By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.

SYNOPSIS: Small fiber neuropathy is a common disorder that causes chronic pain, but rarely progresses to disability or more severe neurological disorders. Management of the pain continues to be the major treatment challenge.

SOURCE: MacDonald S, et al. Longitudinal follow-up of biopsy-proven small fiber neuropathy. Muscle Nerve 2019;60:376-381.

Causing pain in the distal extremities and more prevalent with older age, small fiber neuropathy (SFN) is characterized by diminished pain sensation in the legs, with normal strength, intact deep tendon reflexes, normal position and vibration sensation and electrodiagnostic testing, diminished sudomotor function, and an abnormal skin punch biopsy showing reduced epidermal or sweat gland nerve fiber density, or both. Often idiopathic in nature, SFN is seen commonly in patients with diabetes and alcoholism, but long-term outcomes in these patients have not been well studied. In recent years, many patients with “fibromyalgia” have been diagnosed with small fiber neuropathy. Researchers conducted a retrospective study of Cleveland Clinic patients with biopsy-proven SFN to address the long-term consequences of SFN.

Patients with typical sensory or autonomic symptoms of SFN, including burning, tingling, numbness, lightheadedness, bowel or bladder symptomatology, sweating abnormalities, or tachycardia, and who underwent 3-mm skin punch biopsy of the foot and thigh between 2005 and 2008 at the Cleveland Clinic, were included. Exclusionary factors encompassed significant large nerve fiber involvement, such as weakness, impaired deep tendon reflexes, and impaired position or vibration sensation, or the presence of any significant coexisting neurologic condition. At least one follow-up visit, two years following SFN diagnosis, was required for inclusion. Findings at the final visit, including presence of neuropathic pain, autonomic symptoms, findings on neurological examination, and gait and employment status, were compared to those of the initial visit for assessment of disease progression. A statistical analysis comprised the Kruskal-Wallis, Wilcoxon rank-sum, and Fisher’s exact tests, with P < 0.05 considered significant.

Among 877 patients seen for neuropathic symptoms during the study period and who underwent skin punch biopsy, 343 had normal skin biopsy results, 345 were followed for less than two years, 45 had no follow-up, and 43 had other neurological disorders, leaving 101 patients (39 men and 62 women) with an average age of 51 years, eligible for study. Over an average of 6.2 years following diagnosis, neuropathic pain resolved in 15 but appeared in an additional 13 (neuropathic pain was present in 98% of patients during the study). Ninety-six percent of all patients were taking, on average, 4.4 different medications, most often gabapentin, pregabalin, duloxetine, tricyclic antidepressants, and topical capsaicin or lidocaine. Autonomic dysfunction, present in 25 at the initial visit, encompassing cardiac rhythm irregularities, presyncope, bowel or bladder abnormalities, impaired or excessive sweating, and dry mouth or eyes, resolved in 10 patients and improved in five patients, with a single patient developing new autonomic symptoms. Neurological examination was normal in 33 patients by the final visit, compared to 19 at the initial visit, and abnormal temperature sensation was found in 10 at final visit, compared to 23 at initial visit. By the final visit, 99 of 101 remained ambulatory, and SFN was believed to account for unemployment in 5.3%. No cause for SFN was found in 50.5%. SFN is rarely a cause of disability, unemployment, or impaired ambulation, but pain control remains challenging.


SFN has an incidence of 12 per 100,000 population and may affect children (rare). Its quantification is assessed by skin punch biopsy or noninvasively, using corneal confocal microscopy, which permits visualization of unmyelinated C-nerve fibers from the trigeminal nerve that travel to Bowman’s membrane of the cornea. Functionality of small nerve fibers is measured using: 1) quantitative sensory testing, which quantifies sensory perception thresholds carried by small and large nerve fibers; 2) microneurography, which records C-nociceptor and sympathetic fiber activity; and 3) nociceptive-evoked potentials, which are generated by either radiant heat or contact heat, selectively activating Aδ- and C-fibers. Three voltage-gated sodium channels, Naν1.7, Naν1.8, and Naν1.9, encoded by genes SCN9A, SCN10A, and SCN11A, are preferentially expressed in peripheral neurons and play a role in human pain disorders. Gain-of-function SCN9A variants have been described in inherited erythromelalgia, paroxysmal extreme pain disorder, and SFN, whereas loss-of-function SCN9A variants are associated with congenital insensitivity to pain. Pain relief for SFN will achieve greater efficacy when its pathophysiology is better understood.1


  1. Sopacua M, et al. Small-fiber neuropathy: Expanding the clinical pain universe. J Peripher Nerv Syst 2019;24:19-33.