Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: Small fiber neuropathy (SFN), a subtype of peripheral neuropathy characterized by painful distal neuropathic pain and autonomic symptoms, is increasing in incidence. SFN associated with diabetes and other causes is more likely to progress to large-fiber polyneuropathy and have faster deterioration and higher disability compared to slow progression with idiopathic SFN. Glucose impairment, obesity, and elevated triglycerides are modifiable risk factors of idiopathic SFN. Although major disability and neurologic impairment are uncommon in this slowly progressive condition, higher mortality and cardiovascular events are noted in patients with SFN.
SOURCE: Johnson SA, Shouman K, Shelly S, et al. Small fiber neuropathy incidence, prevalence, longitudinal impairments, and disability. Neurology 2021; Oct 27:10.1212/WNL.0000000000012894. doi: 10.1212/WNL.0000000000012894. [Online ahead of print].
Small fiber neuropathy (SFN) is a subset of peripheral neuropathy caused by selective injury to Aδ and C fibers resulting in neuropathic pain and autonomic dysfunction. Although most cases are idiopathic, diabetes is the most common identifiable cause of SFN.1
Examination features include mild sensory deficits to pain and temperature. Diagnosis is confirmed with electrophysiologic testing and reduced intraepidermal nerve fiber density (IENFD).2 Disease progression typically is slow, and long-term disability is modest.3 However, neuropathic pain control and risk factor mitigation remain unmet clinical needs in this population.
Johnson et al performed a retrospective longitudinal study that included patients with SFN and matched controls in Olmstead County and neighboring regions in Minnesota from January 1998 to December 2017. Patients were required to have examination findings consistent with SFN confirmed with quantitative sensory test (QST), thermoregulatory sweat test (TST), quantitative sudomotor axon reflex test (QSART), or intraepidermal small-fiber nerve biopsy analysis. Patients with weakness, large-fiber nerve involvement on exam or electrodiagnostic testing, and alternate causes of symptoms were excluded. Laboratory tests, including glucose tolerance, thyroid tests, immunofixation, autoimmune profile, HIV, hepatitis C, and genetic testing, were evaluated to determine causality. Standardized assessments using Neuropathy Impairment Scale (NIS), Composite Autonomic Severity Score (CASS), and modified Rankin scale (mRS) were established in all subjects. Mortality data and comorbidity data were extracted from chart review. Statistical analysis was performed using JMP 14.1.0 software with significance level of P < 0.05. The researchers used 2 x 2 testing and Wilcoxon one-way analysis of variance to analyze categorical data and continuous variables, respectively. Kaplan-Meier curves were plotted for SFN patients vs. controls. Hazard ratios for survival were calculated using Cox proportional hazards regression.
Ninety-four of 183 patients with SFN were included in the analysis, establishing an incidence of 1.3/100,000/inhabitants/year (95% confidence interval [CI], 0.9-1.6) and prevalence of 13.3/100,000/inhabitants (CI, 9.9-16.6), with a significant increase in incidence over the course of the study. The SFN group was more likely to be female, be obese, have elevated triglycerides, have sleeping difficulty, and use opiate analgesics than controls. Autonomic symptoms were present in 85% of patients with modest progression (0.08 points CASS/year) over mean 36 months. Of patients with follow-up electromyography (EMG), 36% (22/61) subsequently developed large-fiber, length-dependent axonal neuropathy.
The most common etiologies of SFN were idiopathic (70%) and diabetes (15%). Fifteen percent of patients had glucose impairment at onset and 51% later developed diabetes relative to 22% of controls. Idiopathic patients had minimal worsening of NIS score (1.73 points/year) relative to SFN secondary to an underlying cause (9.7 points/year); this was most significant in patients with hereditary transthyretin amyloidosis, endocrine tumor, and poorly controlled diabetes. Minimal changes in autonomic involvement were noted.
SFN patients had higher morbidity relative to controls (19% vs. 12%; P < 0.0001), mostly due to myocardial infarction. Additionally, most deaths were associated with diabetic complications.
Limitations of the study include retrospective design, small sample size, and limited generalizability of the study population to international cohorts. Additionally, skin biopsy analysis, the current gold standard for SFN diagnosis, was performed only on a small proportion of patients.
The current study confirms prior observations that SFN is a slowly progressive condition characterized mainly by pain but that does not result in significant disability for most patients. Although the majority of SFN cases demonstrate slow evolution, therapeutic and lifestyle intervention to improve glucose control and reduce metabolic risk factors remain vital to mitigate disease progression.
Satisfactory pain control remains an important unmet clinical need as reflected by the proportion of opiate use and sleep disturbances seen in the SFN group and emphasizes the need for new therapeutics.
The higher mortality rate from myocardial infarction observed in the SFN group prompts screening for cardiovascular risk factors and autonomic dysfunction as part of the diagnostic evaluation. Cardiac autonomic neuropathy (CAN) is associated with both diabetes and glucose impairment and confers a five-fold increase in cardiac death.4 Pathologic mechanisms of CAN and SFN likely overlap and merit additional study.
- Terkelsen AJ, Karlsson P, Lauria G, et al. The diagnostic challenge of small fibre neuropathy: Clinical presentations, evaluations, and causes. Lancet Neurol 2017;16: 934-944.
- Devigili G, Rinaldo S, Lombardi R, et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain 2019;142:3728-3736.
- Flossdorf P, Haupt WF, Brunn A, et al. Long-time course of idiopathic small fiber neuropathy. Eur Neurol 2018;79:161-165.
- Eleftheriadou A, Williams S, Nevitt S, et al. The prevalence of cardiac autonomic neuropathy in prediabetes: A systematic review. Diabetologia 2021;64:288-303.