Contribution of Skin Biopsy in Peripheral Neuropathies

Abstract

In the last three decades the study of cutaneous innervation through 3 mm-punch-biopsy has provided an important contribution to the knowledge of small fiber somatic and autonomic neuropathies but also of large fiber neuropathies. Skin biopsy is a minimally invasive technique with the advantage, compared to sural nerve biopsy, of being suitable to be applied to any site in our body, of being repeatable over time, of allowing the identification of each population of nerve fiber through its target. In patients with symptoms and signs of small fiber neuropathy the assessment of IntraEpidermal Nerve Fiber density is the gold standard to confirm the diagnosis while the quantification of sudomotor, pilomotor, and vasomotor nerve fibers allows to evaluate and characterize the autonomic involvement. All these parameters can be re-evaluated over time to monitor the disease process and to evaluate the effectiveness of the treatments. Myelinated fibers and their receptors can also be evaluated to detect a “dying back” neuropathy early when nerve conduction study is still normal. Furthermore, the morphometry of dermal myelinated fibers has provided new insight into pathophysiological mechanisms of different types of inherited and acquired large fibers neuropathies. In genetic neuropathies skin biopsy has become a surrogate for sural nerve biopsy, no longer necessary in the diagnostic process, to study genotype–phenotype correlations.

The neuropathy in hereditary transthyretin amyloidosis: A narrative review

“…40 At this stage, other causes of SFN should be considered in differential diagnosis. 40 Over time in earlyonset ATTRv patients, the initial small fiber neuropathy progresses to the involvement of larger fibers and NCS may demonstrate a sensorymotor neuropathy.…”

Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents—Consensus-Based Practice Guidelines

“…Suspected inherited sensory neuropathy or small-fibre neuropathy (SFN) calls for a skin punch biopsy including immunohistochemistry of epidermal and dermal nerve fibres with staining for Protein Gene Product 9.5 (PGP9.5); it also allows the study of dermal myelinated fibres, autonomic innervation (sweat glands, arrector pili muscle, arteriovenous anastomosis), and mechanoreceptors. It is a less invasive procedure used to obtain diagnosis, but it also requires expertise and the knowledge of norm values appropriate to the given age group [17,29]. Adolescent-onset FAP can be suspected by the presentation of amyloid deposits but needs genetic testing of the TTR gene for confirmation [16].…”

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

“…Diabetic peripheral neuropathy also shares the neuropathological characteristics of small-fiber neuropathy (SFN), such as reduction in the intraepidermal nerve fiber (IENF) density (skin denervation) and development of neuropathic behavior. Skin denervation after diabetes is correlated with neuropathic pain [ 3 ], indicating IENF densities as a predictor of diabetic peripheral neuropathy progression [ 4 ], and neuropathic behavior in diabetic patients [ 5 – 7 ]. However, why some diabetic patients with fewer IENFs experienced no pain during quantitative sensory testing remains unclear [ 8 , 9 ].…”