Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients

Abstract

Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11 patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissner's corpuscles. These results signify a persistent and severe impairment of Aβ, Aδ, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissner's corpuscles.

Perspective: The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.

Figure 1. Skin temperature in patients at the test and the retest

The bar graph shows mean (± S.E.) skin temperature for control subjects (black bars) and from patients with bortezomib-related chemoneuropathy at the time of the initial test (Test, light grey bars) and the long-term follow-up examination (Retest, dark gray bars). The pain patients showed significantly cooler skin in the area of on-going pain (Pain Area), and a non-significant trend toward a decrease in the area of sensory disturbance, but not necessarily pain (Border Area) when compared to control subjects. There was no change over time in these data for the follow-up examination. ** = p <0.01

Figure 2. Touch detection thresholds in patients at the test and the retest

The bar graph on the left shows the mean (± S.E.) von Frey touch detection thresholds obtained from control subjects and from patients with bortezomib-related chemoneuropathy at the test and follow-up examinations. The pain patients showed significantly elevated touch detection within the area of on-going pain (Pain Area, glabrous surface of the index finger), in areas of sensory disturbance but not necessarily pain (Border Area, thenar eminence), and in areas of skin not perceived by the patients as symptomatic (Non-painful Area, volar surface of the forearm) at both test times. The bar graph at the right show the mean (± S.E.) slotted peg-board completion times for the dominant and non-dominant hands in control subjects (black bars) and pain patients at the test (light grey bars) and retest (dark gray bars) examinations. Patients took significantly longer times to complete the pegboard task in both hands and at both testing times. ** = p <0.01

Figure 3. Sharpness detection thresholds for patients at the test and the retest

The bar graph shows the mean (± S.E.) sharpness detection threshold for control subjects (black bars) and from patients with bortezomib-related chemoneuropathy at the test (light grey bars) and retest examination (dark gray bars). The pain patients showed significantly elevated sharpness detection within the area of on-going pain (Pain Area) during both the test and the retest when compared to control subjects. **= p<0.01.

Figure 4. Thermal detection thresholds in patients at the test and the retest

The bar graph in (A) shows the mean (± S.E.) temperature for detection of warming and for heat pain for control subjects (black bars) and for patients with bortezomib-related chemoneuropathy at the test (light grey bars) and retest examination (dark gray bars). The pain patients showed deficits in both the detection of skin warming and increased threshold to heat pain in all three areas tested during the test: the area of on-going pain (Pain Area), the area of sensory disturbance but not necessarily pain (Border Area), and the area of skin not perceived by the patients as symptomatic (Non-painful Area). During the retest, warmth detection in the border area was similar to control subjects. Also during this retest exam, impairments in heat detection were now only evident in the Pain Area. The bar graph in (B) shows the mean (± S.E.) temperature for the detection of skin cooling and cold pain, in which there was little change. * = p <0.05; ** = p <0.01

Figure 5. Epidermal nerve fibers in a patient with chronic bortezomib-related neuropathy

This figure shows immunohistochemistry staining with the pan-neuronal marker PGP9.5 (green) in the biopsies of a patient with bortezomib-related chemoneuropathy in the area of pain (finger tip) (A), the border zone (palm) (B), and the non-painful area (forearm) (C). These biopsies can be compared to similar biopsies from a control subject (D, E, F).Epidermal Nerve fibers (ENF) can be seen in the control subject crossing the dermal-epidermal junction (D/E J) into the epidermis (Epid) in all regions. Note the extensive decrease in epidermal nerve fibers in the patient biopsies. Also within the control subject biopsies from the fingertip and palm, Meissner’s corpuscles (MC) can be clearly seen within the epidermis. These structures are notably absent in the patient biopsies. (scale: 100um)