In a patient with an undefined neuropathy, normal electromyography (no large‑fiber involvement) and a positive T‑cell‑associated immunoglobulin M autoantibody (TIgM by flow cytometry, Net mean fluorescence intensity 295), what is the most likely diagnosis and the recommended first‑line therapy?

Likely Diagnosis: Small‑Fiber Neuropathy with Possible Autoimmune Etiology

In a patient with undefined neuropathy, normal EMG (excluding large‑fiber involvement), and a positive T‑cell‑associated IgM autoantibody (TIgM by flow cytometry, Net MFI 295), the most likely diagnosis is small‑fiber neuropathy with a potential autoimmune or paraprotein‑associated mechanism; first‑line diagnostic confirmation requires skin biopsy with intraepidermal nerve fiber density (IENFD) assessment, and if an underlying IgM monoclonal gammopathy is confirmed, rituximab represents the evidence‑based first‑line immunotherapy. 1, 2

Diagnostic Reasoning and Confirmation

Why Small‑Fiber Neuropathy Is the Leading Diagnosis

• Normal EMG and nerve conduction studies only assess large myelinated fibers and will be completely normal in pure small‑fiber neuropathy, which affects unmyelinated C‑fibers and thinly myelinated Aδ fibers that comprise 79.6–91.4% of peripheral nerve fibers. 1, 3

• The positive TIgM autoantibody suggests an IgM‑mediated autoimmune process, which is a recognized cause of peripheral neuropathy and frequently associates with small‑fiber involvement. 4, 5

• Small‑fiber neuropathy commonly presents with burning pain, tingling, paresthesias, and autonomic symptoms (orthostatic hypotension, gastrointestinal dysmotility, urinary retention, erectile dysfunction) while maintaining normal strength and reflexes early in the disease course. 1, 3

Gold‑Standard Diagnostic Test

• Skin punch biopsy (3 mm) from the distal leg (10 cm proximal to lateral malleolus) with anti‑PGP 9.5 immunohistochemistry to quantify IENFD is the validated gold standard, with sensitivity 77.2–88% and specificity 79.6–88.8%. 1

• A cutoff of ≤8.8 fibers/mm at the ankle demonstrates good diagnostic accuracy. 1

• The biopsy must be sectioned at 50 µm thickness and stained with anti‑PGP 9.5 monoclonal antibodies using bright‑field immunohistochemistry or immunofluorescence. 1

Complementary Functional Testing

• Quantitative sudomotor axon reflex test (QSART) documents small‑fiber (sudomotor) dysfunction with high sensitivity and complements skin biopsy findings. 1, 3

• Thermoregulatory sweat testing provides additional autonomic assessment and is abnormal in approximately 90% of patients with small‑fiber involvement. 4

• Heart‑rate variability (HRV) testing evaluates cardiovagal autonomic function with ≈97.5% specificity when age‑adjusted reference values are applied. 1

Critical Etiological Workup for IgM‑Positive Neuropathy

Mandatory Paraprotein Evaluation

• Serum protein electrophoresis with immunofixation (not standard SPEP alone) is essential to detect IgM monoclonal gammopathy, which underlies many IgM‑associated neuropathies. 1, 3

• Serum free light chain assay should be obtained to assess for underlying plasma cell or lymphoproliferative disorder. 6

• If monoclonal IgM is detected, anti‑myelin‑associated glycoprotein (anti‑MAG) antibodies should be tested via ELISA or Western blot, as anti‑MAG neuropathy is a specific IgM‑mediated demyelinating neuropathy that can present with small‑fiber features. 5

Hematologic Malignancy Screening

• The presence of IgM paraprotein mandates evaluation for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL), which affects up to 22% of patients with paraprotein‑related peripheral neuropathy. 4

• Bone marrow biopsy may be required if serum studies suggest a clonal process or if cytopenias are present. 4

• CT chest/abdomen/pelvis should be considered to evaluate for lymphadenopathy or organomegaly. 4

Additional Autoimmune and Metabolic Screening

• Fasting glucose, HbA1c, and oral glucose tolerance test (impaired glucose tolerance is highly prevalent in unexplained neuropathy). 1, 3

• Vitamin B12 with metabolites (methylmalonic acid ± homocysteine) to increase sensitivity for true deficiency. 3

• Thyroid‑stimulating hormone (TSH) for hypothyroidism. 3, 6

• Anti‑Sjögren antibodies (SSA/SSB) for autoimmune causes. 1

• Antinuclear antibody (ANA), rheumatoid factor, and anti‑CCP antibodies for connective‑tissue diseases. 1

• HIV, hepatitis B/C serology if risk factors present. 1, 3

Paraneoplastic Antibody Panel (If Acute/Subacute Onset)

• If symptom onset was rapid (< 12 weeks), test anti‑Hu (ANNA‑1) antibodies to prompt intensive malignancy search. 1

• Additional onconeural antibodies (Ma2, CV2/CRMP5, Ri, amphiphysin) may be considered in the same context. 1

• Ganglionic acetylcholine‑receptor antibodies if autonomic manifestations are prominent. 1

Genetic Testing (If Appropriate Clinical Context)

• Mutations in sodium‑channel genes SCN9A, SCN10A, and SCN11A (encoding Nav1.7, Nav1.8, Nav1.9) are proven causes of small‑fiber neuropathy and should be considered in early‑onset cases, positive family history, or when secondary causes are excluded. 1

First‑Line Treatment Algorithm

If IgM Monoclonal Gammopathy Is Confirmed

Rituximab is the evidence‑based first‑line immunotherapy for IgM‑associated neuropathy. 4, 2

• Dosing: Standard rituximab regimen (375 mg/m² IV weekly × 4 doses, or 1000 mg IV on days 1 and 15). 4

• Mechanism: Rituximab eliminates CD20+ B cells, reducing IgM autoantibody production over time. 2

• Evidence: Treatment with rituximab produces improved strength (mean increase 23% of normal levels), reduction in serum IgM autoantibodies (to 43% of initial values), and reduction in total IgM levels (to 55% of initial values), with no major side effects even with B‑cell elimination for up to two years. 2

• Meta‑analysis data: Demonstrates improvement of disability at 8–12 months in anti‑MAG neuropathy, though individual trials did not meet primary endpoints. 5

• Herpes zoster prophylaxis: Mandatory with rituximab and steroid combinations. 4

If Mild, Slowly Progressive IgM‑Related Neuropathy

• Single‑agent rituximab can be considered as the first intervention. 4

If Moderate to Severe or Aggressive IgM‑Related Neuropathy

• Plasmapheresis (2–3 months of weekly sessions) may be initiated for rapidly progressing neuropathy, but must be consolidated with chemotherapy as IgM levels return to baseline in 4–6 weeks after stopping. 4

• After plasmapheresis, use rituximab combined with cyclophosphamide and prednisone or rituximab, cyclophosphamide, and dexamethasone to achieve robust paraprotein reductions. 4

• Symptomatic improvement is more likely with rituximab combination therapy versus monotherapy (59.3% vs. 37.0%; P = .007). 4

If Underlying Waldenström Macroglobulinemia/LPL Is Diagnosed

• Avoid bortezomib‑based regimens in patients with disease‑related peripheral neuropathy, as bortezomib is associated with increased risk of treatment‑related peripheral neuropathy in WM/LPL. 4

• Bendamustine alone or in combination with rituximab produces high response rates and durable responses in WM/LPL with neuropathy. 4

If Immune‑Mediated Small‑Fiber Neuropathy Without Paraprotein

• Glucocorticoids with non‑glucocorticoid immunosuppressive agents should be used for active inflammatory disease. 6

• A recent study of acute‑onset small‑fiber neuropathy showed that patients improved after a short course of oral corticosteroids (3/3 patients). 7

• In vitro studies in acute‑onset cases showed IgG immunoreactivity against nerve tissue in 70% of patients, suggesting immune‑mediated origin. 7

Symptomatic Pain Management

First‑Line Agents (Level A Evidence)

• Duloxetine (start 30 mg daily, titrate to 60 mg daily). 3, 6

• Pregabalin (start 75 mg twice daily, titrate to 150–300 mg twice daily). 3

• Gabapentin (start 300 mg daily, titrate to 900–3600 mg daily in divided doses). 4, 3

• Tricyclic antidepressants (e.g., amitriptyline 10–75 mg at bedtime). 3, 6

While Awaiting Immunotherapy Response

• Symptomatic treatment with gabapentin, pregabalin, and duloxetine can be initiated while the patient undergoes plasmapheresis or immunotherapy. 4

Critical Pitfalls to Avoid

• Never rely solely on nerve conduction studies to exclude neuropathy; these tests only assess large fibers and will miss small‑fiber neuropathy entirely. 1, 3

• Do not dismiss patient‑reported symptoms when EMG/NCS are normal; normal findings are expected in isolated small‑fiber disease and should prompt skin biopsy. 1

• Do not use bortezomib if the patient has pre‑existing neuropathy, as it will worsen symptoms. 4

• Do not rely on auto‑antibody testing alone for diagnosis; histologic or functional confirmation of small‑fiber involvement is mandatory. 1

• Do not use plasmapheresis as a permanent modality; it must be consolidated with chemotherapy or immunotherapy. 4

Monitoring and Prognosis

• Symptomatic improvement with rituximab is more likely in patients who achieve a major response (≥50% reduction in serum IgM; 79% vs. 35.5%; P < .0001) and those who receive earlier therapy (≤24 months; 57.3% vs. 42.5%; P = .06). 4

• Serial neurologic examinations are preferred over repeated EMG for monitoring stable neuropathy. 3

• Regular assessment for autonomic dysfunction, falls, and skin breakdown is necessary. 6

• In acute‑onset small‑fiber neuropathy, 65% of patients show partial or complete recovery, while others display relapses or a chronic course. 7