Role Of Varicella Zoster Virus Research Articles

The Spectrum of Neurological Manifestations of Varicella-Zoster Virus Reactivation.

Varicella-Zoster virus (VZV) is a pathogenic human alpha herpes virus that causes varicella (chicken pox) as a primary infection and, following a variable period of latency in different ganglionic neurons, it reactivates to produce herpes zoster (shingles). The focus of this review is on the wide spectrum of the possible neurological manifestations of VZV reactivation. While the most frequent reactivation syndrome is herpes zoster, this may be followed by the serious and painful post-herpetic neuralgia (PHN) and by many other neurological conditions. Prominent among these conditions is a VZV vasculopathy, but the role of VZV in causing giant cell arteritis (GCA) is currently controversial. VZV reactivation can also cause segmental motor weakness, myelitis, cranial nerve syndromes, Guillain-Barre syndrome, meningoencephalitis, and zoster sine herpete, where a neurological syndrome occurs in the absence of the zoster rash. The field is complicated by the relatively few cases of neurological complications described and by the issue of causation when a neurological condition is not manifest at the same time as the zoster rash.

Varicella Zoster Virus Vasculitis and Adult Cerebrovascular Disease.

The role of Varicella zoster virus (VZV) in neurological illness, particularly cerebrovascular disease, has been increasingly recognized. Primary infection by VZV causes varicella (chickenpox), after which the virus remains latent in neuronal ganglia. Later, during aging or immunosuppression, the virus can reactivate causing zoster (shingles). Virus reactivation can also spread to cerebral arteries causing vasculitis and stroke. Zoster is a recognized risk factor for stroke, but stroke can occur without preceding zoster rash. The diagnosis of VZV cerebral vasculitis is established by abnormal brain imaging and confirmed by presence of viral DNA or anti-VZV antibodies in cerebrospinal fluid. Treatment with acyclovir with or without prednisone is usually recommended. VZV vasculitis is a unique and uncommon stroke mechanism that has been under recognized. Careful diagnostic investigation may be warranted in a subgroup of patients with ischemic stroke to detect VZV vasculitis and initiate appropriate therapy. In the following review, we detail the clinical presentation of VZV vasculitis, diagnostic challenges in VZV detection, and suggest the ways to enhance recognition and treatment of this uncommon disease.

Drs. de Boysson and Aouba reply.

To the Editor: We read with great interest the correspondence from Vitiello and Cammelli1, who described their experience on stroke occurring in patients newly diagnosed with giant cell arteritis (GCA). Their observation is concordant with our results, especially regarding the more frequent ophthalmic symptoms, lower biological inflammatory measures, and higher hemoglobin levels in patients with stroke2. Additionally, they observed more frequent large-vessel involvement in patients with stroke. Interestingly, they hypothesized the existence of a different pattern of the disease in these patients with more localized inflammation to the cephalic/supraaortic arterial tree and questioned the potential role of varicella zoster virus (VZV) as an etiological factor for GCA, given its known neurovascular tropism3,4. Three interesting points must … Address correspondence to Dr. H. de Boysson, Department of Internal Medicine, Caen University Hospital, University of Caen-Normandie, Avenue de la Cote de Nacre, 14000 Caen, France. E-mail: deboysson-h{at}chu-caen.fr

Varicella zoster virus and giant cell arteritis.

Giant cell arteritis (GCA) is a serious disease and the most common cause of vasculitis in the elderly. Here, studies describing the recent discovery of varicella zoster virus (VZV) in the temporal arteries of patients with GCA are reviewed. GCA is characterized by severe headache/head pain and scalp tenderness. Many patients also have a history of vision loss, jaw claudication, polymyalgia rheumatica, fever, night sweats, weight loss, and fatigue. The erythrocyte sedimentation rate and C-reactive protein are usually elevated. Diagnosis is confirmed by temporal artery biopsy, which reveals vessel wall damage and inflammation, with multinucleated giant cells and/or epithelioid macrophages. Skip lesions are common. Importantly, temporal artery biopsies are pathologically negative in many clinically suspect cases. The present review highlights recent virological findings in temporal arteries from patients with pathologically verified GCA and in temporal arteries from patients who manifest clinical and laboratory features of GCA but whose temporal artery biopsies are pathologically negative for GCA. Virological analysis revealed that VZV is present in most GCA-positive and GCA-negative temporal artery biopsies, particularly in skip areas that correlate with adjacent GCA disease. The presence of VZV in GCA-positive and GCA-negative temporal arteries reflects the possible role of VZV in triggering the immunopathology of GCA and indicates that both groups of patients should be treated with antivirals in addition to corticosteroids. Whether oral antiviral agents and steroids are as effective as intravenous acyclovir and steroids, and the dosage and duration of treatment, remain to be determined.

Neurologic complications of varicella-zoster virus infection still occur

Investigators from the Hospital for Sick Children in Toronto collected a series of 84 children 1-18 years of age with central nervous system (CNS) complications associated with varicella-zoster virus (VZV) infection between 1999 and 2012. Cases occurred after recommendation by Canada's National Advisory Committee on Immunization for use of VZV vaccine in children 1 year of age and older in 1999, and public funding for universal vaccination in 2004. Only four of 84 patients had a history of VZV immunization. The series serves as an excellent modern compendium of the variety of neurologic syndromes occurring around the time of VZV rash onset (median 5 days, range 6 days before onset to 42 days after onset, and occasionally in absence of rash): cerebellar ataxia, encephalitis, isolated seizures, meningitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and Ramsay Hunt syndrome. Additionally, an under-appreciated complication, stroke, occurred in 10 patients at a median 16 weeks (range 2-26 weeks) after rash onset; typical neuroimaging findings were focal ischemia or infarction, with angiographic evidence of characteristic vasculopathy (ie, narrowing or beading in cerebral arteries). Three important reminders from this study, which hopefully would be the last series possible in the era of widespread availability of VZV vaccine, are: (1) neurologic complications of VZV often are severe and continue to occur, not because of ineffective vaccine, but because of its suboptimal uptake; (2) vaccination of the majority of children has lessened circulation of VZV but has not eliminated exposure; and (3) the role of VZV should be considered for many neurologic conditions, especially in unimmunized individuals and even in the absence of a history of rash. Article page 779▶ Central Nervous System Complications of Varicella-Zoster VirusThe Journal of PediatricsVol. 165Issue 4PreviewTo describe the spectrum of central nervous system complications of varicella-zoster virus (VZV) in children admitted to The Hospital for Sick Children between January 1999 and December 2012. Full-Text PDF

Herpes Zoster and Multiple Sclerosis

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, has been considered multifactorial, and viruses may have a role in disease pathogenesis. Evidence suggests that certain viruses may trigger autoimmune neurological processes that lead to MS in genetically susceptible individuals [1, 2]. In this issue of the Journal, Kang et al analyze a database of 349,477 patients who had herpes zoster (experimental group) as a risk factor for MS (study outcome variable) in a region of the world historically considered low risk for MS. The authors compare their data with a randomly selected control group, more than 3 times as large as the initial sample (n 5 1,262,200), of participants who did not have herpes zoster. Their results show that the herpes zoster group had a 3.96 times greater risk of developing MS than did the control group (95% confidence interval [CI], 2.22–7.07, P % .001). This Kang et al study provides clear epidemiological observations suggesting a role for herpes zoster in the development of MS [3]. Previous studies noted that certain herpes viruses may trigger proinflammatory and autoimmune cascades through particles such as the toll-like receptor 4 (TLR-4) [3, 4], and that infectious environmental factors associated with MS may also belong to the herpesviridae family [4, 5]. This study highlights the time elapsed from the event of shingles until the occurrence of MS (approximately 100 d). In addition, evidence suggests that up to 30% of relapses among MS patients are associated with an infectious process [6, 7]. A possible explanation is the reactivation of latent herpes viruses by other infectious agents, and crossrecognition of common viral antigens with antigens found in the myelin sheath, which thereby induces molecular mimicry or superantigens [8–10]. The time lag for the occurrence of MS could be explained by a series of processes required by the immune systems of genetically susceptible individuals to reach a ‘‘threshold’’ and start the disease process. The threshold may also explain, in part, the observation that some patients have higher recurrence rates of MS around certain months of the year [11]. Some viruses of the herpesviridae family cause B cells to express alpha and beta crystal, a small stress protein that is normally absent from lymphoid tissues and has been considered an immunodominant antigen in the central nervous systems of MS patients [12]. Other studies have suggested a role of varicella zoster virus in the genesis of relapse and progression of some patients with chronic-progressive forms of MS [13, 14]. The evidence provided in this study by Kang et al allows us to better understand the role of these viral factors as an MS risk among certain genetically susceptible individuals. These epidemiological findings should be corroborated in other parts of the world to further clarify the role of varicella zoster virus and other herpes viruses in the pathogenesis of multiple sclerosis.

Púrpura de Schonlein-Henoch asociado a varicela: Caso clínico

In order to discuss the role of varicella zoster virus (VZV) infection as a potential trigger of Henloch-Schonlein Purpura (HSP) we present the case of a 4 year old boy with HSP and varicella. The clinical course was complicated by severe abdominal pain, requiring systemic steroids. On the 5th day of evolution, a vesicular exanthem appeared (VZV confirmed by direct immunoflouescence). Intravenous acyclovir was used empirically considering the risk of using high dose steroids in the presence of VZV. Both pathologies resolved uneventfully.

Multiple sclerosis and varicella zoster virus infection: a review.

We have evaluated the epidemiological evidence for an aetiological role of varicella zoster virus (VZV) infection in the development of multiple sclerosis (MS). A MEDLINE search of the English language literature for 1965-99 identified 40 studies. These studies were categorized as seroepidemiological (13), case-control (23), historical cohort (2) or ecological (2). One study used both case-control and historical cohort methodologies. Studies were then classified according to methodological rigour, using criteria derived from published guidelines for the epidemiological study of MS. There was a large variability in the quality of evidence. The five studies with the best methodology failed to show an increased risk of MS associated with varicella or zoster infections. At the present time there is insufficient evidence to support an important aetiological role of VZV infection in the development of MS.

Acute varicella-zoster virus ventriculitis and meningo-myelo-radiculitis in acquired immunodeficiency syndrome.

A 30-year-old AIDS patient with no history of cutaneous eruption, presented with rapidly progressive flaccid paraplegia, hypoesthesia, urinary retention, moderate psychomotor slowing and fever (39.8 degrees C), leading to death within 1 week. CD4 count was 290/mm3. Cerebrospinal fluid contained 210 white blood cells and 238 mg/100 ml protein. Neuropathology revealed HIV encephalitis and diffuse ventriculitis with Cowdry type A inclusions in the ependymal cells. Extensive necrotic and hemorrhagic changes with marked recrotizing vasculitis involved the entire spinal cord and spinal roots. Immunocytochemistry revealed numerous inclusion bodies positive for varicella-zoster virus (VZV) and negative for cytomegalovirus (CMV) and herpes simplex virus type 1 and 2, in ependymal cells, subpial glial cells, endothelial cells and Schwann cells. Electron microscopy confirmed herpes virus-like particles. In situ hybridization confirmed VZV genome in leptomeninges, brain, spinal cord and spinal roots. Comparable neuropathological findings and numerous VZV inclusion bodies were also found in the brain, spinal cord, and spinal roots of a 40-year-old AIDS patient who died from a fulminant ascending myeloradiculopathy previously reported as "necrotizing vasculitis of the nervous system". Direct infection of the brain by VZV, in AIDS patients, has been shown to cause leukoencephalitis and cerebral non-inflammatory vasculopathies. Our observations demonstrate that, in AIDS patients, VZV infection of the central nervous system may also be responsible for meningo-myelo-radiculitis possibly secondary to ventriculitis as in CMV infection. The role of VZV in the pathogenesis of some AIDS-related vasculitides seems also very likely.

Activation of cytomegalovirus infection in immunosuppressed cynomolgus monkeys inoculated with varicella-zoster virus.

A systemic activated cytomegalovirus (CMV) infection was fortuitously detected in almost all monkeys which had been immunosuppressed with antithymocyte globulin (ATG), cyclophosphamide (CY), and cortisone acetate (CS) before and after experimental inoculation with varicella-zoster virus (VZV). They developed exudative pneumonia, and the lesions in visceral organs and tissues contained cytomegalic cells with intranuclear inclusion bodies, in which viral antigens, specific for CMV, but not inoculated VZV, were detected by immunofluorescence. Serological study of paired sera from these monkeys ascertained preexisting CMV infection. Under the present experimental conditions, this infection was highly reproducible and always occurred within three, but not two, weeks of immunosuppression in monkeys inoculated with VZV. We therefore examined the host factors involved in activation of latent CMV. The immunocompetence of the host was destroyed almost completely with treatment of ATG, CY, and CS, but not with combinations of two of these agents, revealing the systemic depletion of lymphoid cells in tissues including the thymus medulla. Although the role of VZV in the induction of CMV remains uncertain, the heterologous VZV inoculum may have produced some effects equivalent to the allogeneic reaction to release latent CMV. These monkeys may represent an animal model of "opportunistic" CMV infection in immunocompromised and/or allografted humans.