 ± 5.1 vs. 10.2 ± 4.3; p < 0.01) (
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). However, studies in Iran (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ) and Italy (
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ) did not find a difference between PwMS and controls. Similarly, results from a large cross-sectional study (n = 1714 PwMS/269 controls) in the UK did not report significant differences in median symptom severity (GAD-7(IQR): 4(1–8) vs. 4 (1–7);p = 0.81) or frequency of participants with anxiety (19.5% vs. 16.7%; p = 0.29) between PwMS and controls (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). Among a pediatric MS sample in Turkey, the average state anxiety level was significantly higher than among age-and sex-matched controls. However, trait anxiety was not significantly different between groups (
      • Dilek T.D.
      • Boybay Z.
      • Kologlu N.
      • Tin O.
      • Guler S.
      • Saltik S.
      The impact of SARS-CoV2 on the anxiety levels of subjects and on the anxiety and depression levels of their parents.
      ).

      3.4 Depression

      Fourteen studies (73.7%) examined depression among PwMS (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ,
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). They used a variety of scales, including the Beck Depression Inventory-II (BDI-II) (n = 5) (
      • Broche-Perez Y.
      • Jimenez-Morales R.M.
      • Monasterio-Ramos L.O.
      • Vazquez-Gomez L.A.
      • Fernandez-Fleites Z.
      Fear of COVID-19, problems accessing medical appointments, and subjective experience of disease progression, predict anxiety and depression reactions in patients with multiple sclerosis.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ); the Depression Anxiety Stress Scales-21 (DASS-21) (n = 4) (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ,
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ); and the Hospital Anxiety and Depression Scale (HADS) (n = 3) (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ); the Hamilton scales for Depression (HAM-D) (n = 1) (
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ); the PROMIS Short Form v1.0 – Depression 6a (n = 1) (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ); the Patient Health Questionnaire −2 (PHQ-2) (n = 1) (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ); and Patient Health Questionnaire −9 (PHQ-9) (n = 1) (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). Two studies used two different scales to assess depression in their participants (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ).
      Four studies reported the proportion of PwMS with clinically significant depressive symptoms, which ranged from 12 to 39% during the COVID-19 pandemic (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Ramezani N.
      • Ashtari F.
      • Bastami E.A.
      • Ghaderi K.
      • Hosseini S.M.
      • Naeini M.K.
      • Rajabi F.
      • Adibi I.
      Fear and anxiety in patients with multiple sclerosis during COVID-19 pandemic; report of an Iranian population.
      ). Similarly, studies from Egypt (
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ) and Italy (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ) reported severe to extremely severe depression in 39.1% and 3.5% of PwMS sampled, respectively.
      Depression was assessed longitudinally in five studies (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). Two studies found a significant increase in depression scores during the pandemic. A multicentre study among progressive MS cases in North America and Europe found significantly higher depression scores (HADS: 6.7 ± 4.6 vs. 5.8 ± 3.7; p = 0.03) during lockdown compared to baseline. Interestingly, this result was mainly driven by the substantial increase in cases from Belgium (HADS: 6.7 ± 6.1; p < 001) whilst the remaining five countries (Denmark, Canada, the United Kingdom, Italy and the USA) reported minor changes (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ). A Turkish study also showed a significant increase in depression scores during a pandemic peak compared to the early stages of the outbreak (BDI: 16.4 ± 9.5 vs. 12.6 ± 8.2; p < 0.001) (
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ). Conversely, four studies found no significant difference in a least one depression-related outcome measure (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). A large longitudinal study in the UK (n = 2226) showed that the median depressive symptom severity among PwMS had not significantly changed during the outbreak and lockdown compared to the year before (HADS(IQR): 7 (3–10) vs. 6 (3–10); p = 0.23). Similarly, the proportion of participants with clinically significant depression did not change during the follow-up compared with the year before (475 (21.3%) vs. 470 (21.1%) p = 0.81) (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). Three longitudinal studies did not demonstrate a significant change in depression scores (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ) and/or the frequency of clinical depression before and during pandemic (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ).
      In four of the five studies in which it was assessed, PwMS showed significantly higher levels of depression than healthy controls during the pandemic or lockdown period (
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ). For example, studies from Italy (n = 612PwMS/674controls, 43.1 vs. 23.1%;p < 0.001) and the UK (n = 1751PwMS/269controls, 32.7 vs. 23.8%; p = 0.003) reported a significantly higher proportion of depression among PwMS compared to controls (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). Conversely, one study reported a non-significant difference (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ).

      3.5 Health-related quality of life (psychological wellbeing)

      Seven studies (36.8%) reported the impact of the COVID-19 pandemic on HRQOL among PwMS (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ;
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ;
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). Three studies used the Multiple Sclerosis Quality of Life-54 instrument (MSQoL-54) (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ), two used the Quality of Life in Neurological Disorders (Neuro-QoL)(
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ), one used SF-12 (
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ), and one used a multi-attribute utility instrument to assess health state utilities (EuroQol's EQ-5D) and the Multiple Sclerosis Impact Scale (MSIS-29) (
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      ).
      Two cross-sectional studies reported HRQOL among PwMS (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ;
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ). In an online survey in the USA, 4.5% of respondents were below the clinical cut-off for positive affect and wellbeing, which are proxies of emotional health and distress (
      • Alschuler K.N.
      • Roberts M.K.
      • Herring T.E.
      • Ehde D.M.
      Distress and risk perception in people living with multiple sclerosis during the early phase of the COVID-19 pandemic.
      ). A Turkish study reported the average score of the mental health component of HRQOL (SF-12: 43.2 ± 10.4) among a sample of PwMS without any comparator (
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ).
      Three longitudinal studies used the MSQoL-54 to evaluate HRQOL before or during the early months of COVID-19 pandemic and then again during a lockdown period (
      • Capuano R.
      • Altieri M.
      • Bisecco A.
      • d'Ambrosio A.
      • Docimo R.
      • Buonanno D.
      • Matrone F.
      • Giuliano F.
      • Tedeschi G.
      • Santangelo G.
      • Gallo A.
      Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?.
      ;
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). All studies reported a decline in the average mental health subscale score later in the pandemic compared to pre- or early in the pandemic. However, the reduction was only statistically significant (60.5 ± 10.7 vs. 64.4 ± 9.9; p < 0.001) in one study (
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ). Similarly,
      • Chiaravalloti N.D.
      • Amato M.P.
      • Brichetto G.
      • Chataway J.
      • Dalgas U.
      • DeLuca J.
      • Meza C.
      • Moore N.B.
      • Feys P.
      • Filippi M.
      • Freeman J.
      • Inglese M.
      • Motl R.
      • Rocca M.A.
      • Sandroff B.M.
      • Salter A.
      • Cutter G.
      • Feinstein A.
      • CogEx Research T.
      The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
      did not find any difference in the subscales of the MSIS-29 subscale scores or EQ5D dimensions, during lockdown compared to pre-pandemic.
      Two studies compared the HRQOL of PwMS with a control group (
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ;
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ); both found that PwMS had a lower HRQOL. A Serbian study found that PwMS had considerably lower mental health super-dimension scores than healthy controls (47.1 ± 18.4 vs. 77.2 ± 19.7; p < 0.01) (
      • Stojanov A.
      • Malobabic M.
      • Milosevic V.
      • Stojanov J.
      • Vojinovic S.
      • Stanojevic G.
      • Stevic M.
      Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak.
      ). Similarly, an Italian study reported significantly higher scores (i.e., worse QoL) in multiple domains of the NeuroQoL instrument, including depression (15.5 ± 7.0 vs. 13.9 ± 5.8; p = 0.005), emotional dyscontrol (17.9 ± 7.0 vs. 16.5 ± 6.3; p = 0.01) and sleep disturbances (16.7 ± 6.0 vs. 15.4 ± 5.5; p = 0.02), among PwMS compared with a control group of family members or friends not living with MS. The latter study accounted for pre-existing psychiatric conditions and comorbidities in their analysis (
      • Costabile T.
      • Carotenuto A.
      • Lavorgna L.
      • Borriello G.
      • Moiola L.
      • Inglese M.
      • Petruzzo M.
      • Trojsi F.
      • Ianniello A.
      • Nozzolillo A.
      • Cellerino M.
      • Boffa G.
      • Rosa L.
      • Servillo G.
      • Moccia M.
      • Bonavita S.
      • Filippi M.
      • Lanzillo R.
      • Brescia Morra V.
      • Petracca M.
      COVID-19 pandemic and mental distress in multiple sclerosis: implications for clinical management.
      ).

      3.6 Stress

      Eight studies (42.1%) assessed stress among PwMS during the COVID-19 pandemic. All eight reported the frequency of stress-related symptoms. Four studies assessed stress among PwMS during the COVID-19 pandemic using the DASS-21 (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ,
      • Shaygannejad V.
      • Mirmosayyeb O.
      • Nehzat N.
      • Ghajarzadeh M.
      Fear of relapse, social support, and psychological well-being (depression, anxiety, and stress level) of patients with multiple sclerosis (MS) during the COVID-19 pandemic stage.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). Severe to extremely severe stress levels were reported in 16% and 34% of cases in Italy (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ) and Egypt (
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ), respectively. Similarly, studies from Turkey (
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ) and Italy (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ) utilized the Perceived Stress Scale (PSS) to measure stress severity in PwMS and reported high levels of stress among 11.2% (
      • Altunan B.
      • Unal A.
      • Bingol A.
      • Dilek F.
      • Girgin D.
      Coping with stress during the first wave of the COVID-19 pandemic by Turkish people with multiple sclerosis: the relationship between perceived stress and quality of life.
      ) and 58.0% (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ) of their samples, respectively.
      Post-Traumatic Stress Disorder (PTSD) was assessed by two studies using the Short Screening Scale for DSM-IV (SSS DSM-IV) (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ) and the Impact of Event Scale–Revised (IES-R) (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ). Zanghi and colleagues reported PTSD-like symptoms among 31.8% of 432 relapsing-remitting MS cases in Italy (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). Similarly, in a large cross-sectional study in the UK (n = 1714), 23.5% of PwMS was found to have symptoms of PTSD during the pandemic (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ).
      None of the included studies longitudinally assessed stress or PTSD symptoms before and during the COVID-19 outbreak.
      Four studies compared stress in PwMS to healthy controls (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ;
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ;
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ). Studies in Iran (
      • Shaygannejad V.
      • Afshari-Safavi A.
      • Hatef B.
      Assessment of mental health, knowledge, and attitude of patients with multiple sclerosis and neuromyelitis optica spectrum disorder in response to 2019 novel coronavirus.
      ) and Egypt (
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.
      ) found that stress was significantly higher among PwMS compared to healthy controls (Iran: 13.1 ± 9.9 vs. 9.6 ± 8.4; p = 0.02; Egypt: 21.0 ± 12.7 vs. 10.7 ± 8.4; p < 0.001) during the pandemic. Similarly, an Italian cross-sectional study reported that a significantly higher number of PwMS had high levels of perceived stress compared to controls (58% vs. 39.8%; p < 0.001) (
      • Bonavita S.
      • Sparaco M.
      • Russo A.
      • Borriello G.
      • Lavorgna L.
      Perceived stress and social support in a large population of people with multiple sclerosis recruited online through the COVID-19 pandemic.
      ). In contrast, a large study in the UK (n = 1696 PwMS/306 control) found no difference between PwMS and controls in the prevalence of PTSD symptoms during the outbreak (OR: 1.13, 95%CI: 0.84–1.52). Further, this study found that the median PTSD symptom severity was significantly lower in PwMS than controls (IES-R:16(6–32) vs. 20(10–33); p = 0.01) (
      • Garjani A.
      • Hunter R.
      • Law G.R.
      • Middleton R.M.
      • Tuite-Dalton K.A.
      • Dobson R.
      • Ford D.V.
      • Hughes S.
      • Pearson O.R.
      • Rog D.
      • Tallantyre E.C.
      • Nicholas R.
      • Morriss R.
      • Evangelou N.
      • das Nair R.
      Mental health of people with multiple sclerosis during the COVID-19 outbreak: a prospective cohort and cross-sectional case-control study of the UK MS Register.
      ).

      3.7 Sleep quality

      Three studies (15.8%) assessed sleep quality (
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ;
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ;
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ). One study used the Insomnia Severity Index (ISI) to measure sleep quality in participants with RRMS. This study reported that 28.7% of cases had subthreshold insomnia and 29.6% had moderately severe or severe clinical insomnia (
      • Zanghi A.
      • D'Amico E.
      • Luca M.
      • Ciaorella M.
      • Basile L.
      • Patti F.
      Mental health status of relapsing-remitting multiple sclerosis Italian patients returning to work soon after the easing of lockdown during COVID-19 pandemic: a monocentric experience.
      ).
      Sleep quality was longitudinally evaluated in one study. Demir and colleagues used the Pittsburgh Sleep Quality Index (PSQI); they found a significantly higher PSQI score (8.8 ± 1.5 vs. 8.3 ± 1.4; p < 0.001), indicating more acute sleep disturbances, during lockdown compared with the pre-lockdown period among PwMS (
      • Demir C.F.
      • Bilek F.
      • Balgetir F.
      Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients.
      ).
      Similarly, only one of the included studies compared sleep quality between PwMS and health controls. In this Italian study, PwMS showed significantly more disturbed sleep than healthy controls (6.9 ± 3.7 vs. 4.7 ± 2.7; p = 0.001) (
      • Motolese F.
      • Rossi M.
      • Albergo G.
      • Stelitano D.
      • Villanova M.
      • Di Lazzaro V.
      • Capone F.
      The psychological impact of COVID-19 pandemic on people with multiple sclerosis.
      ).

      4. Discussion

      To our knowledge, this is the first systematic review to synthesize evidence on the impact of the COVID-19 pandemic on the mental health of PwMS. We identified 19 studies that met our inclusion criteria. Studies reported a variety of mental health-related outcomes including anxiety, depression, HRQOL, stress and sleep quality, and used a variety of tools to measure these outcomes. Due to the observed heterogeneity in measurement scales and in reporting, we decided to focus this review on data synthesis. The available evidence, which was mainly derived from the early stages of the pandemic, indicates that anxiety, depression and stress have been prevalent among PwMS during the COVID-19 pandemic. Further, there is convincing evidence that PwMS experienced more severe symptoms of depression and stress compared to healthy and more limited evidence that PwMS have worse HRQOL compared to controls during the pandemic. However, these results may reflect the status quo, rather than the impact of the COVID-19 epidemic. Longitudinal studies among PwMS demonstrate that anxiety, depression and the mental health dimensions of HRQOL were generally not significantly affected during the pandemic and/or lockdown compared with the period before the COVID-19 outbreak.
      Anxiety and depression are prevalent coexisting medical conditions among PwMS (
      • Butler E.
      • Matcham F.
      • Chalder T.
      A systematic review of anxiety amongst people with multiple sclerosis.
      ;
      • Siegert R.J.
      • Abernethy D.A.
      Depression in multiple sclerosis: a review.
      ) and the prevalence of anxiety and depression are substantially higher in PwMS than in the general population (
      • Marrie R.A.
      • Reingold S.
      • Cohen J.
      • Stuve O.
      • Trojano M.
      • Sorensen P.S.
      • Cutter G.
      • Reider N.
      The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review.
      ,
      • Marrie R.A.
      • Walld R.
      • Bolton J.M.
      • Sareen J.
      • Walker J.R.
      • Patten S.B.
      • Singer A.
      • Lix L.M.
      • Hitchon C.A.
      • El-Gabalawy R.
      • Katz A.
      • Fisk J.D.
      • Bernstein C.N.
      CIHR Team in Defining the Burden and Managing the Effects of Psychiatric Comorbidity in Chronic Immunoinflammatory Disease
      Estimating annual prevalence of depression and anxiety disorder in multiple sclerosis using administrative data.
      ). A recent meta-analysis reported that the overall prevalence of anxiety and depression in the general population during the COVID-19 pandemic was 23.4% (95%CI: 19.9–27.3%) and 23.9% (95% CI: 18.4–30.3%), respectively (
      • Zhao Y.J.
      • Jin Y.
      • Rao W.W.
      • Li W.
      • Zhao N.
      • Cheung T.
      • Ng C.H.
      • Wang Y.Y.
      • Zhang Q.E.
      • Xiang Y.T.
      The prevalence of psychiatric comorbidities during the SARS and COVID-19 epidemics: a systematic review and meta-analysis of observational studies.
      ). In our review, with the different scales used by the included studies, the prevalence estimates for anxiety among PwMS during the COVID-19 pandemic ranged from 16 to 31%, which does not seem higher than the meta-analysis estimate of 22.1% (95% CI:15.2%−31.0%) of studies conducted prior to the pandemic (
      • Boeschoten R.E.
      • Braamse A.M.J.
      • Beekman A.T.F.
      • Cuijpers P.
      • Van Oppen P.
      • Dekker J.
      • Uitdehaag B.M.J.
      Prevalence of depression and anxiety in multiple sclerosis: a systematic review and meta-analysis.
      ). For depression, the prevalence estimates of our included studies ranged from 12 to 39%, while the meta-analysis estimate of studies prior to the pandemic was 30.5% (95%CI:26.3%−35.1%) (
      • Boeschoten R.E.
      • Braamse A.M.J.
      • Beekman A.T.F.
      • Cuijpers P.
      • Van Oppen P.
      • Dekker J.
      • Uitdehaag B.M.J.
      Prevalence of depression and anxiety in multiple sclerosis: a systematic review and meta-analysis.
      ). However, three other studies included in this review that only assessed different severity levels of anxiety and depression (i.e., mild to extremely severe) found higher frequencies of severe to extremely severe anxiety and depression than those mentioned above (14–45% of PwMS) (
      • Naser Moghadasi A.
      One aspect of coronavirus disease (COVID-19) outbreak in Iran: high anxiety among MS patients.
      ;
      • Talaat F.
      • Ramadan I.
      • Aly S.
      • Hamdy E.
      Are multiple sclerosis patients and their caregivers more anxious and more committed to following the basic preventive measures during the COVID-19 pandemic?.