Small‐fiber sensory neuropathies: Clinical course and neuropathology of idiopathic cases

Abstract

We describe the clinical features, natural history, and neuropathology of 32 patients presenting with "burning feet," for whom no specific cause was identified. All had neuropathic pain in the feet and morphological abnormalities of cutaneous innervation in skin obtained using punch biopsy. Most (29) had an abnormal sensory examination. All had normal strength, proprioception, tendon reflexes, and nerve conductions. Two clinical patterns were apparent, based on natural history and spatial distribution of cutaneous denervation. Most (28) patients presented with neuropathic pain initially restricted to the feet and toes but extending more proximally to involve the legs and hands with time. Intraepidermal nerve fiber (IENF) density was most severely reduced distally, with more normal IENF densities in skin from proximal sites. In contrast, a minority (4) presented with the abrupt onset of generalized cutaneous burning pain and hyperesthesia. In these patients, IENF densities were reduced in skin from both proximal and distal sites. Absolute IENF densities in calf skin were reduced below the lower limit of normal (5th percentile) in 26 (81%). Of the 6 who underwent sural nerve biopsy, 4 had selective loss of small myelinated and/or unmyelinated axons and 2 had normal histology and fiber densities despite reduced IENF densities in skin biopsy specimens. Punch skin biopsy from proximal and distal sites is a useful means of assessing these distinctive patients and may provide further insight into pathophysiology.

The Prevalence, Predictors, and Consequences of Peripheral Sensory Neuropathy in Older Patients

“…Definitions that require electrophysiologic studies (eg, nerve conduction studies), 23 expensive equipment (eg, computer-assisted sensory examination), 24 or invasive testing (eg, skin or nerve biopsy) 15 make large studies impractical. Definitions that require symptoms (eg, the Michigan Diabetes Neuropathy Score) 25,26 exclude large numbers of people with asymptomatic disease.…”

“…It is also possible that a variety of lower extremity complaints such as leg cramps, restless legs syndrome, and nonspecific leg pains can result from neuropathy. 15 An association between peripheral neuropathy and lower extremity ulcers, cellulitis, and amputations has not been excluded.…”

New technologies for the assessment of neuropathies

“…Before the development of anti-PGP9.5 antibodies, visualization of unmyelinated C-fibres and thinly myelinated Aδ-fibres required analysis of a nerve biopsy with electron microscopy. The availability of skin biopsy prompted the recognition of SFN as a distinct clinical entity 117 . Furthermore, skin biopsy has enabled investigation of the innervation of autonomic structures, such as sweat glands, hair follicles and arteriovenous anastomosis, in autonomic neuropathies [118][119][120] .…”

Diabetic Neuropathy: Latest Concepts

“…By this fibre density can be readily quantified, with reported interobserver agreement as high as 96%. [40] Lindberger et al [41] has reported that levels of both substance P and calcitonin gene related peptide (CGRP) are reduced in skin biopsies from diabetic patients before clinical or neurophysiologic evidence of neuropathy. Levy et al [42] showed that there was a progressive loss in the number and area innervated by CGRP positive nerve fibres when normal subjects were compared with diabetic patients with clinical evidence of neuropathy.…”