Varicella zoster virus vasculopathy: analysis of virus-infected arteries

Abstract

Objective: Varicella zoster virus (VZV) is an under-recognized yet treatable cause of stroke. No animal model exists for stroke caused by VZV infection of cerebral arteries. Thus, we analyzed cerebral and temporal arteries from 3 patients with VZV vasculopathy to identify features that will help in diagnosis and lead to a better understanding of VZV-induced vascular remodeling.

Methods: Normal and VZV-infected cerebral and temporal arteries were examined histologically and by immunohistochemistry using antibodies directed against VZV, endothelium, and smooth muscle actin and myosin.

Results: All VZV-infected arteries contained 1) a disrupted internal elastic lamina; 2) a hyperplastic intima composed of cells expressing α-smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-myosin) but not endothelial cells expressing CD31; and 3) decreased medial smooth muscle cells. The location of VZV antigen, degree of neointimal thickening, and disruption of the media were related to the duration of disease.

Conclusions: The presence of VZV primarily in the adventitia early in infection and in the media and intima later supports the notion that after reactivation from ganglia, VZV spreads transaxonally to the arterial adventitia followed by transmural spread of virus. Disruption of the internal elastic lamina, progressive intimal thickening with cells expressing α-SMA and SM-MHC, and decreased smooth muscle cells in the media are characteristic features of VZV vasculopathy. Stroke in VZV vasculopathy may result from changes in arterial caliber and contractility produced in part by abnormal accumulation of smooth muscle cells and myofibroblasts in thickened neointima and disruption of the media.

Figure 1. Morphology of normal cerebral artery

Movat pentachrome stain reveals the 3 layers of a normal cerebral artery. The intima, adjacent to the lumen, is composed of a single endothelial layer (arrows indicate endothelial cell nuclei [pink]). The media is composed of smooth muscle cells, and the adventitia contains collagen and fibroblasts. An internal elastic lamina (IEL) separates the intima and media. Unlike coronary and pulmonary arteries, cerebral arteries do not have an external elastic lamina between the media and adventitia.

Figure 2. Histologic and virologic analysis of a normal human cerebral artery and varicella zoster virus (VZV)–infected temporal and cerebral arteries of patients with VZV vasculopathy

Hematoxylin & eosin (H&E) stain of a normal uninfected middle cerebral artery from subject 3 (A); Verhoeff-Van Gieson (VVG) staining shows an intact internal elastic lamina (E, arrow) devoid of VZV antigen (I). In the temporal artery of subject 1 with early VZV vasculopathy, as well as the right middle cerebral artery of subjects 2 and 3 (both of whom died of protracted VZV vasculopathy), H&E staining reveals a hyperplastic intima in all 3 arteries (B–D, vertical black lines), and VVG staining shows duplication or frank disruption of the internal elastic lamina in the arteries of all 3 subjects with VZV vasculopathy (F–H, arrows). VZV antigen (pink) in seen in the adventitia of subject 1 at 4 weeks after zoster (J, arrow), in the media of subject 2 (without a history of zoster rash) after a 45-week course of VZV vasculopathy (K, arrow), and in the hyperplastic intima of subject 3 at 48 weeks after zoster (L, arrow). Magnification = × 100 in panels A–H and × 600 in panels I–L.

Figure 3. Immunohistochemical analyses of a normal cerebral artery and varicella zoster virus (VZV)–infected arteries from patients with VZV vasculopathy

A thin layer of endothelial cells expressing CD31 is seen in the normal cerebral artery (A, brown color, arrow). The thickened intima of cerebral arteries from subjects 1–3 with VZV vasculopathy (B–D, vertical white lines) does not contain endothelial cells expressing CD31; however, a thin endothelium is seen adjacent to the lumen (B–D, brown color, arrows). In the normal artery, α–smooth muscle actin (α-SMA) is present exclusively in smooth muscle cells of the media (E, vertical black line, brown color). In the VZV-infected artery of subject 1 at 4 weeks after zoster, cells expressing α-SMA are present but less dense in the media and also seen in the hyperplastic intima (F, vertical black and white lines, brown color, respectively); in contrast, the cerebral arteries of subjects 2 and 3 with protracted VZV vasculopathy revealed a striking paucity of cells expressing α-SMA in the media (G, H, vertical black lines, brown color) and a greater abundance of such cells in the hyperplastic intima (G, H, vertical white lines, brown color). Cells expressing smooth muscle myosin heavy chain (SM-MHC) are abundant in the media of the normal artery (I, vertical black line, pink color); such cells are also present but less dense in the arterial media in subject 1 at 4 weeks after zoster (J, vertical black line, pink color) and sparse in the media of subjects 2 and 3 with protracted VZV vasculopathy (K, L, vertical black lines, pink color). Like α-SMA, SM-MHC is expressed by cells in the hyperplastic intima of the cerebral arteries of subjects 1–3 with VZV vasculopathy (J–L, vertical white lines, pink color). Magnification = × 200 in all panels.