What is the clinical significance of elevated cerebrospinal fluid (CSF) IgG (Immunoglobulin G) levels in a middle-aged adult with a history of neurological symptoms, such as numbness, weakness, or vision changes?

Clinical Significance of Elevated CSF IgG

Elevated CSF IgG in a middle-aged adult with neurological symptoms (numbness, weakness, vision changes) most strongly suggests multiple sclerosis (MS), particularly when oligoclonal bands are present in CSF but absent in serum, which occurs in >95% of MS cases. 1, 2

Primary Diagnostic Consideration: Multiple Sclerosis

• Oligoclonal IgG bands detected by isoelectric focusing in CSF (but not in serum) provide the most powerful evidence for MS diagnosis, with sensitivity exceeding 95% when optimized methodology is used 2
• The IgG index (CSF/serum IgG ratio divided by CSF/serum albumin ratio) is elevated in approximately 70% of MS patients, but is less sensitive than oligoclonal bands 1, 2
• Once present, CSF oligoclonal bands persist throughout the disease course regardless of MS activity or treatment, making this a stable diagnostic marker 2

MS-Specific CSF Patterns

• In clinically definite MS, isoelectric focusing demonstrates local IgG synthesis in 95% of cases 3
• The Log IgG-Index detects abnormalities in only 67% of clinically definite MS cases, making it inferior to oligoclonal band detection 3
• Normal CSF cell count with elevated IgG is typical for MS, distinguishing it from acute inflammatory conditions 1

Critical Differential Diagnoses to Exclude

MOG-Encephalomyelitis (MOG-EM)

• Absence of CSF-restricted oligoclonal bands is a key feature supporting MOG-EM over MS (applies particularly to continental European patients) 1
• The presence of oligoclonal bands should prompt reconsideration of MOG-antibody positive results, as this finding is atypical for MOG-EM 1
• Bi- or trispecific MRZ reaction (measles, rubella, zoster antibodies) in CSF suggests MS rather than MOG-EM 1

Autoimmune Encephalitis

• Inflammatory CSF changes (elevated white cells, protein, or oligoclonal bands) suggest autoimmune encephalitis or other CNS inflammatory conditions 4
• CSF analysis should include neuronal autoantibodies (NMDAR, LGI1, CASPR2, VGKC-complex) when encephalitis is suspected 1
• In VGKC-complex antibody encephalitis, significant CSF abnormalities are uncommon, and antibodies may not be detectable in CSF 1

Immune Checkpoint Inhibitor-Related Neurologic Toxicity

• CSF analysis revealing lymphocytic pleocytosis and elevated protein occurs in many cases of immune-related neurologic adverse events 1
• Normal CSF does not exclude immune-related neurologic toxicity in patients on checkpoint inhibitors 1

Guillain-Barré Syndrome

• Elevated CSF protein with normal cell count (albuminocytologic dissociation) distinguishes GBS from MS 4, 5
• In GBS, IgG elevation is typically proportional to albumin elevation (passive transfer), not intrathecal synthesis 5

Diagnostic Algorithm

Step 1: Confirm Intrathecal IgG Synthesis

• Perform isoelectric focusing to detect oligoclonal bands in paired CSF and serum samples 1, 3, 2
• Calculate IgG index: (CSF IgG/serum IgG) ÷ (CSF albumin/serum albumin) 1, 6
• Isoelectric focusing has 0% false positive rate compared to 3.5% for IgG index alone 3

Step 2: Correlate with MRI Findings

• MS diagnosis requires dissemination in space: ≥3 of the following MRI criteria 1:
  • One gadolinium-enhancing or nine T2-hyperintense brain lesions
  • At least one infratentorial lesion
  • At least one juxtacortical lesion
  • At least three periventricular lesions
• Red flags against MS: ovoid periventricular lesions, Dawson's fingers, or inferior temporal lobe lesions suggest alternative diagnosis if oligoclonal bands are absent 1

Step 3: Exclude Infectious Etiologies

• Viral encephalitis typically shows mildly elevated protein with normal glucose and lymphocytic pleocytosis, but 5-10% of HSV encephalitis cases have completely normal initial CSF 5, 7
• Send CSF PCR for HSV-1, HSV-2, VZV, and enteroviruses if infection suspected 5
• CSF protein >220 mg/dL strongly suggests bacterial meningitis; <60 mg/dL makes bacterial disease very unlikely 5

Step 4: Consider Paraneoplastic Syndromes

• Screen for intracellular antibodies (Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin) in patients with subacute onset 1
• Obtain CT chest/abdomen/pelvis and consider PET imaging if paraneoplastic antibodies detected 1

Common Pitfalls to Avoid

• Do not rely on IgG index alone—isoelectric focusing for oligoclonal bands has superior sensitivity and specificity for MS diagnosis 3, 2
• Do not assume elevated CSF IgG always indicates MS—28-40% of CNS infections or immunological diseases show IgG abnormalities 6
• Do not accept MOG-antibody positive results at face value if oligoclonal bands are present—this combination is a "red flag" requiring retesting 1
• Do not diagnose MS in patients with progressive disease from onset without relapses if oligoclonal bands are absent—this pattern is very rare in MOG-IgG positive patients and should prompt alternative diagnosis consideration 1
• Steroid administration decreases IgG index abnormalities but does not affect oligoclonal bands, so timing of lumbar puncture relative to treatment matters for quantitative but not qualitative measures 6

When CSF IgG is Normal Despite Neurological Symptoms

• Re-evaluate the diagnosis entirely—absence of oligoclonal bands in suspected MS should prompt consideration of MS-mimicking conditions 2
• Consider MOG-EM, neuromyelitis optica spectrum disorder (test for AQP4-IgG), or non-inflammatory neurological diseases 1
• In myasthenia gravis, routine CSF parameters including IgG are typically normal, helping distinguish neuromuscular junction disorders from CNS demyelination 4