Multiple Sclerosis Workup

Updated: Jan 03, 2023
  • Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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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 2017 McDonald criteria (see Table 1, below) allow diagnosis of MS even with a first clinical episode. [1]

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 can be present, even in asymptomatic patients, early in the disease process. [63] 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.


McDonald Criteria for MS Diagnosis

The McDonald criteria, which were developed in 2001 by an international expert panel and revised several times, most recently in 2017, provide recommendations on the diagnosis of MS, including diagnosis after a single attack. [1] The criteria consist of a combination of clinical, imaging, and paraclinical tests (ie, CSF, evoked potentials). [4] (See Table 1, below.) 

Table 1. 2017 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis [1] (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 or demonstration of CSF-specific oligoclonal bands

  • 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


Dissemination in time, demonstrated by MRI or second clinical attack

· Insidious neurologic progression suggestive of MS

One 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.

Key changes made to the McDonald Criteria in 2017 include the following:

  • Brain stem and cord lesions can now be counted among the 2 lesions disseminated in space and time.
  • CSF oligoclonal bands can now be used to substitute for demonstration of dissemination in time in some settings.
  • Both asymptomatic and now symptomatic MRI lesions can be considered in determining dissemination in space (optic nerve lesions are still excluded).
  • Cortical lesions have been added to juxtacortical lesions as determinant for dissemination in space.

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. [36]

In patients with movement disorders and ocular manifestations, copper studies may be useful. Wilson disease has been misdiagnosed as MS. [64]


Magnetic Resonance Imaging

Although MRI alone cannot be used to diagnose MS, it remains the imaging procedure of choice for confirming 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. [65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75]

The Consortium of Multiple Sclerosis Centers (CMSC) revised its MRI protocol and guidelines in 2015. The revised guidelines recommend using higher-resolution three-dimensional (3D) imaging over two-dimensional (2D) imaging whenever possible. More frequent scanning is recommended to monitor for progressive multifocal leukoencephalopathy in patients taking natalizumab. [76]

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. [77]

MRI shows brain abnormalities in 90-95% of MS patients and spinal cord lesions in up to 75%, especially in elderly patients. [78] 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.

According to new research, monitoring levels of iron in specific areas of the brain in patients with MS by using novel MRI may track disease progression and assess treatment efficacy in clinical trials. In the study, a new technique known as quantitative susceptibility mapping (QSM) identified different iron patterns in the brains of patients with MS (N=600) compared with healthy controls (N=250). Patients with MS had lower iron content in the thalamus and higher iron content in other deep gray-matter structures compared with controls. [79]

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. [80]

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 could be correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis. [81, 82, 83, 84]

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


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. [85] Further studies may establish a role for ultrasonography in determining the prognosis and guiding treatment of patients with MS. [86]


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.



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. [87]


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.