key: cord-0859972-czbivh9d
authors: Manuela, Altieri; Rocco, Capuano; Alvino, Bisecco; Alessandro, d'Ambrosio; Daniela, Buonanno; Gioacchino, Tedeschi; Gabriella, Santangelo; Antonio, Gallo
title: The psychological impact of Covid-19 pandemic on people with Multiple Sclerosis: a meta-analysis
date: 2022-03-25
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2022.103774
sha: 2e1dc35e64de49f61c9cf9d72dcf37b71b297610
doc_id: 859972
cord_uid: czbivh9d

BACKGROUND: : Covid-19 pandemic caused relevant psychological consequences in the general population. Since people with Multiple Sclerosis (pwMS) are usually at higher risk of psychological distress than age-matched healthy controls (HC), a meta-analytic study was conducted, aimed at evaluating i) differences between pwMS and HC in the psychological variables during the pandemic, ii) differences in the levels of anxiety, depression, stress, sleep disturbances and quality of life before and during the Covid-19 pandemic in pwMS. METHODS: : The literature search on three electronic databases yielded 196 studies (113 after the duplicates removal). Seven studies compared psychological variables between pwMS and HC during the pandemic, while seven studies evaluated the pre- vs during the pandemic differences in pwMS. The following outcomes were selected: depression, anxiety, physical QoL, mental QoL, stress, sleep quality/disturbances. Mean weighted effect sizes (ES) were calculated using Hedges'g, via Prometa3 software. RESULTS: : During the pandemic, pwMS showed higher levels of depression (g=0.51, p=0.001), anxiety (g=0.41, p=0.032), and stress (g=0.51, p=0.016) compared to HC. The comparison on psychological outcomes before and during the pandemic in pwMS revealed no significant increase during the pandemic on levels of anxiety (g=0.08, p=0.380), depression (g=0.02, p=0.772), mental QoL (g= -0.14, p=0.060), physical QoL (g=0.00, p=0.986), whereas sleep quality deteriorated during the pandemic (g=0.52, p<0.001). CONCLUSIONS: : In agreement with pre-pandemic literature, pwMS showed higher levels of psychological distress than HC also during the Covid-19 pandemic. Contrariwise, longitudinal studies revealed that, in pwMS, the only psychological-associated variable that worsened significantly was the sleep quality, but this outcome was evaluated only in two studies. Future studies will have to assess/evaluate the long-term psychological consequences of the pandemic on pwMS.

Coronavirus Disease 2019 was declared a global pandemic on March 11, 2020 by the World Health Organization (Cucinotta and Vanelli, 2020) and rapidly spread all around the word (World Health Organization, 2021) . Being afraid and worried of contracting a yet largely unknown and potentially deadly disease, even in healthy people, together with the stringent health measures adopted by governments to contain the outbreak, such as quarantine, social distancing, or lockdowns, produced dramatic and relevant consequences on psychological health; it is well known, indeed, that prolonged isolation and a sense of uncertainty related to the pandemic may strongly increase levels of psychological distress (Pietrabissa and Simpson, 2020) . To date, several reviews and meta-analyses on psychological consequences of Covid-19 pandemic revealed that healthcare workers, general population at every age (Lebrasseur et al., 2021; Luo et al., 2020; Singh et al., 2020; Xiong et al., 2020) and people affected by chronic diseases (Al-Rahimi et al., 2021; Cohen et al., 2020; suffered of high rates of anxiety, depression, stress, sleep disturbances and post-traumatic stress disorder. Nonetheless, studies on the psychological consequences of the Covid-19 pandemic on people with Multiple Sclerosis (pwMS) revealed inconsistent results: some studies (Naser Moghadasi, 2020; Stojanov et al., 2020) reported an increase of psychological distress during the pandemic, while other studies did not (Capuano et al., 2021; Chiaravalloti et al., 2021) . Therefore, to better understand how the pandemic impacted on psychological status of pwMS, a meta-analytic study was conducted, aimed at i) evaluating possible differences between pwMS and healthy controls (HC) in the psychological variables during the pandemic, ii) evaluating possible differences in the levels of anxiety, depression, stress, sleep disturbances and QoL before and during the Covid-19 pandemic in pwMS.

The literature search was performed on October 11, 2021 on three electronic databases (PsycINFO, PubMed, Scopus), by employing the following keywords: Multiple Sclerosis AND (Covid-19 OR coronavirus OR Sars-Cov-2) AND (psycholog* OR depress* OR anxi* OR sleep OR stress OR quality of life OR coping). The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement (Moher et al., 2009 ) was employed to select eligible articles. To try to better control the publication bias, grey literature (i.e., conference proceedings) was included by manual search (Paez, 2017) . Primary studies were included in the meta-analysis if they: (a) were written in English, (b) included a group of pwMS; (c) reported the comparison between scores of psychological questionnaires (assessing one or more of the following outcomes: anxiety, depression, mental and physical quality of life (QoL), stress, sleep disturbances) completed before and during the Covid-19 pandemic by pwMS, or they compared scores of psychological questionnaires between pwMS and HC during the Covid-19 pandemic.

Two reviewers (MA and RC) performed the data collection and coding; in case of disagreement, agreement was reached by discussion between the two reviewers and authors with expertise on psychology. For the purposes of the present meta-analytic study, psychological variables in the primary studies were coded in the following outcomes: anxiety, depression, mental and physical quality of life (QoL), stress, sleep disturbances, coping strategies. We collected for each primary study, when available, the following data: country of primary study; time period of data collection; government restrictions at the time of data collection, evaluated by means of the government response stringency index (Hale et al., 2021) . The Government Response Stringency Index ranges from 0 to 100, where 100 is the strictest government response). Moreover, for both HC and pwMS groups, we collected a) number of participants, b) mean age of the sample, c) mean years of education, d) percentage of females in the sample. For only pwMS group we collected: a) MS phenotype (RR vs mixed sample) and mean EDSS. Nonetheless, for clarity purposes, we also reported other data (i.e., data reported as number and % of educational qualification, or as number and % of participants <50 years; or as number and % of people with education higher than diploma, or as median and interquartile range) that could not be added in the meta-analysis software.

A random-effect model was used for this meta-analytic study; each effect size (ES) of each primary study was calculated in Hedges' g; all ESs were pooled together as mean weighted ES of each outcome. Positive ESs were indicative of (a) higher levels of psychological distress in the pwMS group compared to HC during the lockdown, or (b) an increase of psychological distress during the lockdown compared to pre-pandemic psychological status, Cochran's Q, and I 2 statistics served to analyze inter-study heterogeneity. Values of I 2 above 25%, 50%, and 75% were interpreted as low, moderate and high inter-study heterogeneity, respectively. Sensitivity analysis was performed on outcomes showing high levels of heterogeneity. A p value <0.05 was considered for significance in both random-effects model and heterogeneity statistics. All statistical analyses were performed by employing ProMeta3 software. (Bonavita et al., 2020; Costabile et al., 2020; Garjani et al., 2021; Motolese et al., 2020; Shaygannejad et al., 2020; Stojanov et al., 2020; Talaat et al., 2020) , whereas seven studies (overall N = 2692) reported a comparison between the psychological status of pwMS before and during the 2020 lockdown (Andreu-Caravaca et al., 2020; Capuano et al., 2020; Chiaravalloti et al., 2020; Demir et al., 2020; Garjani et al., 2021; Sbragia et al., 2021; Stojanov et al., 2020) . Two studies (Garjani et al., 2021; Stojanov et al., 2020) reported data on both the comparisons between HC and pwMS during the Covid-19 pandemic and the scores of pwMS obtained before vs during the pandemic. All primary studies were performed in Government restrictions in the countries of primary studies at the time of data collection were heterogeneous, but always present, ranging from a score of 42.59 for Shaygannejad and colleagues' study (2020) in Iran to a score of 100 of Stojanov and colleagues' study (2020) in Serbia (see table   2 ). It was not possible to perform a meta-analysis on the coping strategies outcome due to lack of primary studies; for the same reason, the meta-analysis on the differences between pwMS and HC on mental and physical QoL, and the meta-analysis on levels of stress in pwMS before and during the 2020 Covid-19 lockdown could not be performed. Mental and physical QoL: Mental and physical QoL were entered in the meta-analysis as separate outcomes. As for mental QoL (table 3, figure 3c), the pooled ES was small and non-significant (N=460; k=5; g= -.14, 95% CI [-.28, .01]; p=.060). The inter-study heterogeneity was not significant (Q=8.31, df =4, p=.081, I 2 =51.86), and the publication bias was not significant (t=-.01, p=.992). As regards physical QoL (table 2, figure 3d) , the results revealed a non-significant pooled ES (N=460; k=5; g= 0; 95% CI [-.10, .10]; p=.986), with non-significant interstudy heterogeneity (Q=4.56, df =4, p=.335, I 2 =12.31). The publication bias was not significant (t=0.14, p=.90). 

This meta-analytic study aimed at evaluating possible differences between pwMS and HC in the psychological consequences during the Covid-19 pandemic, and to explore whether the Covid-19 pandemic and restrictions increased the level of psychological distress within the pwMS population.

Studies carried on before the pandemic revealed that pwMS are at major risk of developing psychological disturbances than their healthy peers; as regards depressive disorders, Patten and colleagues (2003) used data of a large-scale Canadian survey on 115.071 individuals and found that, in adults ranging from 18 to 45 years, the major depression prevalence was 25.7% in pwMS, and 8.9% in healthy peers, with the odds of having depression 2.3 times greater in pwMS with respect to HC. A more recent meta-analysis (Boeschoten et al., 2016) also found a higher pooled mean prevalence of a current depressive disorder in pwMS (17%) with respect with the annual prevalence rates of general population (2-10%). As for anxiety disorders, several studies found that pwMS show higher levels of anxiety with respect to their healthy peers, as revealed by Santangelo and colleagues (2016) , that found that pwMS scored significantly higher on both state-anxiety and trait-anxiety subscales of the State-Trait Anxiety Inventory than HC. Another study that examined populationbased administrative Canadian data revealed that, compared to controls, pwMS patients had an elevated annual prevalence ratio of anxiety disorders of 1.46 (Marrie et al., 2017) . Moreover, levels of stress in pwMS were, on average, slightly higher than those of a healthy population (Wu & Amtmann, 2013) . Studies on sleep disturbances revealed that over 50% of pwMS have significant sleep problems (Stanton et al., 2006) , and that these difficulties were significantly more frequent than the general population (Bamer et al., 2008) .

In analogy with the abovementioned studies, the medium pooled ESs of our meta-analysis revealed that pwMS reported higher levels of anxiety, depression, and stress than HC during the Covid-19 pandemic. However, when considering the high inter-study heterogeneity and after performing a sensitivity analysis, the positive ESs were mainly ascribed to one study for anxiety and depression outcomes (Stojanov et al., 2020) , and to another study (Shaygannejad et al., 2020) for the stress outcome. Accordingly, when these studies were removed from the analyses, the ES became not significant (for the anxiety and stress outcomes) or small (for the depression outcome). This may be due to methodological differences with respect with other studies, or, as in the case of Stojanov and colleagues's study (2020) , to the different severity of government restrictions at the time of the data collection. In fact, government restrictions in Serbia were the most restrictive according to the Government Response Stringency Index based on the database provided by Hale and colleagues (2021) . Such restrictions may have caused more severe psychological disturbances in fragile people like pwMS compared to HC, with a significantly higher ES with respect with other studies on the same outcomes.

The results of our meta-analysis after sensitivity analysis, by revealing none-to-small differences on depression, anxiety and stress outcomes between pwMS and HC during the pandemic, let us argue that, since the Covid-19 pandemic had a strong impact on mental health and well-being in the general population (O'Connor et al., 2020) , the expected differences in the psychological variables between pwMS and HC might have significantly attenuated. Further research is needed to corroborate these results.

When analyzing possible differences between pwMS and HC on sleep disturbances, a non-significant pooled ES between pwMS and HC was found, a finding not consistent with pre-pandemic literature (Stanton et al., 2006; Bamer et al., 2008) . As regards sleep quality in general population during the Covid-19 pandemic, the results are contrasting: some studies reported a proportion of insomnia similar to the population prevalence in the pre-pandemic period (Gupta et al., 2020) whereas other studies highlighted a worsening of sleep disturbances during the pandemic (Gualano et al., 2020) . It has to be noted, however, that no certain conclusion can be drawn from our results, since only two primary studies were available and added in our meta-analytic study As for the second objective of our meta-analysis, aiming at exploring possible differences in the psychological distress of pwMS before and during the Covid-19 pandemic, we observed, indeed, a substantial stability of levels of anxiety, depression and mental and physical QoL in pwMS. The only significant and moderate ES was ascribed to the sleep disturbances outcome, with a reduction of sleep quality during the lockdown. However, this result must be taken with caution, because: a) the resulting ES derived from a pooled ES of only two studies, with a total sample size of 67 participants, and b) one study (Andreu-Caravaca et al., 2020) compared sleep quality before and few days after the end of home confinement, and not during the pandemic.

The stability of levels of psychological distress during the pandemic might seem surprising at first glance, but it may be due to the fact that most pwMS are already accustomed to high levels of anxiety, depression and low levels of QoL, and this may constitute a sort of "ceiling effect". In fact, pwMS already had scores in the upper ranges, so it would have been harder to significantly increase their scores with respect to HC, which usually have/show lower levels of anxiety, depression, stress, and a higher QoL. Moreover, since the disease course of MS is unpredictable, pwMS may be more used to feelings of uncertainty with respect to their healthy peers, and therefore they may have already begun/been trained (the process of acquiring specific strategies) to cope with events characterized by extreme uncertainty (like a pandemic), unlike the HC group. Finally, most MS Centers provide psychological support to their patients and many of them continued to provide this service during the pandemic, so that many pwMS received psychological support and/or underwent specific programs to increase their resilience and coping abilities. This latter hypothesis, however, deserves to be further investigated, since this information was missing from primary studies.

This meta-analytic study is not exempt from limitations. Firstly, we could not assess possible causes of high inter-study heterogeneity due to the low number of primary studies. Indeed, since less than 10 studies were available for each outcome, it was not possible to perform a moderator analysis with a meta-regression approach (Borenstein et al., 2009) . In our opinion, high heterogeneity could be ascribed to differences in the methodology of the study, different tools employed to evaluate the psychological status of pwMS and HC, and/or to the degree of severity of government restriction at the time of data collection of primary studies. Moreover, primary studies were conducted during the first wave of pandemic, so it was not possible to assess long-term consequences of the pandemic on the explored psychological outcomes. Future studies with a longer follow-up/observation period will have to address this issue/question in order to evaluate the long-term effects of Covid-19 pandemic on psychological distress of pwMS as compared to HC. Finally, for some outcomes of the metaanalysis (i.e., sleep disturbances) only two studies were available, so the findings could not be generalized.

In conclusion, our results revealed that, although pwMS seemed to show slightly higher levels of anxiety, depression, and stress than their healthy peers during the Covid-19 pandemic, we were not able to detect a significant increase of psychological distress in pwMS during the Covid-19 pandemic, compared to the pre-pandemic period/phase. Our result of a reduction of sleep quality in pwMS during the Covid-19 pandemic was based on a limited sample size and only on two primary studies, so future investigations are necessary. Funding. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 

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a = Data reported as number and/or % of educational qualification b = Data reported as number and % of participants <50 years c = Data reported as number and % of people with education higher than diploma d = Data reported as median and interquartile range or minimum-maximum