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Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory central nervous system demyelinating disorder resulting in neurologic decline. Patients predominantly have a relapsing and remitting disease course requiring multiple hospitalizations and, occasionally, rehospitalizations. Hospitalization readmission rates are important metrics that have direct financial implications for hospitals and serve as an indicator of disease burden on patients and society. We sought to analyze hospital readmissions of patients with MS and identify the subsequent predictive characteristics/comorbidities for readmission.

All hospital admissions due to MS were queried using the 2017 Nationwide Readmissions Database. All patients with nonelective rehospitalization within 30 days of discharge were examined.

The 30-day readmission rate for MS is 10.6% (range, 10.4%–10.8%). Female sex has a protective role in readmission rates, and age has no effect. Comorbidities, including heart failure, acute kidney injury, chronic obstructive pulmonary disease, chronic kidney disease, respiratory failure, substance abuse, diabetes, hypertension, peripheral artery disease, liver failure, anemia, coagulation disorders, cancer, depression, and infections, are predictive of readmissions, whereas sleep apnea is protective. No effect is seen with neurologic blindness, plasma exchange, or intravenous immunoglobulin treatment.

Several medical comorbidities are predictive of hospital readmission of patients with MS. Most rehospitalizations are due to infectious and neurologic etiologies; thus, targeted interventions may lead to lower readmission rates.

From the Department of Neurology (AP, WK) and Department of Internal Medicine (AA), University of South Alabama College of Medicine, Mobile, AL, USA. 

 Akhil Padarti, MD, Department of Neurology, University of South Alabama College of Medicine, 2451 USA Medical Center Dr, Mobile, AL 36617, USA; 

 Dr Kilgo is on the speakers’ bureaus of Biogen and Genentech; serves as a consultant for Genentech, Biogen, and Alexion Pharmaceuticals; and is a principal investigator for industry-sponsored clinical trials in association with Genentech; EMD Serono, Inc; and Bristol Meyers Squibb. The other authors have disclosed no relevant financial relationships.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system.

 In most patients with MS, the disease follows a relapsing and remitting course resulting in neurologic disability. The prevalence of MS has increased in both developed and developing countries in part due to improvements in diagnosis and the development of novel disease-modifying agents.

 Multiple sclerosis is the leading cause of nontraumatic neurologic disability in younger adults.

 Medical costs of MS rank second only to those of congestive heart failure,

 and hospitalizations remain a significant portion of these costs: patients with MS are 3.5 times more likely to be hospitalized relative to the general population.

 With the growing prevalence of MS, it is imperative to decrease unnecessary readmissions to alleviate the health care system burden.

Hospital readmissions are also associated with negative patient outcomes, including hospital-acquired infections, deconditioning, and negative psychological effects.

 Therefore, readmission rates are an important quality measure, and understanding these rates will lead to identification of preventable adverse outcomes. The 30-day readmission rate is widely used as the indicator for hospital performance associated with financial implications.

 The identification of patients at high risk for readmission is the initial step to decrease readmissions and improve overall disease control.

Many studies have been published on hospital readmission rates,

 but there is minimal readmission data regarding MS. One current study is analyzing the trends in a European cohort.

 The only US study, published by Patel et al,

 analyzed MS readmissions stratified by age and sex. To date, the present study is the largest to analyze MS readmission rates in the general US population and the first study of MS readmission rates to use 

International Classification of Diseases, Tenth Revision (ICD-10)

 codes. Compared with previous versions, the 

 provides more specific diagnosis and procedural codes and minimizes misclassification of patients and procedures.

 The purpose of this study was to identify patients with MS at high risk for readmission within 30 days of their initial discharge.

This study examined MS hospital readmissions using 2017 discharge data from the Nationwide Readmissions Database (NRD) of the Healthcare Cost and Utilization Project (HCUP) developed by the Agency for Healthcare Research and Quality (AHRQ). The data provided a national representative sample of all-age, all-payer discharges from US nonfederal hospitals across 28 states.

 This was 18 million discharges (weighted estimate ~36 million discharges). All hospitalizations and rehospitalizations were determined using a deidentified unique patient linkage number. The data used represented 58.2% of all 2017 US hospitalizations.

The MS definition was determined by codes from Clinical Classifications Software Refined (CCSR) for the 

; all supplemental material is available in a PDF at the end of the online article). The primary outcome was the first unplanned readmission, defined as a nonelective rehospitalization within 30 days of discharge from the patient’s index hospitalization. If a patient had multiple such readmissions, only the first encounter was used for analysis. Exclusion criteria included admission in December, death during the initial hospitalization, and missing discharge data. The study was approved for exempt status by the University of South Alabama’s institutional review board. Similar methods have been used in previous studies.

 codes were used to define pertinent clinical variables. Data on teaching status, metropolitan/non-metropolitan location, control/ownership, and bed size were collected for each hospital (

). A cost analysis covered index admission length of stay, index admission cost, discharge destination, primary expected payer, and quartile of median household income (Table S2). We multiplied the hospital charges with the AHRQ’s all-payer cost-to-charge ratios to determine total cost. Severity of MS at the index hospitalization was measured by risk of mortality and loss of function subclasses (Table S2). Baseline patient comorbidities and procedures during the index hospitalization were determined (Table S2). The first CCSR diagnosis code determined the cause of readmission (

). All CCSR codes used in this study are presented (Table S1).

Statistical analysis was performed using IBM SPSS Statistics for Windows, version 1.0.0.118 (IBM Corp). To reduce bias, the data were weighted as recommended by the NRD. Two-sided 

 tests with a significance level of .05 were used for statistical analysis. Statistical differences in participants’ baseline characteristics were determined using the Pearson χ

 test for categorical variables and the Mann-Whitney 

 test for continuous variables; the reference group was participants with no readmissions. Multivariable logistic regression analysis was performed to determine the predictors of readmission, with adjustments for age group, sex, hospital status, and comorbidities (

Of 95,537 weighted admissions in the 2017 NRD with MS as the primary diagnosis, 10,102 patients were readmitted within 30 days of discharge. Patients with a primary diagnosis of MS were defined as those admitted for MS flare-ups and those admitted for MS workups and subsequently diagnosed as having MS. The 30-day readmission rate for the general population of patients with MS was 10.6% (range, 10.4%–10.8%) (

). The readmission frequency is highest in the first days after discharge, with decreasing frequency over the course of 30 days. Half of all readmissions occurred within 12 days of discharge from the index hospitalization.

The baseline characteristics for the index hospitalization are shown in Table S2. Most of the patients in the study were women aged 46 to 67 years, consistent with the epidemiology of MS. Readmission was less frequent for women than for men (10.2% vs 11.7%; 

 < .001). Patients with a weekend admission (

 = .002), a longer index hospitalization (

 < .001) were statistically significantly more likely to be readmitted. Patients with private insurance were less likely to be readmitted than were patients with Medicare. Patients in the top or bottom quartile of household income were more likely to be readmitted than those in the middle 2 quartiles. Patients with a higher risk of mortality and a loss of function were more likely to be readmitted in a severity-dependent manner. Interestingly, patients discharged to their homes with no services were less likely to be readmitted than those discharged with home health care or those transferred to a short- or long-term care facility.

Patient Comorbidities and Procedures During Index Hospitalization

Table S2 shows the effects of patient comorbidities and intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) treatments on readmission rates. Higher readmission rates were seen in patients with the comorbidities analyzed except for alcohol abuse, hypertension, and obesity. Statistically significantly lower readmission rates were seen with neurologic blindness. There was no significant difference in readmission rates after PLEX or IVIg treatment.

Readmission diagnoses are shown in Table 1. The 3 most common causes of readmission were infectious complications (24.8%), neurologic complications (14.5%), and respiratory complications (6.9%), which correspond to 46.2% of all readmissions. Septicemia was the most frequent diagnosis for readmission (15.4%). The most frequent neurologic diagnosis of readmission was MS (9.0%). Other infrequent causes of readmission include complication of the genitourinary device (5.7%), urinary tract infection (4.1%), acute respiratory failure (2.2%), acute renal failure (2.1%), heart failure (2.1%), and pneumonia (2.0%).

Multivariable logistic regression analysis was preformed to identify the characteristics of patients at high risk for 30-day readmission (Table 2). Age was not predictive of readmission; all age groups studied had similar readmission rates. Relative to the Medicaid population, patients with private insurance (odds ratio [OR] = 0.679; 

 < .001), self-pay patients (OR = 0.776; 

 = .008), no-charge patients (OR = 0.537; 

 = .022), and other (insurance options, eg, workers’ compensation and other government programs) (OR = 0.651; 

 < .001) were protective against readmission (Table 2). Nonmetropolitan hospitals had decreased odds of readmission relative to nonteaching metropolitan hospitals (OR = 0.811, 

 < .001) (Table 2). There was no significance between metropolitan teaching hospitals and metropolitan non-teaching hospitals (OR = 0.999, 

 = .970). Several comorbidities, including heart failure (

 < .001), chronic obstructive pulmonary disease (

 < .001), are predictive of readmissions, whereas sleep apnea (

 = .241) treatment during the index hospitalization affected the odds of readmission.

This retrospective study analyzed 30-day readmission rates in patients hospitalized with a primary diagnosis of MS. Approximately 1 in 10 of these patients (10.6%) had a readmission within 30 days of discharge. This rate is relatively better than the overall readmission rates in the general population (13.9%) and in patients with nervous system diseases (14.0%).

 This finding is likely multifactorial and may be due to the broadening treatment landscape for MS, including more efficacious disease-modifying therapies. The readmission rate in this study is comparable with those in the previous European

Relapsing-remitting MS predominantly affects women, with a prevalence ratio of approximately 3:1.

 A similar sex ratio was seen in MS index hospitalizations, with women being 73.7% of all hospitalizations. However, this study found that female sex protected against readmission (Table 2). Previous studies have found that MS disease activity is more aggressive in men, specifically with earlier disability accumulation. This may be in part due to delays in seeking care, hormonal differences, or the increased percentage of men with primary progressive MS.

 Neither of the previous studies found a statistically significant sex difference for readmission.

 It is possible that the sex difference was discovered only because of the larger sample size in this study. In the general population, age is a factor in readmission rates, with readmission rates increasing as age increases.

 However, although readmitted patients tended to be older (Table S2), age was not predictive of readmissions after accounting for comorbidities (Table 2). This finding suggests that the comorbidities associated with older age play a larger role than age itself, as supported by the findings in earlier studies.

 Patients with Medicaid and patients with Medicare had similar odds of readmission, and all other types of insurance were protective (

). A similar trend was also identified in a previous study

 and is seen in the general population, as private insurance is obtained through employment and employed people have a higher baseline functional status.

 Only a small proportion (8.6%) of patients in this study were admitted to nonmetropolitan hospitals, perhaps because patients with severe MS relapses go to or are transferred to a metropolitan hospital with an affiliated MS specialist. Therefore, the disease severity is likely higher at metropolitan hospitals vs nonmetropolitan hospitals, accounting for the increased readmissions. This difference was not observed in the earlier study, possibly due to the smaller sample size.

Several studies have shown an increase in MS disease burden and hospitalizations over time,

 thought to be due to the progressive nature of the disease leading to higher disease burden in older patients. However, our data showed that, accounting for comorbidities, age is not a factor in hospital readmissions for patients with MS. Therefore, the increased comorbidities associated with aging are the likely cause of hospital readmissions rather than the progressive nature of MS. This is also shown by the stepwise increase in hospitalizations, the loss of function, and likelihood of dying in the All Patient Refined Diagnosis Related Groups (Table S2). These scales represent disease severity and preexisting conditions. Therefore, the higher the number of comorbidities, the higher the risk of loss of function or the likelihood of dying. Other studies reached the same conclusion.

The comorbidities that increased the odds of readmission are shown in 

. Many of these comorbidities have been previously identified as factors in MS rehospitalization, including heart failure,

 Several comorbidities, including hypertension, diabetes, and peripheral artery disease, lead to vascular damage due to oxidative radicals. The increased oxidative stress in the brain parenchyma has been shown to be a mediator of demyelination.

 However, in another study, hyperlipidemia, also a contributor to vessel damage and plaque buildup, was not shown to be predictive of readmission, although hypertension, diabetes, and obstructive lung disease were shown to worsen functional status in MS.

 The reproducibility of this effect may suggest that the oxidative damage of hyperlipidemia has less of an impact in MS than do diabetes and hypertension. In our study, optic neuritis did not affect readmission rates, likely as it is commonly seen in younger females with milder forms of the disease. In a previous study, optic neuritis was found to be protective of readmission.

 An unexpected finding was smoking’s lack of effect on readmission. Smoking has been shown to be a risk factor for MS and is associated with a poorer prognosis.

 However, the present data showed that smoking did not increase readmission odds. Sleep apnea was the only comorbidity protective against readmission in the present study. Further research is needed to determine whether this is an incidental finding or whether sleep apnea has a protective effect in MS.

Two treatment options for acute MS relapses are PLEX and IVIg, which circulate antibodies to decrease the host immune response. However, these treatments are generally reserved for persistent flare-ups that do not improve with intravenous corticosteroid use.

 Previous studies have suggested better outcomes with PLEX

 Treatment with neither PLEX nor IVIg was seen to affect readmission rates (Table 2). Because IVIg and PLEX treatments are reserved for resistant relapses, these patients may already have a higher likelihood of readmission. These second-line treatments may decrease readmissions such that no measurable effect can be identified on statistical analysis. Furthermore, few patients (approximately 0.5%) received PLEX or IVIg during their index hospitalization. These results are in accordance with the previous study in which no association was seen between PLEX/IVIg treatment and readmission in most of the subgroups analyzed, and in the few subgroups that showed statistical significance, PLEX/IVIg treatment increased readmission rates.

Analysis of readmission etiologies showed that the most common were infections (24.8%), predominantly nonspecific septicemia (15.4%) (Table 1). Patients with MS are at increased risk for infections: diaphragmatic weakness can lead to pneumonia, and neurogenic bladder can lead to urinary tract infections. Immunosuppressive drug use also contributes to the overall risk of infection. The second most common readmission cause was neurologic diagnoses (14.5%). This contrast with the previous analysis, which showed that half of all readmissions were due to neurologic complications.

 This difference may be explained by the improved treatment modalities developed for MS during the past several years. Other etiologies of readmissions are respiratory complications (6.9%), surgical device complications (6.7%), and cardiac complications (5.3%). Future research could use artificial intelligence and machine learning to develop algorithms to predict the patients at high risk for rehospitalization, and this could help physicians improve patient care and health care outcomes.

This study successfully used the 2017 NRD to identify characteristics of patients with MS with an increased likelihood of hospital readmission within 30 days and the specific etiologies of those readmissions. Many other studies have been conducted using the same methods.

 This study’s limitations follow. The NRD stores 

 codes for every encounter. Patients admitted through the emergency department and patients admitted for observation are not included in the database. Another constraint is the elements captured by the database. Race and ethnicity data are not available, limiting insight. Geographic information also is not captured by the database,

 although MS has a strong geographic distribution pattern. Importantly, no information is provided about a patient’s current medications or discharge medications, precluding the ability to distinguish patients who are taking disease-modifying agents that help control the disease. These factors likely play a role in readmission rates.

Misclassification bias is also present in this study. Although 

 coding is designed to improve accuracy and decrease coding errors, inaccuracies are likely still present. These are expected drawbacks when using a large database containing approximately 60% of inpatient admissions in the United States. Finally, because this is a retrospective, observational study, no statement about causation can be made from the data. The strength of the study as the largest readmission analysis of patients with MS to date remains.

During the past several decades, significant progress has been made in the management of MS. The disease burden, both financial and patient quality of life, has decreased due to a better understanding of the disease and increased treatment options. Hospital readmissions are a significant portion of the remaining disease burden of MS. This study identified several characteristics of patients at high risk for readmission. The most common causes of readmission are sepsis, MS, and respiratory failure. Future efforts to equip these patients with additional resources for better outpatient transitions might lead to decreased readmission rates, lessening the disease burden on patients with MS and on society at large.

Readmission Rates in Patients With Multiple Sclerosis: A Nationwide Cohort Study

Patients with multiple sclerosis (MS) were vulnerable to the effects of physical inactivity during the COVID-19 pandemic. As patients returned to in-person visits, providers reported seeing increased weakness, balance issues, falls, worsening pain, and spasticity. Social isolation also contributed to increased stress, depression, and anxiety. This study explored whether attending virtual wellness programs was associated with improvements in standard quality of life questionnaire scores for patients with MS.

The purposive convenience sample consisted of 43 patients in the treatment group and 28 in the control group. Patients in the treatment group attended 2 monthly programs for 6 months and completed a demographic questionnaire, the 36-Item Short Form Health Survey (SF-36), the Modified Fatigue Impact Scale, and the Medical Outcomes Study Pain Effects Scale (PES). Patients requested additional topics, resulting in 5 additional programs. The control group consisted of patients who chose not to attend the programs but agreed to complete the questionnaires.

In comparing questionnaire responses (6 months minus baseline) among the participants in the treatment group, an association was found between higher meeting attendance and improvements in emotional well-being (

 = .011), mindfulness on the SF-36 pain scale (

The results of this study suggest that a virtual wellness program may provide beneficial emotional support, physical exercise, and health promotion activities resulting in improved quality of life in people with MS. In addition, mindfulness and exercise programs may be beneficial in pain management.

From the Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA (DJ, NG, VZ); the Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA (SMW); and Philadelphia, PA, USA (ER). 

 Vanessa Zimmerman, MSN, Department of Neurology, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA; 

: vanessa.zimmerman@pennmedicine.upenn.edu.

 The authors declare no conflicts of interest.

 Ms Weinstein provided statistical support and is funded by the National Science Foundation Graduate Research Fellowship Program. External speakers were paid honoraria supported by a grant from the Board of Women Visitors of the Hospital of the University of Pennsylvania and funding earned through successful completion of annual projects with the Neuroscience Service Line of Penn Medicine.

 Aspects of this study were presented in poster form at the Consortium of Multiple Sclerosis Centers Annual Meeting; October 25-28, 2021; Orlando, Florida.

Multiple sclerosis (MS) is a common, chronic, lifelong, unpredictable, and potentially highly debilitating neurologic condition that occurs more commonly in women than in men. It strikes most often in young adulthood but can even start in childhood and adolescence. There are nearly 1 million people living with MS in the United States.

The COVID-19 pandemic affected every activity of the Penn MS and Related Disorders Center at the Hospital of the University of Pennsylvania. Clinic visits were initially halted and then switched to a virtual format. Many patients were isolated by stay-at-home orders. As some patients began to return to in-patient clinic visits, providers found that deconditioning related to limited activity had resulted in increased weakness, spasticity, and balance issues, as well as increased pain. Patients also reported increased stress, depression, and anxiety.

For many, the pandemic created a wide range of long-term challenges, which are correlated with worsening neurologic symptoms in patients with MS.

 Although patients were encouraged to self-isolate for protection from the virus, for some it posed a threat to their physical and mental well-being

 and resulted in reduced quality of life.

 In 1 online survey, researchers found that 50% of patients with MS either reduced or ceased their physical activity during the pandemic and 32% reported that their fitness level had decreased.

To help patients with MS during the pandemic, Penn Center providers decided to offer virtual wellness programs. People with MS are becoming more interested in the concept of wellness,

 and there is evidence to suggest that in addition to disease-modifying therapies, lifestyle strategies that support wellness can help mitigate disease-related complications and comorbidities.

Limited information on virtual wellness programs was found in the literature. Much of the current research has studied programs by businesses, academic institutions, and health care systems for employees and/or students. Initiated during the pandemic, studies dealing with patient populations, including patients who are disabled,

 showed that virtual programs were effective to some degree and were well received.

The National Multiple Sclerosis Society (NMSS) has a Wellness Research Working Group to develop top research priorities.

 Through “social media listening,” 3 topics of interest to patients with MS were identified: diet, exercise, and emotional wellness; essentially, information they can use themselves to promote wellness.

 The researchers focused on these areas when planning the virtual programs.

This exploratory study had a purposive convenience sampling design of patients with MS from the Penn MS and Related Disorders Center at the Hospital of the University of Pennsylvania. No other criteria were required for study inclusion. The study was reviewed by the Office of the Institutional Review Board (IRB), University of Pennsylvania, and received exempt status. The IRB reviewers did not feel that a signed consent form was necessary; however, they suggested that study patients receive a 1-page consent statement that outlined the research purpose, their voluntary participation, study risks/benefits, and study expectations. This IRB-approved consent statement was sent to patients by secure email along with the study invitation.

The recruitment period was only 2 months due to constraints, including pandemic-related stay-at-home restrictions and lack of vaccine availability. In addition, the researchers hoped to intervene with the virtual wellness program when it was most needed and to concurrently collect data and evaluate the program’s potential positive effect on participants. During the 2-month recruitment period, the providers in the MS clinic, including physicians, nurse practitioners, and nurses, were asked to mention the wellness programs and study to the patients seen during that time, either in the clinic or virtually. All patients who expressed an interest or who might benefit from the programs were sent a secure email invitation and the consent statement from the nurse or social worker; 239 emails were sent. Patients were offered the option of being a part of the treatment group or the control group.

The final sample consisted of 43 patients in the treatment group and 28 patients in the control group. Patients in the treatment group were asked to attend 2 monthly wellness programs for 6 months and to complete a demographic questionnaire, the 36-Item Short Form Health Survey (SF-36), the Modified Fatigue Impact Scale (MFIS-5), and the Medical Outcomes Study Pain Effects Scale (PES) at baseline, month 3, and month 6. Patients in the control group chose not to attend the programs but agreed to complete the same questionnaires at the same intervals.

Baseline demographic and patient characteristics are summarized in 

, available online at IJMSC.org. Of the 43 patients in the treatment group, 39 (90.7%) were female and 4 (9.3%) were male; the mean ± SD age was 56.79 ± 10.80 years. Thirty-eight patients (88.4%) were White, 4 (9.3%) were Black, and 1 (2.3%) was Hispanic. Forty-one participants (95.3%) had an education beyond high school, and 18 (41.9%) had a graduate degree (beyond the bachelor level). The mean ± SD number of years since diagnosis was 15.60 ± 10.45, and 22 patients (51.2%) felt isolated. Of the 28 patients in the control group, 20 (71.4%) were female and 8 (28.6%) were male; the mean ± SD age was 49.46 ± 10.29 years. Twenty-two control participants (78.6%) were White, 2 (7.1%) were Hispanic, 2 (7.1%) were Asian American, 1 (3.6%) was Black, and 1 (3.6%) was Native American. Twenty-seven control patients (96.4%) had an education beyond high school, and 17 (60.7%) had a graduate-level degree. The mean ± SD number of years since diagnosis was 12.86 ± 7.11, and 15 control patients (53.6%) felt isolated.

The wellness programs were presented virtually via video conferencing (Zoom or BlueJeans) with links provided in an individual email. When the participants logged on, they could choose to mute their video and/or audio if they wanted to protect their anonymity, but many interacted with the speaker or one another. Patients provided ample messages with positive feedback and requests for different topics. As a result, there were 5 additional programs added to the schedule; in total, there were 17 programs over 6 months. An exercise program was offered 6 times and a mindfulness program was offered 3 times.

After finding significant baseline differences between the treatment and control groups due to lack of randomization, an insufficient sample size to adequately adjust for confounding in the treatment group assignments, and the exploratory nature of this study, the analysis focused on potential differences within the treatment group: evaluation of whether frequency of virtual wellness program session attendance (eg, total number, number of session subtype) was associated with differences in questionnaire response changes. Given the exploratory nature of the study with limited data points, it was decided to limit the scope of the analysis to the 6-month end point. Baseline and 6-month measurements for both groups are presented in 

. Differences across the strata were tested using a Jonckheere-Terpstra test for trend or a 2-sample 

 test, depending on the number of strata being compared.

Changes in questionnaire responses were first analyzed stratified on the total number of meetings attended. Of the 43 participants in the treatment group, 15 (34.88%) attended 0 to 4 total meetings, 14 (32.56%) attended 5 to 9 meetings, and 14 (32.56%) attended 10 to 17 meetings. A Jonckheere-Terpstra test suggested that higher meeting attendance was associated with improvement in emotional well-being (

According to research performed by the NMSS, exercise is a topic of interest for patients with MS.

 Exercise is important for overall health and well-being and is also beneficial in managing MS symptoms, including cardiovascular, strength, bowel/bladder function, fatigue, mood, cognitive function, bone density, and flexibility.

 Exercise can also be beneficial in reducing pain.

 Pain is a common symptom for patients with MS

 and is associated with fatigue, depression, anxiety, and reduced mental health quality of life.

A virtual exercise program was offered each month for a total of 6 sessions. Thirty-five patients (81.4%) in the treatment group attended at least 1 session. The programs were presented by a certified personal trainer who also has MS. Her programs were based on NMSS evidence-based exercise and lifestyle physical activity recommendations for patients with MS throughout the disease course.

 She structured the programs so that patients could perform the exercises from a sitting or standing position.

After stratifying patients into 2 groups (23 [53.5%] who attended 0–2 exercise sessions and 20 [46.5%] who attended 3–6 exercise sessions), it was determined that those who attended 3–6 exercise programs had significant improvement compared with baseline on the PES (

). Exercise program attendance was not associated with improvement on any other outcome measures.

There is also evidence that the practice of mindfulness can be helpful in pain relief, but little work has been done in relation to patients with MS.

 One study conducted a cross-sectional survey to evaluate the association between pain and mindfulness in patients with MS. The results suggested that there is a clinically meaningful and highly significant relationship between mindfulness and pain interference in MS.

 A mindfulness program was offered a total of 3 times during this study.

Differences in questionnaire response changes were also analyzed depending on the number of virtual wellness program subtypes attended. Thirty patients (69.8%) in the treatment group attended at least 1 of the 3 mindfulness sessions. After stratifying patients into 2 groups (23 [53.5%] who attended 0–1 mindfulness sessions and 20 [46.5%] who attended 2–3 mindfulness sessions), it was found that patients who attended more mindfulness programs had a significant level of improvement compared with baseline on the SF-36 pain scale (

). The researchers did not find significant associations between mindfulness program attendance and any other questionnaire responses.

Diet is another key topic requested by patients with MS to promote wellness.

 Although there is no “best diet,” maintaining a healthy diet promotes the overall health and well-being of patients with MS.

 A registered dietitian who also has MS presented a healthy approach to nutrition for people living with MS and addressed questions about specific diets.

Movement is paramount to maintaining mobility, so in addition to the exercise programs, 3 other movement classes were offered. In 1 session, an occupational therapist provided suggestions to address common functional problems that patients with MS face.

 There was also a yoga program led by a trained yoga instructor who has MS. There is evidence that yoga benefits people with MS by reducing depression, decreasing pain and fatigue, increasing lung capacity, improving strength and flexibility, decreasing stress, and promoting muscle relaxation, lower blood pressure, and an improved quality of life.

 Finally, a dancer with MS gave a session. She performed a ballet she choreographed chronicling her recovery from an MS exacerbation using the walker she required at that time and the neurologic examination comparing her weak side with the unaffected side. The results of 1 meta-analysis suggest that dance movement therapy decreases depression and anxiety and increases quality of life and interpersonal and cognitive skills.

 In recent years, research suggesting positive effects from dance therapy on patients with MS has increased.

Sleep difficulties are common among people living with MS, and 1 study found that patients with MS had worse sleep quality during the pandemic than the general population.

 A University of Pennsylvania sleep medicine physician presented “Lessons from a Sleep Physician: Falling Asleep and Staying Asleep, Critical Lessons for Battling MS Fatigue.” Contributing factors to sleep disturbance include vitamin D deficiency; adverse effects from medications, including disease-modifying therapies, steroids, and fatigue medications; fatigue-related daytime napping; decreased exercise related to fatigue or MS-related disability; emotional changes such as stress, anxiety, or depression; and other MS symptoms, such as restless legs, pain, urinary and bowel symptoms, and temperature dysregulation.

 The speaker provided an interactive program on the causes of sleep deprivation and ways to foster quality sleep.

Emotional wellness is also a topic of interest to patients with MS.

 Patients who attended more meetings in this study had a significant level of improvement compared with baseline in emotional well-being (

 = .038) (Figure 1A). A program was presented by a comedian with MS about living with MS. Laughter can be beneficial as it has been found to relieve stress and tension, improve the immune system, increase personal satisfaction, and improve mood.

 In planning the program, the researchers worried whether a comedy program would be well received and/or beneficial to the patients. The comedian was also concerned about conducting a virtual comedy program where the microphone of many participants would be muted; however, the program was very successful and patients offered positive responses in the chat box: “OMG! I needed this so much!!” “Best hour I’ve spent in way too long!! Thank you!!” (

The nurse practitioners from the MS center provided a program on MS symptoms. Because of their training and expertise, they understand the complexity of MS treatments, including treatments for symptom management.

 The program was presented in an open forum that allowed for patient questions and comments on ways to deal with MS symptoms.

Finally, there was a program provided by a primary care provider, an important role in the multidisciplinary team since they will likely see the patient more frequently than the neurologist in a years’ time.

 The primary care provider stressed that the patient with MS must also take care of non-MS issues to maintain overall wellness.

The results of this exploratory study suggest that virtual wellness programs may be a beneficial tool for patients with MS, whether isolation is caused by a pandemic or by disability. The programs provide information and activities to address the physical effect of deconditioning, as well as group interaction and support to address social isolation.

Ten of the 17 programs were presented by individuals who have MS, which may have contributed to the very active group interaction, as well as the positive responses: “I wanted to thank you for the wonderful programs. They have really helped me and have been uplifting. What I really like about the programs is that the presenters also have MS. I was diagnosed in 2011 and have pretty much kept it a secret. The programs are helping to decrease some of my anxiety and worries about somebody at work finding out that I have MS. Hearing the presenters share their stories is encouraging me to also want to open up and share with other people in my life. The programs have been inspirational and I am so happy I was able to join.”

The pandemic provided a perfect opportunity to explore the concept of virtual wellness programs. One researcher found that online opportunities for physical activity for patients with MS were a valued option and recommended that such programs be continued after the pandemic.

 Many of the participants in this study continue to attend the 2 monthly virtual wellness programs that have continued for the patients with MS beyond this study.

The positive feedback the researchers received in this study, both verbally and in writing, confirmed that the wellness programs were valuable to the participants. A patient wrote, “I’ve lived with MS for over 20 years, and the Penn MS Wellness Group has absolutely been the most positive, helpful, caring experience for me in terms of my health care team going out of their way to provide meaningful, relevant, helpful, and regular programming while also creating a supportive, safe, warm community made up of patients, caregivers, and medical providers. The group … provides insight that has helped me live better with MS. Thank you so much for this wonderful group!”

This study has several limitations. The study design changed because (1) the researchers could not compare the 2 groups due to lack of randomization, (2) additional programs were added by patient request, and (3) the scope of the analysis was limited to the 6-month end point. Many of the members of the sample were older white females who were highly educated, with most having degrees beyond high school. Therefore, the findings cannot be generalized to a more diverse population. Vaccine availability during the study may have contributed to the improvement of patient well-being.

The results of this study suggest that a virtual wellness program can be beneficial to patients living with MS. Interventions on diet, exercise, and emotional wellness may be associated with improved MS symptoms, as well as improvement in overall health and quality of life. The study also suggests that mindfulness and exercise programs may be beneficial in pain management. A randomized trial is warranted to further study effectiveness.

Impact of a Virtual Wellness Program on Quality of Life Measures for Patients Living With Multiple Sclerosis During the COVID-19 Pandemic

Telemedicine provides a gateway to specialty care that, otherwise, patients with multiple sclerosis (MS) could have difficulty accessing. Studies have shown that telemedicine provides a valid alternative to in-person visits. There are limited data on the strengths and limitations of telemedicine from the perspective of MS providers.

After reviewing the literature and pilot testing questions about telemedicine in provider focus groups, a 34-question survey was created on the Qualtrics web platform. A stratified sample of MS providers throughout the United States was recruited to participate. The survey initiated in November 2019 and closed in November 2020.

Survey participants (N = 94) included neurologists (43.0%), advanced practice providers (28.0%), nurses (14.0%), mental health providers (7.0%), social workers (3.0%), rehabilitation providers (4.0%), and pharmacists (1.0%). Clinical video telemedicine (CVT) was the most commonly used platform, and 76.6% of respondents indicated that they used telemedicine to care for patients with MS. As a result of the COVID-19 pandemic, the rate of telemedicine use increased from 44.4% to 84.2%. Most health care providers (93.0%) were “very satisfied” or “somewhat satisfied” with their most recent telemedicine visit, and 94.4% of providers reported a desire to continue using telemedicine, although 84.6% found it difficult to perform a full examination.

There was a large uptick in the use of telemedicine when the COVID-19 pandemic forced clinics to cease in-person visits. Providers predominantly used CVT; store-and-forward telemedicine and remote patient monitoring have fewer technical issues than CVT and seem to be underused.

From the Department of Neurology, Johns Hopkins University, Baltimore, MD, USA (PK); Veteran's Administration Multiple Sclerosis Center of Excellence-East, Baltimore, MD, and Washington, DC, USA (HM, ZM, SJ, MW); Department of Neurology, George Washington University, Washington, DC, USA (MW). 

 Peter Keszler, DO, 7315 Wisconsin Ave, Ste 700, Bethesda, MD 20814, USA; 

Thanks to the health care providers who participated in the surveys and responded to the promises and challenges of telemedicine.

The authors declare no conflicts of interest.

 This study was supported by the National Multiple Sclerosis Society (HC-1610-25978) and the US Department of Veterans Affairs Multiple Sclerosis Center of Excellence.

 Preliminary data from this study were presented as part of an abstract poster at the Americas Committee on Treatment and Research in MS Forum 2021 Virtual Conference; February 25-27, 2021.

It is often difficult for patients with multiple sclerosis (MS) to access specialty care; major barriers include geographic distance from providers, traveling restrictions due to neurologic disability, and limited or partial health insurance coverage.

 Access is further impaired by inclement weather and health-related concerns (eg, COVID-19, MS flare). One study showed that 30% of patients with MS do not see a neurologic specialist for their care.

 Patients who are seen by a neurologist are more likely to be prescribed a disease-modifying treatment and receive multidisciplinary services,

Telemedicine, the use of technology to provide access to clinical care when distance separates patients and providers,

 could allow for broader and more convenient access to MS specialty care. There are several types of telemedicine: (1) clinical video telemedicine (CVT), in which a provider and patient communicate through an audiovisual platform (eg, Zoom [Zoom Video Communications, Inc]); (2) pure audio real-time interface (eg, performing telephone surveys); (3) store-and-forward telemedicine, in which patient test results (eg, cognitive tests, optical coherence tomography) are stored and then reviewed by a remote clinician; and (4) remote monitoring, which includes wearing a device or using an app that sends real-time data to a remote provider.

The COVID-19 pandemic forced a shift in how practitioners provided care due to the need for social distancing to decrease potential exposures for a patient population that is at higher risk

 than the general population. Providers and the National Multiple Sclerosis Society issued guidance for using telemedicine to help reduce this risk.

Jonathan Calkwood, MD

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