Università della Campania «L. Vanvitelli»

Emerging dilemmas

• how Covid-19 impacted MS care?
• are patients with MS at increased risk of severe Covid-19?
• does Covid −19 worsen MS?
• do DMTs affect Covid-19 clinical course and/or should be stopped?
• do MS treatments affect the vaccination efficacy?
• may Covid-19 vaccination worsen MS?
• does the pandemic affect the quality of life and mental health of patients with MS? if so,
• there would be any effect in terms of stress-induced increase of disease activity?

How Covid-19 impacted MS care? �

In March 2020, ECTRIMS developed an online international survey delivered to its Council members and MS specialists worldwide to collect information on the impact of Covid-19 on MS management.

98%: practices suffered restrictions

88%: MS patients’ access to care changed.

MRI procedures were drastically reduced (only urgent/mandatory exams were guaranteed)

Laboratory tests: postponed in 37% of cases, performed regularly in 30%, limited to urgent evaluations in 28%, and suspended in 2%.

Management of relapses: 30% of respondents reported a dose reduction and/or shortening of steroid courses; 36% reported to treat only severe relapses, and 28% reduced patient clinic visits by delivering treatment at home.

Use of DMTs changed for 70% of respondents: in treatment-naïve patients, 62% of respondents suggested to start DMT based on clinical judgment, 23% would start DMT refraining from lymphoid-depleting agents; only 8% preferred not to start DMT during the pandemic.

Therapy switch, 47% switched as in routine practice, while 15% avoided DMT switches at all, 19% excluded lympho-depleting agents, and 15% preferred immunomodulating agents versus immunosuppressive ones.

Covid-19 has significantly impacted women for several reasons. Women, are committed with multiple essential roles such as family, household, work, and care taking responsibilities.

Day cares and schools have closed forcing children to stay at home, and women to take on more responsibilities within the household than men.

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As fragile patients, in many cases women with MS have switched to smart-working from home, thus leading to additional stress as managing both home duties and work can be particularly challenging.

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In this context, given the disparity in wages between women and men, the woman may just choose to focus less on work responsibilities or even decide to abandon work. In this regard it should be noted that over 51% of Americans have reported a loss of employment income since the pandemic started.

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Are patients with MS at increased risk of severe Covid-19?�

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Severe Covid-19 is more likely to occur in male individuals with MS, with advanced disability and comorbidities such as obesity, diabetes, and hypertension

The crude risk of developing Covid-19:

anti-CD20 (ocrelizumab, rituximab), 3.45%;

anti-VLA-4 (natalizumab), 1.35%;

S1P modulators (fingolimod, siponimod), 1.07%;

fumarates, 1.01%; dihydro-orotate dehydrogenase inhibitors (teriflunomide), 0.90%;

IFN-ß, 0.61%; and GA, 0.51%.

Compared to the aggregate of all other DMT-treated patients with MS (0.82% [221/26,910]), the risk of developing Covid-19 was higher in anti-CD20-treated patients (3.45% [123/3568]; p < 0.0001) and lower in patients with MS who were prescribed with IFN-ß (0.61% [40/6509] vs 1.27% [304/23,969]; p < 0.0001) and GA (0.51% [35/6840] vs 1.31% [309/23,638]; p < 0.0001) relative to patients prescribed with all other DMTs for MS. The risk of Covid-19-related hospitalization by DMT use was similar to the risk of Covid-19 incidence by DMT.

Some DMTs might even be protective against severe Covid-19 inhibiting the hyper- inflammatory phase by preventing the release of pro- inflammatory cytokines or B cell activity.

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Fingolimod and siponimod, which reduce the recruitment of macrophages to pulmonary tissue

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IFN-β antiviral effects

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Teriflunomide have been supposed to be protective against SARS-CoV-2 replication.

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Natalizumab, by acting via ACE2 receptor, has been suggested to have beneficial effects in Covid-19 patients

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In general, we can conclude that immunomodulatory agents such as IFNβ, GA, teriflunomide, and dimethyl fumarate are less likely to adversely affect the course of Covid-19, unless significant lymphopenia is present, while patients on depleting agents must be monitored for their lymphopenia-related increased risk of infection and impaired viral clearance and possible worse Covid-19 course.

Treatment start in newly diagnosed patients, national and international MS neurology societies recommend

DMTs not associated with significant lymphopenias, such as IFN-ß, GA in mild disease, and natalizumab in highly active disease.

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The MSIF and the European Multiple Sclerosis Platform recommend careful consideration before starting teriflunomide, dimethyl fumarate, fingolimod, and siponimod, during the pandemic

Treatment continuation: to delay dosing for cell-depleting therapies based on individual risk of relapse and infection.

Accordingly, at the start of the Covid-19 pandemic, the Italian recommendation for the use of immunodepleting DMTs suggested that Ocrelizumab should be used sparingly guided by CD19 kinetic

Treatment continuation, in patients tested positive for SARS-CoV-2 infection all the experts recommend maintaining all DMTs;

in patients on fumarates and fingolimod to stop treatment in case of moderate or severe lymphopenia and a monthly check for lymphocytes count.

All experts recommend delaying the administration of depletive agents in patients with active Covid-19

Expert Review of Neurotherapeutics , 2021

216 selected pwMS, 154 completed the survey. Matching the survey responses and incidence of relapses in 2020, there was a significant association between relapses and severe stress (p=0.012) and depression (p=0.005), but not between relapses and anxiety (p=0.092) or PTSD (p=0.052)

Besides impacting on the patient–doctor relationship

and MS care, the Covid-19 emergency

has caused mental health problems

1286 answers from 612 pwMS and 674 control people

A higher proportion of pwMS were depressed (43.1% vs. 23.1%; p < 0.001),

Had a high level of perceived stress (58% vs. 39.8%; p < 0.001) and

felt significantly less social support (median 33 vs. 35; Q1–Q3 28–36 vs. 32–37; p < 0.001) compared to the control

group.

ASSOCIATION BETWEEN RELAPSES, STRESS, AND DEPRESSION IN PEOPLE WITH MULTIPLE SCLEROSIS DURING THE COVID-19 PANDEMIC

Sparaco et al., 2021 under review

Distribution of relapses in 2019 and 2020

according to year’s quarters

SSS DSM-IV and DASS-21 scores in relation to relapses. Box-plot shows means and standard deviations for each mood disorder

Favoring exercise would enhance active attitude and its positive impact on mental well-being

Relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown

Motor disability and cognitive dysfunction contributed to disability

Positive attitude and exercise contributed to active attitude

Avoidance, social support and watching television contributed to passive attitude

Disability contributed to passive attitude

Passive and active attitude significantly influenced depression

 Aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. 

Changes in lifestyle (including exercise), physical disability, as measured with the Patient-Determined Disease Steps scale, and anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system

Negative correlation between disability and physical exercise as well as between physical exercise and mental health outcomes, and a positive correlation between disability and mental health outcomes.

The effect of disability on depression was significant for all levels of physical exercise (low: b = 1.20, 95% C.I. 0.83,1.57, p < 0.001; moderate: b = 0.93, 95% C.I. 0.64, 1.23, p < 0.001; and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003) but was stronger for those who exercised less.

As the effect of disability on depressive symptoms decreases as much as physical exercise increases, this result demonstrates that practicing physical exercise may protect pwMS from the effects of disability on negative mental health outcomes. 

In patients with progressive forms of MS little change was noted in symptoms of depression or anxiety or overall quality of life. Possibly, patients with progressive MS because of their increased risk of infection and subjective feelings of vulnerability, might have adopted increased measures for self-protection, thus mitigating their anxiety and depression. Additionally, individuals with progressive MS already experience a substantial physical disability that often leads to some degree of isolation in daily life

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Increased level of anxiety found in MS patients surveyed during the first phase of the pandemic, the main contributing factor has been identified in the concern about their health as they may feel particularly vulnerable to infection either for MS per se or for the chronic immunotherapy with immunosuppressive or immunomodulatory drugs

Telemedicine has greatly increased to satisfy the need for adequate medical assistance without increasing the infection risk related to unnecessary in hospital visits.

Multiple Sclerosis���EDSS

The possibility of assessing the EDSS remotely has been explored, but would require to use of an “in-home neuro kit” with vision card, tuning fork, pin, cotton swab, and alcohol swab to have a caregiver helping with the examination and to combine records from wearable devices (e.g.accelerometer-based step counts).

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- Robb JF, Hyland MH, Goodman AD. Comparison of telemedicine versus in-person visits for persons with multiple sclerosis: A randomized crossover study of feasibility, cost, and satisfaction. Mult Scler Relat Disord 2019; 36:101258

- Bove R, Bevan C, Crabtree E, et al. Toward a low-cost, in-home, telemedicine-enabled assessment of disability in multiple sclerosis. Mult Scler J 2019; 25: 1526–1534

Relapses

• some elements are relatively easy to evaluate on remote history taking (e.g., timeline, concomitant fever or symptoms of infection), but neurological abnormalities would need to be detected in relation to reported symptoms.
• relapses also affect quality of life and activities of daily living, and, thus, the inclusion of MS-specific PROMs measuring physical and psychological health could support the assessment of relapse severity (MS Impact Scale (MSIS-29) has been used in clinical trials to evaluate recovery from relapses, and has been tested for remote administration

Patient Reported Outcomes (PRO)

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• The Patient Determined Disease Steps (PDDS) has been specifically developed as a PRO of MS disability validated in multiple languages and for online administration

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• The PDDS is strongly correlated to EDSS, and especially to visual, pyramidal, cerebellar, sensory, bowel/bladder, and ambulatory functional systems, leaving brainstem and cerebral functions relatively unexplored.

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Lavorgna L, Miele G, Petruzzo M, Lanzillo R, Bonavita S. Online validation of the Italian version of the patient determined disease steps scale (PDDS) in people with multiple sclerosis. Mult Scler Relat Disord. 2018 Apr;21:108-109.

Cognitive function

• The oral version of the Symbol Digit Modalities Test has already been validated for remote use (e.g., online or during functional-MRI acquisitions), is ideally suitable for all languages and, thus, could be easily used on teleneurology.

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Wojcik C, Beier M, Costello K, et al. Computerized neuropsychological assessment devices in

multiple sclerosis: A systematic review. Mult Scler 2019; 25: 1848–1869

A battery for MS assessment in tele-neurology

• fill in the PDDS and the MSIS-29 before the teleconsultation

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• during the teleconsultation, neurologists can focus on history taking and examination of brainstem function and other neurological systems, as required by patients’symptoms.
• Finally, if necessary, the examiner could administer the oral version of the SDMT by showing the test form on patients’ screen. Alternatively, patients could be provided with an electronic version of the SDMT

Assessing disability and relapses in multiple sclerosis on tele-neurology. Moccia M, Lanzillo R, Brescia Morra V, Bonavita S, Tedeschi G, Leocani L, Lavorgna L; Digital Technologies Web and Social Media Study Group of the Italian Society of Neurology. Neurol Sci. 2020 May 21:1-3.

Bonavita S, Tedeschi G, Atreja A, Lavorgna L. Digital triage for people with multiple sclerosis in the age of COVID-19 pandemic. Neurol Sci. 2020 Apr 17

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Table 1

Triage tool that can be sent to pwMS. The digital triage can be easily setup using Google Forms

• Standard of care for patients with MS has been deeply disrupted by Covid-19 related restrictions imposing limited access to in-person visits, MRI and laboratory tests, changes in the management of relapses, the use of DMTs, the access to rehabilitation facilities, and psychological support programs.
• Severe Covid-19 is more likely to occur in male individuals with MS, with advanced disability and comorbidities such as obesity, diabetes, and hypertension.
• To date, available data from a single study suggest that Covid-19 infection, regardless of its severity, is not associated with an increased risk of relapse shortly following infection; long-term studies are needed to investigate the late effect of Covid-19 on MS activity and progression.
• The risk of developing Covid-19 is higher in anti-CD20-treated and lower in patients on IFN-ß and GA relative to patients prescribed with all other DMTs for MS.
• People with MS are encouraged to get the SARS-CoV-2 vaccine as soon as possible with a correct timing concerning the ongoing therapy; the risks of Covid-19 infection far outweigh any potential vaccine risk
• Covid-19 vaccines are not likely to trigger an MS relapse or to impact long-term disease progression.
• The quality of life and mental health of people with MS have been negatively impacted by the pandemic. Alternative forms of support with digital tools should be encouraged

Conclusions