Multiple sclerosis (MS) is a progressive neuroimmunologic disease of the central nervous system, characterized by multiple areas of demyelination, myelin damage and scarring, loss of oligodendrocytes, and axonal and neuronal injury to the white matter of the brain and spinal cord.1 MS is a leading cause of medical neurologic disability in younger people affecting individuals in the prime of their lives, with age of diagnosis between 20 and 50 years of age.2 MS is at least two to three times more common in women than in men.2
In the majority of patients, MS is characterized by periodic episodes of neurologic dysfunction called “exacerbations” or “relapses.” 1 Exacerbations are highly variable in their duration, frequency, and severity. As a result, the clinical course of MS varies over time and disease prognosis is unpredictable.
There are four clinically distinct subtypes of MS3,4:
- Relapsing-remitting MS (RRMS)
- Secondary progressive MS (SPMS)
- Primary progressive MS (PPMS)
- Progressive-relapsing MS (PRMS).
Each type is characterized by different patterns of symptom progression over time,3,4 as shown in Figure 1.
Approximately 85% of patients with MS are initially diagnosed with RRMS, which is characterized by clearly defined acute exacerbations with full recovery or partial residual deficit. In RRMS, the periods between exacerbations are characterized by lack of disease progression.3,5
The clinical course of SPMS is always preceded by RRMS disease. After the initial relapsing-remitting course, the disease progresses at a variable rate that may include occasional exacerbations and plateaus. Of the 85% of patients who begin with RRMS, approximately 50% will convert to SPMS within 10 years of disease onset, and 8% of untreated relapsing patients develop secondary progressive disease within 20 to 25 years.3,5
Of patients with MS, 10% are diagnosed with PPMS, which is characterized by the progression of disability from onset with no acute attacks or with occasional plateaus, remissions, or minor improvements. In PRMS, which affects approximately 5% of patients diagnosed with MS, there is progression from onset but with clear acute relapses either with or without recovery, with periods between relapses showing continued progression.3-5
Treating Multiple Sclerosis
The treatment of MS involves a combination of pharmacologic and nonpharmacologic strategies.
Lifestyle choices can also serve to alleviate the effects of some of the symptoms of MS. Proper nutrition, exercise, and stress management are all important to maintaining wellness, even in the presence of a chronic illness such as MS.6,7
Rehabilitation, which includes physical and occupational therapies, can contribute to improved mobility, activities of daily living, quality of life (QOL), and patient safety and independence for a broad range of impairments in MS. The National Multiple Sclerosis Society considers rehabilitation to be a necessary component of comprehensive, quality healthcare for people with MS, at all stages of the disease.6 Rehabilitative specialists work with patients to develop a carefully planned program of exercise, functional training, and activities designed to promote good health, general conditioning, and to reduce fatigue.6,8
MS pharmacotherapy typically involves a multipronged approach. Whenever possible, clinicians seek to manage the course of RRMS and slow its progression through the use of disease-modifying therapies (DMTs). With the exception of fingolimod and mitoxantrone, DMTs are not indicated to treat other subtypes of MS. In addition, glucocorticosteroids are prescribed to mitigate the effects of acute exacerbations. Finally, several therapies are available to treat the symptoms of MS, which include bladder disturbance, fatigue, depression, pain, and gait disturbance, to name a few. Treating the symptoms of MS can have a positive effect on the patient’s QOL.
Although considerable medical advances have been made in the treatment of MS, there are currently no therapies available that are capable of repairing the central nervous system or restoring lost neurologic function. However, DMTs can alter disease progression by reducing the number of relapses. DMTs for MS, beginning with the introduction of interferon beta-1b in 1993, fundamentally changed the treatment approach for MS. Since then, a number of additional disease-modifying agents have become available, and as of 2011, seven therapies were on the market. In 2010, the first oral DMT for MS became available.9 For maximum long-term effectiveness, DMT therapy should be started as early as possible in the course of the disease.10
Long-term adherence to DMT presents a significant challenge for patients with MS. Approximately 60% to 76% of patients with MS adhere to DMT for two to five years. However, approximately 50% of patients who discontinue DMT tend to do so within the first two years of initiating treatment.11
High-dose methylprednisolone is the most frequently prescribed medication for the short-term management of acute exacerbations, and is effective in reducing inflammation in the central nervous system, and accelerating recovery from relapses. Methylprednisolone can be administered orally or intravenously.12,13 Because there is no clear benefit based on route of administration, many healthcare providers prescribe the oral formulation, which allows patients to be treated at home. Although high-dose steroids are effective in treating acute exacerbations, they have not demonstrated any improvement in long-term outcomes.13
Although DMTs have demonstrated efficacy in preventing relapses and in delaying disease progression in RRMS, and may delay the accumulation of physical disability, they are not indicated to treat disease-specific symptoms. In fact, some patients report that they feel worse when receiving immunomodulatory therapies.14 The symptoms of MS can be debilitating and can adversely affect the patient’s ability to maintain functionality and QOL.14 Therefore, treatment of symptoms is considered to be an important component of the overall management of patients with MS.14
For patients with MS, symptoms can occur at any time. Patients may experience problems with speech, cognition, sleep, and bowel and bladder function. Up to 90% of patients with MS report fatigue.15 In addition, the majority of patients with MS experience muscle weakness in their extremities and difficulty with coordination and balance. Most people with MS exhibit transitory abnormal sensory feelings, such as numbness, prickling, or “pins and needles” sensations. Additional symptoms may include pain, spasticity, dizziness or vertigo, heat sensitivity, and vision impairment.16-19 Left untreated, individual symptoms may worsen and precipitate other symptoms, thus producing a cycle of interrelated symptoms. For example, fatigue and depression can lead to decreased exercise which, in turn, can lead to increased spasticity and constipation. Bladder dysfunction can lead to a decrease in sleep time, which can affect cognitive function and can aggravate fatigue and depression.20
The symptoms of MS are described and assessed from the patient’s perspective, and symptom evaluation is largely dependent on patient self-report and clinician/ patient interaction, which are difficult to quantify. Efficacy of symptomatic management strategies are often evaluated by patient self-report and not necessarily directly measurable using objective criteria.14
Many pharmacologic agents are available to treat the symptoms of MS. Medication selection is typically determined by the specific symptom or symptoms reported by the patient. Symptom management agents include, but are not limited to, baclofen for spasticity, oxybutynin and tolterodine for bladder dysfunction, amantidine and modafinil for fatigue, gabapentin and carbamazepine for neuralgia, and dalfampridine for walking impairment.8,21
Walking Impairment: A Common and Debilitating Symptom of MS
In a survey conducted by Heesen and colleagues (2008), walking was ranked as the most important function by the greatest proportion of patients with MS, regardless of disability type, severity, or disease duration (Figure 2).22
Patients were asked to rate 13 selected bodily functions in order of personal importance, including cognition, mood, vision, speech and communication, swallowing, upper-limb function, lower-limb function, bladder control, bowel control, sexuality, fatigue, sensory symptoms, and “other disabilities.” The survey population included patients with both short- and long-term disease duration, with 82 patients having MS for less than five years (early MS) and 80 patients having MS for greater than 15 years (long-duration MS).22
Approximately 37% of those with early MS and 27% of those with long-duration MS chose walking as their most important bodily function compared with less than 25% of patients who selected any 1 of the other 12 functions.22 Vision was ranked second among survey participants. The ratings were independent of the patients’ level or type of disability; even patients with severe mood and cognitive disability scores still tended to rate walking as their most important function.22
These results are not surprising given the importance of ambulation in normal everyday functioning. It is difficult to overstate the complexity of walking. Walking requires a great deal of central nervous system motor control. To walk, individuals must be able to maintain an upright posture against the effects of gravity. In addition, balance, coordination, equilibrium reactions, postural control, righting reactions, processing of vestibular, visual and sensory information, and sequencing of movements for smooth motor control are all critical. Finally, muscle strength (lower extremities), normal tone, and flexibility of muscles are also necessary to ensure successful walking.23-25
Measurement of Walking Impairment
A number of different tools are used to measure walking impairment in patients with MS, including the timed 25-foot walk (T25FW), the 6-minute walk, and the 12-item MS Walking Scale (MSWS-12). Although all of these metrics have some utility in measuring walking impairment, they each have limitations.
The T25FW, which is often used in clinical practice, correlates independently with the Expanded Disability Status Scale (EDSS) across disability and MS type. However, because of a floor effect, it is less sensitive for detecting differences in mildly disabled patients.26 In addition, MS roundtable participants indicated that it may not be feasible for all practices to implement the T25FW because of space limitations.
The 6-minute walk correlates well with other measures of disability and is a better measure of walking endurance than the T25FW. However, to implement the 6-minute walk, a walkway of sufficient length is needed. In addition, because it is difficult for patients with moderate-to-severe disability to walk for six minutes, it is not appropriate for all patient populations with MS.26
The MSWS-12, a patient-reported outcome measure, is more responsive than other walking-based measures, including the EDSS and the T25FW, and is used in clinical trials and clinical practice.26,27 However, as a self-reported measure, it may be perceived to be more subjective compared with observer-reported measures.
Ensuing discussions will focus on the utility of these measures, both in clinical practice and as utilization management criteria for payers.
Walking Impairment: Impact on Patients
Walking impairment can manifest early in the disease course of MS, and can have significant effects on patients, their families, employers, and the healthcare system.
A Harris Interactive survey of 1246 respondents with MS found that walking impairment occurs early in the onset of MS symptoms. Approximately two of three people with MS (65%) reported experiencing some type of trouble walking, inability to walk, and/or difficulty maintaining balance at least twice weekly. Among people with MS who have trouble walking, 70% found it to be the most challenging aspect of their MS. Of patients reporting some degree of walking impairment, 92% indicated that it had some impact on their ability to carry out daily tasks.27 In this survey, patients that experienced walking difficulty reported that it led to decreased self- esteem, decreased ability to travel, and adverse effects on their work life.28
The Patient-Determined Disease Steps (PDDS) is a validated 9-point measure that is a patient self-report instrument comparable with the EDSS. In a cross-sectional research study conducted among US MediGuard.org members aged ≥18 years, in the population of MS patients with PDDS 3 and PDDS 4, walking impairment led to significantly more falls, despite the use of a walking device (P <.01).29 Reported visits to the hospital or emergency department and office visits for severe falls increased significantly, along with higher levels of walking impairment, especially for those using a walking device (P <.01).29
Walking Impairment: Impact on Employers
Walking difficulty also negatively impacts work life for employed patients with MS. In a data analysis of the Harris Interactive survey assessing the negative impact on the lives of people with MS who experienced trouble walking, inability to walk, and/or difficulty maintaining balance at least twice weekly, 79% indicated that their work had been negatively affected by MS.30
Even mild walking impairment can adversely affect employment status. An analysis of North American Research Committee on Multiple Sclerosis (NARCOMS) registry data from 8180 patients with MS showed a significant association between unemployment and mild gait disability (P <.0001).31 The greatest loss of income occurs as patients transition from normal mobility to minimal walking impairment.31
In another study estimating the probabilities of employment status transitions among persons with MS, worsening disability, as measured by PDDS or mobility score, increased the probability of transitioning to not working compared to those with improving or stable disability. Specifically, researchers assessed the probability of transition from working full-time or part-time to not working, stratified by a 1-year change in MS severity. For patients with worsening disability, the most frequent transition was from working part-time to not working.32
For most patients, walking impairment occurs early in the onset of MS symptoms, and timely intervention gives patients the best opportunity to maintain optimal ambulation for as long as possible, given the progressive nature of MS. Conversely, lack of intervention may contribute to diminished QOL, reduced ability to work, and increased healthcare utilization.
The Future of MS Treatment
A number of additional oral and injectable agents are currently being investigated for the treatment of MS, and patients and providers alike are hopeful that 1 or more of these new therapies will represent a major clinical advance in modifying the course of the disease. The future treatment landscape of MS is expected to involve more tailored therapies, perhaps including combination therapies, as clinicians have more agents available to treat both the disease and its symptoms.33,34 Although this evolution will give rise to new treatment options for clinicians, it also will result in more coverage and management issues for the health plan and the pharmacist.
- Reynolds R, Roncaroli F, Nicholas R, et al. The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol. 2011;122:155-170.
- National Multiple Sclerosis Society. Epidemiology of multiple sclerosis. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/ who-gets-ms/epidemiology-of-ms/index.aspx. Accessed September 3, 2012.
- Lublin F, Reingold S. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996;46:907-911.
- Kieserer P, Hartung H-P. Current disease-modifying therapies in multiple sclerosis. Semin Neurol. 2003;23:133-146.
- Coyle PK. Diagnosis and classification of inflammatory demyelinating disorders. In: Burks JS, Johnson KP, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos Medical Publishing; 2000: 81-97.
- National Multiple Sclerosis Society. Rehabilitation: recommendations for persons with multiple sclerosis. www.nationalmssociety.org/download.aspx?id=132. Accessed June 12, 2012.
- National Multiple Sclerosis Society. Food for thought: MS and nutrition. www.nationalmssociety.org/download.aspx?id=149. Accessed September 12, 2012.
- Goldman MD, Cohen JA, Fox, RJ, Bethoux, FA. Multiple sclerosis: treating symptoms, and other general medical issues. Cleve Clin J Med. 2006;73:177-186.
- Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation.
- Tintore M. New options for early treatment of multiple sclerosis. J. Neuro Sci, 2009;277(suppl 1):S9-S11.
- Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10:225.
- National Multiple Sclerosis Society. Solu-Medrol (methylprednisolone). www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/ treatments/medications/methylprednisolone/index.aspx. Accessed June 6, 2012.
- Leary SM, Porter B, Thompson AJ. Multiple sclerosis: diagnosis and the management of acute relapses. Postgrad Med J. 2005;81:302-308.
- Panitch H, Applebee A. Treatment of walking impairment in multiple sclerosis: an unmet need for a disease-specific disability. Expert Opin Pharmacother. 2011;12: 1511-1521.
- Branas P, Jordan R, Fry-Smith A, et al. Treatment for fatigue in multiple sclerosis: a rapid and systematic review. Health Technology Assessment. 2000;4:1-61.
- National Institute of Neurological Disorders and Stroke. NINDS multiple sclerosis information page. www.ninds.nih.gov/disorders/multiple_sclerosis/detail_ multiple_sclerosis.htm. Accessed September 14, 2012.
- Haselkorn JK, Leer SE, Hall JA, Pate DJ. Mobility. In: Burks JS, Johnson KP, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos Medical Publishing; 2000: 323-332.
- National MS Society. Walking (gait), Balance, & coordination problems. www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/ symptoms/walking-gait-problems/index.aspx. Accessed September 12, 2012.
- Halper J, Perrin Ross A. Challenges in the treatment of mobility loss and walking impairment in multiple sclerosis. Int J MS Care. 2010;12:13-16.
- Crayton H, Heyman RA, Rossman HS. A multimodal approach to managing the symptoms of multiple sclerosis. Neurology. 2004;63(suppl 11):S12-S18.
- Ampyra [package insert]. Hawthorne, NY: Acorda Therapeutics, Inc.
- Heesen C, Böhm J, Reich C, et al. Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable. Mult Scler. 2008;14: 988-991.
- Chambers HG, Sutherland DH. A practical guide to gait analysis. J Am Acad Orthop Surg. 2002;10:222-231.
- Yim-Chiplis PK, Talbot LA. Defining and measuring balance in adults. Biol Res Nurs. 2000;1:321-331.
- Winter DA. Human balance and posture control during standing and walking. Gait Posture. 1995;3:193-214.
- Bethoux F, Bennett S., Evaluating walking in patients with multiple sclerosis. Int J MS Care. 2011;13:4-14.
- Hobart JC, Riazi A, Lamping DL, et al. Measuring the impact of multiple sclerosis on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology. 2003;60:31-36.
- Harris Interactive. Talking and Learning to Keep Mobile: A Survey About Difficulty Walking Among People with MS [poll]. Poll commissioned by Acorda Therapeutics, Inc, and the National MS Society. July 29, 2011.
- Sidovar M. Patient-reported burden of walking impairment in multiple sclerosis. Poster presented at the ISPOR 17th Annual Meeting; June 2-6, 2012; Washington, DC.
- LaRocca NG. Impact of walking impairment in multiple sclerosis: perspectives of patients and care partners. Patient. 2011;4:189-201.
- Salter A, Tyry T, Campagnola D, et al. Socioeconomic impact of early mobility impairment in patients with multiple sclerosis: results from the NARCOMS registry. Poster presented at the 61st American Academy of Neurology Annual Meeting; Seattle, WA; April 25-May 2, 2009.
- Salter AR, Moreau R, Tyry T, et al. Estimated probabilities of employment-status transitions among persons with multiple sclerosis and exploration of influential factors. Poster presented at the 62nd American Academy of Neurology Annual Meeting; April 10-17, 2010.
- Buck D, Hemmer B. Treatment of multiple sclerosis: current concepts and future perspectives. J Neurol. 2011;258:1747-1762.
- Mangas A, Coveñas R, Geffard M. New drug therapies for multiple sclerosis. Curr Opin Neurol. 2010;23:287-292.
Multiple Sclerosis Disease State Review
Treating Multiple Sclerosis: The Healthcare Provider Perspective
Management of the Multiple Sclerosis Category: An Increasing Focus for Payers
Achieving Consensus between Healthcare Providers and Payers