The Role of Varicella Zoster Virus in Giant Cell Arteritis

  • Maria A. NagelEmail author
  • Don Gilden


Giant cell arteritis (GCA), the most common systemic vasculitis in the elderly, is characterized by excruciating unilateral headache/head pain. The temporal artery (TA) is often nodular and tender. Many patients with GCA have jaw claudication and a history of polymyalgia rheumatica. Erythrocyte sedimentation rates and C-reactive protein are elevated. Diagnosis is confirmed by TA biopsy which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages in skip areas. The pathologies of GCA and that of intracerebral varicella zoster virus (VZV) vasculopathy are identical and characterized by granulomatous arteritis, suggesting that GCA represents an extracranial variant of VZV vasculopathy predominantly affecting the TA. Virological analysis of TAs from patients with GCA or from patients with clinically suspected GCA whose TA biopsies were pathologically negative revealed the presence of VZV in most TA biopsies, particularly in skip areas that correlate with adjacent GCA pathology or adventitial inflammation. The presence of VZV in GCA-positive and GCA-negative TAs implicates the virus in triggering the immunopathology of GCA and indicates the need for treatment with antiviral drugs in addition to corticosteroids in both groups of patients. Whether oral antiviral agents and steroids are as effective as intravenous acyclovir and steroids remains to be determined, as does the dosage and duration of treatment.



Afferent pupillary defect


Cerebrospinal fluid


Giant cell arteritis


Herpes simplex virus type 1


Ischemic optic neuropathy


Right eye


Left eye


Temporal artery


Varicella zoster virus



Supported in part by National Institutes of Health grants NS093716 (Gilden), AG032958 (Gilden and Nagel), and NS094758 (Nagel). The authors thank Marina Hoffman for editorial review and Cathy Allen for manuscript preparation.


  1. 1.
    Gilden DH, Kleinschmidt-DeMasters BK, Wellish BS et al (1996) Varicella zoster virus, a cause of waxing and waning vasculitis: The New England Journal of Medicine case 5-1995 revisited. Neurology 47:1441–1446CrossRefPubMedGoogle Scholar
  2. 2.
    Gilden D, White T, Khmeleva N et al (2015) Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 84:1948–1955CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Gilden D, White T, Galetta SL et al (2015) Widespread arterial infection by varicella zoster virus explains refractory giant cell arteritis. Neurol Neuroimmunol Neuroinflamm 2:e125. doi: 10.1212/NXI.0000000000000125 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Gilden D, White T, Khmeleva N, Boyer PJ, Nagel MA (2016) VZV in biopsy-positive and -negative giant cell arteritis: analysis of 100+ temporal arteries. Neurol Neuroimmunol Neuroinflamm 3:e216. doi: 10.1212/NXI.0000000000000216 CrossRefGoogle Scholar
  5. 5.
    Gilden D, White T, Boyer PJ et al (2016) Varicella zoster virus infection in granulomatous arteritis of the aorta. J Infect Dis 213(12):1866–1871 Pil: jiw101CrossRefGoogle Scholar
  6. 6.
    Mathias M, Nagel MA, Khmeleva N et al (2013) VZV multifocal vasculopathy with ischemic optic neuropathy, acute retinal necrosis and temporal artery infection in the absence of zoster rash. J Neurol Sci 325:180–182CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Minassian C, Thomas SL, Smeeth L, Douglas I, Brauer R, Langan SM (2015) Acute cardiovascular events after herpes zoster: a self-controlled case series analysis in vaccinated and unvaccinated older residents of the United States. PLoS Med 12(12):e1001919. doi: 10.1371/journal.pmed.1001919 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nagel MA, Cohrs RJ, Mahalingam R et al (2008) The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology 70:853–860CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nagel MA, Traktinskiy I, Azarkh Y et al (2011) Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology 77:364–370CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nagel MA, Traktinskiy I, Stenmark KR, Frid MG, Choe A, Gilden D (2013) Varicella zoster virus vasculopathy: immune characteristics of virus-infected arteries. Neurology 80:62–68CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Nagel MA, Russman AN, Feit H et al (2013) VZV ischemic optic neuropathy and subclinical temporal artery infection without rash. Neurology 80:220–222CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Nagel MA, Bennett JL, Khmeleva N et al (2013) Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis. Neurology 80:2017–2021CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Nagel MA, Khmeleva N, Boyer PJ et al (2013) Varicella zoster virus in the temporal artery of a patient with giant cell arteritis. J Neurol Sci 335:228–230CrossRefPubMedGoogle Scholar
  14. 14.
    Nagel MA, White T, Khmeleva N et al (2015) Analysis of varicella zoster virus in temporal arteries biopsy-positive and -negative for giant cell arteritis. JAMA Neurol 72:1281–1287CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nagel MA, Lenggenhager D, White T et al (2015) Disseminated VZV infection and asymptomatic VZV vasculopathy after steroid abuse. J Clin Virol 66:72–75CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Salazar R, Russman AN, Nagel MA et al (2011) Varicella zoster virus ischemic optic neuropathy and subclinical temporal artery involvement. Arch Neurol 68:517–520CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Departments of Neurology and Immunology and MicrobiologyUniversity of Colorado School of MedicineAuroraUSA

Personalised recommendations