Developments in Varicella Zoster Virus Vasculopathy

Abstract

Varicella zoster virus (VZV) is a highly neurotropic human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglionic neurons along the entire neuraxis. VZV reactivation results in zoster (shingles) which is frequently complicated by chronic pain (postherpetic neuralgia). VZV reactivation also causes meningoencephalitis, myelitis, ocular disorders, and vasculopathy, all of which can occur in the absence of rash. This review focuses on the association of VZV and stroke, and on the widening spectrum of disorders produced by VZV vasculopathy in immunocompetent and immunocompromised individuals, including recipients of varicella vaccine. Aside from ischemic stroke, VZV infection of cerebral arteries may lead to development of intracerebral aneurysms, with or without hemorrhage. Moreover, recent clinical-virological case reports and retrospective pathological-virological analyses of temporal arteries positive or negative for giant cell arteritis (GCA) indicate that extracranial VZV vasculopathy triggers the immunopathology of GCA. While many patients with GCA improve after corticosteroid treatment, prolonged corticosteroid use may potentiate VZV infection, leading to fatal vasculopathy in the brain and other organs.

Keywords: Aneurysm; Giant cell arteritis; Stroke; Varicella zoster virus vasculopathy; Zoster.

Fig. 1

Nine aneurysms in varicella zoster virus vasculopathy. Digital subtraction angiography (DSA) demonstrated a total of nine mycotic aneurysms, four of which arose from the right middle cerebral artery (MCA) M3 segments (a, arrows 1–4) in the sylvian fissure and a cluster of left MCA lateral lenticulostriate perforator aneurysms, configured as a dominant oval aneurysm (b, long arrow 8), surrounded by four smaller lesions (b, arrowheads 5–7 and 9). A translucent rendered model from an angiographic 3D spin acquisition (c) further illustrates the complex arrangement of the left lateral lenticulostriate aneurysms. Repeat DSA after antiviral treatment and corona radiata perforator infarction showed interval thrombosis of the dominant aneurysm (d, long arrow 8) and one of the satellite lesions (d, arrowhead 9) that are no longer visible. Permission from Wolters Kluwer Health, Inc., Neurology 2014;82:2139–41

Fig. 2

Immunofluorescence staining and ultrastructural imaging of a varicella zoster virus-infected temporal artery. Immunohistochemical staining with rabbit anti-VZV IE63 antibody revealed VZV antigen in the media (a, pink color), but not after staining with rabbit anti-HSV-1 antibody (b). Immunofluorescence staining with a different mouse anti-VZV IgG antibody than that used in panel a revealed VZV antigen in the adventitia (c, red color), but not when primary antibody was omitted (d). Transmission electron microscopy of sections adjacent to those containing VZV antigen revealed an enveloped virus particle (e, arrow), while both scanning and transmission electron microscopy of these sections showed a cluster of virus particles in the adventitia egressing through an outer cell wall (f, arrows). Virus particles appear slightly larger than 200 nm because they were sputter-coated with a gold alloy. In panels e and f, scale bars = 300 nm. Permission from Wolters Kluwer Health, Inc., Neurology 2015;84:1948–55

Fig. 3

Contrast-enhanced high-resolution MRI (HRMR) over time in a patient with VZV vasculopathy. At presentation, coronal (a) and axial (b) HRMR revealed vessel wall thickening and enhancement of both terminal ICA segments; 3 months later, coronal (c) and axial (d) HRMR showed resolution of thickening and enhancement. Permission from Elsevier, J Neurol Sci 2015;351;168–73