Therapath Neuropathology

Sweat Gland Nerve Fiber Density

A reduction in the innervation of sweat glands has been reported in a number of conditions that can cause autonomic neuropathy.

Autonomic and Small Fiber Neuropathies

Sweat glands are exocrine glands in the deep dermal and subcutaneous layers of skin, whose function is to maintain the body’s temperature and hydration.1 They are innervated by the autonomic nervous system that also regulates other involuntary bodily functions such as heart rate, blood pressure, the bladder, and gut. Symptoms of autonomic neuropathy can include abnormal sweating or temperature regulation, postural hypotension, irregular heart rate, gastroparesis, irregular bowel movements, incomplete bladder emptying, urinary urgency, sexual dysfunction, hair loss, and atrophic nails or skin, among others.2

Biopsy procedure guide

A 50 μm thick section of a 3 mm dia. punch skin biopsy from the thigh, greater than 4 mm deep, immunohistochemically stained for the axonal protein, PGP9.5 (black fibers), to detect and quantify sweat gland innervation (blue arrow) and intraepidermal nerve fibers (red arrow). Also visible in this biopsy are nerves that control an arrector pili muscle, which contracts in response to emotion or cold (green arrow).

Sweat gland nerve fibers, also called sudomotor fibers, are small unmyelinated nerve fibers that are distinguished from somatic epidermal nerve fibers that convey pain and temperature from the skin.3,4 Both the sweat gland and epidermal nerve fiber densities can be reduced in generalized small fiber neuropathies, but in some autonomic neuropathies, the sweat gland nerve fiber density (SGNFD) is selectively affected.5–8 Both the SGNFD and ENFD tests have been reported to be more sensitive than the Quantitative Sudomotor Axon Reflex Test (QSART) in the evaluation of autonomic or sensory small fiber neuropathies, respectively.5,9

A reduction in the innervation of sweat glands has been reported in a number of conditions that can cause autonomic neuropathy including in autoimmune autonomic ganglionopathy,10 diabetic neuropathy,7,11 HIV-1 neuropathy,12 Guillain-Barre syndrome,13 congenital absence of pain with anhidrosis or hyperhidrosis,14–17 familial amyloidosis,18 acquired idiopathic generalized anhidrosis,19 and Parkinson’s disease.6


Anhydrosis and Hypohydrosis in Sudomotor Neuropathy

Anhydrosis can be a manifestation of generalized autonomic neuropathy, or result from selective involvement of the sudomotor nerve fibers that innervate the sweat glands.19,20 Anhydrosis or hypohydrosis can occur in atopic conditions such as atopic dermatitis or cholinergic urticaria, and may contribute to heat or exercise intolerance.21–23 Decreased innervation of sweat glands has been reported in some patients.19,24–26 Cholinergic urticaria can also present with symptoms of stinging or burning paresthesias, overlapping with those in small fiber neuropathy.27


Quantification of Sweat Gland Nerve Fiber Density (SGNFD)

Gibbons et al (2009, 2010) reported that quantification of sweat gland nerve fiber density “provides a reliable structural measure of sweat gland innervation that complements the investigation of small fiber neuropathies,” and that “results correlate well with physical exam findings.” Determination of sweat gland innervation can also help distinguish between central and peripheral causes of dysautonomia. Donadio et al (2010) compared patients with multiple system atrophy (MSA), a central nervous system disorder, to those with Pure Autonomic Failure caused by autonomic neuropathy. They found that sweat gland innervation was reduced in patients with autonomic neuropathy, but normal in those with MSA. Once the diagnosis of autonomic neuropathy is made, further studies can be taken to identify an underlying cause such as amyloidosis or diabetes, and if one found, then therapy can be directed at the cause of the neuropathy, in addition to providing symptomatic treatment.

Therapath is licensed by the state of New York to provide the SGNFD test for patients with suspected autonomic or small fiber neuropathy. Physicians can request the test separately or, to increase the sensitivity of testing, in samples where the Epidermal Nerve Fiber density (ENFD) is found to be normal. Sweat glands are not numerous, however, and are mostly present in the deep dermis, so that skin biopsies should be at least 4 mm in depth, or the full length of the punch biopsy needle, to provide the best yield of sweat glands for analysis.

Skin with normal Sweat Gland Nerve Fiber Density (SGNFD)

Skin with reduced Sweat Gland Nerve Fiber Density (SGNFD)


References

1.
Jablonski N. The naked truth. Sci Am. 2010;302(2):42-49. [PubMed]
2.
Cheshire W, Freeman R. Disorders of sweating. Semin Neurol. 2003;23(4):399-406. [PubMed]
3.
Kennedy W, Wendelschafer-Crabb G, Brelje T. Innervation and vasculature of human sweat glands: an immunohistochemistry-laser scanning confocal fluorescence microscopy study. J Neurosci. 1994;14(11 Pt 2):6825-6833. [PubMed]
4.
Low V, Sandroni P, Fealey R, Low P. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve. 2006;34(1):57-61. [PubMed]
5.
Novak V, Freimer M, Kissel J, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56(7):861-868. [PubMed]
6.
Dabby R, Vaknine H, Gilad R, Djaldetti R, Sadeh M. Evaluation of cutaneous autonomic innervation in idiopathic sensory small-fiber neuropathy. J Peripher Nerv Syst. 2007;12(2):98-101. [PubMed]
7.
Gibbons C, Illigens B, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009;72(17):1479-1486. [PubMed]
8.
Sommer C, Lindenlaub T, Zillikens D, Toyka K, Naumann M. Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome. Ann Neurol. 2002;52(2):247-250. [PubMed]
9.
Hilz M, Axelrod F, Bickel A, et al. Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation. Brain. 2004;127(Pt 9):2090-2098. [PubMed]
10.
Manganelli F, Dubbioso R, Nolano M, et al. Autoimmune autonomic ganglionopathy: a possible postganglionic neuropathy. Arch Neurol. 2011;68(4):504-507. [PubMed]
11.
Luo K, Chao C, Chen Y, et al. Quantitation of sudomotor innervation in skin biopsies of patients with diabetic neuropathy. J Neuropathol Exp Neurol. 2011;70(10):930-938. [PubMed]
12.
Hart A, Wilson A, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 2004;18(11):1549-1560. [PubMed]
13.
Pan C, Tseng T, Lin Y, Chiang M, Lin W, Hsieh S. Cutaneous innervation in Guillain-Barré syndrome: pathology and clinical correlations. Brain. 2003;126(Pt 2):386-397. [PubMed]
14.
Tawa R, Matsuda H, Morimoto T, Nagao H, Matsuda H, Ohnishi A. [Neurophysiologic and histopathologic studies in a case of congenital sensory neuropathy with anhidrosis]. No To Hattatsu. 1992;24(6):542-547. [PubMed]
15.
Langer J, Goebel H, Veit S. Eccrine sweat glands are not innervated in hereditary sensory neuropathy type IV. An electron-microscopic study. Acta Neuropathol. 1981;54(3):199-202. [PubMed]
16.
Juri T, Higuchi R, Shirai T, Miyashiro E, Muta Y, Ohnishi A. [A case of hereditary sensory and autonomic neuropathy type IV diagnosed following the development of acute encephalopathy due to heat stroke]. No To Hattatsu. 1997;29(3):254-260. [PubMed]
17.
Bowsher D, Geoffrey W, Nicholas A, et al. Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation. Pain. 2009;147(1-3):287-298. [PubMed]
18.
Ishiguchi H, Shimoya K, Ohnishi A, Murai Y, Nakazato M, Hoshii Y. [Familial amyloidosis, Finnish type with marked anhidrosis]. Rinsho Shinkeigaku. 1996;36(3):436-441. [PubMed]
19.
Miyazoe S, Matsuo H, Ohnishi A, et al. Acquired idiopathic generalized anhidrosis with isolated sudomotor neuropathy. Ann Neurol. 1998;44(3):378-381. [PubMed]
20.
Nakazato Y, Tamura N, Ohkuma A, Yoshimaru K, Shimazu K. QSART in idiopathic pure sudomotor failure. Clin Auton Res. 2005;15(6):414-416. [PubMed]
21.
Eishi K, Lee J, Bae S, Takenaka M, Katayama I. Impaired sweating function in adult atopic dermatitis: results of the quantitative sudomotor axon reflex test. Br J Dermatol. 2002;147(4):683-688. [PubMed]
22.
Thami G, Kaur S, Kanwar A. Acquired idiopathic generalized anhidrosis: a rare cause of heat intolerance. Clin Exp Dermatol. 2003;28(3):262-264. [PubMed]
23.
Rho N. Cholinergic urticaria and hypohidrosis: a clinical reappraisal. Dermatology. 2006;213(4):357-358. [PubMed]
24.
Nakamizo S, Miyachi Y, Kabashima K. A case of cholinergic urticaria associated with acquired generalized hypohidrosis and abnormal neurological findings: association with incomplete Ross syndrome? Br J Dermatol. 2010;162(4):903-905. [PubMed]
25.
Donadio V, Montagna P, Nolano M, et al. Generalised anhidrosis: different lesion sites demonstrated by microneurography and skin biopsy. J Neurol Neurosurg Psychiatry. 2005;76(4):588-591. [PubMed]
26.
Donadio V, Cortelli P, Falzone F, et al. Isolated generalised anhidrosis induced by postganglionic sympathetic skin nerve fibre degeneration: an incomplete Ross syndrome? J Neurol Neurosurg Psychiatry. 2008;79(8):959-961. [PubMed]
27.
Hirschmann J, Lawlor F, English J, Louback J, Winkelmann R, Greaves M. Cholinergic urticaria. A clinical and histologic study. Arch Dermatol. 1987;123(4):462-467. [PubMed]