Intraepidermal nerve fiber density testing is gaining enthusiastic acceptance for the diagnosis as well as the staging of diabetic neuropathy. Studies have demonstrated reduced intraepidermal nerve fiber density in patients with diabetes type 1 and type 2.1 One major advantage of intraepidermal nerve fiber density testing is the ability to detect the presence of evolving peripheral neuropathy in the presence of normal neurophysiologic studies. 2
Electrodiagnostic studies are reflective of large fiber disease, which is frequently preceded by the presence of small fiber neuropathy between 2 and 10 years. 3 In addition, small fiber neuropathy frequently presents with symptoms such as pain or numbness in the absence of any clinically definable signs. Using an epidermal nerve fiber density study enables the clinician to diagnose peripheral neuropathy in its earliest stages prior to otherwise demonstrable objective evidence of disease. This provides the opportunity to employ therapy aimed at the reduction or reversal of evolving peripheral neuropathic disease.
In addition to the diagnostic value of this test, the epidermal nerve fiber density study allows physicians to assess the response to treatment of peripheral neuropathy. 4 One can also use the intraepidermal nerve fiber density study to assess the regeneration of epidermal nerves in the diabetic and non-diabetic patient with neuropathy. 5
Nerve fiber studies have demonstrated the regeneration of small fiber nerve loss associated with entrapment neuropathy following surgical decompression. This suggests that the intraepidermal nerve fiber density study may be of benefit for the preoperative and postoperative evaluation of entrapment neuropathy, and to gauge the response to decompression surgery for the patient with symptomatic diabetic entrapment neuropathy. 6
Intraepidermal nerve fiber studies have demonstrated the neuroprotective effects of progesterone and its derivatives as well as testosterone on peripheral nerves. 7,8 Similarly, the testing has demonstrated enhanced cutaneous nerve regeneration with the utilization of 4-methylcatechol in resiniferatoxin-induced neuropathy. 9
The technique for epidermal nerve fiber density testing consists of obtaining two 3.0-mm punch biopsy specimens from the supramalleolar area. I generally employ marcaine 0.5% with epinephrine 1/200,000 for anesthesia. I administer local anesthesia between the Achilles tendon and the fibular, 4 cm above the tip of the lateral malleolus. I place the specimens in an appropriate preservative and submit the specimens for the epidermal nerve fiber density study.
What The Literature Reveals
In the patient with diabetic neuropathy, one can demonstrate reduced peripheral nerve branch density and reduced peripheral nerve branch length by utilizing intraepidermal nerve fiber density testing. Increasing severity of peripheral neuropathy, progressing from mild to severe neuropathy, is associated with an increasingly demonstrable loss of peripheral nerve branch density and length. 10
DeSousa, et al., demonstrated reduced epidermal nerve fiber in 71 percent of patients with sensory neuropathy. They also noted morphological nerve changes in the presence of a normal epithelial nerve fiber density study in 21 percent of patients. 11 Other demonstrable morphologic features in the presence of peripheral neuropathy are epidermal axon swelling, dermal axon swelling, thinning of the subepidermal nerve plexus, sprouting of nerve terminals, encapsulation of nerve endings and immunoreactive basal cells. 12
Intraepidermal nerve fiber density testing reliably identifies patients with early stage diabetic polyneuropathy prior to any clinical or electrophysiologic evidence of neuropathy. 13 Researchers have demonstrated the sensitivity of the intraepidermal study for the detection of peripheral neuropathy over other available tests such as quantitative sensory testing or electrodiagnostic studies. 14
In their study, Umapathi, et al., demonstrated a mean ankle intraepidermal nerve fiber density of 9.1 mm in non-symptomatic diabetic patients in comparison to 13.0 mm in non-diabetic control patients. 13 The reduction in epidermal nerve fiber density in patients with diabetes was not associated with age, hemoglobin A1c, height, weight or duration of diabetes.
Researchers have similarly demonstrated the association of diminished epidermal nerve fiber density with increasing loss of pinprick sensitivity.15 Studies have also shown that diminished intraepidermal nerve fiber density is associated with diminished heat-pain perception. 16
Shun, et al., demonstrated intraepidermal nerve fiber density to be lower in patients with diabetes than in age-sex matched, non-diabetic control patients. They further demonstrated a negative correlation between the duration of diabetes and epidermal nerve fiber density, and a strong correlation between reduced epidermal nerve fiber density and heat perception. 17
The intraepidermal nerve fiber density diminishes in a length-dependent manner at the ankle joint with aging. 18 Chang, et al., demonstrated an epidermal nerve fiber density of 7.80 fibers/mm in individuals greater than 60 years of age and an epidermal nerve fiber density of 13.55 fibers/mm in young adults aged 13 to 39. 19 In addition to the effects of aging, males demonstrate increased nerve fiber density reduction at the ankle in comparison to females. 20
Pertinent Insights On Therapeutic Implications
A major advantage of this technique is the earlier opportunity to provide remittive therapy. Combining this remittive therapy with adequate control of diabetes may thwart the development of sensory, motor or autonomic peripheral neuropathic disease.
Head has suggested that a variety of alternatives may provide relief of neuropathic symptoms. Such alternative medicines include alpha-lipoic acid, acetyl-L-carnitine, benfotiamine, methylcobalamin, vitamin B, glutathione, folate, pyridoxine, biotin, myo-inositol, omega 3 and omega 6 fatty acids, L-arginine, L-glutamate, taurine, N-acetylcysteine, zinc, magnesium, chromium and St. John’s Wort. 21
I personally employ a proprietary combination of L-methyl folate, piradoxine and methylcobalamin (Metanx, PamLab) for the management of peripheral neuropathy for these patients. By utilizing the intraepidermal nerve fiber density study to identify the presence of neuropathy prior to the onset of symptomatology, one can combine control of diabetes with the use of the aforementioned agents to reverse or interdict evolving sensory, motor and autonomic neuropathy.
Physicians are increasingly utilizing surgical decompression of the peripheral nerves for the treatment of symptomatic diabetic neuropathy in order to restore sensory function or reduce the paresthesias or dysthesias secondary to diabetic neuropathy. 22,23 The intraepidermal nerve fiber density study may demonstrate the presence of medial plantar nerve neuropathy prior to the demonstration of abnormal routine nerve conduction studies. 24
One can easily perform the intraepidermal nerve fiber density study in the office setting. The test facilitates the identification of patients with peripheral neuropathy prior to the onset of symptoms or positive clinical or electrophysiologic testing. One should consider this study when assessing all patients presenting to the office for an initial diabetic foot evaluation.
Physicians can use this test to establish the presence of previously undiagnosed and non-symptomatic peripheral neuropathy. This, in turn, facilitates the early institution of remittive therapy. Hopefully, use of the test will help physicians thwart the progression of peripheral neuropathy.
One can also utilize a repeat epidermal nerve fiber density study to establish the presence of peripheral entrapment neuropathy in the absence of electrodiagnostic studies, which become positive only after large fiber disease is present.
Dr. Jacobs is a Fellow of the American College of Foot and Ankle Surgeons and a Fellow of the American Professional Wound Care Association. He is in private practice in St. Louis.
Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. He is a Fellow of the American College of Foot and Ankle Surgeons.
1. Beiswenger KK, Calcutt NA, Mizisin AP. Epidermal nerves fiber quantification in the assessment of diabetic neuropathy. Acta Histochema, 2008. In press.
2. Vickova-Moravcoca E, Bednarik J, Dusek L, Toyka KV, Sommer C. Diagnostic validity of epidermal nerve fiber density in painful sensory neuropathies. Muscle Nerve 37(1):50-60, 2008.
3. Walk D, Zaretskaya M, Parry GL. Symptom duration and clinical features in painful sensory neuropathy with and without nerve condition abnormalities. J Neurologic Sci 14(1):3-6, 2003.
4. Ebenezer GJ, Hauer P, Gibbons C, McArthur JC, Polydefkis M. Assessment of epidermal nerve fibers: a new diagnostic and predictive tool for peripheral neuropathies. J Neuropathology Experimental Neurology 66(12):1059-1073, 2007.
5. Polydefkis M. Hauer P, Sheth S, Sidofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fiber regeneration: studies of the normal controls and in people with diabetes, with and without neuropathy. Brain 127(7):1606-1615, 2004.
6. Hsieh CH, Jeng SF, Lu TH, Chen YC, Hsieh MW, Chen SS. Loss of small fibers in entrapment neuropathy and their regeneration after surgical decompression in a rat model. J Neurotrauma 24(10):1658-1666, 2007.
7. Leonelli E, Bianchi R, Cavaletti G, et al. Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 144(4):1293-1304, 2007.
8. Roglio I, Bianchi R, Giatta S, et al. Testosterone derivatives are neuroprotective agents in experimental diabetic neuropathy. Cell Molec Life Sci 64(9):1158-1168, 2007.
9. Hsieh YL, Chiang H, Tseng TJ, Hsieh ST. Enhancement of cutaneous nerve regeneration by4-methylcatechol in resiniferatoxin-induced neuropathy. J Neuropathol Exper Neurol 67(2):93-104, 2008.
10. Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes 569(8):2148-2154, 2007.
11. DeSousa EA, Hays AP, Chin RL, et al. Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibers on skin biopsy. J Neurol Neurosurg Psychiatry 77(8):983-985, 2006.
12. Wendelschafer-Crabb G, Kennedy WR, Walk D. Morphological features of nerves in skin biopsies. J Neurolog Sci 242(1 Supp):15-21, 2006.
13. Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan YH. Intraepidermal nerve fiber density as a marker of early diabetic neuropathy. Muscle Nerve 35(5):591-598, 2007.
14. Loseth S, Lindal S, Stalberg E, Mellgren SI. Intraepidermal nerve fiber density, quantitative sensory testing and nerve conduction studies. Eur J Neurol 13(2):105-111, 2006.
15. Walk D, Wendelschafer-Crabb G, Davey C, Kennedy WR. Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy. J Neurolog Sci 255(1):23-26, 2007.
16. Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 12(10):747-58, 2005.
17. Shun CT, Chang YC, Wu HP, et al. Skin innervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain 127(7):1593-1604, 2004.
18. Umpathi T, Tan WL, Tean NCK, Chan YH. Determinants of epidermal nerve fiber density in normal individuals. Muscle Nerve 33(6):742-6, 2006
19. Chang YC, Lin WM, Hsieh ST. Effects of aging on human skin innervation. Neuro Report 15(1):149-53, 2004.
20. Goransson LG, Mellgren SI, Lindal S, Omdal R. The effect of age and gender on epidermal nerve fiber density. Neurology 62(5):774-7, 2004.
21. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Alt Med Rev 11(4):294-329, 2006.
22. Weiman TJ, Patel VJ, Flint Jr. LM, Vasconez LO. Treatment of hyperesthetic neuropathic pain in diabetics: decompression of the tarsal tunnel. Ann Surg 221(6):660-5, 1995.
23. Wood WA, Wood MA. Decompression of peripheral nerves for diabetic neuropathy in the lower extremity. JFAS 42:268-75, 2003.
24. Hermann DN, Ferguson ML, Pannoni V, Brabano RL, Stanton M, Logigan EL. Plantar nerve AP and skin biopsy and sensory neuropathies with normal routine conduction studies. Neurology 63(5):879-85, 2004.