What is small nerve (peripheral nerve) neuropathy, specifically small fiber neuropathy, in older adults or individuals with diabetes, autoimmune disorders, or exposure to toxins?

What is Small Fiber Neuropathy

Small fiber neuropathy (SFN) is a disorder affecting the thinly myelinated Aδ fibers and unmyelinated C fibers that comprise 79.6-91.4% of peripheral nerves, causing neuropathic pain and autonomic dysfunction that cannot be detected by conventional nerve conduction studies. 1

Anatomical and Pathophysiological Foundation

• Small fibers consist of two types: Aδ fibers (finely myelinated) and C fibers (unmyelinated), both responsible for pain and temperature perception 1
• These fibers constitute the vast majority of peripheral nerve fibers and serve as the primary autonomic effectors, directly controlling tissue blood flow, sweating, heart rate variability, gastrointestinal motility, bladder function, and sexual function 2
• In diabetic neuropathy, small fiber damage precedes large fiber damage, with injury occurring early even when conventional nerve conduction studies remain normal 2

Clinical Presentation

Sensory Symptoms

• Patients present with distal, symmetric, nocturnally exacerbated neuropathic pain described as burning, tingling, or shooting pain 1
• The typical distribution is length-dependent polyneuropathy starting in the feet and ascending proximally, though other distributions can occur 3, 4
• Pain is often accompanied by paresthesia, dysesthesia, and protopathic deficits 5

Autonomic Dysfunction

• Approximately 70% of patients exhibit autonomic dysfunction, which can range from subclinical to severe 1
• Cardiovascular manifestations include resting tachycardia (>100 bpm) in 20-40% of patients and orthostatic hypotension (blood pressure drop >20 mmHg systolic or >10 mmHg diastolic upon standing) in up to 30% of patients 2
• Sudomotor dysfunction affects up to 50% of patients, causing dry, cracked skin and contributing directly to plantar ulceration with a 10-20% incidence in diabetic patients 1, 2
• Gastrointestinal symptoms include gastroparesis (affecting up to 20%), esophageal dysmotility, constipation, diarrhea, and fecal incontinence (10-30% prevalence) 2
• Genitourinary disturbances affect up to 50% of patients with erectile dysfunction and sexual dysfunction, and up to 30% with bladder dysfunction manifesting as incontinence, nocturia, frequency, and urgency 2

Etiological Categories

• Metabolic causes: Diabetes mellitus is the most common, with hyperglycemia driving progressive nerve degeneration through oxidative stress, inflammation, reduced nerve blood flow, and direct toxic effects 2, 3
• Immune-mediated conditions: Systemic autoimmune diseases represent an expanding category of potentially treatable subgroups 5, 4
• Toxic exposures: Drug and toxin exposure can cause SFN 3, 4
• Infectious causes: Various infections have been associated with SFN 3, 5
• Hereditary conditions: Genetic sodium channelopathies (SCN9A, SCN10A, SCN11A encoding Nav 1.7, Nav 1.8, and Nav 1.9) and TRPA1 gene variants have been identified 3, 4
• Idiopathic: Often presents in patients over age 60 with painful feet, with autoimmune mechanisms suspected but rarely identified 6

Critical Diagnostic Pitfall

Conventional nerve conduction studies will be completely normal in isolated small fiber neuropathy because these tests only assess large myelinated fiber function, leading to potential misdiagnosis or underdiagnosis. 1, 2 Relying solely on electrophysiology leads to missed diagnoses, and normal EMG/NCS does not exclude significant neuropathy when small fibers are preferentially affected 2

Diagnostic Approach

Gold Standard Testing

• Skin biopsy with quantification of intraepidermal nerve fiber density (IENFD) is the gold standard for diagnosis, with sensitivity of 77.2-88% and specificity of 79.6-88.8% 1
• A cutoff point of ≤8.8 fibers/mm at the ankle demonstrates good accuracy for diagnosis 1
• IENFD is significantly reduced in diabetic patients even with normal nerve conduction studies 1

Complementary Testing

• Quantitative sensory testing (QST) for thermal thresholds complements skin biopsy with sensitivity ranging from 59-88% 1, 6
• Tests of autonomic function such as QSART (quantitative sudomotor axon reflex test) document small fiber dysfunction with high sensitivity 1
• Cardiovagal testing assesses autonomic involvement 6

Screening Recommendations

• Screen all type 2 diabetics at diagnosis and type 1 diabetics after 5 years, then annually thereafter 2
• Up to 50% of diabetic peripheral neuropathy may be asymptomatic, making systematic screening essential with 80-90% sensitivity for early detection 2

Management Principles

Disease-Modifying Treatment

• Rigorous glycemic control is essential to prevent disease progression in diabetic patients, reducing risk by 30-50%, though it cannot reverse established neuronal loss 1, 2
• Control of other modifiable risk factors including lipids and blood pressure can reduce progression risk by 20-40% 2
• Treat underlying conditions when identified (autoimmune diseases, toxin removal, infection treatment) 4, 7

Symptomatic Management

• Avoid excessive cooling of extremities, as it may worsen tissue damage and lead to ulcerations 1
• Symptomatic pain therapy combined with lifestyle changes and biopsychological interventions 4
• Repeated skin biopsies may be considered in selected cases to monitor disease progression or response to treatment 1