Intraepidermal Nerve Fiber Analysis in Human Patients and Animal Models of Peripheral Neuropathy: A Comparative Review

Abstract

Analysis of intraepidermal nerve fibers (IENFs) in skin biopsy samples has become a standard clinical tool for diagnosing peripheral neuropathies in human patients. Compared to sural nerve biopsy, skin biopsy is safer, less invasive, and can be performed repeatedly to facilitate longitudinal assessment. Intraepidermal nerve fiber analysis is also more sensitive than conventional nerve histology or electrophysiological tests for detecting damage to small-diameter sensory nerve fibers. The techniques used for IENF analysis in humans have been adapted for large and small animal models and successfully used in studies of diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV-associated sensory neuropathy, among others. Although IENF analysis has yet to become a routine end point in nonclinical safety testing, it has the potential to serve as a highly relevant indicator of sensory nerve fiber status in neurotoxicity studies, as well as development of neuroprotective and neuroregenerative therapies. Recently, there is also interest in the evaluation of IENF via skin biopsy as a biomarker of small fiber neuropathy in the regulatory setting. This article provides an overview of the anatomic and pathophysiologic principles behind IENF analysis, its use as a diagnostic tool in humans, and applications in animal models with focus on comparative methodology and considerations for study design.

Calmangafodipir Reduces Sensory Alterations and Prevents Intraepidermal Nerve Fibers Loss in a Mouse Model of Oxaliplatin Induced Peripheral Neurotoxicity

“…Moreover, in this study, the evaluation of calmangafodipir’s effect is not limited to behavioral tests, since it is complemented by the assessment of IENF density, a diagnostic tool for small fiber sensory neuropathy that has been suggested to be an early sign of CIPN [ 3 ]. In our study, this assessment allows the pathological confirmation of the behavioral test results, providing them with a strong and reliable support, but it is also important since IENF density measurement is used in the clinical setting, making the translation of the preclinical results much easier and more reliable [ 26 ]. Furthermore, there are examples of clinical treatment effects with pharmacological agents that correlate with the reversal of IENF reduction [ 27 ].…”

Behavioral, Histopathologic, and Molecular Biological Responses of Nanoparticle- and Solution-Based Formulations of Vincristine in Mice

“…For example, the intraepidermal nerve fibers in the paws of the animals might be less affected by nano-CVR than solution-based VCR, as reported earlier in literature. 73 In a mouse study, solution-based VCR administration caused activation of microglia and astrocyte and TNF-a mRNA upregulation in the spinal cord, and anti-TNF-a mAb attenuated VCR-induced mechanical allodynia. 49 Increased expression of a 2 d 1 Ca channel subunit was also found in the dorsal horn of spinal cord in rats dosed with VCR.…”

Special Issue on Toxicologic Neuropathology of the Peripheral Nervous System: A Special Compendium of Past, Present, and Future Developments in a Neglected Field

“…In animal studies, when clinical signs (such as decreased grip strength in functional observational batteries), excessive grooming, skin lesions, automutilation of digits, or dogs walking on the dorsal surface of their paws are noted, they should be investigated further via nerve conduction velocity tests (DaSilva and Arezzo) 2 or intraepidermal nerve fiber density evaluation (Mangus, et al). 56 End points for sensory neuropathy evaluation in animal toxicity studies is often neglected due to the specialized nature and limited implementation of the available techniques needed for such evaluations. A review of regulatory guidance documents for animal toxicity studies defining PNS evaluation generally reveals meager recommendations for sampling and processing (Bolon et al 57 ).…”

“…In animal studies, when clinical signs (such as decreased grip strength in functional observational batteries), excessive grooming, skin lesions, automutilation of digits, or dogs walking on the dorsal surface of their paws are noted, they should be investigated further via nerve conduction velocity tests ( DaSilva and Arezzo ) 2 or intraepidermal nerve fiber density evaluation ( Mangus, et al ). 56…”

“…The art of nerve fiber teasing is covered by Bolon and Pardo 63 in a piece that includes exquisite diagrams and photomicrographs depicting normal and neuropathological features of myelinated nerve fibers in teased preparations. A histopathological end point (intraepidermal nerve fiber density) for sensory neuropathy evaluation is compared between species in an article by Mangus et al 56 In addition to these pathology-focused articles, a review of electrophysiological end points that are often used to evaluate the functional significance of morphologic data is included in an article by DaSilva and Arezzo . 2 Part 1 concludes with a review of global regulatory guidance documents regarding PNS neuropathology evaluation ( Bolon et al ) 57 and a compilation of useful references to assist in PNS neuropathology evaluation and interpretation ( Bolon et al ).…”