The Pathology of Postherpetic Neuralgia and Postherpetic Itch

  • Anne Louise OaklanderEmail author


Postherpetic neuralgia (PHN) is one of the most studied neuropathic pain conditions because it is common, it is easy to diagnose, and the causal injury (zoster) can be precisely localized anatomically and temporally. Head and Campbell’s 1900 masterpiece mapping the locations of shingles rashes in almost 500 patients and then correlating this with autopsy localization of affected ganglia was how the sensory dermatomes were mapped. It also defined the pathology of zoster-affected spinal cord, nerve root, sensory ganglion, and peripheral nerves. Later studies focused on identifying pathological substrates for PHN. Watson’s group discovered that typical single-ganglion zoster damages up to five segments of the dorsal horn of the spinal cord, helping to explain why the PHN pain is felt in more than the one dermatome affected by the shingles rash. Oaklander’s team reported that PHN arises almost exclusively in patients with fewer than 650 epidermal nerve fibers/mm2 left after zoster, suggesting that PHN involves somatosensory hallucinations generated by deafferented central neurons. They also discovered that clinically unilateral zoster triggers bilateral pathology and that postherpetic itch and associated painless self-injury arise in skin lacking almost all C-fiber innervation, when isolated remaining itch neurons fire spontaneously and can no longer trigger surround inhibition in the dorsal horn. Hamrah’s group applied in vivo corneal confocal microscopy to confirm the presence of bilateral nerve degeneration after clinically unilateral herpes zoster ophthalmicus. Pathological study of patients with acute zoster and its neuropathic sequelae helped to identify normal somatosensory anatomy as well as the mechanisms of neuropathic pain and itch.


Shingles Herpes zoster Neuropathic pain Neuropathic itch Neuropathology Radiculopathy Ganglionopathy Neuronopathy 



Funded in part by the Public Health Service. NINDS R01 AG42866.

Conflict of Interest Statement

None to report.


  1. 1.
    Adams RD (1944) Herpes zoster: Pathologic features. Bull N Engl Med Center 6:12Google Scholar
  2. 2.
    Baron R, Saguer M (1994) Axon-reflex reactions in affected and homologous contralateral skin after unilateral peripheral injury of thoracic segmental nerves in humans. Neurosci Lett 165:97–100CrossRefPubMedGoogle Scholar
  3. 3.
    Baron R, Saguer M (1995) Mechanical allodynia in postherpetic neuralgia: evidence for central mechanisms depending on nociceptive C-fiber degeneration. Neurology 45(12):S63–S65CrossRefPubMedGoogle Scholar
  4. 4.
    Bright R (1831) Reports of medical cases. London 2(Part 1):383Google Scholar
  5. 5.
    Chandelux (1879) Observation pour servir a l’histoire des lesions nerveuses dans le zona. Archives de Physiologie XI:674Google Scholar
  6. 6.
    Cheatham WJ (1953) The relation of heretofore unreported lesions to pathogenesis of herps zoster. Am J Pathol 29:401–412PubMedPubMedCentralGoogle Scholar
  7. 7.
    Denny-Brown D, Adams RD, Fitzgerald PJ (1944) Pathologic features of herpes zoster: a note on ‘geniculate herpes’. Arch Neurol Psychiatr (Chicago) 57:216CrossRefGoogle Scholar
  8. 8.
    Dubler (1884) Ueber Neuritis boi Herpes Zoster. Virchows Arch, XCVI:195Google Scholar
  9. 9.
    Ebert MH (1949) Histologic changes in sensory nerves of the skin in herpes zoster. Arch Dermatol Syphil 60:641–648CrossRefGoogle Scholar
  10. 10.
    Esiri MM, Tomlinson AH (1972) Herpes zoster: demonstration of virus in trigeminal nerve and ganglion by immunofluorescence and electron microscopy. J Neurol Sci 14:35–48CrossRefGoogle Scholar
  11. 11.
    Faure-Beaulieu M, Lhermitte J (1929) Les lesions medullaires du zona idiopathique: La myelite zosterienne. Rev Neurol 1:1250–1258Google Scholar
  12. 12.
    Forbes HJ, Thomas SL, Smeeth L, Clayton T, Farmer R, Bhaskaran K, Langan SM (2016) A systematic review and meta-analysis of risk factors for postherpetic neuralgia. Pain 157(1):30–54CrossRefGoogle Scholar
  13. 13.
    Geha PY, Baliki MN, Wang X, Harden RN, Paice JA, Apkarian AV (2008) Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia. Pain 138(3):641–656CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ghatak NR, Zimmerman HM (1973) Spinal ganglion in herpes zoster: a light and electron microscopic study. Arch Pathol 95:411–415PubMedGoogle Scholar
  15. 15.
    Haanpää M, Dastidar P, Weinberg A (1998) CSF and MRI findings in patients with acute herpes zoster. Neurology 51:1045–1411CrossRefGoogle Scholar
  16. 16.
    Hamrah P, Cruzat A, Dastjerdi MH, Pruss H, Zheng L, Shahatit BM, Bayhan HA, Dana R, Pavan-Langston D (2013) Unilateral herpes zoster ophthalmicus results in bilateral corneal nerve alteration: an in vivo confocal microscopy study. Ophthalmology 120:40–47CrossRefPubMedGoogle Scholar
  17. 17.
    Head H, Campbell AW (1900) The pathology of herpes zoster and its bearing on sensory localization. Brain 23:353–523CrossRefGoogle Scholar
  18. 18.
    Hilliges M, Wang L, Johansson O (1995) Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Invest Dermatol 104:134–137CrossRefPubMedGoogle Scholar
  19. 19.
    Hope-Simpson RE (1965) The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 58:9–20PubMedPubMedCentralGoogle Scholar
  20. 20.
    Jastreboff PJ (1990) Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci Res 8:221–254CrossRefPubMedGoogle Scholar
  21. 21.
    Karanth SS, Springall DR, Kuhn DM, Levene MM, Black JM (1991) An immunocytochemical study of cutaneous innervation and the distribution of neuropeptides and protein gene product 9.5 in man and animals. Am J Anat 191:368–383Google Scholar
  22. 22.
    Koltzenburg M, Wall PD, McMahon SB (1999) Does the right side know what the left side is doing? TINS 22:122–127PubMedGoogle Scholar
  23. 23.
    Lesser E (1881) Beitrage zur Lehre vom Herpes Zoster. Virchows Arch XXXVI:391Google Scholar
  24. 24.
    Lhermitte J, Nicolas (1924) Les lesions spinales du zona: La myelite zosterienne. Rev Neurol 1:361–364Google Scholar
  25. 25.
    Liu J, Hao Y, Du M, Wang X, Zhang J, Manor B et al (2013) Quantitative cerebral blood flow mapping and functional connectivity of postherpetic neuralgia pain: a perfusion fMRI study. Pain 154(1):110–118CrossRefPubMedGoogle Scholar
  26. 26.
    Lombard MC, Nashold BS Jr, Albe-Fessard D, Salman N, Sakr C (1979) Deafferentation hypersensitivity in the rat after dorsal rhizotomy: a possible animal model of chronic pain. Pain 6(2):163–174CrossRefPubMedGoogle Scholar
  27. 27.
    McCormick WF, Rodnitzky RL, Schochet SS et al (1969) Varicella-zoster encephalomyelitis: a morphologic and virologic study. Arch Neurol 21:559–570CrossRefPubMedGoogle Scholar
  28. 28.
    Melzack R, Wall PW (1965) Pain mechanisms: a new theory. Science 150:971–979CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P et al (1999) Heritability of nociception II. Types of nociception revealed by genetic correlation analysis. Pain 80:83–93CrossRefPubMedGoogle Scholar
  30. 30.
    Noordenbos W (1959) Pain: problems pertaining to the transmission of nerve impulses which give rise to pain. Amsterdam, Elsevier. Chapter 1 pp 4–10; ch 10 pp 68–80Google Scholar
  31. 31.
    Oaklander AL, Romans K, Horasek S, Stocks A, Hauer P, Meyer RA (1998) Unilateral postherpetic neuralgia is associated with bilateral sensory neuron damage. Ann Neurol 44:789–795CrossRefGoogle Scholar
  32. 32.
    Oaklander AL (1999) The pathology of shingles; Head and Campbell’s 1900 monograph. Arch Neurol 56:1292–1294CrossRefPubMedGoogle Scholar
  33. 33.
    Oaklander AL (2001) The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain 92:139–145CrossRefPubMedGoogle Scholar
  34. 34.
    Pappagallo M, Oaklander AL, Quatrano-Piacentini AL, Clark MR, Raja SN (2000) Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms. Anesthesiology 92:691–698CrossRefGoogle Scholar
  35. 35.
    Oaklander AL, Cohen SP, Raju SVY (2002) Intractable postherpetic itch and cutaneous deafferentation after facial shingles. Pain 96:9–12CrossRefPubMedGoogle Scholar
  36. 36.
    Oaklander AL, Bowsher D, Galer BS, Haanpää ML, Jensen MP (2003) Herpes zoster itch: preliminary epidemiologic data. J Pain 4:338–343CrossRefGoogle Scholar
  37. 37.
    Oaklander AL, Brown JM (2004) Unilateral nerve injury produces bilateral loss of distal innervation. Ann Neurol 55:639–644CrossRefPubMedGoogle Scholar
  38. 38.
    Reske-Nielsen E, Oster S, Pedersen B (1986) Herpes zoster ophthalmicus and the mesencephalic nucleus. Acta Pathol Microbiol Immunol Scand 94:263–269Google Scholar
  39. 39.
    Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C et al (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886–898CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Rowbotham MC (1996) Relationship of pain, allodynia and thermal sensation in postherpetic neuralgia. Brain 119:347–354CrossRefPubMedGoogle Scholar
  41. 41.
    Rowbotham MC, Yosipovitch G, Connolly MK, Finlay D, Forde G, Fields HL (1996) Cutaneous innervation density in the allodynic form of postherpetic neuralgia. Neurobiol Dis 3:205–214CrossRefPubMedGoogle Scholar
  42. 42.
    Sattler (1875) Ueber das Wesen des Herpes ophthalmicus. Anzelger der K. K. Gesellschaft der Herzte in Wien. Protocoll der sitzung (This will be found at the end of the Medizinische Jahrbuch von der K.K. Gesellschaft der Aertze)Google Scholar
  43. 43.
    Schultz G, Melzack R (1991) The Charles Bonnet syndrome: ‘phantom visual images’. Perception 20:809–825CrossRefPubMedGoogle Scholar
  44. 44.
    Simone DA, Noland M, Johnson T, Wendelschafer-Crabb G, Kennedy WR (1998) Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers. J Neurosci 18:8947–8959Google Scholar
  45. 45.
    Shir Y, Ratner A, Seltzer Z (1997) Diet can modify autotomy behavior in rats following peripheral neurectomy. Neurosci Lett 236:71–74CrossRefPubMedGoogle Scholar
  46. 46.
    Thompson RJ, Doran JF, Jackson P, Dhillon AP, Rode J (1983) PGP 9.5 – a new marker for vertebrate neurons and neuroendocrine cells. Brain Res 278:224–228CrossRefPubMedGoogle Scholar
  47. 47.
    von Bärensprung FGF (1861) Die Gürtelkrankheit. Ann Char-Krankenh Zu Berlin 9:40–238Google Scholar
  48. 48.
    von Bärensprung FGF (1862) Beiträge zur Kenntnis des Zoster. Ann Char-Krankenh Zu Berlin 10:96–104Google Scholar
  49. 49.
    Watson CPN, Morshead C, Van der Kooy D, Deck JH, Evans RJ (1988) Postherpetic neuralgia: post-mortem analysis of a case. Pain 34:129–138CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Watson CPN, Deck JH, Morshead C, Van der Kooy D, Evans RJ (1991) Postherpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 44:105–117CrossRefGoogle Scholar
  51. 51.
    Watson CPN, Midha R, Devor M, Nag S, Munro C, Dostrovsky JO (2000) Trigeminal postherpetic neuralgia postmortem: clinically unilateral, pathologically bilateral. In: Devor M, Rowbotham MC, Wiesenfeld-Hallin Z (eds) Proceedings of the 9th world congress on pain. Progress in pain research and management, IASP Press, SeattleGoogle Scholar
  52. 52.
    Wohlwill F (1924) Zur pathologischen Anatomie des Nervensystems vom Herpes Zoster. Z ges Neurol Psychiatr 89:170–212CrossRefGoogle Scholar
  53. 53.
    Wyss O (1871) Beitrag zur Kentniss des Herpes Zoster. Arch Heilk XVI:261Google Scholar
  54. 54.
    Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL (1998) Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75:141–155CrossRefPubMedGoogle Scholar
  55. 55.
    Zacks SL, Langfitt TW, Elliott FA (1964) Herpetic neuritis: a light and electron microscopic study. Neurology 14:744–750CrossRefGoogle Scholar
  56. 56.
    Zhang Y, Liu J, Li L, Du M, Fang W, Wang D et al (2014) A study on small-world brain functional networks altered by postherpetic neuralgia. Magn Reson Imaging 32:359–365CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of NeurologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Department of Pathology (Neuropathology)Massachusetts General HospitalBostonUSA

Personalised recommendations