What are the causes of asymmetrical small-fibre neuropathy?

Asymmetrical Small Fiber Neuropathy: Causes and Clinical Approach

Asymmetrical small fiber neuropathy should immediately raise suspicion for immune-mediated or vasculitic etiologies, as the classical length-dependent pattern is typically symmetric and distal. 1

Key Distinguishing Feature

• The presence of asymmetry fundamentally changes the differential diagnosis from typical metabolic causes (diabetes, hypothyroidism) toward inflammatory and autoimmune processes. 1
• Immune-mediated small fiber neuropathy characteristically presents with a non-length-dependent pattern rather than the classical distal sensory phenotype, making asymmetry a red flag for autoimmune etiology. 1

Primary Causes of Asymmetrical Small Fiber Neuropathy

Autoimmune and Inflammatory Etiologies

• Sjögren's syndrome is a well-established cause of small fiber neuropathy that can present asymmetrically, accounting for approximately 3% of small fiber neuropathy cases. 2, 3
• Sarcoidosis causes small fiber neuropathy in 40-60% of patients and frequently presents with asymmetric or multifocal patterns due to granulomatous nerve involvement. 4
• Vasculitic neuropathy (including polyarteritis nodosa and other systemic vasculitides) classically presents as mononeuritis multiplex with asymmetric involvement and prominent pain features. 5
• Cryoglobulinemia accounts for approximately 7% of small fiber neuropathy cases and can produce asymmetric patterns. 3

Paraneoplastic and Monoclonal Protein-Related

• Paraneoplastic neuropathy (particularly anti-Hu antibody-associated) presents with acute or subacute onset and can have asymmetric distribution, accounting for 3% of cases. 4, 3
• Monoclonal gammopathy of undetermined significance (MGAM) causes approximately 4.7% of small fiber neuropathy cases and may present asymmetrically. 3

Infectious Causes

• Hepatitis E virus (HEV) genotype 3 has been documented as causing mononeuritis multiplex and asymmetric small fiber involvement, with over 150 neurological cases described, predominantly in immunocompetent European patients. 5
• HIV infection causes distal symmetric sensory neuropathy in approximately 57% of infected individuals, though atypical presentations can occur. 5

Amyloidosis

• Hereditary transthyretin amyloidosis (ATTRv) and wild-type ATTR (ATTRwt) cause polyneuropathy in 17-35% of AL amyloidosis patients, with approximately 30% of ATTRwt patients developing polyneuropathy that may initially present with small fiber involvement and can affect upper extremities simultaneously with lower extremities—an atypical pattern suggesting amyloid etiology. 4, 5

Critical Diagnostic Approach

When to Suspect Asymmetric Pattern

• Consider neurophysiology when symptoms show an asymmetric pattern and/or when clinical examinations are normal despite patient complaints. 6
• Be aware that standard neurophysiological techniques (EMG, nerve conduction studies) will be completely normal in pure small fiber neuropathy, as these tests only assess large myelinated fibers. 6, 4

Essential Diagnostic Testing

• Skin biopsy with intraepidermal nerve fiber density (IENFD) assessment using PGP 9.5 immunohistochemistry remains the gold standard (sensitivity 77.2-88%, specificity 79.6-88.8%). 4
• Quantitative sudomotor axon reflex test (QSART) documents small fiber dysfunction with high sensitivity and complements skin biopsy. 4

Targeted Autoimmune Workup for Asymmetric Presentation

• Anti-Sjögren antibodies (SSA/SSB) should be tested to identify Sjögren's syndrome as a potential cause. 4
• Serum protein electrophoresis with immunofixation for monoclonal gammopathy is essential. 4
• Anti-Hu (ANNA-1) antibodies are indicated for acute or subacute onset (<12 weeks), especially with malignancy risk factors, to prompt intensive cancer screening. 4
• Ganglionic acetylcholine-receptor antibodies should be tested when autonomic manifestations are prominent. 4
• Antinuclear antibody (ANA), rheumatoid factor, and anti-CCP antibodies serve as initial screens for connective tissue diseases. 4

Amyloidosis Screening (Critical in Asymmetric Cases)

• Cardiac evaluation with echocardiography and consideration of cardiac MRI is recommended to screen for amyloidosis, particularly in older patients with upper and lower extremity involvement simultaneously. 4
• Rapid progression of symptoms (15-20 times faster than diabetic neuropathy) strongly suggests amyloidosis. 4
• History of carpal tunnel syndrome preceding neuropathy by years is characteristic of amyloidosis. 4

Sarcoidosis Evaluation

• Chest radiography or computed tomography should be performed because >90% of sarcoidosis patients exhibit pulmonary or hilar lymph node involvement. 4
• Histologic confirmation of non-caseating granulomas in tissue (lung, lymph node, skin) is required for definitive sarcoidosis diagnosis; auto-antibody positivity alone is insufficient. 4

Common Pitfalls to Avoid

• Never assume metabolic causes (diabetes, hypothyroidism) when the pattern is asymmetric—these typically produce symmetric, length-dependent neuropathy. 1
• Do not rely solely on nerve conduction studies, as these will be normal in pure small fiber neuropathy and will miss the diagnosis entirely. 6, 4
• Avoid dismissing patient complaints when neurophysiology is normal—this is expected in small fiber neuropathy and should prompt skin biopsy. 6
• Do not overlook the need for malignancy screening when anti-Hu antibodies are positive or when onset is acute/subacute. 4

Treatment Implications

• Immune-mediated small fiber neuropathy may require immunosuppressive therapy (corticosteroids, IVIG, anti-TNF agents), fundamentally different from symptomatic management of metabolic causes. 4, 5
• For sarcoidosis-related small fiber neuropathy, current evidence is insufficient to endorse routine immunosuppression or IVIG, though 75% of patients in retrospective studies showed symptomatic benefit with these therapies. 4
• TTR silencers (patisiran, vutrisiran, inotersen) are disease-modifying treatments for hereditary transthyretin amyloidosis with polyneuropathy. 7