As the field of neuroimmunology evolves at an unprecedented rate, keeping up with the latest advancements in diagnosis and treatment of multiple sclerosis (MS) proves challenging. Many neurologists—even those who spend most of their time in the MS space&mdash;are overwhelmed in their clinical practice and research endeavors. Therefore, I intend to set aside interleukins and cytokines, pathophysiology, and immunopathogenesis and instead share some clinical pearls to help both simplify and advance your care for patients and families affected by MS.

My goal is to share a simple approach that will serve you and your patients well, with the aim of helping patients with MS be the best version of themselves possible despite their condition. The following recommendations are based on my formal fellowship training; my 13 years of experience dedicated to MS clinical prac- tice; my review and contributions to the canon of MS literature; my participation in over 65 MS clinical trials; and, most important, the things my patients have taught me.

My rubric is straightforward. The goal is for patients to be “4 for 4” in key factors that have a significant impact on this condition. Here’s what you can do:

As the clinician, you should help the patient choose the most effective DMT they are comfortable taking. Forgo the flawed escalation model, in which providers prescribe mildly effective drugs and allow patients to accrue neurological disability before escalating them to a more effective agent. Brain lost is never regained, and early brain and spinal cord damage sets a poor long-term trajectory. It is not the clinician’s job to be paternal and decide what risk a patient should or should not be exposed to. Instead, it is the clinician’s ethical obligation to educate the patient on the seriousness of untreated or undertreated MS and help their family understand how to place the risks and benefits of the given therapeutic in the context of the disease. I cannot stress this point enough.

Once you’ve initiated treatment with an effective medication, monitor the patient by listening to them, examining them to iden- tify disability progression, and reviewing serial neuroimaging.

At each visit, ask the following treatment-related questions:

All ambulatory patients should perform a timed 25-foot walk at each visit. This single test is more predictive of progression of disability than the entire traditional neurological examination. A 20% change in timed walk is both statistically and clinically signif- icant.

 Also, each patient should be screened for cognitive impairment. I’m partial to the Symbol Digit Modalities Test because the 90-second matching quiz is extremely sensitive; in fact, a 4-point drop is statistically and clinically significant.

In addition, a magnetic resonance imaging (MRI) scan of the brain should be performed annually based on The Consortium of Multiple Sclerosis Centers protocol.

 I suggest that you personally review the scan, comparing it with the previous year’s results, and look for (1) new enhancing lesions, (2) new or enlarged T2 bright lesions, and (3) new T1 black holes and visual evidence of accelerated central atrophy (via measurement of the width of the third ventricle). I recommend imaging the cervical spinal cord every few years, even in the absence of new symptoms attributable to the spinal cord.

If the patient experiences breakthrough disease activity (new MRI lesions or clinical attacks), then discuss switching to a different highly effective DMT. Therapeutic inertia—identifying a clinical problem and not making changes to address it&mdash;contributes to poor outcomes, and both patients and practitioners are guilty of participating. I urge you to not sit idly by as your patient accrues brain damage and neurological disability.

It is equally important to not forget about invisible symptoms. If a highly effective DMT slows disability but the patient is miserable, then the clinician has not done the best job. The goal is to both slow disease activity and improve quality of life. Much of MS pathology is invisible and easily missed during a rushed clinic visit. Therefore, I recommend inquiring about invisible symptoms, including cognitive impairment, depression, fatigue, and bladder function, at each visit. When these symptoms are uncovered, I recommend they be aggressively treated.

At each visit, ask patients the following symptom-related questions:

The remaining 3 of 4 factors have to do with patient empowerment. It is now known that untreated cardiovascular risk factors drive MS disease progression faster.

 Sedentary lifestyle, obesity, hypertension, hyperlipidemia, and prediabetes must all be considered in the management of patients with MS.

Although it’s safe to assume that no one in the health care community promotes the smoking of tobacco, I am amazed at how passive our community of treaters is in fighting against tobacco use. It is imperative to educate patients that smoking increases

the risk of developing MS and, if they already have MS, speeds up disability progression.

 Smoking is the single most impactful modifiable risk factor in MS, so help patients who smoke quit by engaging them in a dialogue and connecting them with resources.

Encourage patients to move. Physical activity improves cognition, mood, energy levels, sleep quality, spasticity, and ataxia and buttresses patients against future attacks.

 Exercise programs should be customized to each patient’s interests and limitations but, ideally, address cardiovascular fitness (eg, stationary recumbent bike), balance (eg, chair yoga), core strengthening (eg, Pilates), and flexibility. In my experience, water-based exercises are excellent for patients with MS: A person weighs less in water, so moving on a weak leg is easier; if balance is off and the patient falls to the left, the water pushes back to the right. In addition, heat sensitivity is less of an issue because convection pulls heat off the body. If you are unsure where to start, consider sending the patient to a qualified neurological physical therapist who can introduce appropriate physical activity.

Although no diet to date has proved to slow MS disease progression, many diets can help improve cardiovascular disease; combat obesity; and, importantly, boost energy levels.

 I recommend a heart-healthy diet and avoiding fast food, sugar-laden foods, processed foods, and nearly unpronounceable/unrecognizable ingredients. Eating clean can lead to some amazing changes in a patient.

At each visit, ask patients the following lifestyle-related questions:

As an experienced clinician, I stand by this simple rubric to optimize the health and quality of life of a person affected by MS. If you help the patient and family embrace these 4 factors, you have changed their lives for the better.

1. Schwid SR, Goodman AD, Mcdermott MP, Bever CF, Cook SD. Quantitative functional measures in MS: what is a reliable change? Neurology. 2002;58(8):1294-1296. doi: 10.1212/wnl.58.8.1294.

2. Kragt JJ, van der linden FA, Nielsen JM, Uitdehaag BM, Polman CH. Clinical impact of 20% wors- ening on timed 25-foot walk and 9-hole peg test in multiple sclerosis. Mult Scler. 2006;12(5):594-598. doi: 10.1177/1352458506070768.

3. Benedict RH, Deluca J, Phillips G, LaRocca N, Hudson LD, Rudick R; Multiple Sclerosis Assessments Consoritum. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017;23(5):721-733. doi: 10.1177/1352458517690821.

4. 2018 revised guidelines of the of the Consortium of MS Centers MRI protocol for the diagnosis and follow-up of MS. The Consortium of Multiple Sclerosis Centers website. mscare.org/page/MRI_ protocol. Updated February2018. Accessed October 10, 2019.

5. Moccia M, Lanzillo R, Palladino R, et al. The Framingham cardiovascular risk score in multiple scle- rosis. Eur J Neurol. 2015;22(8):1176-1183. doi: 10.1111/ene.12720.

6. Jakimovski D, Weinstock-Guttman B, Gandhi S, et al. Dietary and lifestyle factors in multiple scle- rosis progression: results from a 5-year longitudinal MRI study. J Neurol. 2019;266(4):866-875. doi: 10.1007/s00415-019-09208-0.

7. Wingerchuk DM. Smoking: effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord. 2012;5(1):13-22. doi: 10.1177/1756285611425694.

8. Motl RW, Sandroff BM. Benefits of exercise training in multiple sclerosis. Curr Neurol Neurosci Rep. 2015;15(9):62. doi: 10.1007/s11910-015-0585-6.

9. Katz Sand I. The role of diet in multiple sclerosis: mechanistic connections and current evidence. Curr Nutr Rep. 2018;7(3):150-160. doi: 10.1007/s13668-018-0236-z.

10. Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: a comprehensive review. Neurol Ther. 2018;7(1):59-85. doi: 10.1007/s40120-017-0086-4. 

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Both the busy clinician and the overwhelmed patient benefit from a pointed approach to disease management.

Treating MS: A Simplified Strategy Boosts Patient and Provider Satisfaction

Multiple Sclerosis (MS) IS a chronic disease that typically begins in early adulthood, with onset during the third or fourth decade of life. Pediatric-onset MS is not common, and it is estimated that 2% to 5% of those with MS experience their first attack before age 16.

 Although the diagnosis of pediatric MS has been on the rise, experts are unsure whether the disease is becoming more prevalent or if it is being better recognized in the clinical setting.

The formal criteria for diagnosing pediatric MS was established relatively recently.

 Jonathan D. Santoro, MD, a pediatric neurologist and assistant professor of neurology at Keck School of Medicine of the University of Southern California in Los Angeles, told NeurologyLiveTM that with the development of formal diagnostic criteria for pediatric MS, there has also been an increase in the identification of incidental or isolated radiologic signs of central nervous system (CNS) demyelination in children. He explained that this upsurge is at least partially due to the greater use of brain magnetic resonance imaging (MRI) in the work-up of relatively common pediatric conditions such as migraine and concussion.

MS can have a major impact on a child’s physical, cognitive, and neuropsychological development. Mary Rensel, MD, assistant professor of medicine at Cleveland Clinic Lerner College of Medicine in Ohio, has been studying risk factors and optimal treatment strategies for pediatric MS at Mellen Center for Multiple Sclerosis, one of 12 national centers that are part of the Network of Pediatric MS Centers. Rensel told NeurologyLiveTM that MS tends to follow a more aggressive disease course and cause more frequent relapses in children than in adults, but brain recovery after an episode tends to better in children than adults. Early treatment in the pediatric population can have a major impact on the disease course and, ultimately, a patient’s physical and cognitive abilities, just as it does for adults with MS.

Because of their similarities in clinical history, symptoms, physical findings, and diagnostic test results, demyelinating episodes defined as acute disseminated encephalomyelitis (ADEM) are often also formally diagnosed as clinically isolated demyelinating syndrome (CIS).

 “In some children, episodes of ADEM or CIS are the first sign of subsequent MS, although ADEM tends to be more severe in the acute phase and less likely to be associated with a recurrence,” Santoro said. However, distinguishing MS from ADEM and CIS is not always straightforward.

Treatment of pediatric MS is often complicated by concerns about the long-term effects of therapy in children. Nevertheless, in addition to the short-term steroids and immunosuppressive therapies typically used for treating acute CNS demyelinating events, neurologists also use maintenance disease-modifying therapies (DMTs) to prevent recurrent demyelinating events in children.

 “Children [who have] MS who are treated with high-efficacy MS medications tend to do better in terms of the cumulative effects of the condition than those who are not treated with these medications,” Rensel said. That is similar to what is being observed in adults.

The FDA approved fingolimod in May 2018 for use in children over age 10—the first DMT approved for that indication.

 A pivotal trial published by Chitnis et al in the 

 compared the outcome of fingolimod with that of interferon beta-1a among a group of 215 pediatric patients (average age, 15.3 years) with MS using a primary end point of annualized relapse rate and a secondary end point of new or newly enlarged lesions on T2-weighted MRI.

 According to the results, fingolimod was associated with better outcomes in both the primary and secondary end points compared with interferon beta-1a. “Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events,” the study authors reported.

New-generation DMTs besides fingolimod are commonly used off-label in the pediatric population to manage MS, Santoro said, adding that he agrees that high-efficacy treatments are more effective than interferons in clinical practice, especially early on. The higher risk of adverse effects (AEs) associated with high-efficacy DMTs, however, can cause a degree of hesitancy in starting treatment in a child who has had just 1 demyelinating event. Furthermore, initiating a DMT in a child who has not had recurrent events eventually raises the question of when to stop the medication. This points to the value of finding measurable markers that could be used to identify the subset of pediatric patients who have the most to gain from early use of high-efficacy DMTs.

Because of the many unanswered questions regarding the long-terms effects of the disease on children and concerns regarding AEs of therapies, there is greater urgency to identify prognostic indicators that can point to the likelihood of recurrent or more severe demyelinating disease and, in turn, identify patients who require DMTs.

Santoro, who has been studying the significance of myelin oligo- dendrocyte glycoprotein (MOG) antibody, told 

 that 50% of children who present with ADEM are MOG antibody positive. The glycoprotein is involved in the myelination of nerves in the CNS; the presence of MOG antibodies is associated with demyelination, but the initial trigger for their production is not clear. “Children who seroconvert to negative have a lower risk of relapse than those who stay positive at the 6-month mark,” Santoro said. His research suggests that MOG seropositivity has complex implications in the prognosis of ADEM.

MOG antibodies are seen in a number of inflammatory disorders, suggesting that this may be an “indiscriminate biomarker,” Santoro said, with variations in the range of positivity, even among similar conditions (

 Santoro, along with coauthor Tanuja Chitnis, MD, professor of neurology at Harvard Medical School and associate neurologist at Brigham and Women’s Hospital in Boston, Massachusetts, wrote that “the rates of MOG antibody seropositivity are much higher in cases of ADEM than in cases of NMOSD [neuromyelitis optica spectrum disorder], CIS, MS, or other less defined demyelinating events such as ON [optic neuritis] or TM [transverse myelitis].”

 This suggests that MOG antibodies may be a good prognostic marker of a patient with ADEM versus CIS or MS, who is likely to not have repeated exacerbations that would eventually be seen in a person with MS, they said.

"Children (who have) MS who are treated with high-efficacy MS medications tend to do better in terms of the cumulative effects of the condition than those who are not treated with these medications," said Mary Rensel, MD.

Although there is not yet a well-defined or reliable prognostic indicator for recurrence of demyelination in pediatric MS, MOG may help identify patients whose acute demyelinating episode may indicate a non-MS disease course.

Although MOG antibodies are among the more promising biomarkers being explored to assist with differential diagnosis and prognostication of pediatric MS, other patient and disease characteristics have shown promise.

Results of a longitudinal study of pediatric patients with CIS9 suggested that female sex and multifocal onset are risk factors for a second demyelinating event. In addition, the analysis suggested that patients with multifocal or isolated spinal cord or optic neuritis involvement at onset have a significantly higher incidence of a first Expanded Disability Status Scale (EDSS) score—worsening event compared with patients with an isolated supratentorial or brainstem syndrome. In agreement with Rensel and Santoro, the study authors found that treatment with DMTs reduced both the risk of relapse and EDSS-worsening events.

Despite the relatively low prevalence of pediatric MS, the Network of Pediatric MS Centers Database is consolidating data and identifying trends that are illuminating our understanding of the risk factors and early signs of the disease. In addition to the early use of high-efficacy DMTs, lifestyle factors have been shown to modify the disease course.

 “Children with MS who consume a diet richer in vegetables have better clinical outcomes than children who consume fewer vegetables,” Rensel said. “Exposure to secondhand smoke is a strong risk factor for childhood MS, and exposure to pesticides may be a risk factor, as well.”

Although there is not a great deal of available information and consensus regarding optimal treatment strategies in pediatric MS,

 the future of managing the disease relies on multiple factors that include disease prevention, lifestyle management, and early diagnosis and treatment. Research geared toward identifying those who stand to gain the most from high-efficacy treatment would provide valuable tools for therapeutic decision making.

1. Yamamoto E, Ginsberg M, Rensel M, Moodley M. Pediatric-onset multiple sclerosis: a single center study. J Child Neurol. 2018;33(1):98-105. doi: 10.1177/0883073817739789.

2. Krupp LB, Tardieu M, Amato MP, et al; International Pediatric Multiple Sclerosis Study Group. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 defini- tions. Mult Scler. 2013;19(10):1261-1267. doi: 10.1177/1352458513484547.

3. Santoro JD, Chitnis T. Diagnostic considerations in acute disseminated encephalomyelitis and the interface with MOG antibody. Neuropediatrics. 2019;50(5):273-279. doi: 10.1055/s-0039-1693152.

4. Rensel M. Long-term treatment strategies of pediatric multiple sclerosis, including the use of disease modifying therapies. Children (Basel). 2019;6(6):pii:E73. doi: 10.3390/children6060073.

5. FDA expands approval of Gilenya to treat multiple sclerosis in pediatric patients [news release]. Silver Spring, MD: FDA; May 11, 2018. www.fda.gov/news-events/press-announcements/fda-ex- pands-approval-gilenya-treat-multiple-sclerosis-pediatric-patients. Accessed October 8, 2019.

6. Chitnis T, Arnold DL, Banwell B, et al; PARADIGMS Study Group. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379(11):1017-1027. doi: 10.1056/NEJMoa1800149.

7. Di Pauli F, Berger T. Myelin oligodendrocyte glycoprotein antibody-associated disorders: toward a new spectrum of inflammatory demyelinating CNS disorders? Front Immunol. 2018;9:2753. doi: 10.3389/fimmu.2018.02753.

8. Hacohen Y, Absoud M, Deiva K, et al. Myelin oligodendrocyte glycoprotein antibodies are associ- ated with a non-MS course in children. Neurol Neuroimmunol Neuroinflamm. 2015;2(2):e81. doi: 10.1212/NXI.0000000000000081.

9. Iaffaldano P, Simone M, Lucisano G, et al; Italian iMedWeb Registry and the MSBase Registry. Prognostic indicators in pediatric clinically isolated syndrome. Ann Neurol. 2017;81(5):729-739. doi: 10.1002/ana.24938.

10. Moss BP, Rensel MR, Hersh CM. Wellness and the role of comorbidities in multiple sclerosis. Neurotherapeutics. 2017;14(4):999-1017. doi: 10.1007/s13311-017-0563-6

Diagnoses have increased with disease awareness, highlighting a great need for markers to help influence treatment decisions.

The Need for Prognostic Indicators in Pediatric Multiple Sclerosis

Patients with multiple sclerosis (MS) experience not only physical symptoms but also an elevated risk of psychiatric comorbidities and cognitive dysfunction, according to the findings of various studies. In a systematic review published in 2015, rates of depression and anxiety were 23.7% (95% CI, 17.4%-30.0%) and 21.9% (95% CI, 8.76%-35.0%), respectively, among patients with MS.

 In other research, depression was 2 to 5 times more common among people with MS compared with the general population.

 Additional findings suggest a greater prevalence of bipolar disorder and other psychiatric illnesses in this group, as well, although research has been limited and results have been variable overall.

The authors of the 2015 review noted that the “prevalence of psychiatric comorbidity is high even at the time of MS diagnosis and rises over the course of the disease.”

 The mechanisms underlying these associations are likely multifactorial, reflecting pathophysiology of the disease—such as immunological and inflammatory changes or structural brain abnormalities that may lead to depression&mdash;and therapies used in MS treatment, along with psychosocial and other factors.

Bridging Gaps in Psychiatric and Cognitive Care

Comorbid mental illness in MS has been linked to lower adherence to disease-modifying therapy, higher levels of fatigue and pain, reduced quality of life, and increased disability progression and mortality.

 In research published in 2018 in Multiple Sclerosis and Related Disorders, approximately one-third of patients with MS reported a need for mental health treatment.

 However, factors such as time, cost, transportation, and mobility limit patients’ access to traditional in-person services, highlighting the need for more accessible modes of treatment delivery. To that end, emerging approaches using digital technology have shown promise in improving both mental health symptoms and cognitive dysfunction, which is estimated to affect more than 50% of people who have MS.

“I believe that we are on the cusp of major innovations in this space for improving both mental health and cognitive function for people living with MS,” Leigh E. Charvet, PhD, associate professor of neurology and director of MS research at NYU Langone Health’s Multiple Sclerosis Comprehensive Care Center in New York, New York, told NeurologyLiveTM. She described a few key areas of development in this setting: “First, the platforms for online connection and support are rapidly developing to provide very targeted symptom management, sometimes even in conjunction with the health care team. Second, there are increasingly sophisticated online and app-based programs that can be used for symptom reduction that have a growing body of research supporting their use.”

For example, a sizable body of research supports the benefits of mindfulness-based meditation (for which numerous digital tools are available) for people living with MS, both in reducing distress and improving mood and cognitive focus. Authors of a systematic review published in 2019 reported that mindfulness-based interven- tions were associated with statistically significant benefits related to mental health, quality of life, and certain measures of physical health in patients with MS.

 These effects were sustained at 3-and 6-month follow-up assessments. There are also well-developed digital pain-management programs that may be useful to patients.

Charvet believes that patients will soon be able to have symptoms routinely monitored from home and that telemedicine will facil- itate greater access to providers and enable in-home delivery of therapies and rehabilitation. Research by Charvet and colleagues indicates that “brain training” programs can improve aspects of cognitive functioning over time. In a double-blind, randomized trial published in 2017, the team investigated the effects of an adaptive online cognitive remediation program called BrainHQ in 135 patients with MS.

 Their results show that 12 weeks (60 sessions) of home-based training with BrainHQ improved cognitive functioning to a greater degree than an active control condition involving ordinary computer games (mean change in composite z score ± SD, 0.25 ± 0.45 vs 0.09 ± 0.37; P = .03; estimated difference = 0.16; 95% CI, 0.02—0.30 [

“[I subsequently] became very interested in the emerging technol- ogies to provide noninvasive brain stimulation to rehabilitate and manage symptoms in MS and, specifically, transcranial direct current stimulation [tDCS], due to its extensive safety and tolerability profile and portability of devices,” Charvet said. “To be effective, tDCS and most rehabilitative therapies must be repeated near daily across multiple sessions, and it is usually too much of a burden for patients to come to a clinic to receive this frequency and duration of treatment. We recently published a study demonstrating this need.”

To address the issue, she and her team developed remotely supervised tDCS (RS-tDCS), a home-based model that can be paired with cognitive or motor rehabilitation. They verified the feasibility of the approach in patients with MS, including those with greater disability who are typically unable to participate in rehabilitation studies, and found that RS-tDCS combined with home-based brain training can reduce MS fatigue and improve the effects of cognitive training.

Among the group’s additional studies under way is a large trial comparing RS-tDCS to sham stimulation for the treatment of MS fatigue and cognitive impairment. The randomized controlled trial, funded by the National Multiple Sclerosis Society, is being completed. Overall, the investigators have delivered >3500 RS-tDCS and rehabilitation sessions to patients at home thus far. “I believe that neuromodulation with noninvasive brain stimulation is a very promising nondrug option for the management and rehabilitation of MS symptoms, but careful and controlled research is still needed to provide parameters and guidelines for optimal clinical implementation,” Charvet said.

Digital Tools for Assessment and Symptom Improvement

Another development on the horizon is a collaboration between Sanofi and Happify Health to create and study a digital app based on cognitive behavioral therapy to help improve mental health symptoms in people with MS.

 “Happify Health has a successful mental health digital solution that has more than 5 years of scientific evidence showing it can reduce depression and anxiety through innovative user experiences and gamification,” a Sanofi spokesperson told NeurologyLiveTM. “This collaboration will build on its existing product to create a product specifically for people living with MS, which Sanofi aims to have validated clinically.” The company will then submit the product for approval by the FDA as a medical device that would be available by prescription.

 Patients are becoming increasingly interested in selfmanagement solutions, and “Sanofi has successfully implemented digital solutions across the business and has a deep understanding of MS therapeutic development and commercialization,” the spokesperson added.

Digital health offers a “particularly exciting” opportunity to enhance continuity of care, according to Charvet: “For instance, the MS Performance Test is an iPad assessment that can be integrated into the clinical visit to provide more comprehensive assessment for monitoring cognitive and motor functioning, as well as quality of life over time.”

Meghan L. Beier, MA, PhD, a rehabilitation neuropsychologist and an assistant professor of physical medicine and rehabilitation at The Johns Hopkins University School of Medicine in Baltimore, Maryland, further elaborated on digital tools that may be used to assess cognition in patients with MS. A range of computerized cognitive test batteries have been examined in this population, such as the Cognitive Drug Research battery, NeuroTrax (previously known as MindStreams)/BrainCare, Cogstate Brief battery, and CNS Vital Signs.

Single domain screeners are also being used, including the processing speed test.

 “These instruments are generally self-administered, meaning that patients can take them without the assistance of a testing technician, and they do very well at detecting difficulties with processing speed, the primary area of cognitive difficulty in people with MS,” Beier told NeurologyLiveTM.

She noted that gaps remain in the use of computerized cognitive assessments, including the issue of ecological validity. Further validation research will be needed before the results of existing cogni- tive assessments can be fully understood and applied. One shortcoming of the current tools is that they do not adequately assess the learning of new information, which is impaired in MS more often than the recall or recognition of previously learned information. In the future, voice recognition may be used help to overcome this limitation as the technology improves.

“The iCAMS, developed by our research team, requires the use of a testing technician, which could be a barrier to adoption; however, it accurately assesses for processing speed and learning new information,” Beier said. In a study reported in the International Journal of MS Care, she and colleagues found no significant difference in scores when comparing the iCAMS—a tablet-based version of the paper-based Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)&mdash;to the BICAMS, and the iCAMS took roughly 10 minutes less to administer.

They are also investigating the use of TestMyBrain.org compared with gold standard assessments like the BICAMS, Beier said. “The TestMyBrain.org platform is promising because the tests are free and can be accessed by anyone with a computer, and they have been validated on a minimum of 5,000 to 10,000 individuals.”

 The preliminary pilot study (which is expected to be published in the near future) demonstrated promising test-retest reliability, known-groups validity, and concurrent validity, and the team is now conducting a follow-up study to establish ecological validity.

Beier recommends that clinicians use computerized cognitive testing as screening tools but notes that, unlike a full neuropsychological evaluation, these do not adequately assess factors such as motivation, effort, and the influence of mood and fatigue. “Therefore, until these instruments are improved or refined, positive findings on computerized cognitive testing should trigger a referral to neuropsychology, as available,” she advised. “If a neuropsychologist is not available in one's area, I would consider adding standardized instruments to assess for mood and fatigue so that these elements can be captured by the clinical team.”

Telephone- and web-based mental health interventions represent another promising area of development in MS care. Dawn M. Ehde, PhD, a clinical psychologist and professor of psychology and rehabilitation medicine at University of Washington Medicine in Seattle, and colleagues have studied interventions for issues including depression and pain interference using one-on-one treatment delivered by phone

 via online platforms such as Zoom. “They have found significant results in all their studies, and individuals tend to miss fewer of the study visits and report positive experiences with the interventions,” Beier said.

The evidence thus far indicates that distance-based mental health interventions are effective and well accepted by MS patients, according to Beier. “These low-cost interventions break down the barriers that traditional psychotherapy might impose—for example, missing a significant amount of time from work to travel to in-person appointments&mdash;and allow for people to attend even if they have geographic, mobility-related, fatigue-related, or transportation-related barriers.” Some of the roadblocks to widespread adoption pertain to payer reimbursement, differences in state regulations, and ethical concerns such as how to address suicidal ideation expressed by a remote patient.

Investigators also continue to explore the use of computerized cognitive interventions. In the meantime, in-person cognitive rehabilitation remains the gold standard in this area. Therefore, if there is no notable improvement in function with computerized interventions, assessment by a neuropsychologist and/or speech pathologist could be helpful. “Again, contributing factors such as mood, fatigue, or motivation could impede progress or improvement in symptoms,” Beier said.

Charvet cautioned that many technologies on the market do not have demonstrated benefits, and those used in clinical care, as well as the assessment or therapy they deliver, should be verified first by research. “Any new technology needs to have demonstrated ability to be accessed by patients, preferably including those living with MS and including adaptation for those living with higher levels of disability,” she said. For example, the telerehabilitation platform used in her team’s research has been extensively developed and tested for its feasibility for access by people with MS across disability levels. In terms of online communities for people with MS, Beier said that it is “important that the community is based on research-validated information and therapeutic tenets and monitored for content, and preferably endorsed by the National MS Society.”

1. Marrie RA, Reingold S, Cohen J, et al. The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review. Mult Scler. 2015;21(3):305-317. doi: 10.1177/1352458514564487.

2. Feinstein A, Magalhaes S, Richard JF, Audet B, Moore C. The link between multiple sclerosis and depression. Nat Rev Neurol. 2014;10(9):507-517. doi: 10.1038/nrneurol.2014.139.

3. Orr J, Bernstein CN, Graff LA, et al; CIHR Team in Defining the Burden and Managing the Effects of Immune-mediated Inflammatory Disease. Factors associated with perceived need for mental health care in multiple sclerosis. Mult Scler Relat Disord. 2018;25:179-185. doi: 10.1016/j.msard.2018.07.043.

4. Charvet LE, Yang J, Shaw MT, et al. Cognitive function in multiple sclerosis improves with telereha- bilitation: results from a randomized controlled trial [erratum in PLoS One. 2018;13(1):e0192317. doi: 10.1371/journal.pone.0192317]. PLoS One. 2017;12(5):e0177177. doi: 10.1371/journal.pone.0177177.

5. Simpson R, Simpson S, Ramparsad N, Lawrence M, Booth J, Mercer SW. Mindfulness-based inter- ventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2019;90:1051-1058. doi: 10.1136/jnnp-2018-320165.

6. Shaw MT, Best P, Frontario A, Charvet LE. Telerehabilitation benefits patients with multiple sclerosis in an urban setting [published online July 15, 2019]. J Telemed Telecare. doi: 10.1177/1357633X19861830.

7. Charvet L, Shaw M, Dobbs B, et al. Remotely supervised transcranial direct current stimula- tion increases the benefit of at-home cognitive training in multiple sclerosis. Neuromodulation. 2018;21(4):383-389. doi: 10.1111/ner.12583.

8. Charvet LE, Dobbs B, Shaw MT, Bikson M, Datta A, Krupp LB. Remotely supervised transcranial direct current stimulation for the treatment of fatigue in multiple sclerosis: results from a random- ized, sham-controlled trial. Mult Scler. 2018;24(13):1760-1769. doi: 10.1177/1352458517732842.

9. Sanofi and Happify Health solidify collaboration around prescription DTx designed to address mental health in people with MS. Sanofi website. sanofi.com/en/media-room/articles/2019/happi- fy-collaboration. Accessed October 4, 2019.

10. Rhodes JK, Schindler D, Rao SM, et al. Multiple Sclerosis Performance Test: technical development and usability. Adv Ther. 2019;36(7):1741-1755. doi: 10.1007/s12325-019-00958-x.

11. Rao SM, Losinski G, Mourany L, et al. Processing speed test: validation of a self-administered, iPad- based tool for screening cognitive dysfunction in a clinic setting. Mult Scler. 2017;23(14):1929-1937. doi: 10.1177/1352458516688955.

12. Beier M, Alschuler K, Amtmann D, Hughes A, Madathil R, Ehde D. iCAMS: assessing the reliability of a BICAMS tablet application. Int J MS Care. In press. doi: 10.7224/1537-2073.2018-108.

13. The Many Brains Project. The Many Brains Project website. manybrains.net/. Accessed October 4, 2019.

14. Ehde DM, Elzea JL, Verrall AM, Gibbons LE, Smith AE, Amtmann D. Efficacy of a telephone-delivered self-management intervention for persons with multiple sclerosis: a randomized controlled trial with a one-year follow-up. Arch Phys Med Rehabil. 2015;96(11):1945-58.e2. doi: 10.1016/j.apmr.2015.07.015.

15. Alschuler KN, Arewasikporn A, Nelson IK, Molton IR, Ehde DM. Promoting resilience in individuals aging with multiple sclerosis: Results from a pilot randomized controlled trial. Rehabil Psychol. 2018;63(3):338-348. doi: 10.1037/rep0000223. 

A growing emphasis on access to care and ease of use drives a digital revolution in the treatment of mental comorbidities in multiple sclerosis.

Tapping Technology to Improve Mental and Cognitive Health in MS

Althought the advent of highly effective disease-modifying treatments for multiple sclerosis [MS] has greatly reduced the risk of disease relapse, it’s still important that clinicians be armed and ready to treat MS exacerbations.

Treatment with systemic steroids is backed by long-standing clinical evidence, but what about patients who have trouble tolerating high-dose steroids or whose relapses persist? In an interview with NeurologyLiveTM, Regina Berkovich, MD, PhD, an assistant professor of clinical neurology at Keck School of Medicine at the University of Southern California in Los Angeles, sat down to review current MS relapse treatment standards and reveal why clinicians might want to consider using an alternative to resolve troublesome exacerbations.

Q: Given the solid track record of corticosteroids for treatment of MS relapse, why should clinicians consider other options?

The use of corticosteroids as a first-line therapy for MS relapse is, first of all, supported by scientific evidence. The clinical experience is vast, and it has been FDA-approved since 1979. A typical dose is 1 g or 1000 mg by IV [intravenously] once a day for 3 to 7 days. Usually, the practices are 3 to 5 days; that is the most-used regimen for daily administration. Lately, we have been aware of clinical data and some publications on the use of oral systemic steroids, but when it comes to the oral steroids, they also have to be used in high dosages, which are equivalent to 1 g of methylprednisolone. In that case, they can be used as an alternative. Although they are not specifically approved with as much clinical evidence as IV steroids, they appear to be a viable option.

The reasons for using alternatives to systemic steroids in my practice are limited mostly to intolerability to the systemic steroids or lack of efficacy. I must say that the lack of efficacy of systemic steroids and the hope that other medications still may work require deeper clinical evaluations and better scientific and clinical support. However, I’m basing this completely on my professional experience, when I have patients not responding to the steroids or being steroid resistant for various reasons. We have good experience accumulated over the years that those patients may respond to corticotropin or ACTH [adrenocorticotropic hormone]. We use the ACTH gel, which is known as Acthar Gel. Some of the cases will respond to that treatment option; I think the reason is that it has a completely different mechanism of action.

Q: What makes ACTH, or corticotropin injection, different from systemic steroids?

Repository corticotropin injection, or what we used to call ACTH, was approved in 1978 after an extensive, multicenter, placebo-controlled study by James Rose, PhD, who was a professor of neurology working at UCLA [University of California, Los Angeles]. He conducted the first clinical trial in multiple sclerosis and enrolled the largest number of participants at that time...This was the first study in which the Disability Status Scale was implemented. Many clinical metrics in relapse evaluations that we now understand as classical actually came from that first study. The study looked at the effects of corticotropin, and it showed that patients treated with ACTH had faster and more robust recovery from MS exacerbation compared with placebo.

I think that the important point for us to remember is that ACTH is not a steroid. It is a hormone, but it is not a steroid. It is a protein. If we remember the HPA [hypothalamic-pituitary-adrenal] axis, we recall that it is a regulatory hormone, which is at a much higher level than cortisol. That may explain why the mechanism of action and the targets of corticotropin are much more diverse than those with the adrenal hormones, such as systemic steroids or cortisol.

Although we know that systemic steroids, cortisol, methylpred- nisolone, and prednisone have a high affinity to the glucocorti- coid receptors, ACTH—as a protein and not a steroid&mdash;has affinity to a different type of receptors, which are called melanocortin receptors. The class of melanocortin receptors represented on adrenal glands is just 1 class of 5. The other receptors are distributed through blood cells, including lymphocytes, microglia, skin, and bone tissue. Their representation is extremely widespread. We used to think that ACTH activates the adrenal glands, and the adrenal glands produce cortisol. However, that seems to be just 20% of the story or maybe even less. ACTH works on different types of receptors spread throughout the body, as well as different tissues and cells.

The mechanism of engaging the anti-inflammatory effect is also different compared with the glucocorticoid receptors. It goes deeper into the anti-inflammatory mechanisms, and as a regulatory hormone, it is expected to have a completely different immunology from the outcomes that have been shown in some of the clinical trials.

"I think that the important point to remember is that ACTH is not a steroid. That may explain why the mechanism of action and the targets of corticotropin are much more diverse than those with adrenal hormones, such as systemic steroids or cortisol," said Regina Berkovich, MD, PhD. 

Q: How would you advise incorporating treatment with repository corticotropin injection?

The use of repository corticotropin injection is mostly reserved for those cases in which we cannot use systemic steroids. Therefore, some of the comparisons between steroids and repository corticotropin injection, in terms of price and efficacy, really don’t seem to hit the target. At least in my practice, I don’t expect there to be competition between the 2. I use repository corticotropin injection when I’m restricted with systemic steroids and when systemic steroids are, unfortunately, not an option. In that situation, I consider repository corticotropin injection versus hospital admission for the plasma exchange, so that is where the comparison is going. Therefore, I think it’s important to remember that it’s a second- or third-line therapy. By definition, it means that other therapies, either tried before or contraindicated, did not show efficacy. This is a limited population of patients we’re talking about. That’s why comparison doesn’t seem to be correct.

When it comes to the dosing, my experience and my clinical recommendation would be to consider between 5 and 15 days. We’re talking about 1, 2, or, on rare occasions, 3 vials, because 1 vial is 5 mL and good for five 1-mL daily injections. It certainly can be used on a daily basis. Those patients who would need it every other day for various reasons can do that, as well. That can be decided clinically on an individual basis. My clinical experience has been that a course of 5 days or 5 mL may not be sufficient for the majority of MS-relapsing patients, and it may need to be extended to 7 to 10 days. I rarely use it more than 10 days. In my practice, I have experience giving 1 cc intramuscularly; there is evidence that it works just the same with respect to the bioavailability and pharmacokinetics compared with subcutaneous injections. It can be used intramuscularly or subcutaneously once a day.

Q: In terms of the risk-benefit ratio, for which clinical situations might repository corticotropin injection be considered?

Repository corticotropin injection is rarely, if ever, used as a first-line therapy; it should be reserved for those options or situations when systemic steroids are not feasible, are contraindicated, or failed previously. Specifically, repository corticotropin injection can be used in patients who have intolerable life-threatening adverse effects [AEs] such as steroid-induced acute psychosis. That would be the most vivid presentation of preference for using repository corticotropin injection.

The list of potential AEs of repository corticotropin injection resembles the list of potential AEs of systemic steroids. Methylprednisolone and repository corticotropin injection have the same list of psychiatric AEs; however, when it comes to the equivalent production of cortisol as a result of the stimulation of ACTH, that production is less than 3% compared with 1 g of meth- ylprednisolone, so you may expect the potential steroidogenic AEs to be just a fraction of what has been experienced in the setting of the systemic steroid use. That has been supported by my clinical experience. So those patients who, for example, had acute psychosis as an AE of the systemic steroids did not have a similar reaction in my practice when ACTH was used.

Clinical Viewpoint

The assistant professor of clinical neurology at Keck School of Medicine University of Southern California in Los Angeles sat down with NeurologyLive for a Q&A discussing using steroids as treatment for multiple sclerosis. 

Why Alternatives to Systemic Steroids Deserve a Second Look

The membership of the Consortium of Multiple Sclerosis Centers (CMSC) represents a unique model of care: the team approach (

). The ability of the multiple sclerosis (MS) center to provide expert care to patients with MS continues to grow with the advent of new medications approved for the treatment of MS. Earlier this year, both siponimod (Mayzent; Novartis) and cladribine (Mavenclad; EMD Serono) were approved by the FDA for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS in adults.

 With the addition of ocrelizumab (Ocrevus; Genentech) for the treatment of primary progressive MS, the MS clinician now has tools to tackle the progressive forms of the disease, although it is likely that more work needs to be done to prevent the associated neurodegeneration.

It is important to note that treatments for progressive forms of MS were the result of clinical trials largely performed in collaboration with MS centers that have long been the home for care of patients with more advanced disease and accumulated disability. During the past 2 decades, that model has evolved, representing the team approach to MS care along with clinical trials. It will also likely be the MS center that offers novel treatments to help stave off neurodegeneration and eventually provide the ability to reverse neurodegeneration in MS.

The neurologist’s ability to prescribe these medications highlights another growing problem in the care of MS, an issue related to the care of almost all complex medical disorders—that of cost. In addition to the steep price of medications, many other aspects of care typically delivered by the MS center also contribute to the high cost of care of these patients. This includes neuroimaging, laboratory testing, and the delivery of services such as physical, occupational, and other forms of rehabilitation that are often required by patients with MS, particularly when using a team approach. For many years, health systems tried to avoid these patients, particularly those with significant disability on government-funded insurance such as Medicare, because the reimbursement for their care did not pay well. As a result, many hospitals viewed neurologists who cared for patients with MS as an expensive luxury who would not be able to cover their salaries via the typical model of reimbursement for clinical billing.

Now MS centers are being recognized for their downstream revenue, particularly as it relates to a health system or academic medical center.

 The various factors that can make care of patients with MS expensive can be viewed in a positive light when one examines the various sources of revenue that also can be generated. The downstream revenue or contribution margin generated by the MS center can be quite lucrative for a health system or academic medical center, particularly one that has a specialty pharmacy and qualifies for Medicare 340B pricing, which allows the specialty pharmacy to obtain at a substantial discount the very expensive medications used in the treatment of MS. When one considers the potential profit from the specialty pharmacy, infusion services, radiological services, and laboratory services, it is not difficult to see how a health system or academic medical center can benefit greatly financially through the MS center that uses all these services in patient care. For example, 2 years ago, the financial contribution of a full-time clinical neurologist in an academic medical center was estimated to be $25 million if all therapies, imaging, and laboratory testing were obtained within that same medical center or health system.

When one begins to examine the contribution of these various factors to MS care, it is clear that the proverbial gorilla in the room is the cost of treatment, particularly the infused therapies that have had a dramatic impact on reducing inflammation and disease activity in MS. Twenty-five years ago, when interferon beta-1b was approved, its annual cost was $10,900. Now the annual cost for MS therapy averages $86,000.4 MS drugs have a number of factors that contribute to this cost, including the cost of the clinical trials that resulted in the approval of these drugs and also benefited the MS centers and their patients who participated in the clinical trials. Our use of these treatments over the past 25 years has resulted in many of the gains observed in the care of patients with MS. Therefore, policies that target drug

costs in MS must not restrict access to these drugs, jeopardize the quality of these treatments, or inhibit the development of novel treatments that could result in the cure of MS.

Notably, prices of MS treatments in the United States dwarf those of medications available in other industrialized countries. However, patients living in the United States typically enjoy access to new treatments before those drugs are available to patients in other countries. Ultimately, the economics of the US pharmaceutical industry benefits patients with MS by allowing earlier access to drugs and development of innovative therapies. The same regulations that result in lower drug costs in foreign markets are also the forces that lead to reduced access to those drugs and many of the innovative treatments available to patients with MS in the United States.

Surprisingly, another area that inhibits lower drug prices in the United States is lack of competition. Patients with MS are often unaware of the actual cost of their medication. This is because insurers, the government, and employers often pay directly for medications, so the true end user—the patient&mdash;does not pay the actual cost. Patients also are often sheltered from trying to find the best price because they have insurance that minimizes out-of-pocket costs. With MS drugs in particular, rebates or other programs provided by the pharmaceutical companies often contribute to the lack of transparency in pricing.

Eliminating regulatory barriers to the supply of new drugs and generics is also needed, as it could enhance the power of competitive pricing. The examples of interferon beta and glatiramer acetate have shown that generic manufacture of these molecules has not led to the kind of price reduction that one typically sees with capsules, tablets, etc. In addition, the same medication can vary dramatically in cost depending on the pharmacy. Interestingly, the cost of the 5 most common generic medications varies by up to a factor of 20. Patients with MS need to be able to shop around for their medica- tion, but how easily that can be accomplished remains to be seen.

Another issue with transparency and prescribing of expensive medications includes pharma industry payments to prescribers, which often go unrecognized by patients. Hartung et al examined the issue of manufacturer payments to the prescribers of corticotropin, an expensive medication neurologists sometimes use to treat MS exacerbations, although neurologists were not the only type of physician studied.

 The investigators found that in a group of 235 specialists who frequently prescribed corticotropin to Medicare recipients, 207 (88%) had received a payment from the drug’s manufacturer, with over 20% receiving payments in excess of $10,000. The authors noted that payments from the drug’s manufacturer correlated with the level of prescribing. Although physicians are supposed to inform patients of these types of conflicts of interest, this is likely an area where increased transparency would be beneficial. It is also likely that similar issues exist with many of the MS medications that have a high annual cost.

The Role of MS Centers in Cost Containment

Because academic medical centers are often more expensive than community neurology practices, payers need to see evidence that the increase in cost accrued at an MS center using the team approach results in benefit to the patient and reduced costs to the payer over the long term. For example, if patients cared for at an MS center had less frequent emergency department visits and hospitalizations, this would more than make up for the increased cost of going to that center. Use of patient-reported outcome measures might also be a way in which the MS center can demonstrate high-quality care and better outcomes, which may then result in enhanced productivity and reduced disability for the patient.

The CMSC will continue to advocate for patients with MS, contribute to the development of new treatments, educate care providers, and improve a care model that provides quality care.

1. Kappos L, Bar-Or A, Cree BAC, et al; EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6.

2. Montalban X, Leist TP, Cohen BA, et al. Cladribine tablets added to IFN-β in active relapsing MS: the ONWARD study. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e477. doi: 10.1212/NXI.0000000000000477.

3. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220. doi: 10.1056/NEJMoa1606468.

4. Berger JR. The financial contribution of the multiple sclerosis specialist. Neurol Clin Pract. 2017; 7(3):246-255. doi: 10.1212/CPJ.0000000000000360.

5. Hartung DM, Johnston K, Cohen DM, Nguyen T, Deodhar A, Bourdette DN. Industry payments to physician specialists who prescribe repository corticotropin. JAMA Netw Open. 2018;1(2):e180482. doi: 10.1001/jamanetworkopen.2018.0482. 

The benefits of a multidisciplinary hub for disease management can mitigate the costs.

Multiple Sclerosis Centers Offer Value

Mutliple sclerosis (MS) the most common neuroinflammatory and neurodegenerative disease in young adults, affecting over 2 million patients worldwide.

 Although the existence of regions of inflammation has been known since the initial anatomical descriptions of MS in the 19th century, the pathophysiology of MS is currently understood to involve autoreactive T and B cells mediating autoimmune damage to the myelin sheath of neurons, which causes chronic neuroinflammation and, finally, degeneration of the axon. This process ultimately affects the brain, spinal cord, and optic nerves.

 The central nervous system (CNS) inflammation that characterizes MS is also associated with gliosis, oligodendrocyte loss, and eventual brain volume decrease, with axonal degeneration thought to be responsible for progressive neurological dysfunction.

The clinical manifestations of MS vary depending on the affected part of the CNS and may include sensory abnormalities such as paresthesia, movement disorders, muscle weakness, muscle cramps, sphincter dysfunction, visual disturbances, speech disorder, and cognitive impairment.

 Although there are no cures for MS at present, the treatment landscape has changed significantly, with over a dozen approved disease-modifying therapies (DMTs) representing multiple classes of agents with different mechanisms of action.

 DMTs attempt to alter the disease course by improving function, managing symptoms, and preventing or slowing disease progression, as well as preventing new episodes of MS-associated dysfunction and arresting the development of further neurological disabilities.

 Although previously underappreciated, B cells, as key mediators of humoral immunity, have emerged as a central target of effective MS therapeutics. The current place of B cell—targeted agents in MS is highlighted by the significant clinical benefit observed with anti-CD20–mediated B-cell depletion in clinical studies of patients with MS.

The precise mechanistic and causal underpinnings of MS are currently incompletely understood; however, a combination of effects mediated by infectious agents, environmental exposures, and genetic factors are thought to affect MS pathogenesis. For instance, observational studies suggest association of increased MS risk with lower sun exposure in childhood and lower 25-hydroxyvitamin D levels in white populations.

 Other factors that have been considered in studies of MS susceptibility and prognosis include viral infections, obesity, and tobacco exposure, with strong associations noted for prior Epstein-Barr virus infection and cigarette smoking.

Among genetic factors, certain human leukocyte antigen (HLA) class I and II alleles have been shown to contribute to MS susceptibility, with the HLA-DRB1*15:01 allele exhibiting one of the strongest associations with MS risk (odds ratio, ~3).

 Genome-wide studies have identified gene variants encoding proteins involved in immune responses as important contributors to MS development, further substantiating the view of MS as an immune-medi- ated disorder.

 Currently, over 100 non—major histocompatibility complex variants associated with MS risk have been identified at 103 genetic loci through genome-wide association studies. The cumulative contribution of these genetic variants to MS risk is estimated at 30%, although this may be revised with discovery of additional loci and variants.

The disease course of MS has been described based on 4 basic clinical types, with associated modifiers, by the United States—based National Multiple Sclerosis Society. These include clinically isolated syndrome, which is the first episode of neurologic symptoms characteristic of MS (CNS inflammation and demyelination) but does not fulfill the diagnostic criteria for MS because no further episodes may occur; relapsing-remitting MS (RRMS), the most common disease course, characterized by clearly defined episodes of new

or increasing neurologic symptoms (relapses or exacerbations), followed by remissions; primary progressive MS (PPMS), characterized by worsening neurologic function from symptom onset in the absence of early relapses or remissions (ie, no initial RRMS course); and secondary progressive MS (SPMS), which involves progressive worsening of neurologic function following an initial RRMS course.

 Disease course modifiers indicate whether activity (clinical relapses and/or new lesions on magnetic resonance imaging [MRI]) and progression (clinically evaluated level of disability) are present within 1 of the above 4 clinical types.

 The goal of adding modifiers to the clinical types is improved assessment of progres- sion and the development of an appropriate therapeutic plan, with greater activity/progression and increasing number or frequency of relapses warranting escalation of treatment.

The role of B cells in MS pathophysiology has long been supported by several key findings: B cells are present in MS plaques and in meningeal follicles of patients with SPMS; oligoclonal bands (OCBs) are secreted by B and plasma cells and are present in the cerebrospinal fluid (CSF) of over 90% of patients with MS, where they persist throughout the course of the disease; and variants of some B cell— specific genes, such as TNFSF13B, which encodes the BAFF cytokine, have been associated with increased MS risk.

 These emerging concepts describe a broader and more central antibody-indepen- dent role of B cells in MS pathogenesis and progression.

Peripheral mature B cells can cross the blood—brain barrier (BBB) into the CNS and also traverse the blood–CSF barrier.

 In the CNS, a restricted number of expanded clones of B cells and plasma cells are thought to generate immunoglobulins and form the OCBs characteristic of MS.

 These B-cell clones persist within the CNS and can undergo dynamic shuttling between different CNS compartments and the periphery, enabling transport, processing, and presentation of CNS antigens, and trigger CNS-targeted inflammatory responses (

B cells mediate MS pathogenesis through several mechanisms, including antibody production, antigen presentation, activation of T cells, cytokine production, and formation of ectopic germinal centers.

 Antibodies in the OCBs characteristic of MS primarily recognize ubiquitous intracellular proteins, rather than specific antigens that are shared across MS patients, suggesting that a B cell—driven humoral response to debris from dead cells, and not a primary pathogenic response, is involved in MS pathogenesis.

Despite the lack of a pathogenic contribution of B cell—derived antibodies, B cells may help generate and maintain pathogenic T-cell repertoires in patients with MS through promotion of T-cell tolerance and autoproliferation, via their antigen-presenting functions.

 Autoproliferation of T cells was found to be higher in patients with MS, driven by memory B cells in an HLA-DR haploype—dependent manner; this effect could be counteracted by treatment with anti-CD20 therapy.

 Myelin-reactive memory B cells have been detected in peripheral blood samples of patients with MS, acting as antigen-presenting cells in response to the presence of myelin antigens such as myelin basic protein and myelin oligodendrocyte glycoprotein, supporting the role of this B-cell subset in MS pathogenesis.

 Memory B cells also express high levels of CD20, and CD20-directed antibody treatment has been shown to deplete these cells, followed by gradual repopula- tion, coincident with attenuation of MS-specific disease activity in treated patients.