Clinical, electrophysiological, and cutaneous innervation changes in patients with bortezomib-induced peripheral neuropathy reveal insight into mechanisms of neuropathic pain

Abstract

Bortezomib is a mainstay of therapy for multiple myeloma, frequently complicated by painful neuropathy. The objective of this study was to describe clinical, electrophysiological, and pathological changes of bortezomib-induced peripheral neuropathy (BiPN) in detail and to correlate pathological changes with pain descriptors. Clinical data, nerve conduction studies, and lower leg skin biopsies were collected from 22 BiPN patients. Skin sections were immunostained using anti-protein gene product 9.5 (PGP9.5) and calcitonin gene-related peptide (CGRP) antibodies. Cumulative bortezomib dose and clinical assessment scales indicated light-moderate sensory neuropathy. Pain intensity >4 (numerical rating scale) was present in 77% of the patients. Median pain intensity and overall McGill Pain Questionnaire (MPQ) sum scores indicated moderate to severe neuropathic pain. Sural nerve sensory nerve action potentials were abnormal in 86%, while intraepidermal nerve fiber densities of PGP9.5 and CGRP were not significantly different from healthy controls. However, subepidermal nerve fiber density (SENFD) of PGP9.5 was significantly decreased and the axonal swelling ratio, a predictor of neuropathy, and upper dermis nerve fiber density (UDNFD) of PGP9.5, presumably representing sprouting of parasympathetic fibers, were significantly increased in BiPN patients. Finally, significant correlations between UDNFD of PGP9.5 versus the evaluative Pain Rating Index (PRI) and number of words count (NWC) of the MPQ, and significant inverse correlations between SENFD/UDNFD of CGRP versus the sensory-discriminative MPQ PRI/NWC were found. BiPN is a sensory neuropathy, in which neuropathic pain is the most striking clinical finding. Bortezomib-induced neuropathic pain may be driven by sprouting of parasympathetic fibers in the upper dermis and impaired regeneration of CGRP fibers in the subepidermal layer.

Pain Management in Patients with Multiple Myeloma: An Update

“…Increased thermal and mechanical detection thresholds derived from quantitative sensory testing reflect the dysfunction of A-beta-, A-delta-, and C-fibers [68]. Histological findings of early BIPN stages demonstrate axonal swelling rather than a diminished intraepidermal nerve fiber density in skin biopsies [66]. Thalidomide and bortezomib combination therapies can lead to a more prominent, reversible, length-dependent, sensory rather than motor, and predominately axonal, large-fiber more than small-fiber polyneuropathy [70].…”

“…Median pain intensity and the McGill pain questionnaire sum score point towards a moderate to severe neuropathic pain within BIPN. In a recent study, up to 77% of patients with MM had a mean pain intensity > 4 (numerical rating scale; 0 = "no pain" to 10 = "most intense pain imaginable") [66]. Grade 1 or 2 BIPN can occur in up to 75%, and Grade 3 or 4 BIPN in 30% of newly diagnosed MM patients [68].…”

“…The abovementioned chemotherapeutic agent bortezomib is a well-established drug for the treatment of multiple myeloma and mantle cell lymphoma. Among other side effects, bortezomib can induce a mild to moderate dose-dependent sensory neuropathy in MM patients [66,67]. Risk factors include the bortezomib dose and a preexisting neuropathy [68].…”

“…Clinical electrophysiology has shown axonal rather than demyelinating sensory neuropathy in BIPN [66] with abnormal sural nerve neurography in 86% of patients with MM. Increased thermal and mechanical detection thresholds derived from quantitative sensory testing reflect the dysfunction of A-beta-, A-delta-, and C-fibers [68].…”

Neuropathy of Connective Tissue Diseases and Other Systemic Diseases

“…90 Skin biopsy demonstrates nonspecific findings of reduction in subepidermal nerve fiber density and increased axonal swelling. 91 Neuropathy generally occurs after the fifth cycle of treatment with a cumulative dose of 42 mg/m 2 . A randomized trial has shown that subcutaneous administration of bortezomib was associated with a lower rate of neuropathy compared with intravenous administration.…”