Multiple Sclerosis Workup

  • Author: Christopher Luzzio, MD; Chief Editor: B Mark Keegan, MD, FRCPC   more...
 
Updated: Feb 16, 2012
 

Approach Considerations

Multiple sclerosis (MS) is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and spinal cord and cerebrospinal fluid examination. Clinically, the attack must be compatible with the pattern of neurologic deficits seen in MS, which typically means that the duration of deficit is days to weeks.

Traditionally, MS could not be diagnosed after only a single symptomatic episode, as diagnosis required repeat attacks suggesting the appearance of lesions separated in time and space. In the past, treating physicians were content to "sit back and watch" after a single episode, as it was assumed the disease would "declare" itself. The 2010 McDonald criteria (see Table 1, below) allow diagnosis of MS even with a first clinical episode.[35]

Early diagnosis is important because there is growing evidence that early intervention is useful. It is known through the work of Trapp et al that axonal loss is present, even in asymptomatic patients, early in the disease process.[36] In addition, studies in patients with a first attack of neurologic symptoms suggestive of MS have demonstrated decreased disability and lower secondary relapse rates with interferon treatment.

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McDonald Criteria for MS Diagnosis

The McDonald criteria, which were developed in 2001 by an international expert panel and revised in 2005 and 2010, provide recommendations on the diagnosis of MS, including diagnosis after a single attack.[30, 33, 35] The criteria consist of a combination of clinical, imaging, and paraclinical tests (ie, CSF, evoked potentials).[33] (See Table 1, below.) The 2010 criteria have not yet become widely adopted by clinicians, and it is suggested that the reader consult the original publication.

Table 1. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis[35] (Open Table in a new window)

Clinical Presentation Additional Data Needed for MS Diagnosis
  • Two or more attacks
  • Objective clinical evidence of 2 or more lesions with reasonable historical evidence of a prior attack
None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,



but must be consistent with MS



  • Two or more attacks
  • Objective clinical evidence of 1 lesion
Dissemination in space demonstrated by MRI or



Await further clinical attack implicating a different site



  • One attack
  • Objective clinical evidence of 2 or more lesions
Dissemination in time demonstrated by



MRI or second clinical attack



  • One attack
  • Objective clinical evidence of 1 lesion (clinically isolated syndrome)
Dissemination in space demonstrated by



MRI or await a second clinical attack implicating a different CNS site



and



Dissemination in time, demonstrated by MRI or second clinical attack



· Insidious neurologic progression suggestive of MSOne year of disease progression and dissemination in space, demonstrated by 2 of the following:
  • One or more T2 lesions in brain, in regions characteristic of MS
  • Two or more T2 focal lesions in spinal cord
  • Positive CSF
Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.
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Blood Studies

Results of blood studies are usually normal in MS patients. Perform blood work to help exclude conditions such as the following:

  • Collagen vascular disease and other rheumatologic conditions
  • Infections (ie, Lyme disease, syphilis)
  • Endocrine abnormalities (eg, thyroid disease)
  • Vitamin B12 deficiency
  • Sarcoidosis
  • Vasculitis

Neuromyelitis optica (NMO, or Devic disease) can be confirmed by the presence of serum antibodies against aquaporin 4, a water channel expressed at major fluid-tissue barriers across the CNS.[5]

In patients with movement disorders and ocular manifestations, copper studies may be useful. Wilson disease has been misdiagnosed as MS.[37]

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Magnetic Resonance Imaging

Although MRI alone cannot be used to diagnose MS, it remains the imaging procedure of choice for diagnosing MS and monitoring disease progression in the brain and spinal cord. MRI is not specific, but it is considered the most sensitive imaging modality for diagnosing spinal cord MS, for evaluating its extent, and for following up the response to treatment.[38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48]

MRI is more sensitive for identifying active plaques than is double-dose computed tomography (CT) scanning or clinical examination. MRI far exceeds CT scanning in the ability to demonstrate intramedullary pathology.[49]

MRI shows brain abnormalities in 90-95% of MS patients and spinal cord lesions in up to 75%, especially in elderly patients.[50] T2-weighted images show edema and more chronic lesions, whereas T1-weighted images demonstrate cerebral atrophy and "black holes." These black holes represent areas of axonal death.

One of the limitations of using MRI in patients with MS is the discordance between lesion location and the clinical presentation. In addition, depending on the number and location of findings, MRI can vary greatly in terms of sensitivity and specificity in the diagnosis of MS.

A subset of patients with MS experiences minimal clinical impairment despite significant lesions on MRI. Functional MRI (fMRI) studies detects changes in blood flow related to energy use by brain cells; fMRI studies suggest that increased cognitive control recruitment in the motor system may limit the clinical manifestations of the disease in such cases.[51]

MR spectroscopy is another MRI-based technique that detects a “spectrum” of chemical shifts; this technique appears capable of depicting changes in white matter that are not detected with routine pulse sequences. Because the findings are correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis.[52, 53, 54, 55]

For more information, see Brain Imaging in Multiple Sclerosis and Spine Imaging in Multiple Sclerosis.

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Other Imaging Studies in Multiple Sclerosis

The advent of MRI has limited the role of CT and radiography in the diagnosis and treatment of MS. Occasionally, plain radiographs may be used to exclude mechanical bony lesions.

Angiography also has a limited role, but may occasionally be considered when CNS vasculitis is part of the differential diagnosis in a patient with undifferentiated findings. No positive angiographic findings are specific to MS.

Ultrasonography is not currently used in the investigation of MS. However, Berg et al used transcranial ultrasonography to determine the size of the ventricles in patients with MS and found that increasing ventricular size is correlated with the MRI-determined brain volume, as well as with cognitive dysfunction and clinical disability.[56] Further studies may establish a role for ultrasonography in determining the prognosis and guiding treatment of patients with MS.[57]

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Evoked Potentials

Evoked potentials (ie, recording of the timing of CNS responses to specific stimuli) can be useful neurophysiologic studies for evaluation of MS. These tests, which are used to identify subclinical lesions but which are nonspecific for MS, include the following:

VEPs are performed by having a patient focus on a reversing black-and-white checkerboard pattern. Delays in latencies indicate demyelination in the anterior visual pathways. VEPs are not typically necessary for patients with clear clinical evidence of optic neuritis (ON).

SSEPs evaluate the posterior column of the spinal cord, the brainstem, and the cerebral cortex. Delays in latencies of various peaks indicate demyelination in the correlated pathway of the spinal cord or brain.

BAEPs are performed to evaluate ipsilateral asymptomatic MS lesions in the auditory pathways. They are less sensitive than VEPs and SSEPs.

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Electroencephalography

Electroencephalographic results have been found to be outside the reference range in some patients with MS, but the findings are nonspecific. Nonspecific electroencephalographic abnormalities can also be seen in normal individuals in the general population. A small study by Vazquez-Marrufo et al found that on quantitative electroencephalography, benign MS and relapsing-remitting MS produce different physiologic profiles.[58]

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Lumbar Puncture

Lumbar puncture with CSF analysis is no longer routine in the investigation of MS, but this test may be of use when MRI is unavailable or MRI findings are nondiagnostic. CSF is evaluated for oligoclonal bands (OCBs) and intrathecal immunoglobulin G (IgG) production, as well as for signs of infection.

OCBs are found in 90-95% of patients with MS, and intrathecal IgG production is found in 70-90% of patients. Although these findings are not specific for MS, CSF analysis is the only direct test capable of proving that the patient has a chronic inflammatory CNS condition.

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Contributor Information and Disclosures
Author

Christopher Luzzio, MD  Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Fernando Dangond, MD  Senior Director of Medical Affairs, Neurology, EMD Serono, Inc

Fernando Dangond, MD is a member of the following medical societies: American Academy of Neurology and American Medical Association

Disclosure: EMD Serono, Inc. Salary Employment

Chief Editor

B Mark Keegan, MD, FRCPC  Assistant Professor of Neurology, College of Medicine, Mayo Clinic; Master's Faculty, Mayo Graduate School; Consultant, Department of Neurology, Mayo Clinic, Rochester

B Mark Keegan, MD, FRCPC is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Minnesota Medical Association

Disclosure: Novartis Consulting fee Consulting; Bionest Consulting fee Consulting

Additional Contributors

Martin K Childers, DO, PhD Professor, Department of Neurology, Wake Forest University School of Medicine; Professor, Rehabilitation Program, Institute for Regenerative Medicine, Wake Forest Baptist Medical Center

Martin K Childers, DO, PhD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Congress of Rehabilitation Medicine, American Osteopathic Association, Christian Medical & Dental Society, and Federation of American Societies for Experimental Biology

Disclosure: Allergan pharma Consulting fee Consulting

Edmond A Hooker II, MD, DrPH, FAAEM Assistant Professor, Department of Emergency Medicine, University of Cincinnati College of Medicine

Edmond A Hooker II, MD, DrPH, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Public Health Association, Society for Academic Emergency Medicine, and Southern Medical Association

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marjorie Lazoff, MD Editor-in-Chief, Medical Computing Review

Marjorie Lazoff, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Emergency Physicians, American Medical Informatics Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Consuelo T Lorenzo, MD Physiatrist, Department of Physical Medicine and Rehabilitation, Alegent Health, Immanuel Rehabilitation Center

Consuelo T Lorenzo, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation

Disclosure: Nothing to disclose.

William J Nowack, MD Associate Professor, Epilepsy Center, Department of Neurology, University of Kansas Medical Center

William J Nowack, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Electroencephalographic Association, American Medical Informatics Association, and Biomedical Engineering Society

Disclosure: Nothing to disclose.

Richard Salcido, MD Chairman, Erdman Professor of Rehabilitation, Department of Physical Medicine and Rehabilitation, University of Pennsylvania School of Medicine

Richard Salcido, MD is a member of the following medical societies: American Academy of Pain Medicine, American Academy of Physical Medicine and Rehabilitation, American College of Physician Executives, American Medical Association, and American Paraplegia Society

Disclosure: Nothing to disclose.

Daniel D Scott, MD, MA Associate Professor, Department of Physical Medicine and Rehabilitation, University of Colorado School of Medicine; Attending Physician, Department of Physical Medicine and Rehabilitation, Denver Veterans Affairs Medical Center, Eastern Colorado Health Care System

Daniel D Scott, MD, MA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, Association of Academic Physiatrists, National Multiple Sclerosis Society, and Physiatric Association of Spine, Sports and Occupational Rehabilitation

Disclosure: Nothing to disclose.

Fu-Dong Shi, MD, PhD Director of Neuroimmunology Laboratory, Barrow Neurological Institute, St Joseph's Hospital and Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Timothy Vollmer, MD Consulting Staff, Department of Emergency Medicine, Geisinger Medical Center

Disclosure: Nothing to disclose.

Sandra F Williamson, MS, ANP-C, CRRN Clinic Coordinator, Department of Rehabilitation Medicine, Denver Veterans Affairs Medical Center

Sandra F Williamson, MS, ANP-C, CRRN is a member of the following medical societies: Phi Beta Kappa, Phi Kappa Phi, and Sigma Theta Tau International

Disclosure: Nothing to disclose.

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The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. MRI reveals multiple lesions with high T2 signal intensity and one large white matter lesion. These demyelinating lesions may sometimes mimic brain tumors because of the associated edema and inflammation.
MRI of the head of a 35-year-old man with relapsing-remitting multiple sclerosis. This MRI, performed 3 months after the one in the related image, shows a dramatic decrease in the size of lesions.
Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.
Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.
Gadolinium-enhanced, T1-weighted image showing enhancement of the left optic nerve (arrow).
Corresponding axial images of the spinal cord showing enhancing plaque (arrow). The combination of optic neuritis and longitudinally extensive spinal cord lesions constitutes Devic neuromyelitis optica.
Table 1. 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis[35]
Clinical Presentation Additional Data Needed for MS Diagnosis
  • Two or more attacks
  • Objective clinical evidence of 2 or more lesions with reasonable historical evidence of a prior attack
None; clinical evidence will suffice. Additional evidence (eg, brain MRI) desirable,



but must be consistent with MS



  • Two or more attacks
  • Objective clinical evidence of 1 lesion
Dissemination in space demonstrated by MRI or



Await further clinical attack implicating a different site



  • One attack
  • Objective clinical evidence of 2 or more lesions
Dissemination in time demonstrated by



MRI or second clinical attack



  • One attack
  • Objective clinical evidence of 1 lesion (clinically isolated syndrome)
Dissemination in space demonstrated by



MRI or await a second clinical attack implicating a different CNS site



and



Dissemination in time, demonstrated by MRI or second clinical attack



· Insidious neurologic progression suggestive of MSOne year of disease progression and dissemination in space, demonstrated by 2 of the following:
  • One or more T2 lesions in brain, in regions characteristic of MS
  • Two or more T2 focal lesions in spinal cord
  • Positive CSF
Notes: An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event.
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