CME Needs Assessment
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. It is the most common non-traumatic cause of neurologic disability in young adults.1 A recent study estimated the prevalence in the US at 47.2-109.5/100,000 people.2 Although the cause of MS is not entirely understood, it appears to results from a complicated interplay of genetic and environmental factors, leading to autoimmune CNS damage. Although MS is incurable, it is increasingly treatable. Studies have indicated that early intervention improves outcomes.3 Therefore, early diagnosis and treatment have become the underlying philosophy of effective disease management with the ultimate goal of lessening the risk of disability and improving quality of life of MS patients.
Research in MS is progressing at a remarkable rate, with more potential therapies in the pipeline than at any other time in history.4 Reports of clinical trials at every phase of drug development are frequently presented at key annual meetings of professional associations in the United States and other countries. Despite their best efforts, it is difficult for healthcare providers to stay abreast of the new information presented at these meetings. Nevertheless, it is important for neurologic clinician learners to remain current on MS research findings.
Learner Practice Gaps:
- The learner must be able to discern the multiple factors that contribute to the risk of MS, its severity, course, and impact on patients to effectively diagnose and manage the disease.
- Clinician learners must be updated on advancements in imaging and biomarkers to monitor disease activity and severity, as endpoints in clinical trials and guides to therapy.
- It is critical that learners receive current information on the pharmacology, mechanism of action, efficacy, safety, and tolerability of established MS therapies to utilize these agents in clinical practice appropriately.
- Neurologic clinician learners must be updated on novel therapies that soon may be included in the treatment armamentarium, including benefit-risk profiles.
- Learners must be aware of symptomatic issues that complicate MS and how best to manage them.
- Neurologic clinician learners must be aware of advancements in non-pharmacologic aspects of MS care.
- Clinician-investigators, non-clinician-scientists and scientists in training require adequate exposure to advances in areas related to both basic and applied investigation to stimulate developing and future contibutors to the field. Therefore, a balance between patient management and treatment and exposure to fundamental advances in neurobiology continues to be a cornerstone of the ACTRIMS and ECTRIMS meetings.
- To assure that fundamental aspects of the disease are accessible to both physicians in training and developing investigators series of teaching courses are offered as part of the overall ECTRIMS and ACTRIMS/ECTRIMS joint meetings.
It is critical that learners receive current information on pathogenic/immunologic targets of established and emerging therapies to effectively utilize these therapies in clinical practice.
MS is a chronic disorder with heterogeneous clinical manifestations, course, and severity that vary both between patients and in individual patients over time. Accordingly, to understand the pathogenic mechanisms underlying the different clinical courses and subtypes of MS requires clinicians to have advanced knowledge of the disease. For example, the molecular mechanisms underlying relapsing forms might differ from those leading to progressive disease. It is essential that clinicians who treat patients with MS appreciate the differences to improve patient outcomes by individualizing and monitoring strategies.5
The etiology of MS remains unknown; three main theories have emerged. Each accounts for some aspects of the disease, but none explains everything. It is likely that MS involves a complex interaction of three mechanisms: abnormal immune function, environmental factors and infectious agents, and genetics.1 In recent years, investigators have gained new insights into the details of the immune mechanisms resulting in the abnormal CNS inflammation that characterizes MS pathology. Important immune components that have been implicated include (but are not limited to) immune cells (e.g. T cells, B cells, antigen presenting cells, NK cells), soluble factors (e.g. antibodies, cytokines, chemokines), and novel antigens. Environmental factors receiving increased attention recently include sunlight and vitamin D, Epstein Barr virus, the microbiome in gut and other tissues, and smoking. Finally, certain loci within the major histocompatibility complex have been recognized for many years to confer genetic risk for MS. Recent genetic studies have added a sizable number of new genes that affect MS risk and disease course.
Although much has been learned about the mechanisms underlying MS risk, severity, and disease course, many gaps in learners’ knowledge of MS etiology and pathogenesis remain. As studies are published that fill some of this missing information, it is critical for clinician learners to remain abreast of these findings, which drive the development and utilization of new therapeutic strategies.
In addition, it is equally important that clinicians are updated on unsubstantiated theories of the etiology of the disease, which often are associated with therapeutic claims, so that they may address patients’ queries and concerns. For example, chronic cerebrospinal venous insufficiency (CCSVI) recently was proposed as the cause of MS6 and venous stenting/venoplasty as an effective treatment.7 This theory has largely been disproven, but initially generated a great deal of interest among patients, fervent communication on the Internet and social media, and contentious debate in the medical community. Accurate and timely information on such issues is essential for clinicians to communicate effectively with patients. The CCSVI story also illustrates the importance of clinicians being aware of the increasing role social media plays in how the public now obtains information about MS and potential treatments.
Multiple factors must be taken into account to individualize treatment of MS patients.
Currently approved MS disease modifying therapies (DMTs) include five “first line” agents (two forms of interferon beta-1b, two forms of interferon beta-1a, glatiramer acetate) and five “second line” agents (mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate). The first line agents have well-established efficacy and short- and long-term safety. However, they have common side effects (flu-like symptoms with the interferons, injection site reactions), are administered by frequent injection which patients dislike, and are inconvenient, all of which can result in decreased patient adherence.8 Moreover, the first line DMTs are only modestly effective and do not completely control MS disease activity in most patients, ultimately allowing disability to accumulate.9
The newer, second line agents are, in general, are more potent. Two are administered by intravenous injection and three are oral, which improves convenience. All generally are well tolerated but are associated some side effects and safety issues, which sometimes are severe. In addition, the long-term experience with the newest agents is modest. Thus, the position of the second line agents in the overall MS treatment algorithm is evolving.
To individualize treatment of MS requires clinicians to assess a sizable number of factors and to continually reassess these factors over time:
- Prognosis in individual patients based on prognosis in general, disease severity and level of
- activity (based on clinical features, imaging, other biomarkers).
- Benefit-risk relationship of the available therapies.
- Patient preference and other patient-related factors.
It is critical for neurologic clinician learners to have up-to-date information about these factors, including how to assess them in clinical practice and how to integrate them to decide among established and emerging therapies. In addition, the overall treatment algorithm must be based on effective methods for monitoring the disease, treatment efficacy, and adverse effects. The goal is to effectively identify patients who require disease therapy, choose the appropriate therapy, communicate the rationale for and goals of therapy to the patient, monitor for effectiveness, monitor for safety and tolerability, identify those patients who need to change therapy, and pick an appropriate alternative therapy.
Neurologic clinician learners should be updated on emerging therapies that may soon be available. While utilization of the currently available pharmacotherapeutic options have resulted in remarkable improvement in outcomes for MS patients, all of the available agents have shortcomings. Some patients tolerate them poorly or experience complications. Some patients have an inadequate therapeutic response with continued disease activity despite therapy.
The number of therapeutic options to treat relapsing MS is expected to continue to increase in the future. Several new medications have been assessed in pivotal clinical trials and submitted for regulatory review or soon will be, including potent monoclonal antibodies (MAbs) alemtuzumab and daclizumab, and pegylated interferon beta-1a. A sizable number of additional agents are currently in phase II or III trials,4 representing a wide-range of mechanisms of action. A partial list includes laquinimod, several anti-CD20 MAbs, several small molecule inhibitors of alpha 4 integrin, several selective sphingosine 1-phosphate modulators, plus a number of selective immunomodulatory strategies.
As this time, the lack of therapeutic options for progressive disease represents a great unmet need. All the currently available therapies primarily target inflammatory mechanisms reflected most directly by MRI lesion activity and clinical relapses. As a result, none is effective in progressive forms of the disease, in which neurodegenerative processes are thought to predominate. It is presumed that novel neuroprotective or repair-promoting strategies will be necessary to prevent or reverse progression. Several approaches, including putative neuroprotective agents, trophic factors, antibodies that target factors that inhibit remyelination, and cell-based therapies, are under investigation.
Neurologic clinician learners need up-to-date information on these emerging therapies to assess their benefit-risk profile, consider them for appropriate patients, and to effectively educate their patients.
Neurologic learners should be updated on aspects of disease management related to symptoms, psychosocial sequelae of the disease, and quality of life.
In addition to DMT, neurologic clinicians must address many neurologic symptoms patients with MS experience that can adversely affect ability to function at home and at work, and quality of life. Key symptoms of MS in this regard include cognitive dysfunction, gait impairment, visual loss, bladder/bowel/sexual dysfunction, fatigue, and depression. These issues clearly are important to both patients and clinicians, although they do not always agree on the prioritization.10 For example, one study reported that clinicians tended to emphasize physical manifestations while patients emphasized mental well-being and cognitive function. Thus, it not only is important for clinician learners to have up-to-date knowledge of the various pharmacologic and non-pharmacologic strategies to address bothersome MS symptoms, they must be aware of the patient’s perspective on these issues. Moreover, there are many sequelae of MS, e.g. employment and family issues, that cannot be treated with medication and require collaboration with other healthcare professionals.
One aspect of MS that often is under-appreciated is the high prevalence of cognitive impairment, which is not typically assessed in routine clinical practice or clinical trials.11, 12 Cognitive impairment has important effects on functioning at home, employment, adherence to disease treatment, and quality of life. It correlates with brain imaging findings more closely than other clinical manifestations. In particular, whole brain and gray matter atrophy correlate with cognitive impairment. Beneficial effects of DMTs on some MRI measures correlate with benefit on cognitive impairment.11, 12 However, many factors affect cognitive function in MS patients in addition to MS pathology, including medication side effects, sleep disorders, fatigue, depression, and other medical illness. Thus, in addition to MS manifestations in general, updating clinician learners on the causes, consequences, and treatment of cognitive impairment is of particular importance.
Rationale for Continuing Medical Education Program: Gap Analysis
To identify educational gaps and needs concerning the diagnosis and treatment of MS and related disorders among neurologists and other clinician learners, we conducted a learner survey of Consortium of MS Centers membership. The questions were based upon a review of current data and evidence, articles in peer-reviewed journals, and feedback from academic and community-based opinion leaders. An analysis of the findings demonstrated these key findings:
100% of respondents replied that they would benefit from additional education on the diagnosis, treatment, and overall management of MS.
When asked “What are the … greatest educational needs among physicians who diagnose and treat MS today?” respondents indicated the following:
- Knowledge of new and emerging therapeutics
- Accurate diagnosis
- How to decide when to switch drugs
- Risks and benefits of new medications and management
- Therapeutic efficacy comparison
- Current, state-of-the-art diagnostic imaging
- Neurobiology of MS
- Neuropathology of MS
- Epidemiology and genetics of MS
When asked about the most difficult issues faced in treating patients with MS, respondents chose the following (they were asked to choose all that apply):
- Treating comorbidities 42%
- Emerging treatments 52%
- Neuropsychiatric symptoms 42%
- Cognitive impairment 42%
- Medication adherence 47%
44% of physicians incorrectly identified axonal loss as secondary or not an important contributor to disability, suggesting the need for education on recent insights into the pathology and pathogenesis of MS.
Although all physicians said they were confident or very confident in diagnosing patients with MS, 22% indicated that identifying disease predictors was a difficult issue, and 18% reported difficulty determining when and how to test for inflammatory markers, suggesting educational gaps in MS pathogenesis, diagnosis, and monitoring.
Regarding the use of DMTs, 100% of physicians indicated that a proportion of their MS patients were on non-approved therapies, despite the fact that approved DMTS with more definitive data supporting benefit and risk were available.
Review of the ECTRIMS 2012 meeting supported these findings (see Appendix 1).
Continuing the Assessment for Further Education
We will continue efforts to improve our understanding and further distill educational gaps in MS through literature reviews, ongoing interviews with expert faculty, and learner surveys. The faculty input and learner feedback we have collected align with and reinforce the literature findings for clinician education in this area. Additionally, we will analyze outcome data derived from this and other educational activities on MS and incorporate the findings into ongoing needs assessments to add to the support of continuing medical education of clinicians. The ultimate goal is to improve patient outcomes.
The abundant new data on the MS disease process, methods to monitor the disease, current therapies, emerging therapies, disease treatment strategies, symptomatic management, and psychosocial sequelae of the disease demand an easily accessible and frequently updated vehicle for educating learners regarding these advances. Incorporation of this new information into clinical practice is essential for improved patient outcomes.
1. ECTRIMS 2012_Minutes_Debriefing Conference
2. ECTRIMS 2013 Teaching Courses
1. Frohman EM, Racke MK, Raine CS. Multiple sclerosis-the plaque and its pathogenesis. N Engl J Med 2006;354:942-55.
2. Noonan CW, Williamson DM, Henry JP, et al. The prevalence of multiple sclerosis in 3 US communities. Prev Chronic Dis 2010;7:A12. http://www.cdc.gov/pcd/issues/2010/jan/08 0241.htm.
3. Coyle PK. Early treatment of multiple sclerosis to prevent neurologic damage. Neurology 2008;71(Suppl 3):S3-S7.
4. http://www.clinicaltrials.gov. Accessed 15 Aug 2013.
5. Lisak RP, Korngold S. Insights for practice: where mechanism of action meets patient management. Neurology 2010;74(Suppl 1):S70-S3.
6. Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patient s with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392-9.
7. Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal nevous insufficiency. J Vasc Surg 2009;50:1348-58.
8. Coyle PK. Existing therapies for multiple sclerosis offer proven efficacy and safety. Curr Opin Neurol 2009;22:S4-S9.
9. Niino M, Sasaki H. Update on the treatment options for multiple sclerosis. Exp Rev Clin Immunol 2010;6:77-88.
10. Heesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable. Mult Scler 2008;14:988-91.
11. Patti F. Cognitive impairment in multiple sclerosis. Mult Scler 2009;15:2-8.
12. Messinis L, Kosmidis MH, Lyros E, Papathanasopoulos P. Assessment and rehabilitation of cognitive impairment in multiple sclerosis. Int Rev Psychiatry 2010;22:22-34.