Q: What are the neurologic manifestations of COVID-19?

A: A wide spectrum of neurologic symptoms have been reported in COVID-19 patients ranging from common symptoms such as dizziness, headache, cranial nerve palsies, anosmia, and ageusia, to less common but more severe symptoms such as stroke, encephalitis, acute demyelination, dysautonomia, seizures, and acute inflammatory demyelinating polyneuropathy. Neurologic symptoms have been reported in 3.6%-36.4% of cases. Additionally, many people who had mild COVID-19 infections not requiring hospitalizations have had a prolonged symptom duration, especially fatigue, and have not returned to their usual state of health when interviewed weeks after their diagnosis. The long-term consequences of this infection are not yet fully understood, and we will not know the total burden of disease for many years.

Q: What is the pathophysiology of the neurologic involvement of COVID-19?

A: SARS-CoV-2, the virus that causes COVID-19, is a singled-stranded RNA virus that utilizes the angiotensin-converting enzyme 2 (ACE2) receptors for entry into the host cells. Once in the host cell, the viral RNA is translated into viral proteins which assemble into new viruses that are released from the infected cell. ACE2 receptors are expressed in the oropharyngeal epithelium, lung, heart, kidney, testicles and brain (on neurons and glial cells).

It is unclear exactly how SARS-CoV-2 affects the nervous system, though there are multiple theories including direct viral invasion, immune-mediated injury, hypoxic injury, endothelial dysfunction, and systemic hypercoagulability.

Q: Do patients with multiple sclerosis have a higher risk of getting COVID-19 and/or having a more severe disease course?

A: There does not appear to be an increased susceptibility for getting COVID-19 or having a more severe course solely due to having MS. Some characteristics associated with increased mortality risk include significant disability (requiring assistive devices or being non-ambulatory) and a progressive MS course. Other risk factors for mortality have been largely consistent with the general population, such as older age and medical comorbidities like diabetes, obesity, and hypertension. Additionally, there may be an increased risk associated with certain medications, including recent high dose steroids and cell-depleting therapies (rituximab, ocrelizumab, ofatumumab, alemtuzumab, hematopoietic stem cell transplantation). Please see below for further details regarding disease modifying therapies (DMTs).

A study by Moss et al. looked at the impact of the COVID-19 pandemic on MS care in three centers, including the Cleveland Clinic, Johns Hopkins, and CEMCAT in Barcelona. This survey-based study of 3028 MS patients found that there were 77 (2.5%) cases of suspected or confirmed COVID-19. They found that these patients were more likely to know or live with someone with COVID-19. There was also increased risk in African Americans and those with lower socioeconomic status (SES).

Q: Are there special precautions MS patients should take?

A: As for the general population, it is important for people with MS to follow the CDC infection protection guidelines, including social distancing, mask wearing, frequent handwashing, avoiding crowded areas, and regularly cleaning surfaces. A study by Moss et al. looking at MS patients treated at several comprehensive MS centers found that overall compliance with social distancing guidelines was strong. Predictors of poor compliance included younger age, need to work on site, lower education levels, and lower SES. Patients with these characteristics should be educated and supported regarding the importance of social distancing guidelines, including letters supporting work restrictions as appropriate.

Q: What are other considerations that affect MS patients?

A: There are other health behaviors that must be considered in MS patients including medical visits, therapy visits, imaging, infusion center visits, and home health services. It is important for patients to not forgo their healthcare-related visits during the pandemic. While we believe that it is safe to come to the clinic given the protocols and restrictions in place, it is prudent to avoid unnecessary exposure. Telehealth visits, on an appropriate case-by-case basis, should be utilized to limit in-person contact. Many support services and therapy services are also offering telehealth options. Additionally, steps can be taken to keep patients out of infusion centers unnecessarily by using oral instead of intravenous steroids in appropriate patients. Patients who rely on home health services that are unavailable during the pandemic should be checked on and supported with social work services if necessary to maintain their safety. Additionally, supporting certain work restrictions may be appropriate for some patients, depending on their risk-level.

In terms of care disruption, the study by Moss et al. found that 4.4% of respondents had a change in their treatment plans. Of those, delay in infusion (71.9%) was most common, though only 51.2% were advised to delay infusion therapy by a healthcare provider. 15.5% of respondents reported a disruption to rehabilitative therapy, and 2.2% with disruption in home health services. Those with disruptions were more likely to be older patients with progressive disease, use a walking aid, and have a comorbid condition.

In addition to the challenges with continuing ongoing services, many patients may require new services during this time, especially regarding mental health. Mental health needs should be addressed at visits regularly, and appropriate support should be offered.

Q: Do multiple sclerosis patients on disease modifying therapy have a higher risk of getting COVID-19 and/or having a more severe disease course?

A: In general, there does not appear to be increased susceptibility to COVID-19 infection or more severe course in MS patients on disease modifying therapy, with the possible exception of cell depleting therapies.

Q: Should patients with multiple sclerosis have their medications stopped or adjusted because of COVID-19?

A: Adequate and effective treatment of MS should remain the primary consideration when addressing DMT during the pandemic. We are not changing most patients’ established DMTs due to COVID-19 because of the risk of breakthrough disease activity. Scheduled infusions should proceed as usual, with assurance that the infusion center is taking all appropriate safety precautions. However, there may be certain patients at especially high risk for COVID-related morbidity (i.e. someone with significant disability living in a congregate living facility) where the risk vs. benefit calculation of continuing DMT warrants further discussion.

On a case-by-case basis, we are considering postponing use of long-acting cell-depleting therapies given the risk of these medications and the need for infusion center visits and possible effects on vaccine efficacy. For example, an older patient with progressive disease and medical comorbidities may be reasonably delayed in starting such treatments until they are fully immunized. Please see below for further discussion regarding vaccination.

Q: Should patients with multiple sclerosis have their medications stopped or adjusted if they contract COVID-19?

A: With all DMT, if patients have a serious infection leading to hospitalization, it is prudent to hold DMT until the infection resolves. Some of the DMTs can be continued during mild COVID-19 infection, while others should be stopped until clinical resolution of infection or clearance from an infectious diseases specialist. This decision should be made on an individual basis considering the severity of infection, laboratory abnormalities, and the risk category of the patient. Other lower-risk medications such as interferon-beta, glatiramer acetate, teriflunomide, and dimethyl fumarate (unless there is significant lymphopenia) can likely be continued. Temporarily pausing therapies such as natalizumab and S1P modulators during moderate-severe COVID-19 infection should be done with caution and for the shortest amount of time possible due to the risk of rebound disease activity. Pausing the longer-acting cell depleting therapies will depend on the timing of infection in relation to the timing of medication dosing. Infusion therapies, in general, should be held until the infection has resolved. Other considerations include the need for visitation to infusion centers and that patients will need to be cleared from their appropriate quarantines to receive treatments.

Patients undergoing autologous hematopoietic stem transplantation need to have a confirmed negative SARS-CoV-2 PCR prior to starting mobilization and harvesting and another test prior to starting the conditioning regimen. Transplant should be delayed if there is a positive infection.

Q: Should patients with multiple sclerosis receive the COVID-19 vaccine?

A: There are currently several types of vaccines available and under development including those utilizing mRNA, protein components, and killed virus, which are all expected to be safe for use in MS patients. Currently, there are no live or live-attenuated vaccines in development, which are contraindicated in patients on DMT. The Mellen Center is following the National MS Society’s guidelines regarding the COVID-19 vaccine in patients with MS, which states that “most people with relapsing and progressive forms of MS should be vaccinated. The risks of COVID-19 disease outweigh any potential risk from the vaccine.” It also states that patients who are in the higher risk group for more serious COVID-19 infection, including those with progressive MS

with higher levels of disability, older patients, and those with other medical comorbidities should get the vaccine as soon as it becomes available to them. There is no evidence of increased risk of vaccination in people with MS for the current vaccines that have FDA emergency use authorization. Patients should be counseled that their MS symptoms may increase transiently if they develop a fever post-vaccine, but that this can be managed by using over-the-counter anti-pyretics.

The Mellen Center has implemented shared medical visits for MS patients specifically to address questions and concerns regarding vaccination.

Q: Considerations of COVID-19 vaccines in patients on disease modifying therapy?

The vaccines are expected to be safe to receive in patients taking DMTs, unless a live or live-attenuated vaccine is developed, which would be contraindicated. Certain DMTs may decrease the effectiveness of the vaccines including B-cell depleting therapies and, to a lesser extent, S1P modulators, as has been in shown with other vaccinations. While some of these agents attenuate the immune response, the relative importance of humoral and cell-mediated immunity is unclear. Patients on these therapies should still be advised to receive the vaccine as soon as it is available to them, due to the logistical challenges of getting the vaccine.

Nevertheless, for patients maintained on B-cell therapies, vaccines should be ideally dosed towards the end of a treatment cycle, or at a minimum 3 months after the previous infusion. For those receiving bi-annual infusions, an ideal timing of vaccination would be to complete the vaccine course 2-3 weeks prior to the next infusion. However, infusions should not be delayed for greater than 4 weeks to accommodate the timing of vaccination. In the case of monthly ofatumumab injections, dosing can be delayed 2 weeks to allow for a vaccination course to be completed 2 weeks prior to the next dose.

Starting new B-cell therapies may be delayed on a case-by-case basis until after full vaccination, based on the estimated timing of vaccine, other medical comorbidities, as well as baseline MS activity. For example, older patients with progressive disease should not be switched to B-cell therapy until at least 2 weeks after the full vaccine course.

These recommendations are subject to change as more evidence and more vaccines become available.

Q: Are there neurologic adverse effects of the COVID-19 vaccines?

A: In the BioNTech (Pfizer) mRNA vaccine trial, 52% and 39% of younger and older participants, respectively, reported a headache in the vaccine group after the second dose vs. 24% and 14%, respectively, in the placebo group. In the trials of the mRNA vaccines, there have been a few cases of transverse myelitis and facial palsy. In the adenovirus trial, there was one report of worsening MS requiring hospitalization. It is not clear whether these events occurred at a rate greater than unexpected for the size of the trials.

It is important to inform patients about the potential for a pseudo-relapse or other transient worsening of their MS symptoms related to vaccination due to the constitutional symptoms from the immune response. Patients should be counseled to take over-the-counter anti-pyretics for fever as needed, to treat these symptoms.

Approach last updated: February, 11 2021

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