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Quantification of sweat gland innervation

A clinical–pathologic correlation

From the Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

Address correspondence and reprint requests to Dr. Roy Freeman, Autonomic and Peripheral Nerve Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center, 1 Deaconess Road, Boston, MA 02215 rfreeman{at}bidmc.harvard.edu

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 patient-reported 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 = 0.93, p < 0.01). Diabetic subjects had reduced SGNFD compared to controls at the distal leg (p < 0.001), distal thigh (p < 0.01), and proximal thigh (p < 0.05). The SGNFD at the distal leg of diabetic subjects decreased as the NIS-LL worsened (r = –0.89, p < 0.001) and was concordant with symptoms of reduced sweat production (p < 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.

Abbreviations: AOI = area of interest; CI = confidence interval; ICC = intraclass correlation coefficient; IENFD = intraepidermal nerve fiber density; IgG = immunoglobulin G; NIS-LL = Neuropathy Impairment Score in the Lower Limb; PLP = paraformaldehyde-lysine-periodate; QSART = quantitative sudomotor axon reflex test; SGNFD = sweat gland nerve fiber density; TH = tyrosine hydroxylase.

Supplemental data at www.neurology.org

Supported by the Juvenile Diabetes Research Foundation 11-2007-143, NIH K23NS050209, the Langer Family Foundation, and the Harriet Lewis Foundation.

Disclosure: The authors report no disclosures.

Medical Devices: BH-2 trinocular head microscope (Olympus, Center Valley, PA); PixeLINK PL-686 (PixeLINK, Ottawa, ON); Zeiss LSM Pascal Exciter (Carl Zeiss, Thornwood, NY).

Received September 19, 2008. Accepted in final form February 2, 2009.

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				Reduced Innervation of Sweat Glands in Diabetic Neuropathy Journal Watch Neurology, July 21, 2009; 2009(721): 2 - 2. [Full Text]