title: Natural history of cutaneous innervation following herpes zoster.
abstract: As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6months. In contrast, cutaneous innervation showed no recovery at all by 6months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.
authors.affiliation: Pain Clinical Research Center, Department of Neurology, University of California, San Francisco, CA, USA Department of Neurology, Mayo Clinic, Rochester, MN, USA Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA.
authors.forename: Karin Lottrup
authors.initials: KL
authors.lastname: Petersen
authors.forename: Frank L
authors.initials: FL
authors.lastname: Rice
authors.forename: Mahkam
authors.initials: M
authors.lastname: Farhadi
authors.forename: Haatem
authors.initials: H
authors.lastname: Reda
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rowbotham
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051474:Neuralgia, Postherpetic / Q000473:pathology* / Q000503:physiopathology; D012867:Skin / Q000294:innervation* / Q000473:pathology
references.citation: Albrecht PJ, Hines S, Eisenberg E, Pud D, Finlay DR, Connolly MK, Pare M, Davar G, Rice FL. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain. 2006;120:244-266.
references.citation: Bennett GJ. Hypotheses on the pathogenesis of herpes zoster-associated pain. Ann Neurol. 1994;35:S38-S41.
references.citation: Bowsher D, Geoffrey Woods C, Nicholas AK, Carvalho OM, Haggett CE, Tedman B, Mackenzie JM, Crooks D, Mahmood N, Aidan Twomey J, Hann S, Jones D, Wymer JP, Albrecht PJ, Argoff CE, Rice FL. Absence of pain with hyperhidrosis: a new syndrome where vascular afferents may mediate cutaneous sensation. Pain. 2009;147:287-298.
references.citation: Coplan PM, Schmader K, Nikas A, Chan IS, Choo P, Levin MJ, Johnson G, Bauer M, Williams HM, Kaplan KM, Guess HA, Oxman MN. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J Pain. 2004;5:344-356.
references.citation: Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912-1925.
references.citation: Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain. 1996;67:241-251.
references.citation: Ebenezer GJ, McArthur JC, Thomas D, Murinson B, Hauer P, Polydefkis M, Griffin JW. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies. Brain. 2007;130:2703-2714.
references.citation: Ebert M. Histologic changes in sensory nerves of the skin in herpes zoster. Arch Dermatol. 1949;60:641-648.
references.citation: Haanpaa M, Dastidar P, Weinberg A, Levin M, Miettinen A, Lapinlampi A, Laippala P, Nurmikko T. CSF and MRI findings in patients with acute herpes zoster. Neurology. 1998;51:1405-1411.
references.citation: Haanpaa M, Hakkinen V, Nurmikko T. Motor involvement in acute herpes zoster. Muscle Nerve. 1997;20:1433-1438.
references.citation: Hahn K, Triolo A, Hauer P, McArthur JC, Polydefkis M. Impaired reinnervation in HIV infection following experimental denervation. Neurology. 2007;68:1251-1256.
references.citation: Head H, Campbell AW. The pathology of herpes zoster and its bearing on sensory localisation. Brain. 1900;XXIII:352-523.
references.citation: Hilliges M, Johansson O. Comparative analysis of numerical estimation methods of epithelial nerve fibers using tissue sections. J Peripher Nerv Syst. 1999;4:53-57.
references.citation: Hoke A, Gordon T, Zochodne DW, Sulaiman OA. A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol. 2002;173:77-85.
references.citation: Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology. 1997;48:708-711.
references.citation: Hope-Simpson R. Postherpetic neuralgia. J R Coll Gen Pract. 1975;25:571-575.
references.citation: Kennedy WR, Wendelschafer-Crabb G, Walk D. Use of skin biopsy and skin blister in neurologic practice. J Clin Neuromuscul Dis. 2000;1:196-204.
references.citation: Lindenlaub T, Sommer C. Epidermal innervation density after partial sciatic nerve lesion and pain-related behavior in the rat. Acta Neuropathol. 2002;104:137-143.
references.citation: Muller S, Winkelmann R. Cutaneous nerve changes in zostera. J Invest Dermatol. 1969;52:71-77.
references.citation: Navarro X, Verdu E, Wendelschafer-Crabb G, Kennedy WR. Immunohistochemical study of skin reinnervation by regenerative axons. J Comp Neurol. 1997;380:164-174.
references.citation: Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135-145.
references.citation: Oaklander AL. The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain. 2001;92:139-145.
references.citation: Oaklander AL, Romans K, Horasek S, Stocks A, Hauer P, Meyer RA. Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol. 1998;44:789-795.
references.citation: Opstelten W, Zuithoff NP, van Essen GA, van Loon AM, van Wijck AJ, Kalkman CJ, Verheij TJ, Moons KG. Predicting postherpetic neuralgia in elderly primary care patients with herpes zoster: prospective prognostic study. Pain. 2007;132:S52-S59.
references.citation: Pare M, Albrecht PJ, Noto CJ, Bodkin NL, Pittenger GL, Schreyer DJ, Tigno XT, Hansen BC, Rice FL. Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes. J Comp Neurol. 2007;501:543-567.
references.citation: Petersen KL, Rowbotham MC. Natural history of sensory function after herpes zoster. Pain. 2010;150:83-92.
references.citation: Petersen KL, Fields HL, Brennum J, Sandroni P, Rowbotham MC. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain. 2000;88:125-133.
references.citation: Petersen KL, Rice FL, Suess F, Berro M, Rowbotham MC. Relief of post-herpetic neuralgia by surgical removal of painful skin. Pain. 2002;98:119-126.
references.citation: Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606-1615.
references.citation: Polydefkis M, Sirdofsky M, Hauer P, Petty BG, Murinson B, McArthur JC. Factors influencing nerve regeneration in a trial of timcodar dimesylate. Neurology. 2006;66:259-261.
references.citation: Polydefkis M, Yiannoutsos CT, Cohen BA, Hollander H, Schifitto G, Clifford DB, Simpson DM, Katzenstein D, Shriver S, Hauer P, Brown A, Haidich AB, Moo L, McArthur JC. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology. 2002;58:115-119.
references.citation: Rajan B, Polydefkis M, Hauer P, Griffin JW, McArthur JC. Epidermal reinnervation after intracutaneous axotomy in man. J Comp Neurol. 2003;457:24-36.
references.citation: Reilly DM, Ferdinando D, Johnston C, Shaw C, Buchanan KD, Green MR. The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations. Br J Dermatol. 1997;137:163-170.
references.citation: Rowbotham MC, Yosipovitch G, Connolly MK, Finlay D, Forde G, Fields HL. Cutaneous innervation density in the allodynic form of postherpetic neuralgia. Neurobiol Dis. 1996;3:205-214.
references.citation: Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998;18:8947-8954.
references.citation: Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 2007;6:632-642.
references.citation: Sulaiman OA, Voda J, Gold BG, Gordon T. FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic Schwann cell denervation. Exp Neurol. 2002;175:127-137.
references.citation: Thyregod HG, Rowbotham MC, Peters M, Possehn J, Berro M, Petersen KL. Natural history of pain following herpes zoster. Pain. 2007;128:148-156.
references.citation: Vlckova-Moravcova E, Bednarik J, Dusek L, Toyka KV, Sommer C. Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies. Muscle Nerve. 2008;37:50-60.
references.citation: Zacks SI, Langfitt TW, Elliot FA. Herpetic neuritis: a light and electron microscopic study. Neurology. 1964;14:744-750.
references.citation: Zhou L, Kitch DW, Evans SR, Hauer P, Raman S, Ebenezer GJ, Gerschenson M, Marra CM, Valcour V, Diaz-Arrastia R, Goodkin K, Millar L, Shriver S, Asmuth DM, Clifford DB, Simpson DM, McArthur JC. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology. 2007;68:2113-2119.