In a patient with unexplained neuropathic pain, a positive T‑cell IgM autoantibody (295 MFI) and a normal EMG, what is the most likely diagnosis and the appropriate diagnostic and treatment plan?

Evaluation and Management of Nonspecific Neuropathic Pain with Positive T-Cell IgM Autoantibody

This patient most likely has small fiber neuropathy (SFN), and the positive T-cell IgM autoantibody suggests a possible immune-mediated mechanism that warrants skin biopsy for confirmation and consideration of immunotherapy.

Most Likely Diagnosis

The clinical picture of neuropathic pain with a normal EMG strongly suggests small fiber neuropathy 1. The normal EMG excludes large fiber involvement, as routine electrophysiological tests cannot investigate small nerve fibers due to their physiologic characteristics 1. The positive T-cell IgM autoantibody (295 MFI) raises the possibility of an immune-mediated etiology, which is increasingly recognized in idiopathic SFN 2, 3.

• Small fiber neuropathy exclusively affects small sensory fibers (typically nociceptors) and is characterized by severe neuropathic pain 2
• Approximately 50% of SFN cases are idiopathic, and autoimmune mechanisms are suspected in many of these cases 2, 3
• Elevated IgM levels occur in 11.5% of neuropathy patients, and neuropathy associated with elevated serum IgM is more likely to have an immune-mediated component 4

Diagnostic Workup

Essential Initial Testing

Skin biopsy with intraepidermal nerve fiber (IENF) density quantification is the highest-yield diagnostic test and should be performed first 1:

• Skin biopsy has a diagnostic efficiency of 88.4% for SFN, significantly higher than quantitative sensory testing (46.9%) or clinical examination alone (54.6%) 1
• The diagnosis of SFN requires at least two abnormal results among clinical examination, quantitative sensory testing (QST), and skin biopsy 1
• Skin biopsy demonstrates loss of intraepidermal nerve fibers in small fiber neuropathy 5

Complete Laboratory Evaluation to Exclude Secondary Causes

Even with a positive autoantibody, you must exclude other treatable causes 5, 6:

• Fasting glucose and HbA1c to screen for diabetes 5, 7, 6
• Glucose tolerance test (GTT) if fasting glucose is normal, as impaired glucose tolerance is found in 25-36% of patients with idiopathic neuropathy 5, 6
• Vitamin B12 with metabolites (methylmalonic acid and homocysteine), as B12 deficiency is present in 2.2-8% of polyneuropathy patients 5, 6
• Serum protein immunofixation electrophoresis (IFE), which is more sensitive than SPEP for detecting monoclonal gammopathies present in 10% of idiopathic neuropathy 5, 6
• TSH to exclude hypothyroidism 5, 6
• Complete blood count, renal function, and liver function tests 6
• ESR/CRP to screen for inflammatory conditions 6

Specialized Autoimmune Testing

Given the positive T-cell IgM autoantibody, consider additional immune workup 6:

• ANA and ANCA if autoimmune or vasculitic neuropathy is suspected 5, 6
• Anti-MAG antibodies if IgM monoclonal gammopathy is present, as anti-nerve antibodies occur in 67% of patients with IgM monoclonal gammopathy 4, 6
• Paraneoplastic antibody panel (anti-Hu/ANNA-1) if malignancy-associated neuropathy is considered 6

Quantitative Sensory Testing (QST)

• QST assesses psychophysical thresholds for cold and warm sensations 1
• While less sensitive than skin biopsy, QST shows significant inverse correlation with IENF density at the leg 1
• QST is useful when combined with skin biopsy to meet the diagnostic criteria requiring two abnormal tests 1

Treatment Plan

Immunotherapy Consideration

Intravenous immunoglobulin (IVIG) should be considered given the positive IgM autoantibody and evidence supporting immune mechanisms 2, 3:

• IVIG has proved effective in SFN associated with autoimmune conditions 2
• Plasma exchange is another option, as sensory symptoms can be relieved with immunotherapies in antibody-mediated pain 2
• Recent preclinical studies demonstrate that passive transfer of patient autoantibodies can cause neuropathic pain, confirming pathogenicity 2
• The efficacy of IVIG and plasma exchange supports an autoimmune etiology in many idiopathic SFN cases 2, 3

First-Line Symptomatic Treatment

While pursuing immunotherapy evaluation, initiate pharmacologic pain management 7:

• Pregabalin or duloxetine are first-line treatments for neuropathic pain 7
• Gabapentin (300-1,200 mg three times daily) is an alternative first-line option 7
• Tricyclic antidepressants (e.g., amitriptyline) are effective but require monitoring for anticholinergic side effects, especially in patients ≥65 years 7

Avoid Common Pitfalls

• Do not assume the neuropathy is idiopathic without completing the full laboratory workup, as diabetes, pre-diabetes, and B12 deficiency are highly prevalent and treatable 5, 7, 8
• Do not order routine EMG/NCS in typical small fiber neuropathy, as these tests evaluate large fibers and will be normal 1
• Do not delay skin biopsy while waiting for other test results, as it has the highest diagnostic yield and is essential for confirming SFN 1
• Do not use opioids for chronic neuropathic pain due to addiction risk 7

Prognosis and Follow-Up

• At 2-year follow-up, 13% of SFN patients show involvement of large nerve fibers, while 45.6% remain stable 1
• Spontaneous remission of neuropathic pain occurs in 10.9% of SFN patients, while pain worsens in 30.4% 1
• In initially idiopathic cases, a potential cause can be determined in 25% of patients at 2-year follow-up 1
• Repeat clinical assessment and consider repeat skin biopsy if symptoms progress or change character 1