Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic immune-mediated and progressive inflammatory disorder that results from the demyelination of the nerve fibers in the spinal cord and the brain.1,2 Multiple sclerosis is characterized by the presence of lesions, also designated as plaques, in the central nervous system (CNS) and by axonal damage in later phases of the disease.3 Demyelination results in an impaired communication with the brain with consequent development of neurological disabilities by the patients. These disabilities are expressed through changes in patients’ mobility, cognition, vision, balance, sphincter function, and sensation.4

Different MS subtypes have been identified, and the presentation of the disease depends on the location of the lesions and whether the disease is relapsing or progressive.4 In about 80% to 85% of patients, relapses, or exacerbations, are associated with the disease.1 These relapses correspond with neurological deficits that last at least 24 hours and then enter a remission phase. Identifying early signs of MS is essential since there are different and effective treatments that can control relapsing-remitting MS.4

An MS diagnosis requires a combination of signs and symptoms, radiologic studies, and laboratory workups, as outlined in the 2017 McDonald criteria.5 These criteria provide recommendations and guidelines on the MS diagnosis, which is ultimately performed on an exclusion basis. The main criteria for an MS diagnosis include the dissemination in space (DIS) and dissemination in time (DIT) of focal neurological disease. Other neurological diseases that mimic MS need to be ruled out for an accurate diagnosis.5

DIS can be demonstrated by 1 or more T2 hyperintense lesions in at least 2 regions of the CNS. DIT can be demonstrated with the simultaneous presence of at least 1 MS lesion with gadolinium enhancement in an MS-typical site and nonenhancing lesions. DIT can also be demonstrated by the presence of a new T2 hyperintense or gadolinium-enhancing lesion on a follow-up scan and with reference to a baseline scan.5

The McDonald criteria also define the diagnosis of primary progressive multiple sclerosis (PPMS). Primary progressive MS diagnosis requires the progression of the disease over 1 year with the simultaneous verification of 2 of the following criteria: 1 or more T2 hyperintense bands in more than 1 MS-typical site, 2 or more T2 hyperintense lesions in the spinal cord, and the presence of cerebrospinal fluid (CSF)-specific oligoclonal bands.5

Traditionally, a single attack was considered insufficient for establishing an MS diagnosis. Several relapses would suggest the existence of lesions in the CNS and would support the diagnosis. The McDonald criteria has been consistently revised  and currently considers the possibility of establishing a diagnosis after a single relapse episode.5

Physical Examination and Blood Tests

Diagnosis of MS is achieved through medical history and a physical and neurological examination. Neurological studies are directed to investigate the dissemination of lesions into the CNS.1 The identification of these lesions and the absence of any other medical condition that may be accountable for the symptoms experienced by patients are key points in establishing an MS diagnosis.6

Initial blood tests will help rule out other conditions, such as rare hereditary disorders or AIDS. Routine tests such as complete blood count and renal and liver function tests are typically requested by physicians.1 However, it is not unusual for patients with MS to have normal blood test results. Complement proteins C1q, C3d, and C5b-9 are suggested MS biomarkers found in patients’ serum that distinguish between MS subtypes, but the clinical use of these tests is unknown.7 Other conditions that are non-MS related, such as endocrine alterations or infections, may be identified with the blood workup.

Brain MRI showing lesions in multiple sclerosis

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is the most useful imaging procedure for investigating DIS and DIT, according to McDonald criteria.5 It can also help when determining differential diagnoses.8

MRI imaging criteria have been revised by the European Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network.9 Changes introduced in the diagnostic criteria when using MRI in MS diagnosis are expected to lead to earlier and more accurate diagnoses.8

The use of contrast-enhanced MRI aids in the identification of recent and active lesions. Gadolinium-enhancing T1 lesions typically correlate with an inflammatory and early phase of the disease and to the breakdown of the blood-brain barrier.10 The use of T2-weighted images and T2-weighted fluid-attenuated inversion recovery (FLAIR) images allows radiologists to study the size and location of MS lesions11 while providing information on inflammatory events.8 These advanced MRI techniques may also help in differentiating MS lesions from T2 hyperintensities encountered in clinical conditions other than MS.5

lumbar puncture multiple sclerosis diagnosis

Lumbar Puncture and the CSF Examination

Lumbar punctures are not required for MS diagnosis, but they can provide supplemental information when other tests, such as MRI, are not conclusive. 

The analysis of the CSF is more important when diagnosing early stages of MS.1 This CSF examination can be performed at different levels: biochemical (for determination of glucose and proteins), microbiological (for performing cell counts), cytopathological (for excluding a cancer diagnosis), and immunological (for quantifying immunoglobulin G [IgG]).4 These analytical results may reveal the presence of IgG antibodies, oligoclonal bands, and an elevated count of the white blood cells, compatible with MS disease.12

More recently, the levels of certain microRNAs (miR-2019 and miR-150) found in the CSF have been suggested as potential biomarkers for the diagnosis of MS.13,14

Evoked Test Potential

Visual evoked potentials (VEPs) and somatosensory evoked potentials (SSEPs) are electrophysiological tests that measure the electrical activity of the brain in response to stimulation (sound, sight, or touch and afferent peripheral nerve fibers, respectively). The electrical signals evoked by these stimuli can be tracked with electrodes on the patient’s scalp. These tests are used after an inconclusive MS diagnosis. Following a neurological examination and a prolonged latency combined with specific patterns of evoked potentials, potential demyelination should be expected.4


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  2. Gul M, Jafari AA, Shah M, et al. Molecular biomarkers in multiple sclerosis and its related disorders: a critical review. Int J Mol Sci. 2020;21(17):6020. doi:10.3390/ijms21176020
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  6. Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269-290. doi:10.1016/B978-0-444-52001-2.00011-X
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  8. Filippi M, Preziosa P, Rocca MA. MRI in multiple sclerosis: what is changing? Curr Opin Neurol. 2018;31(4):386-395. doi:10.1097/WCO.0000000000000572 
  9. Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016;15(3):292-303. doi:10.1016/S1474-4422(15)00393-2
  10. Sahraian MA, Radue EW. Gadolinium enhancing lesions in multiple sclerosis. In: Radue EW, Sahraian MA, eds. MRI Atlas of MS Lesions. Springer; 2007:45-74. Accessed June 17, 2021.
  11. Wang C, Ruiz A, Mao-Draayer Y. Assessment and treatment strategies for a multiple sclerosis relapse. J Immunol Clin Res. 2018;5(1):1032.
  12. Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62(6):865-870. doi:0.1001/archneur.62.6.865
  13. Bergman P, Piket E, Khademi M, et al. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(3):e219. doi:10.1212/NXI.0000000000000219
  14. Bruinsma IB, van Dijk M, Bridel C, et al. Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS. J Neuroinflammation. 2017;14(1):235. doi:10.1186/s12974-017-1006-3

Reviewed by Michael Sapko, MD, on 7/1/2021.