Informing Decisions to Improve the Continuum of Care in Relapsing-Remitting Multiple Sclerosis

Informing Decisions to Improve the Continuum of Care in Relapsing-Remitting Multiple Sclerosis Mirla Avila, MD Texas Tech University Health Sciences Center, Lubbock, Texas Abstract Disease-modifying therapy (DMT) can stall the disabling effects of multiple sclerosis (MS), but it also can cause serious adverse events and disrupt patient lives. During the joint 28 th Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the 19 th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), experts in MS discussed the risk factors for development and progression of the disease, current treatment regimens, factors that affect optimal therapeutic outcomes, scenarios of relapsing-remitting MS that may demand a change in therapy, and strategies to improve patient compliance. Two case studies touched upon important issues that affect MS therapy. An open, honest relationship between the healthcare provider and patient is tantamount to maintaining motivation and adherence. To improve compliance, physicians must provide continuous education and reinforce the long-term value of treatment. T he diagnosis of multiple sclerosis (MS) may be challenging. Findings on physical examination or clinical symptoms may be subtle, and imaging is not always specific. Further, the differential diagnosis of possible demyelination is somewhat extensive. The diagnostic McDonald criteria for MS have been revised several times, with the most recent version made available in 2010. 1 Patients may present in early stages with clinical isolated syndrome (CIS), in which the risk of conversion to MS and the need for treatment must be stratified. In radiologically isolated syndrome (RIS), abnormal magnetic resonance imaging (MRI) findings suggestive of MS may lead patients to seek a second opinion; in these cases, the need for treatment or further workup should be individualized. During the joint 28 th Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the 19 th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), experts discussed many issues related to the initiation of MS therapy and a possible need to change treatment strategies for individuals with relapsing forms of MS. They also described strategies for encouraging patient adherence, monitoring the safety and efficacy of treatment, and following patients with CIS or RIS. n BALANCING THE RISKS AND BENEFITS OF THERAPY Based on a presentation by Scott D. Newsome, DO, Director of Neurology Outpatient Services, Johns Hopkins Neuroimmunology and Neuroinfectious Diseases, Johns Hopkins Hospital, Baltimore, Maryland. MS is an immune-mediated disease associated with demyelination of nerves in the central nervous system (CNS), inflammation, axonal loss, and neurodegeneration. It is characterized by multiple focal areas of myelin loss called plaques or lesions. 2 Demyelination is accompanied by varying degrees of gliosis, inflammation, and axonal loss and preservation. Recent pathologic and imaging studies have shown that lesions are not confined to the white matter; cortical involvement also has been confirmed. 3 5 MS is the most common nontraumatic cause of disability in young people. Its etiology is believed to be multifactorial. Risk factors for MS include the latitude where the person resided during the early years of development, with higher latitudes associated with a greater likelihood of developing the disease. Other risk factors include prior viral infections, smoking, low vitamin D levels, obesity in children, environmental exposure to precipitating factors, and genetic predisposition. Types of MS The natural history of the disease depends upon the type of MS encountered Dr. Avila is a Resident in the Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas. 28 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

on presentation. CIS, the initial stage, may present as an isolated episode or a condition secondary to other disorders affecting the white matter. Typical presentations include optic neuritis, internuclear ophthalmoplegia, and spinal cord involvement. The most common form of MS (85%) is relapsing-remitting MS (RRMS). During its early stages, it is associated with inflammation. With time, the inflammatory component may dissipate, and patients may develop a more progressive stage known as secondary-progressive MS (SPMS). An MS attack is defined as a patientreported symptom or objectively observed signs lasting at least 24 hours in the absence of fever or infection. 1 Although CIS usually is monosymptomatic, it may be polysymptomatic. When MS seems to be the best explanation for the clinical picture, the 2010 revision of the McDonald criteria 1 should be applied. It is not always easy to identify patients who may develop MS in the future or who would remain monophasic. Diagnosis An early brain MRI scan is the most important test for patients with CIS who present with optic neuritis, as the presence or absence of multifocal brain lesions predicts the likelihood of developing MS, and the overall lesion burden correlates with prognosis. 6 Data from the Optic Neuritis Treatment Trial (ONTT) showed a 38% risk of developing MS 10 years after an initial diagnosis of optic neuritis. 7 Patients with abnormal MRI findings have a higher risk of developing MS, depending upon the number of lesions observed. Results of the London Cohort Study showed that the presence of at least five lesions on brain MRI predicted an 85% risk of conversion to MS. 6 The ONTT results showed a 10-year risk of developing MS of 56% when at least one lesion was discovered on brain MRI (Table 1). 7 The most current criteria for MS allow diagnosis at the time of presentation of CIS if the brain MRI findings fulfill certain typical characteristics and no disorders mimicking MS are suspected. Factors associated with more aggressive MS vary TABLE 1 Probability of Developing Multiple Sclerosis After Diagnosis of Clinically Isolated Syndrome MRI findings 5 years 10 years 15 years Normal 16% 22% 25% Abnormal 42% 56% 72% MRI = magnetic resonance imaging Source: Optic Neuritis Study Group 7 TABLE 2 Factors Associated with a More Aggressive Multiple Sclerosis Course Clinical factors Male gender Older age at onset African-American race Motor involvement Cerebellar involvement Frequent relapses and poor recovery Multifocal involvement at onset Sphincter involvement Paraclinical factors High lesion burden on MRI at presentation Two gadolinium-enhancing/new T2 lesions or two or more T1 lesions Two spinal cord lesions Brain atrophy Low vitamin D levels MRI = magnetic resonance imaging Adapted from a presentation by Scott Newsome, MD and include male gender, a high burden of MRI lesions at presentation, older age at onset, spinal cord lesions, and the presence of at least two gadolinium-enhancing lesions on MRI (Table 2). Treatment The treatment of MS has evolved considerably over the past 2 decades. Since the first effective treatments for MS became available in the 1990s, their use has continued to alter the natural course of the disease. MS patients now have both injectable and oral therapeutic options, which have proven to lead to fewer relapses when compared with placebo. Treatment of MS should be individualized, and risk and benefits always should be discussed with patients and their families. The best drug regimen is the one a patient most likely would adhere to, and this can vary from patient to patient. Several drug regimens are recommended for high-risk patients with CIS. These regimens include 30 µg of interferon β-1a injected intramuscularly (IM) once a week, 22 or 44 µg of interferon β-1a injected subcutaneously (SC) 3 times a week, 250 µg of interferon β-1b injected SC every other day, and 20 mg of glatiramer acetate injected SC once daily. With new therapies becoming available to treat MS, including oral choices (fingolimod, teriflunomide, and dimethyl fumarate), therapeutic options are becoming more complex. Treatment choices depend on a full understanding of a patient s clinical condition, perceived understanding of what is important for the patient, and the goals of therapy. Consideration of these factors results in an individualized, personal approach to treatment with the greatest chance of being successful. Adverse Events Side effects of disease-modifying theries (DMTs) and laboratory monitoring should also be considered and explained in detail to each patient. The risks of adverse events related to the use of DMTs can be categorized in three ways. Lowerrisk therapies (interferon β, glatiramer acetate, and dimethyl fumarate), in general, have fewer or less severe side effects than other DMTs. Moderate-risk therapies include fingolimod, teriflunomide, and natalizumab when used for < 24 months of treatment in patients testing positive for John Cunningham virus (JCV) antibody. Higher-risk therapies include mitoxantrone, which has been linked to cardiac toxicity and acute myelogenous leukemia, and the use of natalizumab for 24 months or longer in JCV antibody positive patients. Thus, a wide range of agents are available to treat RRMS, and even more are anticipated in the near future. Low-risk CIS warrants monitoring, whereas early treatment should be considered for highrisk CIS. No one-size-fits-all treatment is available; the duration of therapy, course, burden of disease, and risk of disease progression should be considered when formulating a treatment plan. T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 29

n CASE 1: INITIAL DIAGNOSIS AND TREATMENT OF A PATIENT WITH SUSPECTED MS Based on a presentation by Bruce A. Cohen, MD, Professor, Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. At the joint 2014 CMSC/ACTRIMS meeting, an expert panel and the audience selected case studies for analysis and discussion. The first case study involved the initial diagnosis and treatment of a patient suspected of having MS. History A 32-year-old woman was referred for neurologic testing after abnormal brain MRI findings were observed. She had occasional migraine headaches since adolescence but recently experienced headaches several times a month. Her primary care physician ordered an MRI to rule out a tumor or vascular anomaly. Probing questioning elicited no history of neurologic symptoms other than headaches and some associated visual scintillations. Otherwise, she was healthy. The results of the neurologic examination were normal. A brain MRI scan showed 10 T2 lesions in the periventricular and central hemispheric white matter; 3 lesions were ovoid and had the appearance of Dawson s fingers. One lesion was juxtacortical, and none of the lesions were enhanced by contrast. A cervical MRI was normal, and there were no serologic or metabolic abnormalities. Analysis This case illustrates one of the frequent dilemmas faced by neurologists. A patient with RIS has imaging findings suggestive of MS in the absence of clinical symptoms that are not better explained by the presence of another medical condition. 8 This dilemma has become more frequent, since MRI scans increasingly are performed to characterize headache, damage from motor vehicle accidents, and other brain conditions. This practice has resulted in the identification of incidental CNS abnormalities that may have a nonspecific appearance or that may suggest the presence of an underlying demyelinating pathology. Patients with RIS should undergo further testing, including additional MRI studies such as a cervical MRI scan. An MRI scan of the spinal cord may better identify dissemination of whitematter lesions and improve diagnostic sensitivity than can a brain MRI scan alone. Spinal cord lesions typical of MS are associated with little or no cord swelling, unequivocal hyperintensity on T2-weighted sequences, size 3 mm but less than two vertebral segments in length, and focal location (ie, lesions present in only part of the spinal cord). In the initial study, Okuda et al 8,9 identified radiologic progression in 24 of 41 patients (59%) over a median follow-up of 2.7 years. Conversion to CIS or clinically definitive MS occurred in 30% of these individuals over a median of 5.4 years. The Neuroimaging has made the single greatest impact on our current understanding of MS and its treatment. presence of spinal cord lesions has been identified as a risk factor for conversion to clinical disease. 8,9 In all, 84% of those having silent intramedullary lesions in the cervical spinal cord had a clinical demyelinating syndrome within a median of 1.6 years. 9 Evidence of new radiologic lesions is seen in about two thirds of patients with RIS. Management of these patients remains controversial. Patients with RIS should be followed closely for the development of symptoms. Most experts recommend reimaging after about 6 months; new T2 lesions or gadolinium-enhancing lesions would demonstrate dissemination in time and space, making an MS diagnosis more likely. Factors influencing the decision to treat such patients include lesion location, presence of cerebrospinal fluid markers suggesting MS, and lesion size. Treatment should not begin if the MS diagnosis is still in question, but patients should continue MRI surveillance. Patients should be instructed that symptoms lasting for > 24 hours suggest MS relapse (the so-called 24-hour rule) and should be informed about the risk of conversion to MS. Decisions about treatment should be individualized, and patient preference should always be considered. In conclusion, neuroimaging has made the single greatest impact on our current understanding of MS and its treatment. MRI is currently used to diagnose MS; it helps physicians evaluate the effect of new MS treatments more efficiently in clinical trials and follow patients on and off treatment. The increasing use of MRI to evaluate other conditions has resulted in the identification of incidental whitematter changes; factors associated with conversion to CIS or definitive MS include lesion location (particularly, spinal cord involvement) and morphology of lesions. Further studies investigating prognostic factors to help guide treatment decisions are needed. n MS THERAPEUTIC STRATEGIES: WHAT TO USE, IN WHOM, WHEN TO SWITCH Based on a presentation by Robert Bermel, MD, Staff Neurologist and Medical Director, Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, Ohio. The treatment of MS continues to evolve from the current parenteral and oral immunomodulating drugs. Over the past 21 years, physicians have acquired a considerable selection of different therapies to choose from. Early treatment is important to reduce future disability and burden of disease. Unfortunately, no biomarkers currently are available to predict the efficacy of a specific treatment in a particular patient. Further, available treatments have been tested in similarly designed clinical studies; the outcomes of head-to-head comparison studies would yield valuable information for treatment of MS patients. Symptomatic management and wellness also play an important role in MS treatment. Options for treatment of RRMS are listed in Table 3. Although we 30 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

cannot yet predict the best treatment for a particular patient, we can predict which treatment is best suited for that patient. It is important to have a good understanding of available agents and their efficacy and safety. Importantly, physicians must discern the best use of an available DMT to maximize benefit and minimize harm in controlling RRMS. Factors to Consider Some important factors to consider when choosing MS treatment are disease severity and burden; recovery from prior relapses; disease activity, including relapse frequency; and the presence and extent of MRI-enhancing lesions. In addition, physicians must find out what previous medication the patient has used, what his or her JCV antibody status is, what the patient s tolerance and risk for side effects are, and which personal factors (eg, intent to become pregnant) the patient has. Making a Selection Physicians should guide patients toward decision-making and not overwhelm them with every treatment option available. With each patient, physicians should discuss what is expected from current therapy and how desired results will be achieved. Communication with patients is one of the most important tools available to clinicians. Understanding patient needs and considering individual goals lead to better adherence to treatment. Treatment objectives include reduction of disease progression (eg, clinical and MRI activity), with no worsening in the Expanded Disability Status Scale (EDSS) and no identification of new T2 or gadolinium-enhancing lesions on MRI. A Need for Change? Nonadherence to treatment is one of the most common reasons for transitioning a patient from one DMT to another. Other reasons include development of relapses and identification of gadoliniumenhancing lesions with clinical or subclinical activity. A change in therapy is recommended when changes in physical or neurologic TABLE 3 Current Options for Treating Relapsing- Remitting Multiple Sclerosis Injectable drugs Interferon β-1b, SC every other day Interferon β-1a, IM once a week Interferon β-1a, SC three times a week Glatiramer acetate, 20 mg SC once daily or 40 mg SC three times a week Peginterferon β-1a, SC once every 14 days Oral drugs Fingolimod, once a day Teriflunomide, once a day Dimethyl fumarate, twice a day Intravenous infusions Natalizumab, once a month Mitoxantrone, once every 3 months SC = subcutaneous; IM = intramuscular Adapted from a presentation by Robert Bermel, MD findings denote disability progression or when the presence of neutralizing antibodies to the present treatment is documented. Patient Monitoring Monitoring of disease activity is important and sometimes can be difficult. Reestablishing the baseline with MRI monitoring is recommended. Sormani and others 10 recently evaluated clinical and MRI measurements to assess patient response to interferon β. The proposed score (0 3) was based on the number of new T2 lesions (> 5) and clinical relapses (0, 1, or 2) during the first year of therapy. The risk of disability progression increased with higher scores. MS patients with a score of 0 showed a 3-year progression probability of 24%, whereas those with a score of 1 had an increased probability to 33%, and those having a score 2 had an increased probability of 65%. 10 Thus, there is no one-size-fits-all treatment for MS. Choice of initial therapy depends on multiple factors. The ultimate goal of treatment is personalized disease management using a treat-to-target approach. For patients who seem to be unresponsive to current therapy and who have breakthrough disease, experts recommend that treatment be switched to a medication having a different mechanism of action. n CASE 2: OPTIMIZING THE TREATMENT OF MS ONE PATIENT AT A TIME Based on a presentation by Bruce A. Cohen, MD. The second case study selected by experts and the audience involved the need to switch therapy in a patient who had received treatment for MS. History A 27-year-old woman had taken glatiramer acetate for the past 4.5 years. Her symptoms began with an episode of optic neuritis 5 years ago. She was started on interferon β but did not tolerate the drug s flu-like side effects; she was then switched to glatiramer acetate. In comparison to an image taken a year before, a surveillance brain MRI scan revealed two new lesions. No new neurologic symptoms developed since presentation. She had no comorbid medical conditions. Previous imaging of her cervical spinal cord was normal. Neurologic examination disclosed a left optic disc pallor; her corrected visual acuity was 20/25, and mild vibratory loss in her left foot remained unchanged from her initial examination 6 years ago. A new brain MRI scan showed five T2 hyperintense lesions, including periventricular lesions with the appearance of Dawson s fingers. Her EDSS score was 1.5. Analysis Subclinical inflammatory disease activity is common in MS and may be captured, to some extent, by conventional MRI. Serial MRI scans can be employed in a number of clinical scenarios. For patients who are treated with a DMT, an MRI scan is commonly used to assess the efficacy of the selected therapy. A followup MRI scan should be performed 6 12 months after a new DMT is started. The presence of more than two gadoliniumenhancing lesions 1 year after the start of therapy may predict a poor clinical outcome at 5 years. 11 Because new lesions were found on surveillance MRI in this patient, the need to switch therapy should be considered, even if the patient has remained clinically stable. The results of clinical trials and T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 31

observational cohort studies have shown that development of new MRI lesions during the first year of treatment is associated with later clinical changes. Most patients in clinical trials do not achieve a disease activity free state, in which no clinical or MRI changes are noted over the entire study period. In natural-history studies, the best predictors of future disability have been the EDSS score obtained at intermediate periods and whether this score is derived from sensory, motor, or cerebellar deficits. Whether brain imaging should be repeated annually or biannually in patients with RRMS is unclear; however, serial imaging is common in these patients and recommended. MRI monitoring offers a snapshot of contrast-enhancing lesions. However, new or enlarging T2 lesions and new T1 hypointensities should also be monitored, since they can impart relevant information on disease activity. Current disadvantages of monitoring patients with serial imaging include the inability to follow changes in brain atrophy and the false sense of disease stability a patient may feel if a conventional MRI sequence is unchanged, because conventional sequences may be relatively insensitive to subtle changes. Conventional MRI sequences lack a true specificity for underlying lesion pathology. Hyperintense T2 lesions may contain a variable extent of demyelination, remyelination, axonal loss, inflammation, and edema, which may explain some of the inconsistency that can be seen between T2 lesion load and clinical disability. Diffusion tensor imaging, magnetization transfer imaging, and proton magnetic resonance spectroscopy have been increasingly considered and are being incorporated as secondary outcome measures in several clinical trials. Ultrahigh-field and functional MRI provide additional measures to understand disease mechanism and progression. 12 Thus, following initiation of a DMT, patients with MS should undergo a brain MRI scan at 6 or 12 months (or before if new symptoms appear). Surveillance cervical MRI is less commonly performed, but it may be beneficial because spinal cord lesions may lead to further disability. Decisions to switch therapy should consider patient tolerance, clinical status, and the risks and benefits of other treatment options. n ADHERENCE: MONITORING, ACHIEVING, AND OPTIMIZING Based on a presentation by Kathleen Costello, MS, ANP-BC, MSCN, Adult Nurse Practitioner and Research Associate, Johns Hopkins Multiple Sclerosis Center, Johns Hopkins Medicine, Baltimore, Maryland. Although the armamentarium of agents for treating MS has grown in recent years and even more therapies are being developed, many patients do not adhere to their therapeutic regimens. In fact, Osterberg and Blaschke 13 documented that more than half the 3.8 billion general medicine prescriptions written annually are not taken correctly. 13 In a 2009 national survey of 1,000 Americans, 14 more than half indicated that they do not take their prescribed medications consistently 37% said they did not finish taking all the prescription medicine as instructed, 31% said they skipped doses, and 23% said they did not refill their prescriptions as instructed. The cost of noncompliance to the US healthcare system may be as high as $289 billion (in 2012 dollars). 15 Reasons for Noncompliance Treatment adherence can sometimes be limited for MS patients because of their disability, economic status, or fear of side effects. Adherence to MS medications has a substantial impact on clinical and economic outcomes, because patients who follow therapeutic instructions are less likely to be hospitalized, relapse, or suffer disability. In several large adherence studies in MS patients, nonadherence has been reported in 18% 36% of participants. 16 18 The main reasons patients do not adhere to therapy are that they forget to take their medicine, experience side effects such as injection-site reactions, and lack little motivation or do not think they are benefiting from treatment. 19 The cost of DMTs is also a significant factor in medication adherence; some patients lose their insurance coverage or cannot afford the copayments at the pharmacy. 15 Because DMTs are not intended to relieve ongoing symptoms, patients begin to feel indifferent about therapy over time. Thus, physicians must remind MS patients that DMTs are designed for long-term use and are meant to reduce underlying disease activity, not cure the disease or make them feel better. Reasons for Stopping Therapy Common reasons for patients discontinuing DMT include not being well informed when they begin treatment and having unrealistic expectations for therapy. 19 Physicians can resolve these problems by establishing a good relationship with patients, keeping them motivated, and reinforcing the relevance of treatment during each visit. Some patients have more severe adverse reactions, and they may be more willing to discontinue therapy. Side effects of therapy should be discussed and managed by the healthcare team and the drug manufacturer s support program. Patients who experience intolerable side effects should consider switching to a medication that is better tolerated. Helping Patients to Follow Therapeutic Regimens The first 6 months are the most critical time for adherence. 20 Healthcare teams should educate MS patients in detail about the purpose of treatment, expectations, adverse effects, and management regimens. Adherence may improve if nurses have follow-up phone conversations with patients to address individual issues. 15,17 Likewise, physicians can address important problems, such as patient forgetfulness, support networks, adverse effects, treatment fatigue, and financial costs during each visit. REFERENCES 1. Polman CH, Reingold SC. Diagnostic criteria for multiple sclerosis: 2010 revision to the McDonald criteria. Ann Neurol. 2011;69:292 302. 2. Popescu BF, Lucchinetti CF. Pathology of demyelinating disease. Annu Rev Pathol. 2012;7:185 217. 3. Calabrese M, Filippi M, Gallo P. Corti- 32 T H E N E U R O L O G Y R E P O R T V o l u m e 7 N u m b e r 2

cal lesions in multiple sclerosis. Nat Rev Neurol. 2010;6:438 444. 4. Peterson JW, Bo L, Mork S, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389 400. 5. Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol. 2008;7:841 851. 6. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain. 2008;131:808 817. 7. Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol. 2008;65:727 732. 8. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72;800 805. 9. Okuda DT, Mowry EM, Cree BA, et al. Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology. 2011;76:686 692. 10. Sormani MP, Rio J, Tintore M, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler. 2013;19:605 612. 11. Romeo M, Martinelli V, Perego M, et al. Brain MRI activity after disease-modifying treatment may predict disability progression after 5 years in relapsing remitting multiple sclerosis patients. Presented at the 5 th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ ACTRIMS); October 19 22, 2011; Amsterdam, The Netherlands. Abstract 29. 12. Tallantyre EC, Dixon JE, Donaldson I, et al. Ultra-high-field imaging distinguishes MS lesions from asymptomatic white matter lesions. Neurology. 2011;76:534 539. 13. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487 497. 14. National Council on Patient Information and Education. New survey: more than half of Americans do not take prescription medicines as instructed, pointing to growing public health problem [news release]; November 12, 2009. http://www. talkaboutrx.org/documents/adherencesurveymediarelease.pdf. Accessed June 15, 2014. 15. Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence to selfadministered medications for chronic diseases in the United States: a systematic review. Ann Intern Med. 2012;157:785 795. 16. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256:568 576. 17. Devonshire V, Lapierre Y, Macdonell R, et al; GAP Study Group. The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2011;18:69 77. 18. Arroyo E, Grau C, Ramo-Tello C, Parra J, Sánchez-Soliño O; GAP Study Group. Adherence to disease-modifying therapies in Spanish patients with relapsing multiple sclerosis: two-year interim results of the Global Adherence Project. Eur Neurol. 2011;65:59 67. 19. Devonshire V. Adherence to Disease-Modifying Therapy: Recognizing the Barriers and Offering Solutions. Ridgewood, NJ: Delaware Media Group, LLC; 2007. 20. Tremlett HL. Interrupted therapy: stopping and switching of the beta-interferons prescribed for MS. Neurology. 2003;61:551 554. T H E N E U R O L O G Y R E P O R T S u m m e r 2 0 1 4 33