Is immunofixation (immunoelectrophoresis) indicated in a patient with bilateral foot burning/numbness?

Immunofixation Electrophoresis in Bilateral Foot Burning/Numbness

Immunofixation electrophoresis (IFE) is strongly recommended for patients with bilateral foot burning/numbness as it can detect monoclonal gammopathies that may cause peripheral neuropathy, which are found in approximately 10% of patients with polyneuropathy of unknown etiology. 1

Rationale for IFE Testing

• Distal symmetric polyneuropathy (DSP) with symptoms like bilateral foot burning/numbness requires screening laboratory tests, with serum protein immunofixation electrophoresis being one of the tests with the highest yield of abnormality 1
• IFE is more sensitive than serum protein electrophoresis (SPEP), especially for detecting small or non-malignant monoclonal gammopathies 1
• In patients with polyneuropathy of otherwise unknown etiology, approximately 10% have monoclonal gammopathy, which is a significant increase over the general population 1

Conditions Detectable by IFE That Can Cause Neuropathy

• Monoclonal gammopathies associated with peripheral neuropathy include:
  • POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) 2
  • Waldenström's macroglobulinemia, which often presents with neuropathy 1
  • AL amyloidosis, which can cause peripheral neuropathy with autonomic features 1
  • Multiple myeloma with neuropathic manifestations 1

Diagnostic Value of IFE

• IFE has superior sensitivity compared to SPEP, with studies showing IFE can detect monoclonal proteins in approximately 30% of cases that were missed by SPEP 1, 3
• IFE is essential for accurate diagnosis of monoclonal gammopathies due to its superior sensitivity and specificity 3
• IFE can detect IgM antibodies associated with myelin-associated globulin (anti-MAG), which are found in approximately 50% of patients with demyelinating symmetric sensory peripheral neuropathy 1

Testing Algorithm for Bilateral Foot Burning/Numbness

1. Initial laboratory evaluation should include:

   • Blood glucose and glycated hemoglobin (HbA1c) 1
   • Serum B12 with metabolites (methylmalonic acid with or without homocysteine) 1
   • Serum protein immunofixation electrophoresis (IFE) 1

2. If routine blood glucose testing is not clearly abnormal, consider glucose tolerance test (GTT), especially if the neuropathy is painful 1

3. If IFE detects a monoclonal protein:

   • Collaborate with a hematologist to determine whether findings represent MGUS, AL amyloidosis, or multiple myeloma 1
   • Consider additional testing for specific conditions:
     • For suspected POEMS: evaluate for sclerotic bone lesions, organomegaly, endocrinopathy, and skin changes 2
     • For suspected Waldenström's: assess for cold agglutinins, cryoglobulins, and anti-MAG antibodies 1
     • For suspected amyloidosis: consider tissue biopsy and serum free light chain assay 1

Common Pitfalls and Caveats

• Relying solely on SPEP can miss approximately 30% of monoclonal gammopathies that would be detected by IFE 1, 3
• It's important to differentiate polyclonal increases in immunoglobulins (which appear as broad-based elevations) from monoclonal gammopathies (which appear as discrete peaks) 4
• When evaluating polyneuropathy, consider both common causes (diabetes, B12 deficiency) and less common causes (monoclonal gammopathies) 1
• In patients with neuropathy, even small monoclonal bands detected by IFE may be biologically meaningful and potentially predictive of disease progression 5

By following this approach, clinicians can effectively identify potentially treatable causes of bilateral foot burning/numbness, including monoclonal gammopathy-associated neuropathies that might otherwise be missed without IFE testing.