What is the role of blood testing in diagnosing multiple sclerosis (MS)?

Blood Testing in Multiple Sclerosis Diagnosis

Blood tests do not diagnose multiple sclerosis—there is no blood biomarker for MS, and the diagnosis relies on demonstrating dissemination of CNS lesions in time and space through clinical assessment, MRI, and cerebrospinal fluid analysis. 1, 2

Primary Diagnostic Approach

The diagnosis of MS requires objective evidence of inflammatory-demyelinating lesions separated in both time and space within the central nervous system. 1 Blood testing plays only an exclusionary role to rule out MS mimics, not a confirmatory role. 3, 4

Core Diagnostic Tools (in order of importance):

• MRI is the most sensitive and specific test for MS diagnosis, showing characteristic lesions in brain and spinal cord with dissemination in space (≥2 of: periventricular, cortical/juxtacortical, infratentorial, or spinal cord) and time (gadolinium-enhancing and non-enhancing lesions simultaneously, or new lesions on follow-up). 2, 5

• Cerebrospinal fluid analysis provides evidence of inflammation through oligoclonal bands (detected by isoelectric focusing, different from serum) or elevated IgG index, with sensitivity 69-91% and specificity 59-94%. 1, 2, 5 CSF is particularly valuable when imaging is atypical or insufficient. 1, 2

• Clinical assessment requires objective neurological signs of attacks lasting ≥24 hours, separated by ≥30 days between onset of events. 1 Historical symptoms alone are insufficient. 1

• Visual evoked potentials showing delay with preserved waveform provide additional support when MRI abnormalities are few or less specific (e.g., older patients with vascular risk factors). 1, 2

Role of Blood Testing

Blood tests serve exclusively to exclude alternative diagnoses that can mimic MS clinically or radiologically. 6, 3 The differential diagnosis requiring blood work includes:

• Infectious diseases: HTLV-1, Lyme disease, HIV, syphilis 6, 3
• Inflammatory conditions: Systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis 3, 4
• Metabolic disorders: Vitamin B12 deficiency, copper deficiency 3
• Neuromyelitis optica spectrum disorder: Aquaporin-4 antibody testing is critical to distinguish NMOSD from MS, as treatment differs fundamentally 6, 3

Diagnostic Algorithm

For patients with suspected MS (typical age 10-59 years with neurological symptoms): 2, 6

1. Obtain brain and spinal cord MRI to assess for dissemination in space and time 2
2. Perform lumbar puncture if MRI criteria not fully met or presentation atypical 1, 2
3. Order blood tests only to exclude mimics, not to confirm MS 6, 3
4. Consider VEP if MRI shows few lesions or patient has progressive myelopathy 1, 2

Combination of MRI and CSF provides enhanced sensitivity (56-100%) and specificity (53-96%) compared to either test alone. 5

Critical Pitfalls

• Do not diagnose MS based solely on MRI results—at least one clinical event consistent with acute demyelination is required. 6
• A positive test for an MS mimic does not automatically exclude MS—patients can have concurrent conditions. 4
• In patients >50 years or with vascular risk factors, apply more stringent MRI criteria (higher number of periventricular lesions required) to avoid misdiagnosing vascular disease as MS. 6
• Distinguish MS from NMOSD through aquaporin-4 antibody testing, as these require different treatments. 6, 3
• Patients with equivocal findings are classified as "possible MS" (not "probable" or "clinically definite"—these outdated terms are no longer recommended). 1, 2

Diagnostic Certainty

Following complete evaluation, patients are classified as: MS, possible MS (equivocal findings), or not MS. 1, 2 If paraclinical tests (MRI, CSF) are performed and negative in a patient with suggestive clinical features, extreme caution is required before diagnosing MS—alternative explanations must be thoroughly excluded. 1