References for this Review were obtained from personal reprint files, supplemented by searches of PubMed with the search terms “varicella zoster virus”, “varicella zoster virus vasculopathy”, “VZV vasculopathy”, “varicella encephalitis”, “varicella zoster encephalomyelitis”, “herpes zoster encephalitis”, “herpes zoster myelitis”, “herpes zoster ophthalmicus”, “granulomatous angiitis”, and “cerebral angiitis” from 1948 to May, 2009. The bibliographies of the most recent articles were also
ReviewVaricella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment
Introduction
Primary VZV infection, which usually occurs in children, results in chickenpox (varicella), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. Years later, as cell-mediated immunity to VZV declines with age or from immunosuppression (such as in organ-transplant recipients or patients with cancer or AIDS), VZV can reactivate to cause zoster (shingles). Zoster is often followed by chronic pain (postherpetic neuralgia), as well as vasculopathy, myelopathy, retinal necrosis, and cerebellitis (figure 1). VZV reactivation can also cause pain without rash (zoster sine herpete); in fact, all neurological complications of VZV reactivation can occur without rash.
Over the past few decades there has been an increasing number of reports of vascular disease after VZV reactivation. Unlike early cases of acute hemiplegia after contralateral zoster caused by large-artery disease, the recognised clinical range of this disease has expanded to include transient ischaemic attacks and protracted illness involving both small and large arteries. In addition to ischaemic infarction, VZV can cause aneurysm, cerebral and subarachnoid haemorrhage, and arterial ectasia, and might be a co-factor, along with trauma, in the pathogenesis of cerebral arterial dissection. Furthermore, VZV can also cause peripheral arterial disease. In adults, the exact incidence of VZV vasculopathy is difficult to estimate, although it is more common in immunocompromised individuals. In children, VZV vasculopathy has been proposed to account for 31% of all arterial ischaemic strokes;1 moreover, stroke was preceded by chickenpox in 44% of children with transient cerebral arteriopathy.2
In this Review, we outline the ever-widening spectrum of vascular disease after VZV reactivation (zoster), as well as after primary infection (varicella), and discuss the underlying mechanisms of the disease. We also emphasise the importance of accurate diagnosis to enable appropriate treatment of VZV vasculopathies.
Section snippets
History
The earliest recorded description of VZV vasculopathy was about 50 years ago when Cravioto and Feigin3 described what they believed was “a non-infectious granulomatous angiitis with a predilection for the nervous system, characterized by thrombosis in cerebral arteries and distinguished from other vasculitides by the nature of the inflammatory response, which consisted predominantly of histiocytes, mononuclear cells and multinucleated giant cells”. Years later, Rosenblum and Hadfield4 described
Clinical presentation
Although early case reports emphasised that patients present with acute stroke, many patients have transient ischaemic attacks with protracted neurological symptoms and signs. Common clinical features are not limited to acute hemiplegia and include headache, changes in mental status, aphasia, ataxia, hemisensory loss, and both hemianopia and monocular visual loss. Less frequently, patients with VZV vasculopathy present with aneurysm, subarachnoid or cerebral haemorrhage, carotid dissection,
Spinal-cord infarction
Rare cases of putative spinal-cord infarction produced by VZV vasculopathy have been diagnosed on the basis of acute-onset myelopathy associated with zoster or on the basis of virological evidence of VZV infection in acute myelopathy cases without rash. Only a few cases of VZV spinal-cord infarction have been verified pathologically.21 Before diffusion-weighted MRI, postmortem spinal-cord necrosis secondary to VZV vasculitis with productive VZV infection was the only way to establish the
VZV vasculopathy in children
As in adults, VZV vasculopathy in children also often occurs weeks to months after zoster or varicella. There are many case reports; the first, reported by Kamholz and Tremblay,36 was of a patient with varicella followed by hemiparesis with angiographic evidence of vasculopathy. Another case of loss of balance and increasing right-sided weakness occurred in a 17-month-old boy who had had a vesicular rash in the ophthalmic and mandibular division of the left trigeminal nerve 4 weeks earlier; his
Large-vessel and small-vessel vasculopathy
Large infarctions that follow trigeminal-distribution or cervical-distribution zoster are usually ischaemic40 and are only rarely haemorrhagic.30 Clinical and radiological evidence of multifocal large and small infarction should suggest the possibility of VZV infection. Large calibre vessels at the base of the brain or over the convexities can be damaged, and large-sized ischaemic or haemorrhagic infarctions can be produced. Ovoid, well-demarcated lesions (figure 3), mostly at the grey–white
Treatment
VZV vasculopathy is caused by productive viral infection in arteries, as evidenced by the presence of multinucleated giant cells, Cowdry A inclusion bodies and herpes virus particles, and VZV antigen and VZV DNA in cerebral vessels.20 Thus, all patients are typically treated with intravenous aciclovir on the basis of category 3 evidence (ie, opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees). The largest study so far consists of
VZV vasculopathy versus encephalitis
Nearly all CNS diseases caused by VZV infection include stroke. Most diseases are not primary encephalitis, but are instead caused by unifocal or multifocal infarction that develops secondary to productive virus infection in large and small cerebral arteries. The question arises as to whether primary VZV encephalitis exists at all. Earlier reports of clinical cases of encephalitis associated with varicella55 and zoster56 do not provide a definitive answer. For example, MRI, which allows
Conclusions
VZV vasculopathies can complicate zoster or varicella and are caused by productive viral infection in cerebral arteries. The important features of VZV vasculopathy are summarised in the panel. Unlike most cases of acute viral encephalitis, VZV vasculopathy is often chronic and protracted. Lesions at grey–white matter junctions are a clue to diagnosis, which is best confirmed by the presence of anti-VZV IgG antibody in the CSF with reduced serum to CSF ratio of anti-VZV IgG compared with albumin
Search strategy and selection criteria
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