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Migraine in Multiple Sclerosis: Underlying Mechanisms, Shared Symptoms, and Approaches to Management

Vocal disorders are frequent in people with multiple sclerosis (MS). Cognitive impairment, fatigue, depression, and other clinical characteristics can be associated with treatment effectiveness in rehabilitation. Finding baseline characteristics that identify those who are responding to treatment can help the clinical decision-making process, which can then help improve the effectiveness of voice treatment. We developed a model to identify factors associated with treatment-related improvement on voice intensity in people with MS.

Data are from a randomized controlled trial of the effects of voice therapy. Forty-four people with MS were enrolled and randomized to receive Lee Silverman Voice Treatment LOUD, specifically addressing voice intensity, or conventional speech-therapy group. Voice intensity (dB) was measured during monologue before and after treatment and was used to differentiate those who responded (posttreatment voice intensity > 60 dB) from those who did not. Possible associated factors were cognitive impairment, fatigue, depression, disability, and disease duration. Associations were assessed by univariate logistic regression and univariate and multivariate linear regressions.

Mean ± SD monologue voice intensity is improved in the whole sample (before rehabilitation: 51.8 ± 4.2 dB; and after rehabilitation 57.0 ± 6.5 dB; 

 < .001), and 11 people with MS (27.5%) responded to treatment. Specificity of treatment was associated with the return to normal voice intensity (OR, 14.28; 95% CI, 12.17–309.56) and we found a linear association between voice improvement and the specificity of treatment (6.65 [SE = 1.54] dB; 

 < .05). Moreover, the analysis revealed a nonlinear association between improvement and fatigue, suggesting increased benefits for people with MS with moderate fatigue. Other factors were not significantly associated with treatment effectiveness.

Moderate fatigue and the specificity of the intervention seem to be key factors associated with clinically relevant improvement in voice intensity even in people with MS with a high level of disability and long disease duration.

From the ASTeR Lab Adult Speech-therapy Team Research (VC, CB, FT, DC, CV) and Department of Neurorehabilitation (MB, SG, MR), IRCSS Fondazione Don Carlo Gnocchi, Milano, Italia; Ospedale San Paolo - ASST Santi Paolo e Carlo, Milano, Italia (EG); Department of Physiopathology and Transplants, University of Milano, Italia (DC). 

Davide Cattaneo, PhD, Department of Pathophysiology and Transplantation, University of Milano, Via Capecelatro 66 - 20148 Milano, Italia; 

We would like to thank Kevin Russell Bateman and Dr Elisa Gervasoni for helping revise the manuscript. Thanks also to Ilaria Giavarini for supporting the study.

 The authors declare no conflicts of interest.

Multiple sclerosis (MS) is a progressive, degenerative neurologic disease leading to demyelination and neurodegeneration involving different parts of the motor system,

 including control systems for speech and voice.

 Vocal disorders are common problems in people with MS.

 The predominant voice impairments are harshness, breathiness, phonatory instability,

 inability to maintain adequate adduction for phonation,

 and higher variability in fundamental frequency and sound pressure level (SPL). Consequently, the voice during conversation is unstable and hypophonic, leading to difficulties at work, participating in conversations with a wide range of people, using the telephone, and communicating in noisy environments.

Although voice is a significant aspect of quality of life, only 2% of people with MS receive speech therapy.

 Studies of vocal rehabilitation in people with MS are scarce with contradictory results,

 low methodological quality, and small samples without instrumented assessment of voice. More consistent results may stem from randomized controlled trials that include individuals with specific baseline characteristics allowing for easier identification of those who respond to treatment. The rationale of the present study is that the identification of these factors will contribute to enhancing our understanding of how voice rehabilitation works in MS, thus allowing for more effective voice rehabilitation interventions to be developed and for better resource allocation. In addition, more information is necessary to identify the baseline characteristics associated with treatment-related changes to the voices of people with MS.

To date, no studies have investigated predictors of voice rehabilitation in people with MS. There is only 1 study on Parkinson disease

 showing that age and cognitive status influence the magnitude of voice treatment-related changes. In the same study, a specific treatment, the Lee Silverman Voice Treatment (LSVT) LOUD, which aims to increase vocal fold adduction and respiratory support, was associated with better voice intensity after treatment.

Along with these factors, we hypothesized that treatment specificity, defined as “treatment directed at the cause of the functional disorders,”

 could also predict voice improvements. The importance of specificity as an outcome predictor was supported by studies in other domains of MS rehabilitation, including walking and balance. Because voice and mobility rehabilitation share general motor control and learning principles,

 we hypothesized that some prognostic factors identified in balance and gait rehabilitation in people with MS could also be effective for voice treatment. For example, Cattaneo et al

 showed that individuals with more impaired balance benefit more from rehabilitation treatment and that MS type is not associated with improved mobility. Long disease duration and neurologic status measured by the Expanded Disability Status Scale (EDSS) are commonly considered predictors of the reduced benefit of balance rehabilitation, along with more severe pyramidal, cognitive, sensitive, verbal, and cerebellar impairments.

 showed that fatigue is a predictive factor for cognitive outcomes and that people with higher fatigue are more likely to have improved processing speed after exercises. Finally, depression is associated with fatigue

Thus, the potential impact of all the aforementioned factors—MS type, disease duration, neurological and cognitive status, fatigue, and depression—on treatments should be considered, and this study was designed to identify whether these factors were associated with a documented treatment-related improvement in voice intensity in functional communication in people with MS.

In the present prospective study, we collected data from a randomized controlled trial.

 Forty-four consecutive inpatients were recruited from January 2018 to July 2019 at IRCCS Fondazione Don Carlo Gnocchi (Milan, Italy). Details of the study are provided elsewhere.

 In brief, people with MS were randomized after completion of a baseline assessment using a randomization list and the following inclusion criteria: (1) a diagnosis of MS according to Thompson and McDonald criteria

; (2) older than 18 years; (3) ability to understand the Italian language and the aims of the study; and 4) impairments in voice intensity during conversation (defined as a maximum voice intensity <60 dB SPL).

The exclusion criteria were: (1) the presence of other neurological disorders; (2) visual/hearing impairments that would hinder participation in the rehabilitation program; (3) clinical history of laryngeal cancer, chemotherapy, radiotherapy, head and/or neck trauma, or endotracheal intubation; (4) relapse or sudden changes in MS symptoms within the previous 3 months; and (5) drug regimen changes during the intervention period.

The study was approved by the ethics committee of the IRCSS Fondazione Don Carlo Gnocchi and all participants signed informed consent paperwork before beginning the study.

The primary outcome measure was monologue intensity because it reflects a more natural, fluent speech output. Praat, software that is freely available online (www.praat.org), was used to record and analyze speech intensity at baseline and at the end of treatment. A specific task, identical for each participant, was given: 

 Recording setup followed published recommendations,

 and mouth-to-microphone distance was kept equal at approximately 15 cm.

/ or reading voice intensity as the primary outcome measure in voice rehabilitation. However, we used monologue intensity to evaluate the effectiveness of treatment because it is more difficult than vocalization, requiring more dynamic laryngeal movements, attention, and concentration and it is closer to functional communication.

 Monologue can be a less replicable measure compared with other more standardized voice measures. Thus, we adopted some strategies to increase reproducibility: first, we asked individuals to talk about their favorite subject, avoiding emotional topics and relying on a discussion of daily living activities to avoid prosodic shaping and lengthy pauses. Second, we suggested an alternative topic when the individual could not provide enough monologue for 60 seconds, and we used a stopwatch to inform individuals of the duration of their speech.

 we included the following factors as potential variables associated with improvement of voice intensity (

Clinical characteristics: age, type of MS, time since diagnosis, and neurological status rated using the EDSS.

Cognitive impairment: The Mini-Mental State Examination (MMSE) is the most common screening tool used to assess global cognitive functioning. The maximum score is 30 points; the most widely used and accepted cutoff score for the MMSE is 23 points or less.

Depression: The Beck Depression Inventory-II (BDI-II) is one of the most widely used instruments to assess the severity of depression. The score ranges from 0 to 63 points, with a higher score suggesting a higher level of depressive symptoms and a score above the 14-point cutoff score revealing the presence of depressive symptoms.

Fatigue: The Modified Fatigue Impact Scale (MFIS) is self-reported, is composed of 21 items, and is used to evaluate fatigue in a multimodal way. Scores range from 0 to 84, with higher scores indicating a greater impact of fatigue. A total score of 38 is used as a cutoff to differentiate fatigued from nonfatigued individuals.

Intervention Type: People with MS were randomized into 2 groups: the specific group received LSVT LOUD and the nonspecific group received conventional treatment. Both interventions are described later herein.

The Barthel Index for Activities of Daily Living was used to depict functional status at baseline. This tool evaluates a person’s function in terms of their level of independence or dependence when performing certain activities required for daily living. Total scores range from 0 (complete dependence) to 100 (complete independence).

The clinical assessments were performed by a speech therapist blinded to group allocation before the beginning of the rehabilitation program and monologue voice intensity was assessed before and after treatment.

Both the LSVT LOUD and conventional treatments were intensive and focused on hypophonia, with 4 sessions per week for 4 weeks. In addition, participants in both groups were asked to complete 5 to 10 minutes of home practice on treatment days and up to 30 minutes of home practice on nontreatment days.

The specific group performed LSVT LOUD, a specific, evidence-based, effective program

 for hypophonia rehabilitation that is used for individuals with different neurological conditions, including MS.

 This intervention facilitates phonation, enhances vocal quality, and reduces dysphonia by having participants practice “daily tasks” and by using a “speech hierarchy.”

 Daily tasks aim to increase vocal amplitude through multiple repetitions of sustained /

/, high/low pitch range exercises, and functional sentences. The speech hierarchy improves functional communication by training individuals to maintain enhanced vocal amplitude in more complex speaking situations (eg, reading, monologue).

The nonspecific group underwent conventional treatment consisting of tailored but less specific exercises,

 including some or all of the following components.

Respiratory and phonatory exercises to increase diaphragmatic and respiratory functions, ie, using natural or sibilant phonemes expiration, phonation time by pronouncing the vowel /

/, and exercises to reduce oral spasticity.

Prosody exercises and articulation: repetition or reading aloud lists of possibly long and complex words, sentences, and texts without diminishing or increasing the rhythm of speech. If necessary, participants were asked to hyperarticulate, accelerate or slow down their rate of speech, or exaggerate intonation.

Data are reported as number (percentage), mean ± SD, or median (first-third quartile). Improvement from before to after the intervention was assessed by paired 

Participants were “responders” if they had posttreatment voice intensity greater than 60 dB.

 The association between predictors and probability to return within the normal range of voice volume in monologue was assessed via univariate logistic regression models. The variables listed in 

 are predictors and responding/nonresponding is the dichotomous dependent variable. Treatment type was the only predictor showing a clinically and statistically significant association with responders in both univariate and multivariate logistic models. Thus, in the present study, we present only univariate logistic models.

Univariate linear regression models assessed the association between predictors and magnitude of pretreatment and posttreatment improvement in voice intensity, with voice intensity as a continuous dependent variable and the same variables reported previously herein as predictors (

). A squared and cubic polynomial transformation of MFIS was included to account for nonlinear associations between MFIS and voice intensity.

A multivariate linear regression model that included variables showing univariate statistically significant association between predictors and response was used to assess the multiple contributions of collected variables in predicting improvement in voice intensity.

Variance explained by the models was provided by adjusted 

 values for logistic models. We also checked for collinearity among predictors by using pair-wise correlation plots among different predictors and calculating the variance inflation factor. A variance inflation factor less than 4 was considered good for the model. R (2008) (R Foundation for Statistical Computing) was used for analysis.

The study included 44 people with MS; the demographic and clinical characteristics are reported in Table 1. The specific group had 23 participants (52.3%) and the nonspecific group had 21 participants (47.7%).

After treatment, individuals showed a statistically significant improvement in mean ± SD monologue voice intensity (before rehabilitation: 51.8 ± 4.2 dB; after rehabilitation 57.0 ± 6.5 dB; 

Overall, 10 individuals (43.5%) from the specific group and 1 person from the nonspecific group (4.8%) crossed the threshold (60 dB SPL) discriminating between normal and abnormal voice intensity and were considered responders. Univariate logistic analyses showed that the posttreatment likelihood of crossing the 60 dB threshold was 14.28 times greater for the specific group than for the nonspecific group (

Univariate linear analyses comparing pretreatment and posttreatment changes are shown in Table 2. We found an association between change in voice intensity and type of treatment. Participants in the specific group showed a significant 6.65 dB improvement compared with participants in the nonspecific group. In addition, we found a statistically significant nonlinear association between change in voice intensity and the MFIS.

, all supplementary material is available in a PDF at the bottom of this article), improvement in monologue voice intensity was associated with treatment type and fatigue.

We found a nonlinear relationship between the MFIS and the probability of a good outcome (

): improvement is more relevant for individuals in the specific group with MFIS scores ranging from 40 to 60 points. Considering that 38 points is the cutoff score between fatigued and nonfatigued individuals,

 a hypothetical person with MS not reporting fatigue (MFIS score = 28 points) treated with the specific treatment is expected to improve 5.74 dB (95% CI 3.19–8.29 dB), and a person with higher fatigue (MFIS score = 48 points) treated with the specific treatment is expected to improve 9.25 dB (95% CI, 5.80–12.69 dB). According to the multivariate model, a smaller improvement (8.06 dB; 95% CI, 4.38–11.74) is expected for a person with MS with severe fatigue (MFIS score = 58 points). Likewise, 2 hypothetical individuals with the same baseline MFIS score of 48 points and receiving specific and nonspecific treatment are expected to improve 9.25 dB (95% CI, 5.80–12.69 dB) and 5.68 dB (95% CI, 2.76–8.63 dB), respectively.

This study aimed to assess factors associated with treatment-related changes in voice intensity in people with MS. Overall, the data showed higher percentages of people with MS with voice intensity greater than 60 dB in monologue discourse in the specific group after treatment compared with the nonspecific group and highlighted that specificity of treatment and fatigue were predictors of improvement.

Data analyses revealed that the type of intervention was the most important predictor of a clinically meaningful improvement, highlighting the importance of a specific treatment. Participants treated with LSVT LOUD for hypophonia showed larger improvement than participants treated with the conventional approach, and almost half of the people with MS in the specific group obtained normal values of monologue voice volume compared with 4.8% in the nonspecific group. Both treatments were intensive and directed toward increasing vocal loudness, but the LSVT LOUD treatment is specific to hypophonia. LSVT LOUD focuses on the load of the larynx and the expiratory muscles enhancing glottal closure

 and incorporates some of the recognized principles of motor learning and neuroplasticity, such as intensity of practice with high repetition.

 In addition, LSVT LOUD addresses deconditioning and learned nonuse

 because it is intensive, including significant repetition and an increase in task complexity over time. Tackling deconditioning is a key feature in the treatment of MS because disability often leads to inactivity, resulting in muscle disuse atrophy.

 Deconditioning prevents people with MS from efficiently using their residual capacities,

 Conversely, conventional treatment is more tailored to a person’s needs, but is less systematic and focuses on other voice aspects (such as prosody, articulation, posture, etc).

The importance of intervention specificity in predicting treatment-related changes was also reported in another study of factors associated with improvement after balance rehabilitation in people with MS.

Fatigue was the second most important predictor. The present results (Figure S1) suggest a nonlinear relationship between fatigue and voice improvement. Participants who reported moderate fatigue (MFIS score = 40–60) benefited more from the voice treatment than participants with lower or higher fatigue. Of note, our results cannot be generalized to severely fatigued people with MS since our sample did not include MFIS scores higher than 60 points. Mixed results on the association between fatigue and motor improvements are reported in the literature. Petajan et al

 suggested that intensive training can improve function in those parts of the body that are prone to fatigue. Coghe et al

 found a linear association between fatigue (measured by the MFIS) and balance rehabilitation outcome in people with MS. Conversely, Liberatore et al

 found no evidence of fatigue impacting balance rehabilitation, and a preceding study found that the short version of the MFIS had no predictive capacity on outcomes from a respiratory exercise intervention in a similar cohort of people with MS and an EDSS score greater than 7.5.

To the best of our knowledge, no studies have investigated the impact of vocal fatigue and lack of endurance on voice in patients with MS. Clearer results could be obtained by using a specific scale to measure vocal fatigue as well as laryngoscopy or specialized manometry to assesses strength and endurance. Also, it may be important to verify if persons with MS would benefit more from voice treatments adapted to their level of disability and when the exercise difficulty follows their improvements.

Disease duration and age did not correlate with improvement in voice intensity. There was also no correlation with the EDSS, meaning that individuals with a higher level of disability could also benefit from voice interventions; this expands the range of individuals who could benefit from treatment. It should be noted that most of the individuals in our sample were severely affected (median EDSS = 8; mean disease duration = 26 years). This is important since individuals with high levels of disability usually have a progressive form of MS and disease-modifying therapies are less effective in preventing functional loss: rehabilitation is the only viable solution to improve function.

The present results are in contrast to those reported by Grasso et al

 in a large sample of people with MS showing that disease duration and neurologic status measured by EDSS are important factors related to posttreatment improvement in activities of daily living and mobility. They hypothesized that the presence of severe impairment and long disease duration could be responsible for the lack of the neurophysiopathologic compensation mechanism that is likely required for any rehabilitation. Differences between the present results and those reported by Grasso et al

 might be due to use of the EDSS to assess the presence of severe impairments. The EDSS mainly measures walking impairment in severely impaired individuals

 without assessing speech and voice characteristics. However, further research is needed to examine less severely impaired and recently diagnosed people to verify the generalizability of treatment effects across all stages of MS.

In the present study, depression did not influence treatment effects; a similar result was reported by Ramig et al

 in individuals with Parkinson disease. However, our participants did not report a high level of depressive symptoms (mean ± SD BDI-II score = 8.25 ± 7.53), and it is thus possible that higher levels of depression could hinder the effects of the treatment.Similarly, cognitive impairments did not correlate with treatment-related changes. However, most of the people in this study were in the mild to moderate cognitive disorder range (mean ± SD MMSE score = 26 ± 4.3). Moreover, use of the MMSE to identify cognitive impairment in people with MS has been questioned because many people who score higher than the suggested cutoff of 24 exhibit severe focal or global cognitive deficits.

 Further research should be conducted using a more specific and extensive battery of neuropsychological tests or newer cognitive screening tools, such as the Symbol Digit Modalities Test or the Montreal Cognitive Assessment.

This study contains a variety of biases. First, the small number of participants prevented the use of more robust statistical methods to assess the real predictor power of fatigue and the specificity of the intervention. Moreover, this is a monocentric study that engaged very neurologically compromised (median EDSS score = 8) people with MS. Therefore, we must be very careful in the generalization of results. Second, the evaluation of voice intensity does not exhaust all the expected benefits of voice rehabilitation, and so future studies are needed, including a multidimensional assessment. Voice intensity in conversation reflects more natural outcomes and increased ecological validity; however, its assessment results in less consistent and less controlled data collection compared with more standardized measures. Third, the participants were instructed to perform at-home exercises after treatment. However, we did not formally assess adherence; it is impossible to say how compliance to the home program affected results. Finally, increasing voice intensity to within the normal range may not necessarily be a meaningful improvement for the individual. For example, higher voice intensity could come at the cost of added vocal effort and fatigue. To verify this hypothesis, future studies should assess vocal fatigue before and after treatment.

Overall, these results show that speech therapy has a significant beneficial effect on voice intensity in people with MS. Neurologic status was not associated with improved voice intensity, suggesting that even people with MS with severe neurological impairments and a long disease duration can benefit from voice treatment. Moreover, we observed an association between the specificity of the intervention and improvements in monologue voice intensity in people with a moderate level of fatigue.

Factors Associated With Treatment-Related Changes in Voice Volume in People With Multiple Sclerosis

It is recommended that patients taking immunosuppressive anti-CD20 monoclonal antibodies (mAbs) receive pneumococcal vaccinations before their first dose to ensure optimal immune response. An initial medication use evaluation reviewed adherence to Centers for Disease Control and Prevention (CDC) pneumococcal immunization recommendations at the study site, and room for improvement was identified. The nursing team implemented workflow changes to increase nursing involvement in vaccination coordination, education, tracking, and administration. We sought to evaluate the impact of a nursing intervention on optimal pneumococcal vaccination administration rates in patients receiving anti-CD20 mAbs at a multiple sclerosis (MS) center.

We performed a single-center, retrospective, pre/post medication use evaluation. Inclusion criteria were older than 18 years with a diagnosis of MS and received their first anti-CD20 mAb infusion at the study site during the preintervention or postintervention time frame.

We included 406 and 73 patients in the preintervention and postintervention studies, respectively. The nursing intervention significantly improved the percentage of patients receiving optimal pneumococcal vaccination before their first infusion from 58% to 84% and significantly reduced the number with unknown vaccination status from 17% to 3%. Patients who received optimal follow-up vaccination with 23-valent pneumococcal polysaccharide vaccine after optimal 13-valent pneumococcal conjugate vaccine administration improved from 9% to 56%.

A nursing team intervention improved adherence to CDC pneumococcal immunization recommendations for patients receiving anti-CD20 mAb therapy. This project highlights the value of interdisciplinary team collaboration between health system specialty pharmacies and specialized nursing teams in the care of patients with MS.

From the Department of Pharmacy (KR, ER, JW), Clinical Nursing Research Center (BWQ), and Department of Neurology (JSD), University of Rochester Medical Center, Rochester, NY, USA. 

: Julie Wawrzyniak, PharmD, 601 Elmwood Ave, Box 617, Rochester, NY, 14642, USA; 

The authors thank Mary Carey, PhD, RN; Cathy Snider, MS, RN; and Kay Vonglis, BSN, RN, for their support with the nursing intervention and project planning. We also thank Justin Foster, PharmD; and Stephanie Pilat, PharmD, for their support with data collection.

 Julie Wawrzyniak, PharmD, has participated in a focus group discussion with Alexion. The other authors declare no conflicts of interest.

 Aspects of this study were presented in abstract form at the 54th Annual American Society of Health-System Pharmacists Midyear Clinical Meeting; December 8–11, 2019; Las Vegas, Nevada; as a virtual poster at the Eastern States Conference; April 26–28, 2021; and as a virtual poster at the American College of Clinical Pharmacy Virtual Poster Symposium; May 24–28, 2021.

Ocrelizumab and rituximab are monoclonal antibodies (mAbs) that target the CD20 antigen found on B cells, leading to B-cell lysis.

 Ocrelizumab was approved by the United States Food and Drug Administration in 2017 for relapsing forms of multiple sclerosis (MS) as well as primary progressive MS in adults.

 Rituximab is not United States Food and Drug Administration approved for MS; however, it has been used off-label for the treatment of MS for many years. Evidence suggests that ocrelizumab and other mAbs may have greater efficacy compared with self-injectable disease-modifying therapies, thus their use is becoming more common in patients with MS.

Patients with depleted B cells from treatment with anti-CD20 mAbs are at an increased risk for infection while receiving this immunosuppressive therapy. The Centers for Disease Control and Prevention (CDC) recommends that all patients 6 years and older who are immunocompromised, including iatrogenic immunosuppression, receive vaccinations against pneumococcal diseases.

 At the time this study was completed there were 2 pneumococcal vaccines available in the United States, 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23), both of which are inactivated.

, and the latter contains 12 of the same serotypes as found in PCV13 as well as 11 additional serotypes. It is recommended that immunocompromised patients receive PCV13 first and PPSV23 at least 8 weeks later.

 Although PPSV23 contains more serotypes of 

, PCV13 is administered first because studies have shown that a greater immune response is achieved when administered in this sequence.

The prescribing information for ocrelizumab indicates that all inactivated vaccines should be administered at least 2 weeks before the initiation of ocrelizumab infusions.

 Guidance for rituximab extends this recommendation, stating that all inactivated vaccinations should be administered at least 4 weeks before initiating treatment.

 Vaccinating patients before initiation allows time to develop an immune response to the disease before B-cell stores are diminished.

In 2014, the University of Rochester Specialty Pharmacy added a fully integrated clinical pharmacist dedicated to caring for patients at the University of Rochester Multiple Sclerosis Center (UR MS Center). There are now 2 clinical pharmacists integrated in the UR MS Center working closely with providers, nurses, social workers, and clinic support staff. Growth of clinical services provided by the integrated clinical pharmacists and expanded, specialized nursing positions fostered interdisciplinary working relationships and ultimately led to this collaborative project.

At the start of this medication use evaluation, there was not a standard procedure at the UR MS Center for tracking whether patients received pneumococcal vaccinations in the optimal timing and sequence before and after starting anti-CD20 mAb therapy. The purpose of this study was to evaluate adherence to CDC pneumococcal vaccination recommendations for patients with MS receiving ocrelizumab or rituximab at an MS center in an academic medical center before and after a nursing intervention.

This single-center, retrospective, pre/post medication use evaluation was granted institutional review board exemption.

All individuals who received rituximab or ocrelizumab at the UR MS Center during the study periods were screened for inclusion. Patients were included if they were older than 18 years and received their first anti-CD20 mAb infusion at the study site. For the initial study period, all the participants had received their first dose or were scheduled to receive their first dose before September 20, 2019. For the follow-up evaluation, all the participants had received their first dose between February 1, 2020, and December 31, 2020. The electronic medical record (EMR) was reviewed to obtain demographic information, infusion dates, and vaccination dates for PCV13 and PPSV23.

Participants were considered to have received optimal vaccination sequence if they received PCV13 or PPSV23 as per CDC recommendations before their first anti-CD20 mAb infusion.

 Subsequent pneumococcal vaccine administrations were collected to determine whether the optimal sequence was completed.

The primary study outcome was the difference between the number of patients receiving pneumococcal vaccination as recommended by the CDC within the recommended interval (≥2 weeks before starting ocrelizumab or ≥4 weeks before starting rituximab) before and after the nursing intervention. Secondary outcomes included percentage difference in patients who received follow-up vaccination after initial optimal pneumococcal vaccination before and after the nursing intervention, median difference in the number of days between receiving initial optimal pneumococcal vaccination and follow-up vaccination, and location of PCV13 administration preintervention and postintervention.

Nursing Workflow Preintervention and Postintervention 

Before the nursing intervention there was no standardized procedure to monitor patients’ vaccination status in the UR MS Center. A nurse clinical care manager/educator position was created in the Multiple Sclerosis and Neuroimmunology Division of the Department of Neurology in March 2019; this nurse was responsible for coordinating pneumococcal vaccinations for patients starting B-cell–depleting disease-modifying therapy. If the dedicated nurse was not available, the triage nurse or an infusion nurse assumed this responsibility. All nurses involved with the intervention were registered nurses. Providers notified the nurse of the plan to initiate therapy during the office visit or via a routed office note describing the plan. Plan-Do-Study-Act cycles were used to establish an effective process.

 Plan-Do-Study-Act is a method of testing change in real work settings. Pilot testing may begin after a team is formed, measurable goals are established, and changes are identified. A series of cycles are required as learning occurs and refinements are made. Once there is a successful cycle, a broader-scale change is put into place. In February 2020, the nurse began contacting patients by phone or secure messages through the EMR. This practice was stopped after 2 weeks because it proved to be inefficient, and patients who were in the clinic were being missed. By mid-February 2020, first-dose vaccinations of PCV-13 were administered to patients in the clinic during scheduled office visits before initiation of B-cell–depleting therapy. Subsequent doses of PCV13 and PPSV23 were administered per the CDC guidelines without regard to the timing of the upcoming or postinfusion schedule. Patients received second- and third-dose vaccinations during their scheduled infusion appointments if they had tolerated 1 or more doses of rituximab or ocrelizumab. Using these same criteria, sequential PCV13 and PPSV23 doses were administered during follow-up office visits. If pneumococcal vaccine doses could not be administered in the clinic, the nurse would assist the patient in receiving the correct vaccine dose at the patient’s or insurance provider’s preferred location (eg, primary care physician’s office, local pharmacy) by coordinating with the neurology provider to prescribe the optimal pneumococcal vaccine.

Nursing interventions included reviewing the neurology infusion center schedule to identify patients, importing outside records from linked EMRs and the New York State Immunization Information System (NYSIIS), managing the clinic inventory of PCV13 and PPSV23, educating patients and obtaining NYSIIS consent during infusion appointments, requesting orders for and administrating vaccinations, and completing documentation.

During the early stages of the second study period, the burden of care and monitoring rested solely on the neuroimmunology clinical care manager/educator. To relieve that burden, the safety nurse was identified as additional support. A Training of Trainer model was used to explain the rationale, process, and documentation of patients requiring vaccinations.

 The Training of Trainer model uses expert trainers to teach subject matter to novice trainers. Initial training is followed by discussion, listening, observation, and support. The novice trainer then becomes a subject matter expert and can train others in the same cyclical pattern.

 tests for categorical variables; statistical significance was set at 

 < .05. Additional categorical data measures are described by a percentage or frequency of occurrence. Continuous data are reported using mean with SD or median with interquartile range (IQR), whichever was appropriate.

A total of 444 patients were screened for inclusion in the preintervention analysis, and 406 were included. In the preintervention group the first rituximab infusion was administered in August 2013 and the first ocrelizumab infusion was in June 2017. In the postintervention analysis, 87 patients were screened, and 73 were included (

). In both the preintervention and postintervention analyses, most patients were initiated on ocrelizumab: 73% in the preintervention group and 92% in the postintervention group.

In the preintervention and postintervention groups, 57.6% and 83.6% of patients, respectively, were confirmed to have received the optimal initial pneumococcal vaccination (

). The percentage of patients with unknown vaccination status was 16.7% in the preintervention group and 2.7% in the postintervention group (

 = .004). In the preintervention and postintervention groups, 25.6% and 13.7% of participants, respectively, were confirmed not to have received the initial optimal vaccination (

After receiving the initial optimal PCV13, 9.0% of patients in the preintervention group and 55.7% in the postintervention group received the follow-up PPSV23 immunization (

 < .001). For those who received optimal PCV13 followed by PCV23, the median interval difference was 480 days (IQR, 328–813 days) in the preintervention group and 119 days (IQR, 74–238 days) in the postintervention group. Administration of PCV13 occurred at the UR MS Center in 39% of participants before the nursing intervention and in 52% postintervention.

The nursing team intervention significantly improved adherence to CDC pneumococcal immunization recommendations for patients receiving anti-CD20 mAb therapy at the MS center. There was also a significant increase in patients who received follow-up PPSV23 after receiving initial optimal PCV13. In addition to the improvement in optimal vaccination practices, this study showed an increase in patients who received their immunizations at the MS center after the nursing intervention. This highlights the improved coordination of care from the nursing intervention as more patients were able to receive their immunizations at the MS center.

Immunizing patients at the clinic ensures that patients receive the correct sequence and clear documentation before their first dose of B-cell–depleting therapy. After establishing a standardized procedure, the safety nurse then assumed the responsibility of vaccinating patients in the neurology infusion center. Once the workflow was established, the remaining infusion center nurses were trained by the safety nurse to vaccinate per protocol. This provided the clinical care manager/educator with additional time to administer vaccines in the clinic during patient office visits. Implementation of this process allowed for expansion of the vaccination program. The nurses began to cover a second neurology ambulatory care clinic for patients receiving rituximab and other high-risk medications, a nurse schedule was created with the availability to schedule patients 4 days a week at times more convenient to the patients, and additional vaccinations were administered, including influenza, herpes zoster, and meningococcal.

As a retrospective medical record review medication use evaluation, this study was limited by the information documented in the EMR. In the preintervention group, there was a larger percentage of patients with unknown vaccination status; postintervention, this number significantly decreased because part of the intervention was to confirm and document immunizations before initiation of ocrelizumab or rituximab. Improvement in documentation practices may have contributed to the differences in vaccination statuses between preintervention and postintervention groups. This study was limited by a smaller cohort of patients in the postintervention analysis given a shorter study window, with approximately 6 years for the preintervention and 10 months for the postintervention study periods. In addition, fewer participants initiated therapy as a result of concerns about the safety of starting immunosuppressive therapy during the COVID-19 pandemic. A future direction to consider is examining whether a difference in vaccination rates is observed based on patient characteristics (eg, age, sex), type of MS, and/or previous treatments.

The project highlights the value of interdisciplinary team collaboration and coordination in the care of patients with MS. This collaboration led to improved patient care and safety.

Pneumococcal Vaccination Practices in Patients With Multiple Sclerosis Receiving Anti-CD20 Monoclonal Antibodies After Pharmacy and Nursing Collaboration

Assessing motor functioning is important to monitor the disease course of multiple sclerosis (MS). Video-assisted rating of classic neurologic tests and activities of daily living may improve the detection of changes in motor functioning. We investigated the value of using video-assisted composite measures for the detection of changes in mobility and upper extremity function (UEF).

 Forty-three patients with MS were recorded performing motor function tests before and during treatment with fampridine. Patients were classified as improved or not improved on mobility composite (MOB-COM) and UEF composite (UEF-COM) measures based on neurologists’ ratings of the tests. The proportional agreements between the composite measures and the conventional measures—the Timed 25-Foot Walk test (T25FW) and the Nine-Hole Peg Test (NHPT)—were determined and compared with patient-perceived improvement, which was determined using patient-reported ratings of changes in mobility and UEF.

Agreement between MOB-COM and T25FW was 79.5%, and agreement between UEF-COM and NHPT was 82.1%. Twenty-six of 39 patients (66.7%) reported mobility improvement; 6 of these reports were confirmed by both T25FW and MOB-COM, 4 were confirmed by T25FW only, and 2 were confirmed by MOB-COM only. For UEF, 13 of 39 patients (33.3%) reported improvement; 3 of these were confirmed by the NHPT and 3 were confirmed by the UEF-COM.

Compared with the conventional NHPT measure, the video-assisted composite measure of UEF detected additional patient-perceived improvement. This was less evident for mobility measures. Video-assisted composite measures may enhance the detection of treatment effects in MS clinical practice and trials.

From the Department of Neurology, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (K-HL, CEPvM, JB, JK, BU); Neurologic Clinic and Polyclinic, Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland (MD, LK); Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland (SS, CPK); Department of Neurology, Neurology and Neurorehabilitation Center, Luzerner Kantonsspital, Lucerne, Switzerland (CPK); Microsoft Research UK, Cambridge, UK (MJ, YZ); Novartis Pharma AG, Basel, Switzerland (JD, FD). 

: Caspar E.P. van Munster, MD, PhD, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; email: c.vanmunster@amsterdamumc.nl.

*Ka-Hoo Lam, MD, and Caspar E.P. van Munster, MD, PhD, contributed equally to this paper.

 Caspar E.P. van Munster, MD, PhD, has received travel support from Novartis Pharma AG, Sanofi Genzyme, and Teva Pharmaceuticals and honoraria for lecturing and consulting from Biogen Idec and Merck Serono. Marcus D’Souza, MD, has received travel support from Bayer AG, Teva, and Genzyme and research support from the University Hospital Basel. Saskia Steinheimer, MD, has received travel support from Bayer and Merck and honoraria for consulting from Bayer, Merck, Roche, and Teva. Christian P. Kamm, MD, has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Bayer Schweiz AG, Teva, Lilly, Merck, Genzyme, Roche, and the Swiss MS Society. Jessica Burggraaff, MD, has received travel support from Novartis Pharma AG. Messrs Johnson and Zaykov are employees of Microsoft Research. Jonas Dorn, PhD; and Frank Dahlke, MD, PhD, are employees of Novartis Pharma AG. The institution of Ludwig Kappos, MD, PhD, University Hospital Basel, has received funding for research support during the past 3 years from the Department of Neurology steering committee and advisory board; consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, df-mp, Excemed, GeNeuro SA, Genzyme, Merck, Minoryx, Mitsubishi Pharma, Novartis, Receptos, Roche, Sanofi-Aventis, Santhera, Teva, and Vianex; and royalties from Neurostatus. The hospital also received funding for departmental educational activities and honoraria from Allergan, Almirall, Bayer, Biogen, Excemed, Genzyme, Merck, Novartis, Pfizer, Sanofi-Aventis, Teva, and UCB. Joep Killestein, MD, PhD, has received speaker and consultancy fees from Merck, Biogen, Teva, Genzyme, Roche, and Novartis. Bernard Uitdehaag, MD, PhD, has received consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, and Teva. Ka-Hoo Lam, MD, has disclosed no relevant financial relationships.

 This research was funded by Novartis Pharma AG.

 Data from this study were presented as a poster presentation at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 10-12, 2018; Berlin, Germany.

Clinical assessment of patients with multiple sclerosis (MS) is notoriously difficult largely due to the heterogeneous clinical symptoms.

 With the availability of increasing numbers of effective disease-modifying therapies and expanding treatment targets, selecting appropriate outcome measures is increasingly important.

 For example, in a large phase 3 trial of patients with secondary progressive MS, the effect of natalizumab on progression was assessed using various measures. Although no treatment effect was found on Expanded Disability Status Scale (EDSS) score progression, a reduction in progression of upper extremity function (UEF) impairment was detected.

 The accurate assessment of disability is also relevant in the evaluation of symptomatic treatment options such as fampridine (also called dalfampridine).

 Fampridine improves walking speed and UEF in a subset of patients with MS, albeit patient-perceived improvement does not fully correspond with improvement measured using clinical instruments.

The EDSS is the most widely used outcome measure in MS trials, although it has several limitations (eg, high interrater and intrarater variability, disproportional impact of ambulation on the total score).

 To improve the assessment of commonly affected functional domains in MS, the Multiple Sclerosis Functional Composite is used to assess ambulation (Timed 25-Foot Walk test [T25FW]), UEF (Nine-Hole Peg Test [NHPT]), and cognition.

 Despite generally good psychometric properties, the individual components have several shortcomings.

 The T25FW and the NHPT measure only certain aspects of ambulation and UEF (walking speed and manual dexterity, respectively), which do not fully capture the broader aspects of functioning. Also, the T25FW may not be sensitive enough to detect abnormalities in patients with mild ambulatory impairment.

 Because of these shortcomings, clinically relevant treatment effects might be missed.

Video-assisted assessment of motor functioning has the potential to improve disability evaluation. Recording patients’ movements on video may improve certain psychometric properties, such as intrarater and interrater variability, and promotes data quality by allowing a visual check on compliance relative to the standardization of performance.

 Also, standardized activities of daily living (ADLs) can be added to the assessment and are valuable in measuring patients’ functioning.

We investigated the additional value of video-assisted composite measures, consisting of classic neurologic tests and ADLs, in relation to conventional measures and aimed to enhance the detection of changes in mobility and UEF in patients with MS.

Written informed consent was obtained from all patients before study participation, and the study was approved by the respective ethics committees. Data used in this study were part of a multicenter project to develop the ASSESS MS system, performed in 4 large European MS centers located in Amsterdam, the Netherlands, and in Basel, Bern, and Lucerne, Switzerland.

 Patients with MS were recorded using a three-dimensional depth-sensing and color camera (Kinect, Microsoft Corp) with the aim of training machine learning algorithms to automatically quantify motor functioning.

Patients were recruited at the Amsterdam University Medical Center, Vrije Universiteit Medical Center between August 1, 2017, and April 30, 2018. Patients initiating treatment with fampridine were eligible for study participation because fampridine can have positive treatment effects on mobility and UEF.

 Inclusion criteria conformed to the official treatment label of fampridine, a diagnosis of MS according to the revised 2010 McDonald criteria,

 age older than 18 years, ambulatory impairment defined as an estimated EDSS score between 4.0 and 7.0, and no additional diseases that contributed to disability. Contraindications as stated in the fampridine product label were handled as exclusion criteria.

 Patients were assessed at baseline before fampridine treatment and at follow-up after a minimum of 2 weeks of fampridine treatment. Patient and disease characteristics were collected during the baseline visit: age, sex, EDSS score,

The T25FW was used to measure mobility, and the NHPT was used to measure UEF. Each test was performed twice during each visit, as implemented in the Multiple Sclerosis Functional Composite.

 For each visit, 2 trials were averaged for each patient. A decrease of at least 20% in baseline walking time was used to indicate significant improvement in mobility function.

 For the NHPT, trial results of the dominant and nondominant hands were averaged. Similar to the T25FW, a decrease in completion time of at least 20% between visits was used as the determinant of significant UEF improvement.

In addition to the conventional measures, the mobility composite (MOB-COM) consisted of 3 traditional neurologic tests and 4 ADLs (

Pavika Thevar, MPsych

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