Quantification of sweat gland innervation

Abstract

Objective: To evaluate a novel method to quantify the density of nerve fibers innervating sweat glands in healthy control and diabetic subjects, to compare the results to an unbiased stereologic technique, and to identify the relationship to standardized physical examination and patientreported symptom scores.Methods: Thirty diabetic and 64 healthy subjects had skin biopsies performed at the distal leg and distal and proximal thigh. Nerve fibers innervating sweat glands, stained with PGP 9.5, were imaged by light microscopy. Sweat gland nerve fiber density (SGNFD) was quantified by manual morphometry. As a gold standard, three additional subjects had biopsies analyzed by confocal microscopy using unbiased stereologic quantification. Severity of neuropathy was measured by standardized instruments including the Neuropathy Impairment Score in the Lower Limb (NIS-LL) while symptoms were measured by the Michigan Neuropathy Screening Instrument.Results: Manual morphometry increased with unbiased stereology (r ϭ 0.93, p Ͻ 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p Ͻ 0.001), distal thigh (p Ͻ 0.01), and proximal thigh (p Ͻ 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r ϭ Ϫ0.89, p Ͻ 0.001) and was concordant with symptoms of reduced sweat production (p Ͻ 0.01). Conclusions:We describe a novel method to quantify the density of nerve fibers innervating sweat glands. The technique differentiates groups of patients with mild diabetic neuropathy from healthy control subjects and correlates with both physical examination scores and symptoms relevant to sudomotor dysfunction. This method provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies. Assessment of small myelinated and unmyelinated nerve fibers is a central component of the evaluation of peripheral nerve disease. 1,2 Most polyneuropathies prominently target small nerve fibers; the subsequent small fiber dysfunction, impaired sensory perception, and sudomotor deficits lead to a predisposition to limb ulceration, infection, and amputation.3 Small sensory fiber function is evaluated with quantitative sensory testing while skin biopsy quantification of intraepidermal nerve fiber density (IENFD) provides a structural measure of small fiber cutaneous innervation. 4 Functional measures of peripheral postganglionic autonomic sudomotor nerves include the quantitative sudomotor axon reflex test (QSART) and silicone impression

Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates

“…However, there was limited pathologic evidence demonstrating the denervation of autonomic targets, such as a report on postmortem tissues, which showed amyloid depositions and neuronal cell loss in sympathetic ganglia with microscopic resolution 2, 30. Sweat gland innervation was reduced in type 2 diabetic neuropathy,6, 7, 9 and we have documented that this reduction of SGIIPGP 9.5 was attributed to sudomotor nerve degeneration as demonstrated at the ultrastructural level 6. The current report is the first to provide direct pathologic evidence of sudomotor denervation in FAP.…”

Skin biopsy: an emerging method for small nerve fiber evaluation

“…This method showed high interand intra-rater reliability. 31 Sweat gland nerve fiber density (SGNFD) by this method was decreased significantly in diabetic patients compared with healthy controls and correlated well with standardized neuropathy examination scores and IENFD. 31 The limitation of this method is it takes a lot of time and effort.…”

“…[28][29][30] Manual and automated quantification are more recent ways to quantify the sweat gland innervation. 30,31 In manual quantification, standardized grid of circles is placed over the sweat gland image and intersecting nerve fibers with the circle are counted. The results are expressed as the number of circles intersected out of the total number of circles.…”

Autonomic thermoregulatory dysfunction in neurofibromatosis type 1

“…For instance, after sympathectomy, local sweating responses to pilocarpine becomes exacerbated, but it subsequently decreases and, in some cases, ceases completely 22 . Decreased pharmacologically induced sweat production observed in type 1 diabetes and multiple sclerosis is an early sign of neuropathy, and it has been associated with reduced sympathetic nerve fiber density in the sweat glands 10,23,24 . In NF1, the development of large cutaneous and subcutaneous neurofibromas may cause dysfunctions in peripheral nerves leading to chronic pain, sensory loss, weakness or even palsy.…”