Sweat Gland Nerve Fiber Density (SGNFD)

Autonomic And Small Fiber Neuropathies


Skin biopsy

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 glands are exocrine glands in the deep dermal and subcutaneous layers of skin, whose function is to maintain the body's temperature and hydration (Jablonski, 2010). 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 (Cheshire and Freeman, 2003).

Sweat gland nerve fibers, also called sudomotor fibers (Kennedy et al, 1994; Low et al, 2006), are small unmyelinated nerve fibers that are distinguished from somatic epidermal nerve fibers that convey pain and temperature from the skin. Both the sweat gland and epidermal nerve fiber densities can be reduced in generalized small fiber neuropathies (Novak et al, 2001; Dabby et al, 2007; Gibbons et al, 2009), but in some autonomic neuropathies, the sweat gland nerve fiber density (SGNFD) is selectively affected (Sommer et al, 2002). 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 (Hilz et al, 2004) or sensory (Novak et al, 2001) small fiber neuropathies, respectively.

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 (Manganelli et al, 2011), diabetic neuropathy (Gibbons et al, 2009; Luo et al, 2011), HIV-1 neuropathy (Hart et al, 2004), Guillain-Barre syndrome (Pan et al, 2003), congenital absence of pain with anhidrosis or hyperhidrosis (Tawa et al, 1992; Langer et al, 1981; Juri et al, 1997; Bowsher et al, 2009), familial amyloidosis (Ishiguchi et al, 1996), acquired idiopathic generalized anhidrosis (Miyazoe et al, 1998), and Parkinson's disease (Dabby et al, 2006).

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 (Miyazoe et al, 1998; Nakazato et al, 2005). Anhydrosis or hypohydrosis can occur in atopic conditions such as atopic dermatitis or cholinergic urticaria, and may contribute to heat or exercise intolerance (Eishi et al, 2002; Thami et al, 2003; Rho, 2006). Decreased innervation of sweat glands has been reported in some patients (Miyazoe et al, 1998; Nakamizo et al, 2010; Donadio et al, 2005, 2008). Cholinergic urticaria can also present with symptoms of stinging or burning paresthesias, overlapping with those in small fiber neuropathy (Hirschmann et al, 1987).

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.


Reduced SGNFD


Normal SGNFD

Skin sweat gland nerve fiber density (SGNFD)

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