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Early Recognition and Diagnosis of Multiple Sclerosis

Emmanuelle Waubant, MD, PhD

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

Pathophysiology and Presentation of MS

Multiple sclerosis (MS) is an autoimmune disorder in which neurons in the brain and spinal cord lose the ability to communicate effectively due to inflammation and demyelination (AV 1). Substantial neuronal loss also occurs in affected tissues. Patients with MS may present with a wide range of clinical symptoms, either monofocal or multifocal, all of which are related to the central nervous system and may involve the optic nerve, brainstem, cerebellum, spinal cord, and, less commonly, brain hemispheres.

AV 1. The Role of Nerve Demyelination in Multiple Sclerosis (0:33)

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Patients with optic neuritis present with decreased vision, typically with pain upon moving the eye. If the brainstem or cerebellum is involved, symptoms can include double vision, imbalance, difficulty pronouncing words, and incoordination. When damage has occurred in the spinal cord, the patient can experience motor deficits, numbness in the limbs, and bowel, bladder, or sexual dysfunction. Very rarely, patients will present with involvement of the cerebral hemispheres, and these patients will typically have motor deficits and larger white matter lesions due to demyelination than other patients with MS. Fatigue and cognitive changes are also common MS symptoms.

Diagnosis of MS

The diagnosis of MS is made based on the patient’s history, the presence of demyelinating lesions on brain or spinal cord MRI scans, and the exclusion of alternative diagnoses. The recently updated diagnostic criteria1 for MS require the objective demonstration of white matter lesion dissemination in at least 2 locations and at 2 or more points in time. MRI of the brain and spinal cord can objectively demonstrate the presence of these lesions and is recommended by the criteria as a strategy for the early recognition of MS (AV 2). MRI can also rule out alternative diagnoses and be helpful in identifying patients with more active forms of MS.

AV 2. Criteria for Diagnosing Multiple Sclerosis With MRI (0:23)

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A patient’s first neurologic event is referred to as a clinically isolated syndrome (CIS), but not all patients who experience a CIS will go on to develop MS. The MS criteria should be used when patients have a CIS that is suggestive of MS or have symptoms of a demyelinating disease. Tests besides MRI that help to predict a patient’s risk of conversion from CIS to MS include spinal taps and evoked potentials. Spinal taps can be done to determine the number of oligoclonal bands and immunoglobulin (IgG) index in the patient’s cerebrospinal fluid2,3; however, spinal taps are no longer performed on the majority of patients due to the specificity of MRI in identifying lesions. Sensory evoked potentials can help to identify additional lesions within the CNS that are not yet clinically eloquent.4 The earlier a diagnosis is made, the sooner that disease-modifying therapy can be initiated, if deemed appropriate, to delay the progression of disability.5,6

Clinical Subtypes of MS

The 4 clinical subtypes of MS are relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing (AV 3).7 Patients with relapsing-remitting MS experience bouts of symptoms that fully resolve, with periods of remission between flare-ups. However, some patients may not fully return to their baseline status, and these patients will accrue disability over time from exacerbations with limited recovery. About 85% of patients who have MS have the relapsing-remitting form when they first present with the disease.8

AV 3. Clinical Subtypes of Multiple Sclerosis (0:31)

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About 50% of patients with relapsing-remitting MS will make the transition to secondary progressive MS within 10 to 15 years of disease onset.8 In the secondary progressive form, patients experience insidious worsening of disability, and, in some cases, additional exacerbations.

In primary progressive MS, patients experience a steady worsening of symptoms after they first notice neurologic symptoms, although the rate of progression can vary over time. Primary progressive MS involves about 10% of MS patients.8

The most infrequent form of MS is progressive relapsing, in which patients have a steady neurologic decline but also experience rare acute exacerbations. About 5% of patients have this form of MS.8

Psychiatric Issues for Patients With MS

The clinical course of MS is largely uncertain, which is stressful for both patients and their physicians. Patients are unsure if they will have full recovery from exacerbations, and the time between flare-ups, the rate of progression of the MS, and the time to accrual of disability are all mostly unpredictable. Patients also face uncertainty about their ability to remain employed and to maintain relationships with their spouses, parents, children, friends, and colleagues. All of these circumstances contribute to patients either transiently or chronically losing self-esteem and developing anxiety or depression.

Patients with MS can experience fatigue that disrupts their daily activities, and family and friends may not understand the severity of this symptom. Patients without visible disability in terms of imbalance or weakness may require naps once or twice a day and may be unable to maintain physical or neuropsychological activities due to this fatigue.

In addition to the stress of disease progression that results in coping issues and inability to perform at work or at home, some of the drugs prescribed for MS can affect the patient’s mood and emotions. Although the relationship between certain medications and depression is unclear, physicians should consider the patient’s current level of depression when choosing among medications.

Environmental and Genetic Factors and Prevalence of MS

The trigger for MS is not clear, but evidence suggests that both environmental and genetic factors contribute to MS susceptibility. The Epstein-Barr virus appears to increase susceptibility to MS, while the cytomegalovirus is associated with a lower risk of developing the disease.9 Other environmental factors that increase susceptibility include exposure to smoking10 and a deficiency in Vitamin D that may be related to decreased sun exposure.11 The main genetic risk factors are in the HLA region, and the gene that has the highest association with MS in white populations is HLA-DRB1*1501.12 The interaction between environment and genetics can be seen in findings that suggest that the herpes simplex virus increases the risk of MS in people without the DRB1*15 allele but decreases the risk in those with the allele.9

The disease is 3 to 4 times more common in women than men, and the overall prevalence estimate in the United States has been reported as 85–100 cases per 100,000 people, although this may underestimate the actual number of cases.13 Also, prevalence estimates vary widely based on geographic location, with the lowest rates found in the southern states and the highest rates found in the northern states. Geographic differences in the risk for MS may be due to environmental risks (such as amount of UV exposure or exposure to viruses) or may be due to genetic markers resulting from ancestry variations in different regions.

For Clinical Use
  • Understand the basic pathophysiology and etiology of MS
  • Recognize the broad range of symptoms associated with MS
  • Use the updated diagnostic criteria to confirm diagnosis of MS earlier
  • Determine the patient’s subtype of MS through examining the patient’s history and current course of illness
Abbreviations

CIS = clinically isolated syndrome, CNS = central nervous system, HLA = human leukocyte antigen, IgG = immunoglobulin, MRI = magnetic resonance imaging, MS = multiple sclerosis, UV = ultraviolet

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References
  1. 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. Abstract
  2. Brettschneider J, Tumani H, Kiechle U, et al. IgG antibodies against measles, rubella, and varicella zoster virus predict conversion to multiple sclerosis in clinically isolated syndrome. PLoS One. 2009;4(11):e7638. Abstract
  3. Masjuan J, Alvarez-Cermeño JC, Garcia-Barragán N, et al. Clinically isolated syndromes: a new oligoclonal band test accurately predicts conversion to MS. Neurology. 2006;66(4):576–578. Abstract
  4. Pelayo R, Montalban X, Minoves T, et al. Do multimodal evoked potentials add information to MRI in clinically isolated syndromes? Mult Scler. 2010;16(1):55–61. Abstract
  5. 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. Abstract
  6. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8(11):987–997. Abstract
  7. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907–911. Abstract
  8. 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 August 26, 2011.
  9. Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology. 2011;76(23):1989–1995. Abstract
  10. Palacios N, Alonso A, Brønnum-Hansen H, et al. Smoking and increased risk of multiple sclerosis: parallel trends in the sex ratio reinforce the evidence. Ann Epidemiol. 2011;21(7):536–543. Abstract
  11. Ramagopalan SV, Handel AE, Giovannoni G, et al. Relationship of UV exposure to prevalence of multiple sclerosis in England. Neurology. 2011;76(16):1410–1414. Abstract
  12. Sadovnick AD. Genetic background of multiple sclerosis [published online ahead of print May 18, 2011]. Autoimmun Rev. doi:10.1016/j.autrev.2011.05.007. Abstract
  13. Noonan CW, Williamson DM, Henry JP, et al. The prevalence of multiple sclerosis in 3 US communities. Prev Chronic Dis. 2010;7(1). http://www.cdc.gov/pcd/issues/2010/jan/pdf/08_0241.pdf. Accessed August 26, 2011.
From the Series:
Overview of Current Issues in the Management of Multiple Sclerosis

Independently developed by the CME Institute of Physicians Postgraduate Press, Inc.

CME Background Information

Independently developed by the CME Institute of Physicians Postgraduate Press, Inc.

Objective

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

  • Accurately diagnose multiple sclerosis in a timely manner so as to initiate early treatment

Financial Disclosure

The faculty for this CME activity and the CME Institute 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 has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Waubant is a consultant for and has received honoraria from Roche, Actelion, and Sanofi-Aventis; has received grant/research support from the NIH, National MS Society, Nancy Davis Foundation, Biogen Idec, and Sanofi-Aventis; and is a member of the speakers/advisory board of Teva.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

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

Release, Review, and Expiration Dates

This Neurology Reports activity was published in November 2011 and is eligible for AMA PRA Category 1 Credit through November 30, 2014. The latest review of this material was August 2011.

Statement of Need and Purpose

A diagnosis of multiple sclerosis (MS) is generally made using the McDonald criteria, which require objective proof of lesions disseminated in both time and space and which provide guidelines on how to obtain this objective evidence. Although these criteria are accurate and sensitive, many clinicians still have difficulty diagnosing this disease. Patients may present with a variety of symptoms, such as subjective sensory complaints, or may have another condition commonly mistaken for MS, such as some infectious diseases and inflammatory disorders. Further, MS has a highly variable course of illness. Early recognition is critical because early treatment with disease-modifying drugs can slow the progression of MS. Additionally, recent advancements in disease-modifying drugs, such as approval of the first oral medications and the development of agents with possible neuroprotective effects, have the potential to revolutionize MS treatment. Clinicians need more information on the early detection and treatment of MS to optimize their patients’ overall outcomes. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MS.

Disclosure of Off-Label Usage

Dr Waubant has determined that, to the best of her knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration–approved labeling has been presented in this activity.

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 CME activity is derived from the planning teleconference “Overview of Current Issues in the Management of Multiple Sclerosis,” which was held on May 24, 2011. This activity is one in a series of independent projects undertaken by the CME Institute of Physicians Postgraduate Press, Inc., as a service to its members and the broader academic and clinical community.