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New/Enlarging T2 Lesions in a Progressive Multiple Sclerosis Trial Cohort: Computer vs Human Detection

For individuals with multiple sclerosis (MS), treatment interruption can result in relapse/recurrence of the disease activity. Currently, there are no consensus guidelines about whether an abrupt stop with a short washout period or gradual tapering is better for fingolimod (Gilenya) cessation. We investigated the impact of the fingolimod discontinuation strategy on the recurrence of disease activity and the rebound occurrence of symptoms during washout.

This was a retrospective, observational, multicenter study of individuals with MS in Egypt and Kuwait. The charts of patients on fingolimod therapy were screened to collect data on the impact of drug cessation strategies on disease activity and relapse occurrence. Disease relapse after cessation was defined as a relapse that occurred in the previous 12 months despite using a first-line treatment option or 2 relapses in the previous 12 months.

In a cohort of 100 patients, 58 had an abrupt cessation and 42 had a gradual tapering. Compared with abrupt cessation, gradual tapering was associated with a significantly lower rate of disease relapse (4.8% vs 81%, respectively; 

 = .001). Abrupt cessation also resulted in increased MRI findings of new lesions (24.1%; 

 = .59); however, none of the MRI findings were significant. Other risk factors showed no significant association with disease relapse after fingolimod cessation.

Gradual fingolimod tapering is highly recommended to decrease the risk of rebound and severe disease reactivation. A prolonged washout should be avoided for lymphocyte recovery.

From the Department of Neurology (NMS, NM, HS, MN, AG, AH, NK, SH, MA, MH, SA, HES) and the Department of Pediatrics (RR), Cairo University, Cairo, Egypt; the Department of Neurology, Al-Amiri Hospital, Kuwait City, Kuwait (RA); the Department of Neurology, Minia University, Minia, Egypt (SA); the Department of Neurology, Ibn Sina Hospital, Kuwait City, Kuwait (SA, JA-H); and the Department of Neurology, Misr University for Science and Technology, Giza, Egypt (A-RA-A). 

Nevin M. Shalaby, M.D., 4th district, 7th Neighborhood, 6th October City, Giza, Egypt; 

The authors thank the study patients, hospital staff, and investigators for their active participation. Medical writing assistance and editorial support were provided by Ahmed Salah Hussein, MD, of RAY, a contract research organization. We also extend our gratitude to Dr Reham Elgarhy and Dr Fady Adel for their efforts.

 The authors have declared no relevant conflicts of interest.

 The abstract was published as an oral presentation at the 7th Middle East North African Committee for Treatment and Research in Multiple Sclerosis Congress; November 11-12, 2022; Cairo, Egypt.

Multiple sclerosis (MS) is a highly prevalent autoimmune disease. MS is a global challenge, affecting more than 2.9 million people worldwide, and its prevalence continues to rise.

 The disease involves immune-mediated attacks on the central nervous system (CNS) and is characterized by demyelination, inflammation, and degenerative changes.

 In addition to a significant impact on individuals' quality of life, it also has a considerable economic burden, ranked second among all chronic conditions in direct costs. In the United States, the total financial burden is estimated to be $2.5 billion, and individual lifetime costs exceed $4 million.

Fingolimod (Gilenya) is an oral disease-modifying drug (DMD) that works through in vivo phosphorylation, resulting in the formation of fingolimod phosphate. This phosphorylated form resembles the important, naturally found sphingosine 1-phosphate (S1P). S1P has at least 5 receptor subtypes (S1P

 is significantly expressed in B and T lymphocytes and plays a critical role in the immune system because it regulates the egress of lymphocytes from lymphoid tissues into blood circulation.

 Through high-affinity receptor binding, fingolimod phosphate can activate lymphocyte S1P

 down-regulation, thus inhibiting lymphocyte egress and reducing auto-aggressive lymphocyte infiltration into the CNS.

Treatment interruption in patients with active MS can be caused by comorbidities, disease progression, adverse events (AEs), treatment failure, and life cycle events such as pregnancy.

 This interruption can result in relapse/recurrence of the disease activity.

 After the withdrawal of a DMD (eg, fingolimod or natalizumab [Tysabri]), severe disease reactivation exceeding the pre-DMD baseline can be referred to as a rebound event even though no consensus definition of severe disease reactivation has been approved yet.

 Many reports have described increased clinical and radiographic disease activity after fingolimod cessation.

 Still, the frequency and common features of disease reactivation have not been discussed.

Results of a previous study revealed that the risk of rebound disease after discontinuation of a DMD is highest in younger patients with recent relapses or MRI activity.

 Results of another study demonstrated that neither age nor disease subtype strongly influenced rebound.

In 2018, the US Food and Drug Administration warned of potential worsening following fingolimod cessation,

 leading to the suggestion of various strategies to mitigate the risk of fingolimod discontinuation. These included tapered withdrawal (not tested yet),

 monthly pulses of intravenous methylprednisolone (IVMP) as a bridge to the subsequent therapy,

 a 3-day course of pulse IVMP 10 days after stopping fingolimod,

 However, the safety and efficacy of these approaches have not yet been fully described.

No consensus guidelines concerning the method of fingolimod cessation, whether abrupt, short washout, or gradual tapering, exist. Due to the growing evidence of a possible rebound after fingolimod cessation,

 our centers started to adopt a more cautious tapering strategy whenever feasible (ie, the discontinuation is not due to significant AEs or unplanned pregnancy) to observe the pattern of disease reactivation following discontinuation. Our objective is to investigate the influence of the gradual tapering of fingolimod on the recurrence of disease activity and the rebound occurrence of disease symptoms during the washout.

We conducted a retrospective, observational, comparative, multicenter study to collect data on individuals with MS receiving fingolimod. The study protocol was approved by the research and ethics committees of the included centers in Egypt and Kuwait (Kasr Al-Ainy MS unit of Cairo University, Egypt; MS unit at Al-Amiri Hospital, Kuwait; N-105-2021).

We screened medical records for patients receiving fingolimod between January 2011 and October 2020. Data on the impact of cessation strategies on disease activity were extracted. Baseline data, including patients' demographics, MS disease history, fingolimod use–related data, Expanded Disability Status Scale (EDSS) score before fingolimod use, and baseline laboratory values, were also collected.

Patients receiving fingolimod were divided into 2 study groups: abrupt cessation and gradual tapering. Abrupt cessation was used in nonoptimal situations such as unplanned pregnancy, the emergence of AEs related to fingolimod use, or other patient-related factors; gradual tapering was used in cases of family planning or as a response to the drug's failure for that particular person. There were 2 strategies for gradual tapering. In the Egyptian centers, patients were placed on every other day dosing for 2 weeks, then 3 times weekly for 2 weeks, then twice weekly for 2 weeks. In Kuwait, patients had every other day dosing over 1 month. The washout for switching DMDs was scheduled to last 6 weeks, but varied due to factors such as delayed conception, logistic causes, or persistence of lymphopenia for long periods.

Individuals on fingolimod therapy between January 2011 to October 2020 who met the French health authority's label indications were included in the study. Included were all patients who had highly active disease and started fingolimod as first DMD or received it after another first-line DMD due to at least 1 disease relapse that occurred in the previous 12 months, or 2 relapses that occurred in the previous 12 months and were associated with at least 1 lesion on brain MRI without passing through a complete neurological recovery.

In addition, all patients with relapsing-remitting MS or secondary progressive MS treated with fingolimod therapy at any of the included centers were included in our study if they stopped fingolimod therapy, had a washout of less than 60 days, and were older than 20 years. Patients treated with fingolimod for less than 6 months were excluded because of the inability to assess disease stability or treatment failure in such a short period of time.

The primary objective of this study was to compare the effect of gradual tapering vs abrupt cessation of fingolimod on the recurrence and rebound of MS disease activity during the washout. Secondary objectives were to observe MRI findings after the washout and determine the associated risk factors for relapses during the washout. Disease rebound for MS has been defined as severe disease reactivation exceeding the pre-DMD baseline.

Data collected from each patient's chart included baseline demographics and clinical characteristics (age, sex, smoking status, comorbidities, vitamin D levels, disease characteristics, and recovery rate from relapses), fingolimod discontinuation strategy and causes, laboratory values (including mean total leukocyte count [TLC] and mean lymphocyte count [MLC]), clinical and radiological activity after fingolimod cessation, and disease activity within the study period (including use of IVMP, use of DMDs, relapse occurrence rate, the mean number of relapses, annualized relapse rate [ARR], recovery rate from disease relapses, and MRI findings after the washout period). In addition, data from brain and spinal cord MRIs with contrast after 12 weeks of fingolimod cessation were collected to show any changes in radiological activity (new, enlarging, or enhancing lesions). Disease relapse severity was defined as a relapse that impaired quality of life and required assistance for 3 months or longer due to delayed or incomplete recovery, as per the Canadian MS Working Group's 2013 updated recommendations.

 MRI lesions were defined as either gadolinium-enhancing lesions, new/enlarging T2 lesions, or stable lesions. Stable lesions were defined as lesions that presented without any change in size or contrast intake. New or enlarged lesions were signs of active disease. MS contrast-enhancing lesions on post contrast MRI were considered markers of the inflammatory responses associated with blood-brain barrier breakdown and markers of suboptimal response to MS medications. We didn't use advanced techniques for automatic detection of active T2 lesions, but instead compared imaging 6 months and 1 year after treatment with baseline scans.

Statistical Analysis and Sample Size Calculation

We analyzed the collected patient data using IBM SPSS Statistics 26.0 software. Categorical variables were reported as frequency (n) and percentage (%); quantitative variables were reported using descriptive measures such as mean, SD, and range. A χ

 test was used to determine the association among different risk factors with relapse occurrence during the washout. A P value of less than .05 determined significance. Multivariate logistic regression analysis was used to analyze the relationship between the dependent variable (relapses, yes/no) and multiple predictors or independent variables.

Sociodemographic and Clinical Characteristics of Study Patients 

The cohort's mean age (± SD) was 36 (± 8) years. There were 77 women and 23 men, 76 individuals with low/insufficient vitamin D levels, and 26 smokers. Comorbidities were more common in the gradual tapering group (21.4%) than in the abrupt cessation group (3.4%) (

 = .005). Baseline EDSS was similar between both groups, with a median value of 2. Half of the cohort was on fingolimod treatment for more than 30 months, and 73 individuals were switched to fingolimod from another DMD. Demographic and baseline disease characteristics were comparable across study groups (

Relapse and Recovery Rates During Fingolimod Therapy 

Before fingolimod treatment, 84% of patients had a disease relapse within the previous 2 years; 45% had a relapse after beginning fingolimod therapy. The abrupt cessation group had a higher percentage of patients with an ARR of 1 or 2 during fingolimod therapy (46.6%) compared with the gradual tapering group (34.2%). Rapid recovery rates were comparable across study groups before and after fingolimod therapy. The median EDSS during fingolimod therapy was lower in the abrupt cessation group than in the gradual tapering group (medians 1.5 and 2, respectively) (

Fingolimod Discontinuation Strategies and Laboratory Findings During Washout  

Treatment-response failure was the primary cause of drug discontinuation in the abrupt cessation group (48.3%) and the gradual tapering group (45.2%); other causes included pregnancy, drug-related AEs, and other reasons (

). Causes of fingolimod discontinuation are detailed in 

Abrupt cessation of fingolimod led to higher TLC and MLC values after the washout than gradual tapering. TLC had a mean difference of 1.8 (SE , 0.3; 95% CI, 1.17-2.40) in the abrupt cessation group and 1.0 (SE, 0.35; 95% CI, 0.03-1.70) in the gradual tapering group. MLC had a difference of 0.5 (SE, 0.08; 95% CI, 0.33-0.67) in the abrupt cessation group and 0.3 (SE, 0.09; 95% CI, 0.10-0.50) in the gradual tapering group (

). The 2 groups also had significant differences in TLC and MLC after the washout. The mean TLC was 6.5 (± 1.9) in the abrupt cessation group and 5.4 (± 1.7) in the gradual tapering group (P=.007); MLC was 1.3 (± 0.5) in the abrupt cessation group and 1 (± 0.5) in the gradual tapering group (

The gradual tapering group had a significantly higher need for IVMP (21.4%) compared with the abrupt cessation group (5.2%; 

 = .01). On the other hand, the need for other DMDs was comparable between groups (3.4% vs 2.4%; 

The gradual tapering group had a significantly lower rate of disease relapse compared with the abrupt cessation group (4.8% vs 82.8%; 

 = .001). In the abrupt cessation group, more patients had new lesions (24.1%; 

 = .59) on MRI. The full details of clinical and radiological activity after fingolimod cessation are shown in 

Risk Factors Associated With MS Relapse Occurrence  

Female sex (OR, 0.37; 95% CI, 0.14-0.99), absence of comorbidities (OR, 0.09; 95% CI, 0.01-0.69), nonsmoking (OR, 0.36; 95% CI, 0.13-0.93), and abrupt cessation (OR, 0.012; 95% CI, 0.002-0.056) were found to be significant risk factors for MS disease relapse during the washout. Other factors, including age at onset, disease duration, vitamin D levels, duration of fingolimod treatment, switching to or starting on fingolimod, relapses before fingolimod, response failure on fingolimod, use of IVMP, and use of other DMDs had no significance on disease relapse (

Abrupt cessation was the only statistically significant risk factor for MS disease relapse in the multivariate logistic regression analysis (OR, 0.01; 95% CI, 0.002-0.055; P < .001), whereas female sex, absence of comorbidities, and smoking status had no significant risk (OR, 0.36; 95% CI, 0.044-2.89; OR, 0.24; 95% CI, 0.015-3.81; OR, 0.50; 95% CI, 0.06-3.81, respectively; 

Forty-nine percent of participants experienced relapses after discontinuing fingolimod, with abrupt cessation associated with a significantly higher rate of relapse occurrence (81%) than gradual tapering (4.8%). Abrupt cessation was also linked to more severe relapses and delayed recovery. Fingolimod prevents auto-aggressive lymphocytes from entering the CNS, and withdrawal leads to a rapid invasion of self-reactive T cells from lymph nodes to the blood, T-cell–dependent B-cell activation, and reduced S1P receptor actions on CNS cells.

 overexpression causes the release of inflammatory cytokines and nitric oxide, which may contribute to MS rebound after fingolimod cessation.

 Gradual tapering may release these inflammatory mediators in lower amounts, resulting in a lower risk of disease relapse (as indicated by our study results).

Another plausible hypothesis is that different types of lymphocytes have varying vulnerabilities for entrapment in secondary lymphoid organs and, thus, for facilitating recovery after fingolimod withdrawal. It has been shown that CD4+ T cells are the most susceptible to entrapment, followed by CD8+ T cells.

 Hence, CD4+ T cells are the last to recover after fingolimod withdrawal.

 During this period of consecutive lymphocytes returning to the peripheral circulation, a state of dysregulation may occur when autoreactive cytotoxic CD8+ T cells return to the peripheral circulation earlier than the regulatory CD4+ T cells, leading to inflammation and tissue damage in the CNS.

 Therefore, gradual discontinuation of fingolimod may help lessen the number of CD8+ cytotoxic T cells released into the CNS and help in the gradual repair of lymphopenia. Moreover, this may support the theory that bridging with other DMDs such as dimethyl fumarate (DMF) may also help mitigate the fingolimod rebound by depleting the CD8+ T-cell population.

New lesions on MRI after washout were found in 19% of the cohort. The development of new MRI lesions did not differ between the abrupt discontinuation and gradual tapering groups. Previous reports have shown increased MRI activity and tumefactive lesions after fingolimod discontinuation.

 In addition, multiple studies reported multiple enhanced lesions with increased disease activity on brain MRI after fingolimod cessation.

 It has been suggested that bridging with monthly pulses of intravenous steroids

 and a 3-day course of pulse IVMP 10 days after stopping fingolimod might mitigate the risk of increased disease activity after fingolimod cessation.

 In our study, 12% of participants received IVMP, and 3% were bridged with interferon beta. However, the use of IVMP or other DMDs during the washout did not affect relapse occurrence.

Previous studies suggest that baseline ARR should be considered a risk factor for disease relapse after fingolimod discontinuation.

 patients who developed a severe relapse had a baseline ARR of 1.5 compared with that of 0.8 in those who did not. However, baseline ARR was not a risk factor in cases with disease control on fingolimod (relapse-free for at least 6 months). Also, patients who had a breakthrough in fingolimod therapy had a higher risk for severe relapses after fingolimod cessation. Women had a significantly higher relapse occurrence than men, but age did not appear to be a factor. In a study by Frau et al,

 all of the patients with severe disease reactivation were women and younger than others in the study.

Fingolimod reduces lymphocyte count by 76% of the baseline value, which recovers to 80% by 3 months. Rapidly switching to another DMD without considering lymphocyte recovery can increase the risk of infection. Thus, considering lymphocyte recovery time is crucial when managing discontinuation of fingolimod. Nagy et al

 reported that patients with lower lymphocyte counts before fingolimod therapy who were pretreated with mitoxantrone were at a higher risk for prolonged lymphopenia. They also found that patients with low peripheral TLC (especially < 500/μL lymphocytes) at the time of fingolimod cessation might be at a higher risk for disease exacerbation.

 In our study, no patient had a true rebound, possibly because the mean TLC was 4.6 (± 1.6) at the time of drug discontinuation and 6.1 (± 1.9) after the washout.

Sato et al investigated the clinical and laboratory status of patients with MS who switched from fingolimod to DMF.

 Patients with disease exacerbations and patients without exacerbations all had significantly higher TLCs 4 weeks after fingolimod cessation than at baseline.

 Based on this, the researchers suggested that lower values of TLCs at fingolimod cessation should be considered a risk factor for MS exacerbations. Therefore, gradual discontinuation of fingolimod therapy, such as tiered dosage reduction or alternate-day administration, may reduce the incidence of disease exacerbation after discontinuation. These recommendations align with our study results and hypothesis that using gradual tapering for fingolimod discontinuation would decrease the risk of rebound or severe disease reactivation.

To avoid disease rebound, we only included patients with a washout of less than 60 days in our study. In our clinical practice, patients with a longer washout (> 60 days) have experienced more relapses or worsened disease status, especially those with highly active disease who require dose escalation or treatment adjustment. This observation is supported by Członkowska et al,

 who described severe disease reactivation in 3 patients with MS after 2 months of fingolimod discontinuation.

 Pardo and Jones also recommend a short washout after fingolimod cessation to avoid disease rebound,

 but the safety and efficacy of this approach are not well-defined.

In our study, over 80% of patients with MS who abruptly stopped fingolimod therapy experienced disease relapse and increased disease activity. To avoid disease relapse, our study suggests using gradual tapering with a short washout when discontinuing fingolimod. As our study only included patients with a washout of less than 60 days, additional research is needed to investigate the association between washout duration and disease relapse after fingolimod cessation. Disease monitoring and strict follow-up, especially during the first 2 months, are highly recommended for patients discontinuing fingolimod for any reason.

Impact of Fingolimod Discontinuation Strategy on Recurrence of Disease Activity in Individuals With Multiple Sclerosis

Author Nina Bozinov, MD, MS, was the first author of 

Integrating Clinical Pharmacy Services Into Comprehensive Multiple Sclerosis Care Teams: A Narrative Review of 4 Models

International Journal of Multiple Sclerosis Care

Bozinov is the director of the Kootenai Clinic Center for Comprehensive MS Care in Coeur d’Alene, Idaho, serving patients across North Idaho, Eastern Washington, and Western Montana. She is also a clinical assistant professor at the University of Washington School of Medicine.

to talk about the paper, her career path, and her research.

Integrating Clinical Pharmacy Services into Comprehensive MS Care Teams: A Narrative Review of 4 Models

.” Where did the idea come from, and how did you form the team of researchers?

It was actually pretty interesting. We used to have these…meetings that were multidisciplinary, as part of the National MS [Multiple Sclerosis] Society Health Care Council, and one of them was about pharmacy models in the clinic. Usually, the meetings [were about an hour long] and at the end of the hour, we all just wanted to keep talking about it. We were excited to discuss the challenges we found in advocating for having a pharmacy team or pharmacists within the clinic, how the models can look so different…. We wanted to show how different clinics that were all considered comprehensive MS care centers can have different ways [of integrating] pharmacy. One of the things we heard from the people who were not utilizing pharmacy is that they didn’t really understand all the roles that pharmacy could play within a clinic…. This seemed like a good opportunity for everybody to share how they were utilizing pharmacy and whether that was directly within the clinic or off-site, or as official visits that pharmacists were able to bill for or not bill for. We realized that with the unique nuances of these different clinic models, it was a great way to highlight how [integrating pharmacy] can look different.

What about this research was surprising or interesting to you?

 I would say, it is the structure of the different ways a pharmacy team can be set up. Whether or not the clinic, like my clinic, has a number of specialty pharmacists and then, perhaps, a single pharmacy technician, vs another clinic where they have maybe 1 specialty pharmacist and many pharmacy technicians. And thinking a little bit about the different ways that we can show our value, whether that’s through prescriptions, through specialty pharmacy, or whether it’s through direct billing for a clinic visit. Within each different organization, that process could look different, and certainly, as we think about even things like different state laws.

 Every time a pharmacy team is integrated into a system, it can look different based on your needs and your setup. [There’s] not one prescribed pathway [for] having a pharmacist or a pharmacy team integrated into comprehensive MS care. It has to work for the type of environment and patients and the organization that you are functioning in. There has to be flexibility…and that’s why we highlighted 4 different ways that we had it set up. However, it may look totally different for you, and you may be able to take different pieces from each of those models and figure out what works for your team, your organization, and your patients.

You’d like the clinical impact to be an empowering story of how to make a multidisciplinary team that includes pharmacy?

 Yes. I think that what I’ve seen throughout the last 5 years of working with pharmacy [is] what a critical role that they can play in patient access to disease-modifying therapies and other symptomatic medications, safety, polypharmacy, monitoring treatments, and safety monitoring. Sometimes I see that pharmacy is so separated that it ends up being more of [sending a prescription] off to a prior authorization team that you never interface with. I think it’s really important to try to take it to the next level and integrate them in some capacity into the MS care team.

Are there next steps for this line of research? Are there things that you think could or should be studied further?

 One of the biggest things that we struggled with in this paper is understanding what outcomes we could measure. Sometimes that can be tricky because of our different systems…we’re not all on the same electronic medical record system. We may have different ways of tracking things, like time to fill, time to infuse. How do we objectively show the value the pharmacy team can bring? Certainly, for a pharmacy team that is billing direct patient visits, you can show some revenue generation from that, but I think the other tricky part is, how do you show all those other things, like reduced hospitalizations because you’re more cautious with medication interactions, or capturing near misses as we think about things from a safety standpoint? Or comparing something like not having to go through step therapy, if we think it’s inappropriate for a certain patient for a disease-modifying therapy, getting earlier access to better treatment, as we know that for many people, access to high-efficacy treatments at the beginning leads to better outcomes overall. But how do you show that in a real-time clinic setting? I think if we came up with some metric to track some of these outcomes that would be important….

Throughout our conversation, you’ve talked about multidisciplinary care and how it’s integral, and you’ve even spoken about some challenges. Are there pros and cons that you see? What are the challenges to fully implementing multidisciplinary care in the MS clinic?

 I think [from the perspective of] an integration of pharmacy services, the challenges [could] include many things, simple things like space. If your clinic doesn’t have the space to have pharmacists within the clinic, they may be off-site. And so sometimes those conversations that just happen about patient care can be different when they’re talking face-to-face about the nuances vs a staff message through an electronic medical record system, or vs some other kind of messaging. If you can’t have them embedded within the clinic physically, you may miss out on some of those opportunities for them to understand the complexity of a patient situation as you’re thinking about a treatment option. Another thing that can be tricky, depending on the model, is that sometimes it is helpful to have formal clinic visits because then you have the pharmacist doing documentation in your electronic medical record system, rather than in the background where it may not be captured in the same way. I think there are a lot of nuances to different structures within that patient interaction, whether that’s more formalized as a clinic visit or a pharmacy-initiated clinic visit or something that’s more in the background.

Did you take anything from the other models in the paper?

I’m most jealous of the ability of the pharmacist to [have] face-to-face interaction with the patient, almost set up like a visit. In my model, it’s sometimes in real time. I’ll be with a patient, we’ll have a question about treatment access…or something, and thankfully, because my pharmacists are within the clinic, they can pop into my exam room with me and help address those questions. I love that aspect of our model. I think the part that I wish I had available was the ability for that pharmacist to set up and independently have more of a structured clinic visit with a patient, like some of the other models have.

How did you choose to specialize in neurology and then find your way to MS care?

 [Washington, Wyoming, Alaska, Montana, Idaho] program. I spent the first year of that program in Bozeman, Montana, and then moved to Seattle, Washington, for the next 3 years. I was paired with a mentor, and my mentor happened to be a neurologist, and so I got some early exposure to neurologic care, especially as we would go and see patients in the hospital setting…. I think that was really important, because oftentimes in those rotations, neurology ends up being something you’re not exposed to early on, and [that can] lead to fewer people going into neurology. Out of my graduating class, I think I was the only one out of more than 200 people who chose to go into neurology for residency. We definitely need more neurologists in general. Then I went to Stanford [University] for intern year and my neurology residency. As part of that, I connected with another great MS specialist, Jeffrey Dunn, [MD,] who’s the division chair, and so got to spend time in clinic within that first year of the residency. I got to see the deep connection that you can form with a person with MS, and I think that really got me interested in that comprehensive model of MS care and the treatments, whether that’s disease-modifying therapy, symptomatic management, lifestyle management, all of those aspects. I really became interested in MS early on in my residency program, and then I ended up staying at Stanford for a 2-year fellowship. I had a 

 through the National MS Society, so I did a 2-year fellowship, and also did a master’s degree in epidemiology and clinical research that allowed me to get a deeper understanding of patient-related outcome measures, which is what I did my master’s thesis on using the 

 database as part of the Accelerated Cure Project. That helped me shape how I think about patient care and research, and these outcomes that are really important for the quality of life for a person with MS. Rather than only focusing on 1 piece, [I was] focusing on that more global view. After that, I decided to come here to Coeur d’Alene, Idaho. They were looking for an MS specialist to fill the gap after the one prior had left, and it ended up just being a perfect alignment of vision because they wanted a comprehensive MS care center.

One of the hopes and goals of the WWAMI program is that people end up practicing in one of the states or regions where we that the population can be underserved. Much of the focus is on those primary care specialties, pediatrics, internal medicine, and family medicine, although we certainly know there are a lot of neurology deserts out there as well. I was the only fellowship-trained MS provider in the state until recently. There is now another one in Boise, so she’s at the bottom of the state, and I’m at the top of the state.

Is it difficult to offer care to that many people? What are the challenges and opportunities out west for an area where, like you said, there are many neurology deserts without providers?

 I’m very lucky that I have a great team. In addition to a dedicated medical assistant, I have 2 nurses who started with me 5 years ago, and [they now] have the international certification for MS care for nursing. They help a lot because treating people with MS who live in different states or live many hours away from you creates a lot of challenges, as we think about just logistics of care. Can people even get to you in the winter months? But also, not everybody can just come here for physical therapy or speech therapy or all these other discipline services. We have to think [beyond] our local referral network. How do you refer out to these other locations when [the patient has] to go some place closer to home? There’s a lot of care coordination that happens when people aren’t in your direct vicinity. And then I have an advanced practice provider who has been with me for 2 and a half years, and he helps us so we can continue to take new [patients with MS]. We basically have a shared model, so we alternate clinic visits. Instead of at some point me saying, “OK, I’m capped, I’m not able to take any more [patients],” we came up with different ways so that we could continue to have [patients with MS] get established here.

We’re also lucky that we have a physiatrist, Glen House, [MD,] a physical medicine and rehab specialist who joined our clinic over 2 years ago. It’s incredibly helpful when patients have more complex spasticity, neurogenic bowel, bladder, or ambulation issues to have that shared patient model of them following with both of us, because he has a completely different skill set than I do.

The other thing I didn’t want to do is a model where you’re only seeing patients who are on a disease-modifying therapy or have active [disease], and otherwise, primary care is following up. I think some of the approach to MS can be unique to having that MS mindset. And I do feel like even if [the patient is not on] an MS therapy, or even if people are not on medication management, there’s so much that we can do from an education perspective that I do think it can be beneficial for people to still follow an MS clinic.

It highlights the importance of multidisciplinary care. Do you have a current research project? Are you working on something in clinic?

 There’s always something to be working on in clinic! From a research standpoint, we are participating in the 

Multiple Sclerosis Implementation Network

 (MSIN) through the MSAA [Multiple Sclerosis Association of America]. It’s a patient registry. We’re one of the sites for that. And I am always looking for opportunities to participate in other kinds of research. I certainly think one of the challenges, unlike at a big MS center, is [for] things like [Expanded Disability Status Scale] raters, it’s me and my [advanced practice provider]. We don’t have multiple people to do it. Sometimes trials require a bigger staff. We do have 2 clinical research coordinators, so they help us collaborate when we participate in research studies. The other big thing I’ve been working on is we have patients fill out a lot of patient-reported outcome measures, such as the timed 20-foot walk, the Modified Fatigue Impact Scale. [We’re] trying to capture this patient experience [more] than just based on MRIs and exams. We are still working to get that implemented within our electronic medical record system, so that even if it’s a virtual patient, we could still have that information to help guide care, and so patients don’t have to necessarily come in and fill it out during their clinic visit.

That’s the advantage, I guess, of our expanding digital footprint.

 For sure. As we think about broadening our view and not just thinking about relapses, but about clinical symptoms changing over time and how to capture things like MS progression, I think we have to take all of those different pieces that are available to us [and] try to put them together, to…bring us more information. I just had a patient the other day, and she was telling me, “Well, after I did this treatment, my walking improved, but my cognition worsened,” and we were able to look back from [today] to 2021 and see how much faster her timed walk test had become, and that some of her cognitive testing had worsened over time. Having that data to track longitudinally to help support what the patient may be telling you can be really helpful.

How do you see clinical care and research meeting? How do they influence each other, and how do they interact?

 That’s a pretty big question. I think it depends on how we think about clinical care and research. I think we can think about many of those traditional models, like enrolling in clinical trials and bringing patients access to potentially newer medications that are not yet available, [and] clinical care and research can integrate that way. We can think about some of these things like the registry or understanding the patient experience, and how [they can allow] the patient to track their symptoms over time, as well as inform the clinician. I think it’s important for us to think about research integrating into clinical care because I do think it brings something to our patient experience. Circling back to that access piece, if we only have these research-related things happening at academic centers, we’re missing a big portion of people [who may have] MS. That’s why some of us are also trying to work to bring those things into our clinical practice.

: Do you have any opinion about the growing use of artificial intelligence [AI] in research, in the clinic, in any of the various ways that seem to be proliferating right now?

 I think that utilizing AI as an ancillary tool can be incredibly beneficial. I use AI [when] I’m trying to look certain things up and provide additional information, or honestly, even coming up with things like comparison charts or tables. It can be so much faster to implement those things then putting it all together ourselves, step by step, going through the nitty-gritty. Of course, like anything that we’re reviewing, we have to be mindful of making sure that that is in alignment with what we know. That’s always going to be the case. I think the key in the clinical space, or even the research space, is some of that transparency. If we’re using those things, we need to say, “Hey, here’s where I’ve used it….” I would say I’m optimistic about some of the uses because I think [AI] can help us see things, maybe like big data, that we just can’t always fully grasp. Of course, we need to continue to use our clinical acumen and judgment to make sure that we’re not misled, and just like we can have things like implicit bias, we know that artificial intelligence can also have things like implicit bias, so we just need to be very mindful as we use it.

 We need to continue to advocate for these models that seem to enhance and improve MS care. I would say they’re sometimes not the obvious models that bring in revenue, so there is sometimes a little bit of a discrepancy between knowing how to give the best MS care and helping our organizations understand why that’s important. As clinicians and other team members continue to advocate for why this is important for the person with MS and the MS care model, hopefully, we can continue to get this implemented in more MS clinics.

IJMSC Author Spotlight shines a light on the people behind the research.

IJMSC Author Spotlight: Nina Bozinov, MD, MS

Tamanna Islam and Lisa Walker discuss their paper about a clinic improvement project designed to identify mental health concerns, cognitive impairment, and fatigue for patients at a multiple sclerosis clinic.

Identifying Invisible Symptoms in Clinic: Islam and Walker

Authors Tamanna Islam, MSc, and Lisa Walker, PhD, published

 Implementation of Cognition, Fatigue, and Mental Health Screening at a Canadian Multiple Sclerosis Center: A Quality Improvement Initiative

Lisa Walker obtained her PhD in psychology at the University of Windsor. She has worked as a clinical neuropsychologist at the Ottawa Hospital for over 25 years. Walker is also a clinician investigator with the Ottawa Hospital Research Institute where she leads the Cognitive Health in Multiple Sclerosis lab. She is also a founding members of MSCanRehab, an interdisciplinary group of MS researchers and rehabilitation professionals from across Canada.

Tamanna Islam is a PhD candidate in experimental psychology at the University of Ottawa. Her research focuses on cognitive fatigability in individuals with multiple sclerosis. She has successfully defended her doctoral thesis proposal.

Authors Walker and Islam recently sat down with 

to talk about their paper, their career paths, and their continuing research.

International Journal of Multiple Sclerosis Care 

 Please introduce yourselves and tell us about how you got involved in multiple sclerosis (MS) research. 

 I am a doctoral candidate in the Experimental Psychology Program at the University of Ottawa, working under the supervision of Dr Lisa Walker. I have always been drawn to rehabilitation research, particularly the opportunity to address mental health concerns in the context of physical disability. When I was looking for mentors who could guide me in developing and implementing behavioral interventions, I came across Dr Walker’s work in MS, and I was intrigued immediately, and this is how I became involved in the field of MS.

My story is a bit of a fluke. Back in graduate school, I was working with a mentor, Byron Rourke, [PhD], and his interest was in nonverbal learning disabilities, which is, of course, far from the field of MS. Part of his theory about how nonverbal learning disabilities worked was that it had to do with white matter pathology. He was a pediatric neuropsychologist, and I wanted to work with adults. What was the adult white matter disease? At that time, it was, of course, multiple sclerosis. Since then, we certainly have learned a lot more about MS and that it’s much more than a white matter disease, but that was how I fell into it, and then I stayed in it because of the patients. They’re wonderful to work with. They’re amazingly inspiring people, and that’s what keeps me motivated to continue.

 I always love to hear people's stories, how they found their line of work, so thank you. Tell us the story of this paper. Where did the idea come from?

 We know that there’s a very high prevalence of mental health [issues], cognitive [impairment], and fatigue in people with MS, so that was the starting point in our clinic here at the Ottawa Hospital. We realized that we were probably not addressing those issues well enough. Frankly, we’re still not…but we’re working on it. Our group then did a paper that was about the gaps between research [data] and what we’re actually doing in clinic, and we realized that we were not picking up the degree of difficulties in mental health and cognitive issues in particular. We knew we had to do better. And that’s when we started looking at what we can do to improve this situation, and…one of the very simple things we can do is to put in screenings at our clinic.

 Dr Walker asked me to contribute to this project, [which] started before I joined her lab. She approached me [to see] if I could help her with the analysis and writing.

Was anything about this research surprising?

 The main surprising thing was how long it took to implement. It was a relatively simple thing, or so we thought. But of course, there are roadblocks, and one of those was how we were going to implement this in a way that works for the clinic and how we were going to integrate it with our electronic health record. That involves IT [information technology], and they, of course, have their own priorities…so it was finding the right IT person with the time to help us. Then the pandemic happened, and that threw a wrench into everything. So it became a multiyear process, which I did not expect when we started.

"Our clinic serves over 4000 patients. We have a very large catchment area, and so the physicians are already quite burdened by the tasks…to serve this great number of people. [They did not have the] ability to implement something that takes a lot of time, so we needed to find a way to do something…that was time efficient, and that’s why [we thought of] incorporating it into the electronic health record." ~LW

When I read the paper, 2 terms that I keyed into were "low burden" and "invisible symptoms." Can you talk about those concepts in relation to the paper? 

 Our clinic serves over 4000 patients. We have a very large catchment area, and so the physicians are already quite burdened by the tasks…to serve this great number of people. [They did not have the] ability to implement something that takes a lot of time, so we needed to find a way to do something that didn’t overburden them…that was time efficient, and that’s why [we thought of] incorporating it into the electronic health record. All of our patients [have an] electronic health record [with] MyChart, where they can access their own information. One of the beautiful things about MyChart is it sends reminders about upcoming appointments, and when it sends those reminders by email, it can link to questionnaires and other information that can [be] filled out before [an appointment]. It doesn’t require a staff person…. That’s the low-burden aspect of it. In terms of invisible symptoms, these are things that a great majority of people with MS experience but that are not objectively observable to other people. They don’t have a big Band-Aid on their head when they have cognitive difficulties, but [the] experience is no less impactful. In fact, we know that cognitive difficulties and mental health challenges have a greater impact on quality of life than physical disability does in MS. We needed a way to address these things, because these are the [symptoms] that are important to patients.

Could you both choose something that you would like clinicians to take away from the paper? 

Based on my experience, I have noticed that newly diagnosed people often do not realize these invisible symptoms can be related to their MS, and as a result, they do not mention [them] to their clinician. Having this formal screening in place will help both physician and patient to better address these symptoms. And I would suggest that clinicians go over the scores and see [whether] there is a consistent pattern in cognitive issues, mental health issues, or fatigue concerns and if they need extra support to address these issues.

I would add that relatively simple changes can make a big difference, particularly with regard to mental health. These changes can be lifesaving because if someone is experiencing suicidal ideation related to their depression symptoms, we can now highlight that in a timely manner and connect them with the resources they need….

"I have noticed that newly diagnosed people often do not realize these invisible symptoms can be related to their MS, and as a result, they do not mention [them] to their clinician. Having this formal screening in place will help both physician and patient to better address these symptoms." ~TI

 Do the data show that patients are up-front on the form? 

 That’s an excellent question. Psychologists are used to assessing what we call performance validity or symptom validity when we do larger psychology evaluations, [but] it’s a little bit harder to do at the level of a screening test because you really don’t know somebody’s motivation as they’re filling it out. I suppose we just have to trust [that] our patients are going to report how they feel; otherwise, they won’t be able to access the care that they need. I think people are motivated to represent themselves truthfully because they are the ones asking for support. In our clinic, we don’t have a lot of the time, but at least we have a way, a mechanism now, to connect people with adequate support.

My next question is about clinical practice and how this paper could imact it. Could you answer in 2 parts? One, have you seen an impact in your clinic already? And, two, your hopes for the future: How do you see findings like yours impacting clinical practice as a whole?

 In our clinic, we know from the data analysis that we definitely increased the number of people who are being screened for mental health issues, for cognitive impairment, and for fatigue. We also know that we have increased the amount of people who are receiving resource information, so there’s a very direct impact in our clinic.

What I hope from the paper is that it will let other clinics know that there are things that are low burden…that can be relatively easily implemented…that will allow them to not only identify the issues but, as Tamanna mentioned, monitor people over time. I think we’re moving toward using this information to help guide treatment decisions. It’s not there yet, but I think that we’re moving in that direction.

That goes right into my next question, the next steps for this line of research. What needs to be studied next?

I think the next steps in this line of research could involve exploring the impact of improved screening on patient outcomes—for example, access to better services, perceived support, day-to-day symptom management. With this initiative, we didn’t look at barriers to implementing formal screening and initiating discussions about invisible MS symptoms in clinical practice, so future studies should focus on identifying and addressing these barriers to strengthen physician and patient engagement and also to optimize screening practices.

 I also want to explore how this is working from our physicians’ perspectives. So that’s one of the next steps as well: to try to interview them about how this is working. Is it working? What are they noticing that’s different? Is it helping them to guide their treatment decision-making? So I really think that we need to have both the patient perspective as well as the frontline clinician perspective on how this is working.

 Did you have any initial feedback from clinicians, either casually or in development of the next phase?

 I think that the response has been quite positive so far. The way that we’ve set it up in the electronic health record is when someone reaches a cutoff for moderate mental health concerns, so moderate depression or moderate anxiety, they get what’s called a best practice advisory pop-up. Literally, they cannot proceed with the clinic visit until they have indicated in the electronic health record that they’ve addressed the issue, so it gives them a reminder to do it.

IJMSC: A quick curveball: I am interested in the resources. Did you find that they were easily available and you just had to gather them? For the best practice tips, was it just compiling information that's already out there and putting it into a package that was available and accessible? 

 I had a trainee help with this project, [and] we looked at the low- and no-cost options. In Canada, we have universal health care, but that has its limitations, and many services, especially with other health professions besides medicine, are not covered. Some people have extended health insurance. Some don’t, and so many of our patients are in situations where they do not have coverage for external, private services. We wanted to make sure we put in place a resource list of low- and no-cost options, so that’s what we did, and we put it on the MS clinic website, so you don’t have to talk to your physician about it. It’s there, very visible. We have drop-down menus [that] show telephone services, in-person services, distress line services, and so on. It’s quite easy to navigate for them when looking for specific resource information, and we wanted it to be as universally accessible as possible.

"In Canada, we have universal health care, but that has its limitations, and many services, especially with other health professions besides medicine, are not covered. Some people have extended health insurance. Some don’t.... We wanted to make sure we put in place a resource list of low- and no-cost options..." ~LW

As an American, I want to ask a systems question. When you say that some people don't have access, does that mean, say, going to a private mental health provider?Or does that mean that mental health providers are not included in universal coverage?

LW: It’s a complicated question, but essentially, at least in Ontario, which is the jurisdiction that I work in, we have something called OHIP, the Ontario Health Insurance Plan. Everybody who’s a resident of Ontario is covered by that plan, and other provinces have similar plans. So the MS clinic visit is free. They don’t have to pay out of pocket for that, and in our MS clinic, we have physicians, nurses, a physician assistant, but what we don’t have, because of cutbacks to the system, is social work, psychology, OT [occupational therapy], or physio[therapy]. We have a rehabilitation center affiliated with our hospital that does have physio[therapy], OT, a physiatrist, and so on, but in the actual acute care MS clinic, those services don’t exist…. Unless someone is an inpatient where they can get those services for free in the hospital setting, outpatients must pay out of pocket for many of those services, so they must go to private OT, private physio[therapy], or a private psychologist. People who have extended health insurance through their workplace or their spouse’s workplace usually have good coverage for much of that—usually not all of the cost, but much of the cost. But many people with MS are not working because of their illness. They don’t have those extended health benefits through an employer, and so they…have difficulty accessing services like that, at least from a mental health perspective. There are some community-based programs that do provide low- and no-cost options, and those are the ones that we tried to focus on in our resource list. Most people who can afford private services know how to access those, but it’s the folks who are not able to afford those that we really wanted to focus on…. I know they are very different systems.

It’s one of the things that runs constantly in the background as an international journal, but when it comes down to the particular details of each country’s system and coverage limits, coverage inclusions, it does get a bit complicated. Can you give us the 10,000-foot view of how this research fits into the larger world of MS care in general?

 It’s about trying to close that gap between research and clinical practice. There are so many amazing researchers out there doing fabulous things, and we need to move toward better implementation…. Even in our own organization, we have implementation scientists, and so we’re getting better at that, but we still have quite a way to go. This project was a good example of that. We know that mental health issues are important, we know that cognitive issues are important, but how can we actually make sure that we’re serving people in a way that they deserve to be served? That’s where we need to do better in terms of actually implementing those things into practice.

 and CMSC [Consortium of Multiple Sclerosis Centers] is multidisciplinary care, and I am interested in how it was to get IT involved in the implementation. What was it like to get someone not in clinical care involved?

 The IT people here at the hospital are used to working with health care professionals, so they do have a bit more knowledge than an IT person who works [in another field]. When we implemented this in the electronic health record…there was a lot of training that went into it with our IT people and our clinical people and trying to coordinate things. They are quite good at that, and they know things that we don’t about what might work. This best practice advisory was not something I was aware of that could happen in terms of flashing on the screen, and so they gave us information as much as we gave them information. We said, “Here’s what we want to do. We want to implement these questionnaires. We want it to go in MyChart. We want the patients to be able to access it. But what can we actually do with those data? How do we record them? How do we incorporate cutoffs and those kinds of things?” [We had] all sorts of negotiations between us in terms of how to do [what we wanted to] in a way that made sense and that was also accessible to patients…. How do we make it visually appealing? And [what] about things like font size for people with visual acuity difficulties? There’s a lot that goes into it to make the interface something that’s easily accessible.

The other aspect of the interdisciplinary nature of the project [is our team]; I’m a neuropsychologist, and Tamanna is a graduate student. We worked with physicians, nurses, the physician assistant. We also had to work with hospital administration, given that it’s sort of a [quality improvement] project. It was truly multidisciplinary.

Both of you are now pursuing other avenues of research. Ms Islam, what research are you working on now?

We just completed a needs assessment survey looking at unmet patient-reported needs in MS care, with a particular focus on cognitive fatigability. To guide the design of interventions that are responsive to what patients say they need most, we are currently testing a group-based multidimensional behavioral intervention for cognitive fatigability, so continuing our focus on invisible MS symptoms that have a big impact on daily life.

 One of the exciting things that I’m doing is working with a group called MSCanRehab. It’s a group of rehabilitation-focused MS researchers from across Canada—incidentally, all women. They’re the most amazing, brilliant, wonderful women. I have learned so much from working with them. We were fortunate to get funding from the International Progressive MS Alliance, among very few groups globally. We’re looking at pairing brain priming with either transcranial direct current stimulation and/or aerobic exercise with task-specific training for a more comprehensive rehabilitation approach. That initiative is ongoing, and we’ve just applied for stage 2 funding…. One of the other things that I’m doing with another graduate student in my lab…we’ve realized is that there’s very little research in working with the 2SLGBTQAI+ [two-spirit, lesbian, gay, bisexual, transgender, queer, asexual, intersex] community in MS…. It’s a big gap in the literature in terms of how we can better serve [them] so we are currently conducting a scoping review…and we are going to adapt [Tamanna’s needs assessment] to really get a sense of how their needs are the same [as] and different from people who are not in that community. That’s a project that I’m quite excited about.

"I feel like there are too many options when it comes to AI, so we need to be very careful which ones we’re using for which purposes. English is my second language, so I use Grammarly, and I feel like it’s reasonable to use Grammarly, but I recently attended a webinar that was organized by our hospital, and they discouraged us from using ChatGPT..." ~TI

 is focusing on this year is the influence and possible influence of artificial intelligence [AI] on clinical care in MS and research writing. I’d love to hear, from both of you, any perspective you have on it, pros and cons that you’ve seen in either area or any experience that you’ve had with it so far.

Stephen E. Jones, MD, PhD

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