This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (133)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in this journal  Topic Collections  • Neurology, Other  • Alert me on articles by topic

Normative Reference Range and Diagnostic Efficiency

Justin C. McArthur, MBBS, MPH; E. Adelaine Stocks, MS; Peter Hauer, BS; David R. Cornblath, MD; John W. Griffin, MD

Arch Neurol. 1998;55:1513-1520.

Background  The sensitivity of neuron-specific antibodies permit the identification of the small unmyelinated nerve fibers within the skin.

Objectives  To develop a reference range of epidermal nerve fiber density in humans, and to evaluate their diagnostic efficiency for sensory neuropathies.

Methods  Ninety-eight normal controls (age range, 13-82 years) were examined with both directed neurologic examinations and quantitative sensory testing. The diagnostic utility was examined in 20 patients with sensory neuropathies. Each subject had 2 punch biopsies performed at each site in the thigh and distal part of the leg (total of 392 biopsies). After formalin fixation, 50-µm-thick free-floating sections were stained with a polyclonal antibody to neuron-specific ubiquitin hydrolase, anti–protein gene product 9.5. We enumerated intraepidermal nerve fibers per millimeter to derive a "linear density." The linear density technique was validated against a stereological technique that used the fractionator to measure the total length of intraepidermal nerve fibers per 3-mm punch.

Results  The biopsy technique was well tolerated, with no notable complications. The linear density quantitation was rapid and had high intraobserver and interobserver reliability. We determined that the density of intraepidermal fibers in normal controls was 21.1±10.4 per millimeter (mean±SD) in the thigh (fifth percentile, 5.2 per millimeter), and was 13.8±6.7 per millimeter at the distal part of the leg (fifth percentile, 3.8 per millimeter). Significantly higher intraepidermal fiber densities were seen in the youngest group (P=.004), and we observed no significant effect of race, sex, height, or weight. The density at the thigh was significantly correlated with that at the distal part of the leg (P=.01) and was consistently higher by about 60%, a reflection of the normal proximal-distal gradient. The results obtained with stereology and the linear density correlated significantly (P=.001), providing internal validation for the technique. Epidermal nerve fiber density was significantly reduced (P=.001) in patients with sensory neuropathies. With a cutoff derived from the fifth percentile of the normative range for the distal part of the leg, the technique had a positive predictive value of 75%, a negative predictive value of 90%, and a diagnostic efficiency of 88%.

Conclusions  We have established a reference range for intraepidermal nerve fiber density in normal humans by means of a simple quantitation method based on enumeration of individual intraepidermal nerve fibers on vertical sections of punch skin biopsy specimens stained with the sensitive panaxonal marker anti–protein gene product 9.5. The utility of the density measurement was confirmed for sensory neuropathy with a diagnostic efficiency of 88%. Skin biopsies may be useful to assess the spatial distribution of involvement in peripheral nerve disease and the response to neurotrophic and other restorative therapies.

From the Departments of Neurology (Drs McArthur, Cornblath, and Griffin, Ms Stocks, and Mr Hauer) and Neuroscience (Dr Griffin), The Johns Hopkins University School of Medicine, Baltimore, Md.

RELATED ARTICLE

Intraepidermal Nerve Fiber Assessment: A New Window on Peripheral Neuropathy
Richard J. Barohn
Arch Neurol. 1998;55(12):1505-1506.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

IN VIVO CONFOCAL MICROSCOPY OF MEISSNER CORPUSCLES AS A MEASURE OF SENSORY NEUROPATHY
Nolano et al.
Neurology 2008;71:536-537.
FULL TEXT  

Non-length dependent small fibre neuropathy/ganglionopathy
Gorson et al.
J. Neurol. Neurosurg. Psychiatry 2008;79:163-169.
ABSTRACT | FULL TEXT  

In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy
Herrmann et al.
Neurology 2007;69:2121-2127.
ABSTRACT | FULL TEXT  

Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes
Kellogg et al.
Diabetes 2007;56:2997-3005.
ABSTRACT | FULL TEXT  

Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies
Ebenezer et al.
Brain 2007;130:2703-2714.
ABSTRACT | FULL TEXT  

Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy
Quattrini et al.
Diabetes 2007;56:2148-2154.
ABSTRACT | FULL TEXT  

Review: Microvascular complications: evaluation and monitoring relevance to clinical practice, clinical trials, and drug development
Greenstein et al.
British Journal of Diabetes & Vascular Disease 2007;7:166-171.
ABSTRACT  

Dwindling Indications for Sural Nerve Biopsy
Pleasure
Arch Neurol 2007;64:935-936.
FULL TEXT  

Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy
Zhou et al.
Neurology 2007;68:2113-2119.
ABSTRACT | FULL TEXT  

Epidemiology of distal symmetrical neuropathies in the Italian elderly
Baldereschi et al.
Neurology 2007;68:1460-1467.
ABSTRACT | FULL TEXT  

Impaired reinnervation in HIV infection following experimental denervation
Hahn et al.
Neurology 2007;68:1251-1256.
ABSTRACT | FULL TEXT  

Peripheral Neuropathy in Primary Sjogren Syndrome: A Population-Based Study
Goransson et al.
Arch Neurol 2006;63:1612-1615.
ABSTRACT | FULL TEXT  

Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.
Roosterman et al.
Physiol. Rev. 2006;86:1309-1379.
ABSTRACT | FULL TEXT  

Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy.
De Sousa et al.
J. Neurol. Neurosurg. Psychiatry 2006;77:983-985.
ABSTRACT | FULL TEXT  

HIV neuropathy natural history cohort study: Assessment measures and risk factors
Simpson et al.
Neurology 2006;66:1679-1687.
ABSTRACT | FULL TEXT  

Protective Effect of Erythropoietin and Its Carbamylated Derivative in Experimental Cisplatin Peripheral Neurotoxicity
Bianchi et al.
Clin. Cancer Res. 2006;12:2607-2612.
ABSTRACT | FULL TEXT  

The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes
Sorensen et al.
Diabetes Care 2006;29:883-887.
ABSTRACT | FULL TEXT  

Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort
Cherry et al.
Neurology 2006;66:867-873.
ABSTRACT | FULL TEXT  

Small-diameter nerve fiber neuropathy in systemic lupus erythematosus.
Goransson et al.
Arch Neurol 2006;63:401-404.
ABSTRACT | FULL TEXT  

Factors influencing nerve regeneration in a trial of timcodar dimesylate
Polydefkis et al.
Neurology 2006;66:259-261.
ABSTRACT | FULL TEXT  

Evaluation of a clinical screening tool for HIV-associated sensory neuropathies
Cherry et al.
Neurology 2005;65:1778-1781.
ABSTRACT | FULL TEXT  

Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24
Spring et al.
Brain 2005;128:2797-2810.
ABSTRACT | FULL TEXT  

Noninvasive Monitoring of Diabetes-Induced Cutaneous Nerve Fiber Loss and Hypoalgesia in thy1-YFP Transgenic Mice
Chen et al.
Diabetes 2005;54:3112-3118.
ABSTRACT | FULL TEXT  

Clinical spectrum of cryoglobulinaemic neuropathy
Gemignani et al.
J. Neurol. Neurosurg. Psychiatry 2005;76:1410-1414.
ABSTRACT | FULL TEXT  

Skin Denervation in Vasculitic Neuropathy
Lee et al.
Arch Neurol 2005;62:1570-1573.
ABSTRACT | FULL TEXT  

Small-Fiber Neuropathy/Neuronopathy Associated With Celiac Disease: Skin Biopsy Findings
Brannagan et al.
Arch Neurol 2005;62:1574-1578.
ABSTRACT | FULL TEXT  

Painful small-fiber neuropathy in Sjogren syndrome
Chai et al.
Neurology 2005;65:925-927.
ABSTRACT | FULL TEXT  

Peripheral neuropathy in patients with inflammatory bowel disease
Gondim et al.
Brain 2005;128:867-879.
ABSTRACT | FULL TEXT  

Distal symmetric polyneuropathy: A definition for clinical research: Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation
England et al.
Neurology 2005;64:199-207.
ABSTRACT | FULL TEXT  

Plantar nerve AP and skin biopsy in sensory neuropathies with normal routine conduction studies
Herrmann et al.
Neurology 2004;63:879-885.
ABSTRACT | FULL TEXT  

The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy
Polydefkis et al.
Brain 2004;127:1606-1615.
ABSTRACT | FULL TEXT  

Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments
Shun et al.
Brain 2004;127:1593-1605.
ABSTRACT | FULL TEXT  

The Diagnostic Yield of a Standardized Approach to Idiopathic Sensory-Predominant Neuropathy
Smith and Singleton
Arch Intern Med 2004;164:1021-1025.
ABSTRACT | FULL TEXT  

The effect of age and gender on epidermal nerve fiber density
Goransson et al.
Neurology 2004;62:774-777.
ABSTRACT | FULL TEXT  

Electrically Stimulated Axon Reflexes Are Diminished in Diabetic Small Fiber Neuropathies
Kramer et al.
Diabetes 2004;53:769-774.
ABSTRACT | FULL TEXT  

Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies
Singer et al.
Neurology 2004;62:612-618.
ABSTRACT | FULL TEXT  

Expression of protein gene product 9.5 in lepromatous eyes showing ciliary body nerve damage and a "dying back" phenomenon in the posterior ciliary nerves
Ebenezer and Daniel
Br. J. Ophthalmol. 2004;88:178-181.
ABSTRACT | FULL TEXT  

New Insights Into Diabetic Polyneuropathy
Polydefkis et al.
JAMA 2003;290:1371-1376.
ABSTRACT | FULL TEXT  

Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies
Lauria et al.
Neurology 2003;61:631-636.
ABSTRACT | FULL TEXT  

Cutaneous innervation in Guillain-Barre syndrome: pathology and clinical correlations
Pan et al.
Brain 2003;126:386-397.
ABSTRACT | FULL TEXT  

The spectrum of neuropathy in diabetes and impaired glucose tolerance
Sumner et al.
Neurology 2003;60:108-111.
ABSTRACT | FULL TEXT  

Chronic Idiopathic Axonal Polyneuropathy and Successful Aging of the Peripheral Nervous System
Wolfe
Arch Neurol 2002;59:520-522.
FULL TEXT  

Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy
Polydefkis et al.
Neurology 2002;58:115-119.
ABSTRACT | FULL TEXT  

Epidermal nerve innervation in impaired glucose tolerance and diabetes-associated neuropathy
Smith et al.
Neurology 2001;57:1701-1704.
ABSTRACT | FULL TEXT  

Autonomic impairment in painful neuropathy
Novak et al.
Neurology 2001;56:861-868.
ABSTRACT | FULL TEXT  

Subclinical sensory neuropathy in late-onset restless legs syndrome
Polydefkis et al.
Neurology 2000;55:1115-1121.
ABSTRACT | FULL TEXT  

Distal Sensory Polyneuropathy in a Cohort of HIV-Infected Children Over Five Years of Age
Araújo et al.
Pediatrics 2000;106:35e-35.
ABSTRACT | FULL TEXT  

Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy
Kilo et al.
Neurology 2000;54:1246-1252.
ABSTRACT | FULL TEXT  

A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection
McArthur et al.
Neurology 2000;54:1080-1088.
ABSTRACT | FULL TEXT  

Sensory nerves in skin
Kennedy and Said
Neurology 1999;53:1614-1614.
FULL TEXT  

Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies
Herrmann et al.
Neurology 1999;53:1634-1634.
ABSTRACT | FULL TEXT  

Intraepidermal Nerve Fiber Assessment: A New Window on Peripheral Neuropathy
Barohn
Arch Neurol 1998;55:1505-1506.
FULL TEXT