Small fiber involvement is independent from clinical pain in late-onset Pompe disease

Abstract

Background: Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients.

Methods: In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy (19 females; 51 ± 15 years), pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis.

Results: Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale (NRS; anchors: 0-10). According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy.

Conclusions: Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD.

Keywords: Intraepidermal nerve fiber density; Late onset Pompe disease; Pain; Skin biopsy; Small nerve fiber.

Fig. 1

Pain distribution in patients with LOPD: twenty-four (69%) of the patients reported pain including axial and joint pain in most of the cases. Only on patient (P19) reported neuropathic pain in the distal legs (large black rectangular frame). Reduction of IENFD was detected in 57% of the patients (small red rectangular frames)

Fig. 2

Correlation between the pain intensity and the A degree of anxiety symptoms (HADS-A score) and the B degree of depressive symptoms (HADS-D score). C Distribution of the HADS-A and HADS-D scores in patients with vs. without pain (x = mean)

Fig. 3

Scatter plot showing intraepidermal nerve fiber density (IENFD) values in A female patients (black dots) and healthy controls (grey dots) and B male patients (black dots) and healthy controls (grey dots). Solid line depict 50th and dotted line 5th percentiles of normative values from Lauria et al. Values below the 5th percentile (grey area) are considered as reduced

Fig. 4

Bar chart showing time periods (duration of symptoms to onset of ERT therapy, onset of ERT therapy to biopsy) and patients with reduced (red) and normal (blue) intraepidermal nerve fiber density (IENFD) at time of biopsy (right end of bar). Each patient is represented by a bar, with the sum of the left and right values representing the total time from symptom onset to the time of biopsy. The distribution of patients with reduced fiber density is evenly distributed across the cohort

Fig. 5

Correlation scatter plot matrix of fiber densities (z-score IENFD) and clinical data. i.e. time between symptoms onset and start of ERT (duration symptoms to ERT), start of ERT therapy to time of biopsy (duration ERT to biopsy) and PDQ-score in patients with reduced (red) and normal (blue) fiber densities. The lines indicate a linear fit (and confidential intervals) for visual guidance of possible correlations. The diagonal shows the data distribution as probability density function