New phenotyping questionnaire for diagnosing sarcoidosis-associated small fiber neuropathy

Abstract

Small fiber neuropathy is a common complication in patients with sarcoidosis and its prevalence is estimated at 40-86%. The underlying mechanism influences the presentation of small fiber neuropathy. For example, patients with metabolic diseases are often associated with a classic length-dependent small fiber neuropathy pattern, while patients with inflammatory diseases are more often present with a non-length-dependent small fiber neuropathy. Detailed phenotyping may be useful to improve diagnostic efficiency, as a clue to underlying mechanisms and as a precondition for personalized medicine. This study examined four phenotypes distinguishing between length-dependent and non-length-dependent presentation with a new subdivision for continuous and intermittent presentation. Forty-eight sarcoid patients with symptoms and at least two clinical signs of small fiber neuropathy and normal nerve conduction studies were classified as having probable small fiber neuropathy. A new small fiber neuropathy phenotyping questionnaire has been developed that allows patients to mark the anatomical locations of pain at three different levels: the skin, muscles, and joints. The location of symptoms was used to define length dependence, and two colors were used to distinguish continuous (red) from intermittent (blue) symptoms. In addition, skin biopsy, corneal confocal microscopy, Sudoscan and water immersion skin wrinkling were used to investigate a correlation between the four phenotypes, sensory function, nerve fiber density, and autonomic nerve function. Overall, 35% of patients with probable small fiber neuropathy showed length-dependent symptoms and 44% showed non-length-dependent symptoms while 21% suffered from non-neuropathic musculoskeletal pain. The distinction between intermittent and continuous symptoms showed significantly less continuous than intermittent non-length-dependent symptoms (odds ratio = 0.3, P = 0.01). Moreover, continuous length-dependent symptoms were the only phenotype that correlated with thermal threshold testing (R = 0.3; P = 0.02) and the small fiber neuropathy screening list (R = 0.3; P = 0.03). In addition, thermal threshold testing (TTT) also correlated with the small fiber neuropathy (SFN) screening list (R = 0.3; P = 0.03). Other diagnostic methods showed no correlation with any of the four defined phenotypes. A novel finding is that TTT is only associated with continuous length-dependent pain, suggesting that TTT could result in more false negatives in patients with other pain phenotypes. Determining the pathophysiologic mechanisms could help develop new diagnostic methods. If patients suspected of SFN show symptoms without a length-dependent continuous presentation, the diagnosis should focus less on the diagnostic methods used.

Keywords: SFNSL; nerve fiber density; pain; sensory testing; thermal threshold testing.

Graphical abstract

Figure 1

Pain phenotypes. Definition of (A) length-dependent and (B) non-length-dependent pain phenotypes.

Figure 2

Inclusion process. Schematic overview of inclusion and clinical diagnosis of SFN in this study. A total of 79 participants provided informed consent, of whom six were excluded. One participant showed low vitamin B12 levels, four patients were excluded based on low nerve conduction velocity, and one was diagnosed with neurosarcoidosis. Of the 74 patients with sarcoidosis and symptoms of SFN, 48 were diagnosed with probable SFN. Abbreviations: SFN, small fiber neuropathy.

Figure 3

Results of the phenotyping questionnaire. (A) Example of a completed small fiber neuropathy phenotyping questionnaire (SFNPQ). It shows length-dependent continuous pain in combination with non-length-dependent intermittent pain. (B) Prevalence of length-dependent and non-length-dependent pain for continuous and intermittent presentations (n = 48). Continuous non-length-dependent pain was significantly less reported, (OR = 0.3, P = 0.01, chi-square tested).

Figure 4

Correlation plot. (A) Correlation between patient-reported outcome measures and diagnostic methods for SFN. The correlation coefficient ranges between −1 for a negative correlation, 0 for no correlation, and +1 for perfect positive correlation (n = 48, ). (B) Boxplots with median TTT NOAs and min-max whiskers for patients with sarcoidosis and probable SFN, with (Present) and without (Absent) continuous length-dependent pain (n = 48, P = 0.02, Mann-Whitney U tested). Abbreviations: LD int, intermittent length-dependent pain; LD con, continuous length-dependent pain; NLD int, intermittent non-length-dependent pain; NLD con, continuous non-length-dependent pain; SFNSL, small fiber neuropathy screening list; TTT NOAs, thermal threshold testing number of abnormalities; IENFD, intraepidermal nerve fiber density; CNFD, corneal nerve fiber density; CNFL, corneal nerve fiber length; CNBD, corneal nerve branch density; ESC, electrochemical skin conductance; WISW, water immersion skin wrinkling.