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Accurately Diagnosing and Comprehensively Managing MS

Emmanuelle Waubant, MD, PhD

Department of Neurology, University of California San Francisco Multiple Sclerosis Center, San Francisco

Multiple sclerosis (MS) is a chronic autoimmune disorder in which neurons in the brain and spinal cord become damaged from inflammation and demyelination and lose the ability to communicate effectively. Early diagnosis and comprehensive management of MS is crucial in reducing patients’ disability and helping them maintain functionality and independence as long as possible. To aid clinicians, diagnostic criteria and appropriate tests can assist in making a timely and accurate diagnosis, and a range of treatments is available for managing MS, including disease modification, acute relapse, and breakthrough disease.

Making a Timely and Accurate Diagnosis

The course of MS varies among patients and is classified as 1 of 4 categories, each of which can be mild, moderate, or severe: relapsing-remitting, primary progressive, secondary progressive, and progressive relapsing. Most people with MS are first diagnosed with the relapsing-remitting form; about half of these people go on to develop secondary progressive MS, meaning that they experience a steady progression and accumulation of neurologic damage with or without apparent symptom exacerbations (also called attacks or relapses).1 Early recognition of MS and initiation of treatment is necessary because, typically, when the disease has been present for 6 to 12 months, no available treatment is expected to reverse the extent of the damage.

An accurate diagnosis of MS is made by collectively recognizing suggestive clinical symptoms, using diagnostic criteria, performing appropriate diagnostic tests, and excluding other disorders.

Clinical symptoms. Patients typically develop MS symptoms between the ages of 20 and 50 years. Symptoms of MS result from damage to the optic nerve, brainstem and cerebellum, spinal cord, or cerebral hemispheres (AV 1).2 About 20% of patients with MS initially experience optic neuritis3 and about 50% have spinal cord myelopathy4; cerebral hemispheric onset of MS does not occur as often. Fatigue and cognitive impairment are common nonspecific symptoms, although MS symptomatology varies greatly among patients.

AV 1. Selected Symptoms of Multiple Sclerosis (0:35)

AV 1. Selected Symptoms of Multiple Sclerosis

Diagnostic criteria. A diagnosis of MS is based on the patient’s clinical history of attacks, the presence of demyelinating lesions on the brain or spinal cord MRI scans, and the exclusion of alternative diagnoses. The McDonald Criteria, revised in 2010,5 can be applied to patients who present with an initial event suggestive of MS, referred to as a clinically isolated syndrome (CIS), or who have symptoms of a CNS inflammatory demyelinating disease. To meet the diagnostic criteria for MS, dissemination of lesions in space and in time must be demonstrated in at least 2 of the 4 CNS areas at any time, including on a baseline or follow-up MRI. If a patient is suspected to have MS but has only 1 lesion, clinicians can wait and see if the patient has another CIS or try to confirm the diagnosis with diagnostic tests other than an MRI.

Diagnostic tests. Tests used to inform a diagnosis of MS include MRI and, less often, spinal tap and evoked potential tests. A brain and/or spinal cord MRI detects the presence of lesions in the CNS. This test is considered the most effective identification tool for MS and is one of the most important steps in establishing an early diagnosis. However, the lack of lesions on an MRI does not rule out a diagnosis of MS.

Occasionally, cerebrospinal fluid is tested via a spinal tap to establish the presence of oligoclonal bands or increased IgG index—an indication of an abnormal autoimmune response, which can be but is not necessarily indicative of MS. Therefore, spinal tap results alone cannot confirm or deny an MS diagnosis.

Evoked potentials can detect slowed electrical activity in the brain, revealing demyelination that may not appear on the MRI scan. When necessary, evoked potentials may identify a second demyelinating event needed to confirm an MS diagnosis.

Differential diagnosis. Several medical conditions can mimic MS and should be excluded prior to making an MS diagnosis. Infectious diseases such as Lyme disease, syphilis, HIV, and PML should be ruled out. Clinicians should also consider lymphoma, metabolic disorders such as adrenoleukodystrophy and vitamin B12 deficiency, and rheumatologic or inflammatory conditions such as lupus, rheumatoid arthritis, neurosarcoidosis, Behçet’s disease, Sjőgren’s syndrome, Wegener’s granulomatosis, and neuromyelitis optica. Many of these conditions can be excluded with additional tests, such as blood tests, spinal taps, and biopsies.

Managing MS

Disease-modifying treatments are effective in managing the early stages of relapsing-remitting MS, but patients will experience an irreversible progression of neurologic damage if therapy is not initiated within 6 to 12 months (AV 2).6 Additionally, nonrelapse-related tissue loss also develops, so, over time, subsequent MRIs may show that lesions are developing more quickly than clinical exacerbations are occurring. Therefore, medication that can prevent or delay relapse can slow the disease’s progression, but it still cannot cure the disease. Therapy should always be customized to the patient to promote treatment adherence and optimize tolerability.

AV 2. Treatment Window for Multiple Sclerosis (0:31)

AV 2. Treatment Window for Multiple Sclerosis

Approved relapse prevention treatments. IFNβ-1a,7 IFNβ-1b,8 glatiramer acetate,9 and fingolimod10 are approved by the FDA to prevent MS exacerbations and may be considered first-line treatments for patients with relapsing forms of MS. Patients with relapsing-remitting MS treated with IFNβ-1a, IFNβ-1b, or glatiramer acetate (all injectable formulations) have shown similar relapse rates, and similar proportions of patients remained relapse-free at 2 years.11 MRI-assessed lesions and disability progression was also similar among the 3 groups. Injection site pain, a common side effect with injectable agents, can be minimized with over-the-counter analgesics. Fingolimod, an oral treatment, has shown improved relapse rates and lesion activity in patients with MS compared with placebo and IFNβ-1a but was also shown to increase the risk of infections, ocular problems, and cardiovascular problems.12

For patients who experience frequent relapse, disability progression, or lesion activity changes, switching to a different medication is a viable option. For example, a study13 found that patients with relapsing-remitting MS had improved relapse rates after switching from either IFNβ to glatiramer acetate or from glatiramer acetate to IFNβ. However, some patients may not adequately respond to IFNβ, glatiramer acetate, or fingolimod and may need to switch to a second-line agent.

Approved second-line relapse prevention treatments. For patients with worsening MS, clinicians may decide to proceed with treatment using a second-line agent for breakthrough disease. Natalizumab14 and the immunosuppressant mitoxantrone,15 both administered intravenously, are approved to delay the accumulation of physical disability caused by MS and reduce the number of MS exacerbations. One study16 reported decreased relapse rates for patients with relapsing-remitting or relapsing secondary progressive MS who switched from IFNβ or glatiramer acetate to a second-line treatment (AV 3).16 These agents are relegated as second-line treatments because natalizumab increases the risk for PML,14 and mitoxatrone is not indicated for the treatment of primary progressive MS.15

AV 3. Relapse Rates Before and After Switching to a Second-Line Treatment for Multiple Sclerosis (0:42)

AV 3. Relapse Rates Before and After Switching to a Second-Line Treatment for Multiple Sclerosis

Acute relapse treatment. For patients currently taking medication but experiencing acute exacerbations that disrupt daily activity, 2 treatment options are available. The first option is short-term, high-dose corticosteroid treatment (eg, IV methylprednisolone or oral dexamethasone), which can reduce inflammation as well as shorten the duration of the attack.17 In rare, severe, acute episodes of relapsing forms of MS in which steroids are not clearly beneficial, the second option is plasmapheresis, or plasma exchange, which can also aid in recovery.7

Additional treatment options. Several off-label treatments that may be used for progressive MS include vitamin D3,18 mycophenolate mofetil,19 rituximab, daclizumab, and alemtuzumab.20 Drugs that may become available in the future include fumaric acid, laquinimod, teriflunomide, and ocrelizumab.20

Progressive MS treatment. No drugs are approved to treat purely primary progressive MS. Off-label treatments may include pulse steroid therapy, such as cyclophosphamide, and rituximab.21 Exercise is an underrated but crucial addition to treatment because it helps prevent muscle deconditioning and osteoporosis, assists in maintenance of balance and reducing falls, and helps alleviate anxiety and depression.22,23

Patients’ role in treatment. In addition to exercising, patients should be encouraged to lead healthy lifestyles, which includes stopping smoking. Patients need to understand the necessity of preventative treatment and remain engaged in educating themselves about the risks and benefits of MS treatment options. Clinicians need to understand individual patients’ lifestyles, expectations, preferences for particular treatments and methods of medication administration, and fears. The unpredictability of the time between exacerbations and the time to secondary progression can cause patients considerable anxiety, which may need to be addressed or allayed. Additionally, regular monitoring for medication adherence and tolerability is essential to help patients achieve the best possible outcomes.

Conclusion

Recognizing and treating MS as early as possible can only improve outcomes for patients diagnosed with this debilitating disorder. Many treatments are available, including medications to slow progression of the illness, to reduce the number of relapses, and to treat acute exacerbations (or breakthrough disease). To successfully tailor treatments to patients with MS, clinicians must involve patients in the decision-making process as well as systematically assess their symptoms and side effects. Patients should be encouraged to be proactive in their treatment regimen, to stop smoking, and to start exercising.

For Clinical Use
  • Use diagnostic criteria, appropriate diagnostic tests, and differential diagnosis to recognize MS early
  • Select appropriate treatment for disease modification and acute exacerbations
  • Educate patients about MS and involve them in the treatment process
Drug Names

alemtuzumab (Campath), cyclophosphamide (Cytoxan and others), daclizumab (Zenapax), dexamethasone (Maxidex, Ozurdex, and others), fingolimod (Gilenya), glatiramer acetate (Copaxone), interferon beta-1a (Avonex and Rebif), interferon beta-1b (Betaseron and Extavia), methylprednisolone (Medrol, DepoMedrol, and others), mycophenolate mofetil (Cellcept and others), natalizumab (Tysabri), rituximab (Rituxan)

Abbreviations

CIS = clinically isolated syndrome, CNS = central nervous system, FDA = US Food and Drug Administration, HIV = human immunodeficiency virus, IgG = immunoglobulin G, IFN = interferon, IV = intravenous, MRI = magnetic resonance imaging, MS = multiple sclerosis, PML = progressive multifocal leukoencephalopathy

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References
  1. National Multiple Sclerosis Society. What is Multiple Sclerosis? http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/what-is-ms/index.aspx. Accessed September 20, 2012
  2. National Multiple Sclerosis Society. Symptoms. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/index.aspx. Accessed September 20, 2012
  3. Voss E, Raab P, Trebst C, et al. Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis. Ther Adv Neurol Disord. 2011;4(2):123–134. PubMed
  4. Mowry EM, Pesic M, Grimes B, et al. Demyelinating events in early multiple sclerosis have inherent severity and recovery. Neurology. 2009;72(7):602–608. PubMed
  5. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. PubMed
  6. Freedman MS. Multiple sclerosis therapeutic strategies: use second-line agents as first-line agents when time is of the essence. Neurol Clin Pract. 2011;1(1):66–68. doi.10.1212/CPJ.0b013e31823cc2c2.
  7. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169–178. PubMed
  8. Extavia (interferon beta-1b) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4cfdb571-ec4c-478f-bedc-e0669eeea504. Accessed September 20, 2012.
  9. Copaxone (glatiramer acetate) [package insert]. Kansas City, MO: Teva Neuroscience, Inc; 2009. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=aa88f583-4f5f-433b-80b4-1f4c9fb28357. Accessed September 20, 2011.
  10. Gilenya (fingolimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9. Accessed September 20, 2012.
  11. Carter NJ, Keating GM. Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis and in delaying the onset of clinically definite multiple sclerosis. Drugs. 2010;70(12):1545–1577. PubMed
  12. Wipfler P, Harrer A, Pilz G, et al. Recent developments in approved and oral multiple sclerosis treatment and an update on future treatment options. Drug Discovery Today. 2011;16(1/2):8–21. PubMed
  13. Gajofatto A, Bacchetti P, Grimes B, et al. Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis. Mult Scler. 2009;15(1):50–58. PubMed
  14. Tysabri (natalizumab) [package insert]. Cambridge, MA: Biogen Idec Inc.; 2010. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=6fa00cb8-4229-4770-9d2a-d4a8542b3180. Accessed September 20, 2012.
  15. Mitoxantrone [package insert]. Irvine, CA: Teva Parenteral Medicines, Inc; 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4d0f0f1a-31af-40fa-9c64-e90891fa6ce4. Accessed September 20, 2012.
  16. Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6(2):e16664. PubMed
  17. Repovic P, Lublin FD Treatment of multiple sclerosis exacerbations. Neurol Clin. 2011;29(2):389–400. PubMed
  18. Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double-blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta 1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5):565–571. PubMed
  19. Frohman EM, Brannon K, Racke MK, et al. Mycophenolate mofetil in multiple sclerosis. Clin Neuropharmacol. 2004; 27(2):80–82. PubMed
  20. Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R, et al, for the Post-ECTRIMS Group. Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)(pt II). Rev Neurol. 2012;54(12):734–749. PubMed
  21. Olek MJ. Treatment of progressive multiple sclerosis in adults. Published 2012. http://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults?view=print. Accessed September 19, 2012.
  22. Patti F, Ciancio MR, Cacopardo M, et al. Effects of a short outpatient rehabilitation treatment on disability of multiple sclerosis patients: a randomised controlled trial. J Neurol. 2003;250(7):861–866. PubMed
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From the Series:
Improving Outcomes in Multiple Sclerosis Through Early Diagnosis and Effective Management

Supported by an educational grant from Pfizer.

CME Background Information

Supported by an educational grant from Pfizer.

Objective

After completing this educational activity, you should be able to:

  • Recognize and correctly diagnose MS, especially during the early stages
  • Develop an individualized, evidence-based treatment plan that includes a disease-modifying treatment and any other appropriate interventions to maintain optimal functioning and quality of life
  • Educate patients about their disease and foster their involvement in the treatment process

Financial Disclosure

The faculty for this CME activity, the CME Institute staff, and the University of North Texas Health Science Center staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute and the University of North Texas Health Science Center have resolved any conflicts of interest that were identified. No member of the CME Institute staff or the University of North Texas Health Science Center staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Waubant is a consultant for Actelion and Chugai; has received grant/research support from Sanofi Aventis, Roche, Teva, and Biogen Idec; and has provided 3 educational talks for Teva and Biogen Idec in the past year.

Accreditation Statement

The University of North Texas Health Science Center at Fort Worth is accredited by the American Osteopathic Association to award continuing medical education to physicians.

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The University of North Texas Health Science Center and the CME Institute of Physicians Postgraduate Press, Inc. The University of North Texas Health Science Center is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation

The University of North Texas Health Science Center has requested that the AOA Council on Continuing Medical Education approve this program for 0.5 hour of AOA Category 2B CME credits. Approval is currently pending.

The University of North Texas Health Science Center designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in October 2012 and is eligible for AMA PRA Category 1 Credit™ through October 31, 2013. The latest review of this material was September 2012.

Statement of Need and Purpose

Multiple sclerosis (MS) is one of the most common diseases of the central nervous system, and the prognosis for this disorder is highly variable. The diagnostic criteria for MS were updated in 2001 and are both accurate and sensitive; however, many clinicians are not confident in their ability to diagnose MS. Additionally, patients often receive an incorrect diagnosis due to having diverse and vague symptoms and an unpredictable disease course. Timely recognition is critical because the progression of MS can be delayed, and clinically definite MS can possibly be prevented if treatment with a disease-modifying drug (DMD) is initiated early. DMDs can help reduce the number of MS relapses, help patients maintain functioning, delay the progression of disability, and improve quality of life. Despite the benefits of DMD treatment and guidelines recommending them for MS, only slightly more than half of patients with the most common form of MS receive a disease-modifying therapy. Also, most patients with MS prefer an active role in their treatment and need to be informed about their illness and available treatments. Unfortunately, cognitive deficits common in MS may make informed decision-making difficult. Clinicians need information on the importance of early recognition, strategies for making an accurate and timely diagnosis, educating patients about the MS and its treatments, implementing disease-modifying therapy, and developing a treatment plan to help patients maintain functioning and experience optimal quality of life. This activity was designed to meet the needs of the participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on multiple sclerosis.

Disclosure of Off-Label Usage

Dr Waubant has determined that, to the best of her knowledge, alemtuzumab, cyclophosphamide, daclizumab, dexamethasone, mycophenolate mofetil, rituximab, laquinomod, ocrelizumab, and teriflunomide are not approved by the US Food and Drug Administration for the treatment of multiple sclerosis.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “Improving Outcomes in Multiple Sclerosis Through Early Diagnosis and Effective Management,” which was held on March 19, 2012, and was independently developed by the University of North Texas Health Science Center and the CME Institute of Physicians Postgraduate Press, Inc., also an accredited provider, pursuant to an educational grant from Pfizer. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider, publisher, or the commercial supporter.