Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts

Abstract

Background: The Contact Heat Evoked Potential Stimulator (CHEPS) rapidly stimulates cutaneous small nerve fibres, and resulting evoked potentials can be recorded from the scalp. We have studied patients with symptoms of sensory neuropathy and controls using CHEPS, and validated the findings using other objective measures of small nerve fibres i.e. the histamine-induced skin flare response and intra-epidermal fibres (IEF), and also quantitative sensory testing (QST), a subjective measure.

Methods: In patients with symptoms of sensory neuropathy (n = 41) and healthy controls (n = 9) we performed clinical examination, QST (monofilament, vibration and thermal perception thresholds), nerve conduction studies, histamine-induced skin flares and CHEPS. Skin punch biopsies were immunostained using standard ABC immunoperoxidase for the nerve marker PGP 9.5 or the heat and capsaicin receptor TRPV1. Immunoreactive IEF were counted per length of tissue section and epidermal thickness recorded.

Results: Amplitudes of Adelta evoked potentials (muV) following face, arm or leg stimulation were reduced in patients (e.g. for the leg: mean +/- SEM - controls 11.7 +/- 1.95, patients 3.63 +/- 0.85, p = 0.0032). Patients showed reduced leg skin flare responses, which correlated with Adelta amplitudes (rs = 0.40, p = 0.010). In patient leg skin biopsies, PGP 9.5- and TRPV1-immunoreactive IEF were reduced and correlated with Adelta amplitudes (PGP 9.5, rs = 0.51, p = 0.0006; TRPV1, rs = 0.48, p = 0.0012).

Conclusion: CHEPS appears a sensitive measure, with abnormalities observed in some symptomatic patients who did not have significant IEF loss and/or QST abnormalities. Some of the latter patients may have early small fibre dysfunction or ion channelopathy. CHEPS provides a clinically practical, non-invasive and objective measure, and can be a useful additional tool for the assessment of sensory small fibre neuropathy. Although further evaluation is required, the technique shows potential clinical utility to differentiate neuropathy from other chronic pain states, and provide a biomarker for analgesic development.

Figure 1

Contact Heat Evoked Potentials (Aδ) from a control subject (left panel) and a patient (right panel) on stimulation of different regions (reported from FCz electrode). Latencies (ms); Control: Face 380, Arm 410, Leg 500; Patient: Face 440, Arm 560, Leg not recordable. Amplitudes (μV); Control: Face 20.86, Arm 20.07, Leg 14.46; Patient: Face 8.45, Arm 5.22, Leg not recordable.

Figure 2

Contact Heat Evoked Potential Aδ amplitudes following stimulation of the face, arm and leg of controls (white bars) and patients (black bars). * = 0.034, ** p = 0.02, *** p = 0.0032.

Figure 3

Two superimposed Aδ evoked potentials from a control subject on stimulation of the face, recorded on different occasions.

Figure 4

Intra-epidermal fibres for both the nerve marker – (PGP 9.5; a, b) and capsaicin receptor (TRPV1; c, d) are reduced in patient's skin. Scale bar = 50 μm.

Figure 5

Plot of histamine induced flare area vs. Contact Heat Evoked Potential Aδ amplitudes after leg stimulation.

Figure 6

Plot of patient intra-epidermal nerve fibres (PGP 9.5) in skin biopsies and Contact Heat Evoked Potential Aδ amplitudes after leg stimulation.