Editorial commentary: varicella zoster virus infection: generally benign in kids, bad in grown-ups.

Varicella zoster virus (VZV), an exclusively human neurotropic double-stranded DNAvirus, is 1 of 8 human herpesviruses. Primary infection causes varicella (chicken pox), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia, and autonomic ganglia along the entire neuraxis. As VZV-specific cellmediated immunity declines in elderly individuals, as well as in patients with AIDS and other immunocompromising conditions, VZV reactivates from 1 or more ganglia to cause herpes zoster (shingles). Zoster is frequently complicated by chronic pain (postherpetic neuralgia) as well as meningoencephalitis, cerebellitis, myelitis, VZV vasculopathy, and multiple ocular disorders. Among the most debilitating and life-threatening complications of zoster is VZV vasculopathy, a cause of transient ischemic attack (TIA) and stroke. Historically, VZV vasculopathy was known to present as acute hemiplegia after contralateral herpes zoster ophthalmicus or as a postvaricella arteriopathy in children. However, in recent years, the clinical spectrum of VZV vasculopathy has expanded to include TIA, ischemic stroke, and hemorrhagic stroke often involving both large and small vessels, multifocal VZV vasculopathy with temporal artery infection mimicking giant cell arteritis, extracranial vasculopathy, aneurysm with and without subarachnoid hemorrhage, arterial dissection and dolichoectasia, ischemic cranial neuropathy, cerebral venous sinus thrombosis, spinal cord infarction, and peripheral thrombotic disease. VZV is the only human virus that has been proven to replicate in cerebral arteries and produce stroke. Studies of the pathogenesis of disease reveal that upon reactivation from ganglia, VZV travels transaxonally to the adventitia of arteries where productive infection is established, followed by transmural migration of virus to the arterial media and intima, pathological vascular remodeling, and stroke. The notion that virus spreads transaxonally after reactivation from trigeminal and other cranial nerve ganglia is supported by the demonstration of afferent fibers from trigeminal ganglia to intracranial blood vessels, venous sinuses, and dural structures [1, 2]. Evidence for productive VZV infection of affected arteries was first provided by virologic analysis of a patient who died after VZV vasculopathy; the infected arteries contained Cowdry A inclusion bodies, multinucleated giant cells, herpes virions, and both VZV DNA and antigen [3]. The mechanism(s) by which VZV causes pathological vascular remodeling can be surmised from studies of VZVinfected arteries from patients with virologically confirmed VZV vasculopathy. Immunohistochemical analyses using antibodies directed against VZV, endothelium, and smooth muscle actin and myosin revealed the presence of VZV antigen in the outermost arterial layer (adventitia) early in infection and later in the media and intima layers, consistent with both transaxonal spread of reactivated VZV to the arterial adventitia followed by transmural spread of virus [4]. Moreover, virus-infected arteries revealed a disrupted internal elastic lamina, a thickened intima composed of cells expressing α smooth muscle actin and smooth muscle myosin heavy chain, but not endothelial cells expressing CD31 and decreased numbers of medial smooth muscle cells [4]. The loss of medial smooth muscle cells and the presence of cells expressing myosin in the thickened intima suggest that some of these latter cells are of medial smooth muscle origin. A follow-up study of inflammatory cells and their distribution in normal cerebral arteries and in VZV-infected arteries at 3 days after onset of disease (early) Received 4 February 2014; accepted 5 February 2014; electronically published 2 April 2014. Correspondence: Don Gilden, MD, Department of Neurology, University of Colorado School of Medicine, 12700 E 19th Ave, Mail Stop B182, Aurora, CO 80045 (don.gilden@ ucdenver.edu). Clinical Infectious Diseases 2014;58(11):1504–6 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/ciu099