Multiple Sclerosis

Medical Experts

Contributor

SmithT

Tammy Smith, MD, PhD

Assistant Professor of Neurology, Division of Neuroimmunology, University of Utah

GRECC Investigator, George E. Wahlen Department of Veterans Affairs Medical Center

Clinical Consultant, Autoimmune Neurology, ARUP Laboratories

Contributor

Delgado

Julio Delgado, MD, MS

Professor, University of Utah

Vice Chair and Chief of the Division of Clinical Pathology, Executive Vice President, ARUP Laboratories

Multiple sclerosis (MS) is a chronic immune-mediated disease characterized by inflammation and demyelination within the central nervous system (CNS). This process disrupts neural signal transmission, which can cause symptoms such as impaired motor function, sensory deficits, and cognitive decline. Although the precise cause of MS is unknown, the disease is understood to arise from a multifactorial interplay of genetic susceptibility, environmental factors, and infectious triggers, most notably Epstein-Barr virus (EBV). Diagnosis of MS can be challenging due to variable disease presentation and significant clinical overlap with diseases such as neuromyelitis optica spectrum disorders (NMOSDs) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Early and accurate diagnosis is crucial to prevent irreversible CNS damage. Diagnostic evaluation includes clinical history and neurologic examination. Imaging studies, cerebrospinal fluid (CSF) analysis, and blood tests to exclude alternative causes help support the diagnosis. For patients with diagnosed MS, laboratory testing may be used to determine appropriate treatment, monitor side effects from medication, and stratify patients at risk for opportunistic infections.

Quick Answers for Clinicians

What is the role of cerebrospinal fluid marker testing in the diagnosis of multiple sclerosis?

Cerebrospinal fluid (CSF) markers may be useful to support a diagnosis of multiple sclerosis (MS), although in patients with typical clinical presentations and sufficient characteristic imaging findings, obtaining CSF may not be necessary to make the diagnosis. The presence of CSF-restricted oligoclonal bands (OCBs) is commonly used to support a diagnosis of MS, but the process is time-consuming and technically challenging, which limits the availability of this testing to specialized reference laboratories. Kappa free light chain (kFLC) testing in CSF may be used in place of OCB testing to demonstrate intrathecal inflammation in suspected MS and may be used interchangeably with OCB testing when confirming central nervous system (CNS)-restricted immune activity. Studies show that kFLCs have a comparable diagnostic accuracy to OCBs, with sensitivity and specificity of approximately 95% relative to OCB detection. Because kFLCs can fulfill the dissemination in time (DIT) requirement in MS diagnostic criteria, these CSF markers may accelerate diagnosis by reducing reliance on interval magnetic resonance imaging (MRI) to demonstrate new lesions. Importantly, both OCBs and kFLCs may be present in the CNS in inflammatory conditions other than MS, and they are not diagnostic of demyelinating disease in the absence of the appropriate clinical syndrome.

Which conditions are important to exclude when evaluating a patient with suspected multiple sclerosis?

Multiple sclerosis (MS) shares overlapping clinical, radiologic, and laboratory test result features with several other demyelinating disorders. This overlap is particularly pronounced in the early stages of disease, during which differentiation from conditions such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), subacute neuroinfectious processes, and autoimmune encephalitis can be challenging. For a comprehensive list of alternative diagnoses to consider based on clinical findings, refer to the “Alternative Diagnoses To Consider” table in the “Differential Diagnosis of Suspected Multiple Sclerosis: An Updated Consensus Approach” article by Solomon et al.

Is genetic testing useful to diagnose multiple sclerosis?

No, genetic testing should not be performed to diagnose multiple sclerosis (MS). There are many single nucleotide polymorphisms (SNPs) associated with an increased risk of MS; however, they cannot be used to accurately predict or diagnose MS.

How does the diagnostic approach differ between pediatric and adult patients with suspected multiple sclerosis?

Pediatric multiple sclerosis (MS) is diagnosed using the same 2024 McDonald criteria as adult MS; however, diagnosis in children is more challenging because other demyelinating disorders (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease [MOGAD] and acute disseminated encephalomyelitis [ADEM]), are more common in this age group. To improve diagnostic accuracy, clinicians often incorporate additional testing, including serum antibody assays (i.e., myelin oligodendrocyte glycoprotein [MOG] and aquaporin-4 [AQP4]), and may require longer observation periods or repeat imaging before confirmation of MS. Refer to the Pediatric Multiple Sclerosis section for more information.

Indications for Testing

Initial suspicion of MS typically arises as a result of clinical symptoms (e.g., optic neuritis) or magnetic resonance imaging (MRI) findings.

Laboratory testing provides supportive diagnostic evidence, especially when clinical and imaging findings are insufficient for a definitive diagnosis. Laboratory testing is not required in all cases but should be considered in the following situations:

Presentation is not consistent with a typical clinically isolated syndrome (e.g., in primary progressive MS)
Clinical, imaging, or initial laboratory test result findings indicate features of atypical MS
Patient belongs to a population in which MS is less likely (e.g., children or elderly individuals)

Diagnostic Criteria

Diagnosis of MS requires exclusion of alternative causes and confirmation of MS-specific demyelination using the 2024 McDonald criteria. These criteria integrate clinical presentation, imaging, and laboratory test findings to assess lesion distribution and inflammatory activity. Dissemination in space (DIS) refers to evidence of demyelinating lesions in different characteristic CNS regions; dissemination in time (DIT) shows that inflammatory activity has occurred at more than one point in time.

Although MRI remains central for demonstrating DIS, the 2024 criteria update expanded the role of laboratory testing to reduce time to diagnosis. In addition to traditional oligoclonal bands (OCBs), kappa free light chains (kFLCs) are now recognized as an alternative CSF marker for MS-related inflammation. Importantly, a positive CSF test result can substitute for DIT, allowing for diagnosis at initial evaluation when combined with DIS.

Key diagnostic pathways for MS include:

DIS and DIT demonstrated by clinical findings or imaging
DIS and a positive CSF test (with OCBs or kFLCs)
Presence of typical lesions in at least four of five MS-anatomic regions (i.e., periventricular, juxtacortical/cortical, infratentorial, spinal cord, and optic nerve regions) for patients with typical clinical presentations
Imaging-based marker (e.g., central vein sign, paramagnetic rim lesions) plus DIT or positive CSF test

Pediatric Multiple Sclerosis

Pediatric MS is diagnosed using the same McDonald criteria as is used for adult patients. However, when a child presents with acute disseminated encephalomyelitis (ADEM), the 2024 McDonald criteria outline additional requirements that must be met before the criteria can be applied.

MOGAD is more prevalent in pediatric populations than MS, but the two conditions overlap in clinical features and MRI findings. Therefore, myelin oligodendrocyte glycoprotein immunoglobulin G (MOG IgG) antibodies play a critical role in the diagnostic workup of pediatric cases. Specific pediatric recommendations include the following: All children younger than 12 years with incident CNS demyelination should undergo serum MOG IgG testing; for children 12 years and older, MOG IgG testing is recommended only in the presence of atypical MS features or symptoms suggestive of MOGAD.

Other Special Populations

The 2024 McDonald criteria provide guidance for other atypical presentations of MS, including radiologically isolated syndrome, progressive MS, and late-onset MS (age ≥50 years). Individuals with these presentations may require additional diagnostic testing or modified thresholds to improve specificity and reduce the risk of misdiagnosis. Clinicians encountering these presentations should consult the full 2024 McDonald criteria for detailed diagnostic pathways.

Laboratory Testing

Laboratory testing plays an important role in diagnosis and treatment of MS. Testing can help confirm a diagnosis early in the disease process, exclude mimics, and monitor for side effects from disease-modifying therapies.

Cerebrospinal Fluid Markers

CSF markers may provide evidence of CNS inflammation, enable alternative diagnoses to be ruled out, and support fulfillment of MS diagnostic criteria. Currently recognized markers include OCBs and kFLCs; the latter were recently accepted as an alternative to OCBs.

Oligoclonal Bands

CSF-restricted OCBs serve as a key marker of intrathecal antibody production. They are uncommon in NMOSDs and MOGAD, which enhances their diagnostic specificity for MS. The main technical challenge in OCB testing is reproducibility, largely due to complexities in laboratory methods such as electrophoresis, immunoblotting, and pattern interpretation. Therefore, analysis should be performed in specialized laboratories with expertise in CSF diagnostics.

Kappa Free Light Chains

CSF kFLCs serve as markers of intrathecal antibody production because excess light chains are generated alongside immunoglobulins during inflammatory activity. Compared with OCB testing, kFLC testing is less labor intensive and more objective. The 2024 McDonald criteria recognize kFLCs as an acceptable alternative to OCBs for establishing a positive CSF result.

Additional CSF Studies

Routine CSF findings such as a high inflammatory cell count, very low glucose, or very high protein can indicate alternative disorders.

Blood Tests

Blood tests can help rule out conditions that mimic MS symptoms, including infections (e.g., Lyme disease, syphilis, HIV), vitamin deficiencies (e.g., B₁₂), and autoimmune diseases (e.g., lupus, Sjögren syndrome).

Autoantibody testing may be used to differentiate MS from conditions such as NMOSD and MOGAD. Aquaporin-4 immunoglobulin G (AQP4 IgG) serum autoantibody is specific to NMOSD, whereas MOG IgG is specific to MOGAD. For antibody testing, cell-based assays are preferred over enzyme-linked immunosorbent assays (ELISAs) due to their higher sensitivity and specificity.^, In addition, antibody testing for AQP4 IgG and MOG IgG is most sensitive when performed on serum. Testing is most informative when performed soon after a clinical episode and ideally before initiating immunotherapy. Antibody testing should not be used as a broad screening tool for all patients being evaluated for MS. Instead, testing should be guided by clinical features that suggest NMOSD or MOGAD rather than MS.

AQP4 IgG testing is appropriate in patients presenting with either of the two hallmarks of NMOSDs: acute longitudinally extensive transverse myelitis and/or acute optic neuritis (unilateral or bilateral), and may also be considered in patients with suspected encephalitis or brainstem encephalitis.

MOG IgG testing is recommended only when a patient presents with one of the core demyelinating syndromes (most commonly optic neuritis, ADEM, or transverse myelitis) and no alternative diagnosis better matches the clinical picture. Low titers of MOG IgG have poorer positive predictive value for a diagnosis of MOGAD than higher titers.

Monitoring

MRI and laboratory markers are used to monitor the safety and efficacy of disease-modifying therapies (DMT) in patients with MS. Although MRI is the primary tool for monitoring disease activity, laboratory testing provides complementary information for treatment management. Laboratory markers of brain cellular injury, such as neurofilament light, are well-established in clinical trials, but the use of these markers in routine clinical practice for individual patients is still evolving. DMT-specific laboratory monitoring for safety is critical and varies by medication; key safety parameters include lymphocyte counts to detect lymphopenia, immunoglobulin levels, autoimmunity surveillance, John Cunningham virus (JCV) serology, and COVID-19 vaccination seroresponse. The specific laboratory tests required depend on the DMT in use, as different medications carry distinct safety profiles requiring tailored monitoring approaches.cite.