Assessing Biomarker Validity for Neuropathic Pain

A challenge facing clinicians regarding the diagnosis of small fiber neuropathies lies in the scarcity of objective biomarkers. Indeed, neuropathic pain-associated symptoms are currently mainly assessed using subjective measures such as the Neuropathic Pain Symptom Inventory, a questionnaire filled out by patients.¹

Although objective tests to assess small sensory fiber dysfunction are available — with skin biopsies to determine the density of intraepidermal Aδ and C nerve fibers and quantitative sensory testing — additional tests would allow for more accurate diagnoses. An objective alternative — contact heat-evoked potentials (CHEPs) — is routinely used in clinical practice to evaluate the health of small sensory fibers.² However, CHEPs may lack the necessary sensitivity to detect neuropathic pain-associated symptoms (eg, skin nerve degeneration-associated sensory phenotypes).

In the present study, researchers sought to determine whether CHEPs could be used as a diagnostic test for neuropathic pain syndromes. With CHEPs, the integrity of Aδ fibers that mediate thermonociceptive information can be assessed. For these noninvasive tests, heat is applied to the skin, and Aδ-mediated cortical responses are recorded using electroencephalograms.

Small nerve degeneration, as assessed by reduced fiber densities in skin biopsies, is associated with CHEPs displaying longer latencies and reduced amplitudes.³ Aging also affects CHEPs, as older adults have reduced CHEP amplitude compared with younger individuals.⁴

In this study, researchers sought to examine small nerve fiber density and CHEPs in both patients with neuropathy and controls, and to determine whether changes in CHEPs could predict neuropathic pain-associated symptoms.

The study conducted at National Taiwan University Hospital, Taipei, included 188 patients (115 men; age 20 to 87; mean age, 53.7), presenting with symmetric and length-dependent limb paresthesias (numbness, n=145; neuropathic pain, n=144), lasting for ≥3 months and reduced sensory fiber density in the distal legs. In all patients, paresthesias were described and categorized as spontaneous pain, including tingling (n=115), electric shocks (n=41), heat or burning (n=61), cold or freezing (n=17), and evoked pain (n=64). Control subjects (n=57; 27 men; age 22 to 84; mean age, 50.2) were free of both paresthesias and neurological abnormalities.

Heat stimuli were delivered every 20 to 22 seconds at temperatures ranging from 32⁰C to 51⁰C in the vicinity of the lateral malleolus and recorded using a NeuroScan system. Central responses to CHEPs were assessed with electroencephalograms, and patients were asked to rate pain evoked by each stimulus on a scale of 0 to 10.

An initial neurophysiological assessment of patients was conducted and consisted of CHEPs, quantitative sensory testing, and nerve conduction velocity. These studies showed that patients had lower CHEP amplitude (n=115, 61.2%; P <.001) and longer initial wave (P =.001) than controls. In addition, patients reported lower pain rating scores than healthy controls. Quantitative sensory testing indicated abnormal temperature thresholds in patients (warm, n=96, 51.1%; cold, n=34, 18.1%; overall thermal, n=98, 52.1%). Nerve conduction velocity in the lower limbs was affected in 94 patients (50%), indicating large fiber involvement.

In healthy subjects, studies revealed a positive correlation between CHEP amplitude and nerve fiber density (r = 2.06, P <.001), a negative correlation between CHEP latencies and nerve fiber density (r = -3.72, P <.001), and a negative correlation between CHEP amplitude and age (r = -0.39, P <.001). In patients with neuropathy, CHEP amplitude was positively correlated with small nerve fiber density (r = 1.87, P =.009) and negatively correlated with age (r = -0.31, P =.001).

In order to further investigate the relevance of CHEPs in the diagnosis of neuropathies, the researchers analyzed the correlation between this and other relevant parameters (ie, small nerve fiber density, quantitative sensory testing, and nerve conduction velocity). A correlation was established between small nerve fiber density and “age, sex, CHEP amplitude, thermal thresholds in the feet, and NCS [nerve conduction study] parameters.”

CHEP amplitude was found to be the most accurate among the parameters of neuropathy-associated skin denervation examined. In addition, for similar small fiber density, CHEP amplitudes were larger in patients presenting with thermal- or mechanical stimulus-evoked pain.

The researchers conclude that the study “demonstrate[s] the superiority of CHEPs in the diagnosis of small-fiber sensory nerve degeneration compared with thermal thresholds and its usefulness as a physiological signature of evoked pain symptoms.”

In addition, “Contact heat-evoked potentials are an objective and noninvasive physiological biomarker of small-fiber sensory nerve degeneration. The combination of CHEPs, skin biopsies, and [quantitative sensory testing] not only offers integrative information for the diagnosis of neuropathy with small-fiber sensory nerve involvement, but also provides information representing the signatures and underlying mechanisms of neuropathic pain,” the investigators wrote.

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References

1. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of the Neuropathic Pain Symptom Inventory. Pain. 2004;108(3):248-257.
2. Atherton DD, Facer P, Roberts KM, et al. 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. BMC Neurol. 2007;7:21.
3. Casanova-Molla J, Grau-Junyent JM, Morales M, Valls-Solé J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain. 2011;152(2):410-418.
4. Chao CC, Hsieh ST, Chiu MJ, Tseng MT, Chang YC. Effects of aging on contact heat-evoked potentials: the physiological assessment of thermal perception. Muscle Nerve. 2007;36(1):30-38.
5. Wu SW, Wang YC, Hsieh PC, et al. Biomarkers of neuropathic pain in skin nerve degeneration neuropathy: contact heat-evoked potentials as a physiological signature. Pain. 2017;158(3):516-525.