Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study

Abstract

Autonomic and somatic denervation is well established in Parkinson's disease (PD).

Objectives: (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD.

Methods: Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose.

Results: PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction.

Conclusion: CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD.

Keywords: Confocal microscopy; Cornea; Intraepidermal nerve fiber density; Parkinson's disease; Small fiber neuropathy.

Fig. 1

Representative examples of 50 μm sections from skin biopsies immunostained for PGP9.5. Healthy control (A) shows numerous long branching intraepidermal nerve fibers (red arrows) reaching upper layers of epidermis and well developed sub-epidermal nerve plexus (green arrows). Biopsy from a patient with Parkinson's disease (B) showing scant, faintly staining intraepidermal nerve fibers (red arrows), some branches with axonal swellings (red star) and a biopsy from another patient with Parkinson's disease (C) showing an area of epidermis with only one short intraepidermal nerve fiber and signs of degeneration in the sub-epidermal nerve plexus (red stars). Note short nerve fibers, barely crossing epidermal basement membrane (B, C, blue arrows). A–C at the same magnification, scale bar = 100 μm. Corneal confocal image of a healthy control (D) compared to a patient with Parkinson's disease (E) showing a reduction in overall corneal nerve fiber density and increased corneal nerve branch density. Quantification of corneal nerve fiber density, branch density and fiber length is calculated using a semi-automated process. Main fibers are highlighted in red, branches are highlighted in blue and branch origins are represented by the green dots (F&G). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Mean ± SEM of corneal nerve fiber density (CNFD) (A), intraepidermal nerve fiber density (IENFD) (B), corneal nerve fiber branch density (CNBD) (C) and fiber length (CNFL) (D) in Parkinson's disease (PD) compared to controls with significance level and effect size.