Which laboratory tests should be obtained in an adult being evaluated for possible multiple sclerosis presenting with new‑onset neurologic symptoms such as optic neuritis, sensory changes, weakness, or gait disturbance?

Laboratory Testing for Multiple Sclerosis Evaluation

When evaluating an adult with new neurologic symptoms suggestive of multiple sclerosis, obtain serum AQP4-IgG and MOG-IgG antibody testing immediately at presentation, and reserve lumbar puncture for cases where CSF findings would directly alter management—such as atypical presentations or when oligoclonal bands combined with MRI lesions would substantially modify MS risk assessment. 1

Essential Serum Antibody Testing

Obtain serum testing for AQP4-IgG and MOG-IgG at the initial presentation to differentiate MS from neuromyelitis optica spectrum disorder (NMOSD) and MOG-antibody disease, as these conditions require fundamentally different immunotherapy rather than standard MS disease-modifying drugs. 1, 2

• Use cell-based assays employing full-length human MOG as the target antigen—peptide-based ELISA and Western blot techniques lack sufficient specificity and are no longer recommended. 1
• Serum is the preferred specimen because MOG-IgG is predominantly produced extrathecally, resulting in higher sensitivity than CSF testing. 1
• Early detection prevents inappropriate use of MS-directed therapies (e.g., interferon-β) that can increase relapse rates in NMOSD and MOG-antibody disease, and allows prompt initiation of appropriate agents such as rituximab. 1, 2

Clinical Red Flags That Mandate Immediate Antibody Testing

Order antibody testing urgently when any of these features are present, as they markedly increase pre-test probability:

• Bilateral optic neuritis, especially simultaneous involvement 1, 3
• Prominent optic disc edema or papilledema 1
• Longitudinally extensive optic nerve lesions (≥4 of 5 segments or >50% of nerve length) 1, 3
• Posterior optic nerve or chiasm involvement 1, 3
• Severe visual loss with good recovery potential 1
• Longitudinally extensive transverse myelitis (≥3 contiguous vertebral segments) 3
• Intractable nausea, vomiting, and hiccups (area postrema syndrome) 3

Selective Use of Lumbar Puncture

Routine lumbar puncture is not required for first-episode demyelinating events; reserve it for specific clinical scenarios where CSF analysis would directly change management. 1

When to Perform Lumbar Puncture

• Atypical presentations requiring infectious or broader inflammatory work-up beyond demyelinating disease 1
• When CSF oligoclonal bands combined with brain MRI lesions would substantially modify MS risk stratification—oligoclonal bands are present in 85-95% of MS cases but typically absent in NMOSD 3, 2
• To support diagnosis when MRI is not entirely diagnostic or reveals features unusual for MS 4
• In primary progressive MS (PPMS) where paraclinical support may be needed and brain MRI can be normal 4

CSF Findings That Support MS Diagnosis

• Presence of oligoclonal bands (found in 85-95% of MS patients) 3
• CSF oligoclonal bands combined with brain MRI lesions dramatically reduce the likelihood of monophasic illness and predict MS conversion 1, 2
• Oligoclonal bands are typically absent in NMOSD, helping distinguish it from MS 3

Critical Diagnostic Pitfalls to Avoid

• Do not delay antibody testing waiting for dissemination in space—many NMOSD and MOG-antibody disease patients present with isolated syndromes that warrant immediate testing. 3
• Do not assume all NMOSD is AQP4-positive—approximately 25% are seronegative, and some may have anti-MOG antibodies requiring different management. 3
• Do not apply MS diagnostic criteria without excluding alternative diagnoses—application in atypical presentations increases misdiagnosis risk. 4
• Do not use MS disease-modifying therapies before excluding NMOSD—some MS treatments can worsen NMOSD outcomes. 2

Additional Laboratory Considerations

While not part of routine MS diagnostic criteria, consider these tests in specific contexts:

• Routine blood work to exclude mimics such as vitamin B12 deficiency, thyroid dysfunction, or systemic inflammatory conditions 5
• Serologic tests for infectious or inflammatory etiologies in atypical presentations 6
• Visual evoked potentials (VEPs) provide objective evidence of optic nerve dysfunction with delayed conduction, useful when imaging is equivocal 1

Integration with Imaging

Laboratory testing must be interpreted alongside MRI findings, which remain the cornerstone of MS diagnosis:

• Brain and spinal cord MRI with gadolinium should be performed to assess for dissemination in space and time per 2017 McDonald Criteria 4, 2, 7
• Even one clinically silent T2 hyperintense brain lesion in optic neuritis patients is highly associated with eventual MS diagnosis (hazard ratio 5.1 for 1-3 lesions, 11.3 for ≥10 lesions) 1, 2
• MRI scans should be interpreted by experienced readers aware of clinical and laboratory information 4