What is Small Fiber Neuropathy
Small fiber neuropathy (SFN) is a disorder of the peripheral nervous system affecting the thinly myelinated Aδ fibers and unmyelinated C fibers, which constitute 79.6% to 91.4% of all peripheral nerve fibers and are responsible for pain, temperature sensation, and autonomic regulation. 1, 2
Pathophysiology and Nerve Fiber Involvement
The affected small fibers include Aδ fibers (finely myelinated) and C fibers (unmyelinated), which control pain and temperature perception, as well as autonomic functions including tissue blood flow, sweating, heart rate variability, gastrointestinal motility, bladder function, and sexual function. 1, 2
Small fiber damage characteristically precedes large fiber damage in diabetic neuropathy, meaning patients can have significant neuropathy even when conventional nerve conduction studies remain completely normal. 1, 2, 3
In diabetes specifically, hyperglycemia drives progressive nerve degeneration through oxidative stress, inflammation, reduced nerve blood flow, and direct toxic effects on nerve fibers, preferentially damaging small fibers first. 2
Clinical Presentation
Sensory Symptoms
Patients typically present with distal, symmetric, nocturnally exacerbated neuropathic pain described as burning, tingling, or shooting pain, usually starting in the feet and ascending proximally. 1, 4
Physical examination reveals pinprick and thermal hypoesthesia in approximately 50% of patients. 5
Neuropathic pain intensity is more severe in SFN compared to large or mixed fiber neuropathy. 5
Autonomic Dysfunction
- Autonomic dysfunction occurs in approximately 70% of patients with SFN, manifesting across multiple organ systems. 1, 5
Cardiovascular manifestations:
- Resting tachycardia (>100 bpm) from parasympathetic denervation affects 20-40% of patients. 2
- Orthostatic hypotension (blood pressure drop >20 mmHg systolic or >10 mmHg diastolic upon standing) affects up to 30% of patients. 2
- Reduced heart rate variability from autonomic denervation. 1
Sudomotor dysfunction:
- Loss of sweating from denervation of sweat glands leads to dry, cracked skin in the extremities, affecting up to 50% of patients. 2
- Sudomotor dysfunction contributes directly to plantar ulceration in diabetic patients through loss of skin hydration and impaired thermoregulation, with an incidence of 10-20%. 1, 2
Gastrointestinal manifestations:
- Gastroparesis from vagal nerve damage causes erratic glycemic control and upper GI symptoms in up to 20% of patients. 2
- Esophageal dysmotility, constipation, diarrhea, and fecal incontinence affect 10-30% of patients. 2
Genitourinary manifestations:
- Erectile dysfunction and retrograde ejaculation in men, decreased sexual desire and arousal difficulties in women affect up to 50% of patients. 2
- Bladder dysfunction (urinary incontinence, nocturia, frequency, urgency, weak stream) affects up to 30% of patients. 2
Diagnostic Approach
Gold Standard Testing
Skin biopsy with quantification of intraepidermal nerve fiber density (IENFD) is the gold standard for diagnosis, with a sensitivity of 77.2-88% and specificity of 79.6-88.8%. 1, 3
A cutoff point of ≤8.8 fibers/mm at the ankle demonstrates good accuracy for diagnosis. 1
IENFD assessment using PGP 9.5 immunohistochemistry is the validated, reproducible marker. 3
Skin biopsy shows a diagnostic efficiency of 88.4%, significantly higher than other testing modalities. 5
Complementary Testing
Quantitative sensory testing (QST) for thermal thresholds complements skin biopsy, with a diagnostic efficiency of 46.9%. 1, 5
Autonomic function tests including quantitative sudomotor axon reflex test (QSART) and thermoregulatory sweat testing document small fiber dysfunction with high sensitivity. 1, 3
Clinical examination alone has a diagnostic efficiency of only 54.6%. 5
Critical Diagnostic Pitfall
Relying solely on conventional nerve conduction studies will completely miss SFN because these tests only assess large myelinated fiber function, not small fibers. 1, 2, 3
Normal EMG/NCS does not exclude significant neuropathy when small fibers are preferentially affected. 2
IENFD is significantly reduced in diabetic patients even with normal nerve conduction studies, confirming early small fiber damage. 1, 3
Etiologic Associations
A large variety of underlying conditions are associated with SFN, including metabolic disorders (diabetes, pre-diabetes), immune-mediated diseases, infectious causes, toxic exposures, and hereditary conditions. 4, 6
Genetic sodium channelopathies (variants in SCN9A, SCN10A, SCN11A genes encoding Nav1.7, Nav1.8, and Nav1.9 channels, as well as TRPA1 gene) have been found in nearly 30% of patients with idiopathic SFN. 6, 7
SFN remains idiopathic in 41.8% of patients initially, though a potential cause can be determined in 25% of these at 2-year follow-up. 5
Screening Recommendations for Diabetic Patients
Screen all type 2 diabetics at diagnosis and type 1 diabetics after 5 years, then annually thereafter, using clinical evaluation, laboratory tests, and specialized diagnostic procedures. 2
Up to 50% of diabetic peripheral neuropathy may be asymptomatic, making systematic screening essential with a sensitivity of 80-90% for early detection. 2
Management Principles
Disease Modification
Rigorous glycemic control is essential to prevent disease progression in diabetic patients, with a reported reduction in risk of 30-50%, though it cannot reverse established neuronal loss. 1, 2, 3
Control of other modifiable risk factors including lipids and blood pressure can aid in prevention of progression, with a reported reduction in risk of 20-40%. 2
Symptomatic Management
Avoid triggers that exacerbate symptoms while maintaining normal activities. 3
Caution patients against excessive cooling of extremities as a pain relief strategy, as this may worsen tissue damage and lead to ulcerations. 1, 3
Treatment prioritizes addressing the underlying condition if identified, combined with symptomatic pain therapy, lifestyle changes, and biopsychological interventions. 6