One of the most common complaints patients brought to clinical neurologists continues to be "burning sensations" in their toes and feet. Many of these individuals undergo neurologic evaluation in the community and in tertiary centers and are found to have evidence of diseases of the peripheral nervous system predominantly affecting small diameter myelinated and unmyelinated fibers, called small fiber neuropathy (SFN).
In the last 20 years, researchers have made significant strides in developing methods to identify the mechanisms underlying the disorders that may produce these symptoms. Advances in the diagnosis of SFN can be grouped into the arenas of pathology, neurophysiology, and molecular genetics.
By Dr. Benn E. Smith
The most significant step forward in the pathology of small diameter nerve fibers is the introduction of readily available techniques to quantitate epidermal nerve fiber density by counting small myelinated fibers at the dermal-epidermal junction. This process involves removing one or more 2- to 4-mm circular pieces of superficial skin, most often from the distal and proximal lower limb, and immunohistochemical staining with panaxonal markers such as protein gene product 9.5. This allows for microscopic assessment of the number of myelinated fibers per mm2 and comparison with known normal values. Guidelines for using these techniques have been published (Eur. J. Neurol. 2010;17:903-12). Other investigators are using similar approaches to study diabetic autonomic neuropathy by examining small fibers in the gastric or intestinal mucosa (Neurology 2010;75:973-81). The density of sweat gland nerve fibers also has been quantitated as a surrogate marker of SFN (Muscle Nerve 2010;42:112-9).
The nonlaser method of evaluating contact heat–evoked potential stimulation (CHEPS) has helped to study somatic small diameter nerve fibers between skin and cerebral cortex. CHEPS builds on the investigations of the last few decades in a variety of neurologic disorders, including SFN, and it is currently under comparison against other diagnostic techniques for SFN (BMC Neurol. 2007;7:21). Another new approach that uses cardiac scintigraphy with 123I-metaiodobenzylguanidine (123I-MIBG) was able to detect a high percentage of cardiac autonomic neuropathy in diabetes mellitus even when heart rate variation, a common test of cardiac vagal function, was found to be normal (Eur. J. Nucl. Med. Mol. Imaging 2010;37:1698-705).
Known causes of peripheral SFN include diabetes mellitus, impaired glucose tolerance, celiac disease, HIV infection, alcoholic neuropathy, autoimmune dysautonomia, amyloidosis, hereditary sensory and autonomic neuropathies, erythromelalgia, and Fabry disease. Industrial toxin exposure, however, is unlikely to manifest itself as peripheral SFN. In recent years, 24%-93% of SFNs were grouped into the idiopathic category (Muscle Nerve 2002;26:173-88; Brain 2008;131:1912-25; Diabetes Care 2010;33:2285-93). Headway has been made more recently in identifying novel SFNs associated with specific mutations. A previously unrecognized form of hereditary sensory and autonomic neuropathy with dementia and hearing loss was reported in a number of patients with mutations in DNA methyltransferase 1 (Nat. Gen. 2011;43:595-600).
At the 2011 biennial meeting of the Peripheral Nerve Society, Dr. Catharina G. Faber of University Medical Center Maastricht (the Netherlands) and her colleagues reported on gain-of-function Nav1.7 mutations in idiopathic SFN. These investigators studied patients with possible idiopathic SFN who met specific criteria of at least two SFN-related symptoms; normal strength, tendon reflexes, vibration sense, and nerve conduction studies; reduced intraepidermal nerve fiber density; abnormal quantitative sensory testing; and no underlying etiology for SFN.
Of 248 patients screened over 2 years, 28 met criteria and were assessed by screening of the SCN9A gene for mutations and functional analyses. Overall, 8 (28.6%) of these 28 patients had mutations in SCN9A. Dr. Faber concluded that missense mutations in this gene encoding the Nav1.7 sodium channel occur in a substantial proportion of patients with biopsy- and QST-confirmed idiopathic SFN. These mutations confer hyperexcitability to dorsal root ganglion cells, which give rise to small axons. Expression of Nav1.7 and the sodium-calcium exchanger NCX in small diameter axons may poise these fibers to degenerate in response to gain-of-function changes produced by Nav1.7 mutations. These mutations may predispose individuals to the development of channelopathy-associated SFN. SCN9A gene analysis might be considered for patients with SFN in whom other causes are excluded (Ann. Neurol. 2012;71:26-39).
This line of research has been continued by Dr. Janneke G. J. Hoeijmakers and others from the Netherlands, who have described a unique phenotypic presentation of a missense SCN9A gene mutation in the Nav1.7 sodium channel with distal burning, dysautonomia, and small hands and feet (Brain 2012;135:345-58).
As neuroscientists continue to use the tools of pathology, neurophysiology, and molecular genetics to study these painful neuropathies, the field anticipates further useful discoveries of mechanisms underlying SFN and hopes that the knowledge leads to efficacious treatments for these often debilitating disorders.