Less commonly, VZV vasculopathy can present as aneurysms with subarachnoid hemorrhage and sinus thrombosis [10, 11]. Among adults, the ophthalmic division of the trigeminal nerve is one of the most common sites of involvement. Neurol Clin Pract. Varicella zoster virus (VZV)-induced vasculopathy is an uncommon cause of stroke in a young immunocompetent host. For permissions, e-mail: journals.permissions@oup.com. Furthermore, if during a prednisone taper, patients’ symptoms recur or worsen, along with increases in ESR or CRP, oral antivirals should be added rather than increasing the prednisone dose. In virologically verified cases that contain VZV antigen and/or VZV DNA in TA biopsies and/or have a recent history of zoster, antiviral therapy should be considered because 50% of GCA in general progress or relapse during corticosteroid therapy or taper, and oral antiviral therapy (acyclovir, valacyclovir, famciclovir) is low risk with the exception of nephrotoxicity; hence the risks and benefits of antiviral treatment in GCA patients with renal dysfunction need to be considered. In elderly and immunocompromised individuals, VZV reactivates and typically produces herpes zoster. Most patients with VZV vasculopathy have findings on brain imaging. 2015 Sep;350(3):243-5. doi: 10.1097/MAJ.0000000000000327. 33 Gilden D. The ever-widening spectrum of varicella zoster virus vasculopathy. A cumulative study [20] detected VZV antigen in 73/104 (70%) GCA-positive TAs and in 58/100 (58%) GCA-negative TAs; the presence of VZV antigen in these 2 groups was statistically significant (P < .0001) compared to 11/61 (18%) normal TAs that contained VZV antigen. VZV vasculopathy occurs in immunocompetent and immunocompromised individuals and involves both large and small vessels. Varicella-Zoster Virus Vasculopathy: The Growing Association Between Herpes Zoster and Strokes. Sehl J, Hölper JE, Klupp BG, Baumbach C, Teifke JP, Mettenleiter TC. This study investigated characteristics of clinical and laboratory features in patients with VZV infection. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Studies show that VZV induces amyloid formation that may aggravate vasculitis. Case Rep Transplant. Richter ER, Dias JK, Gilbert JE2nd, Atherton SS. The patient presented with GCA and Takayasu arteritis; VZV antigen was found in her TA biopsy. Varicella zoster virus (VZV) vasculopathy is caused by productive virus infection of cerebral arteries, leading to inflammation, pathological vascular remodeling, and ischemic or hemorrhagic stroke. Al-Abdulla NA, Kelley JS, Green WR, Miller NR. It is important to recognize that the absence of rash, a CSF pleocytosis, or VZV DNA in CSF does not exclude the diagnosis, particularly in immunosuppressed individuals. We describe an extraordinarily protracted case of varicella zoster virus (VZV) multifocal vasculopathy in a man who presented initially with ischemic optic neuropathy and then suffered 4 episodes of stroke manifesting as multi-infarct dementia over a 2-year period. It acts to suppress the immune system through interaction with its receptor, programmed cell death protein 1 (PD-1), which is expressed specifically on activated T cells, B cells, and macrophages. Following virus deposition, persistent inflammation may occur, resulting in pathological vascular remodeling and stroke. VZV infection of various vascular cells in vitro lead to downregulation of PD-L1 expression, which only occurred after the VZV-mediated downregulation of major histocompatibility complex-I (MHC-I). 2019 May;94(5):742-744. doi: 10.1016/j.mayocp.2019.03.020. Subsequently, affected cerebral arteries from patients with VZV vasculopathy were examined postmortem and found to have VZV DNA, VZV antigen, and herpesvirus particles [3], thus demonstrating that VZV vasculopathy was due to productive virus infection of arteries. VZV vasculopathy is a potentially treatable cause of vascular disease and should be suspected in patients with zoster or varicella followed by transient ischemic attacks, ischemic and hemorrhagic stroke, aneurysm, sinus thrombosis, and GCA. Chickenpox follows initial exposure to the virus and is typically a relatively mild, self-limited childhood illness with a characteristic exanthem. Tocilizumab, combined with a 26-week prednisone taper, was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with GCA [24]. Cutaneous Vasculitis and Central Nervous System Infarctions due to Varicella Zoster Virus Vasculopathy in an Immunocompromised Patient. Due to the nature of VZV being present in skip areas, it is imperative that immunohistochemical studies be conducted in numerous sections at varying sites per TA biopsy and that comparisons between studies investigating VZV prevalence be methodologically similar with respect to number/location of sections and immunohistochemical protocols. Because vision loss frequently occurs, patients are immediately treated with corticosteroids, with 50% relapsing after discontinuation of therapy or progressing to stroke and vision loss despite therapy. These discrepancies can be explained largely through methodological differences—specifically, the lower number of TA slides examined. [ Links ] 34 Nagel MA, Gilden D. The challenging patient with varicella-zoster virus disease. Clipboard, Search History, and several other advanced features are temporarily unavailable. Potential conflicts of interest. Herpes Zoster, a Rash of Cerebrovascular Events. Jones D, Neff CP, Palmer BE, Stenmark K, Nagel MA. Of 23 patients analyzed by angiography, 70% had abnormalities predominantly in both large and small arteries (50%), small arteries exclusively (37%), and large arteries exclusively (13%). Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis. Both authors: No reported conflicts of interest. Thus, in these challenging cases, VZV vasculopathy should be on the differential diagnosis because antiviral treatment can potentially improve outcomes. COVID-19 is an emerging, rapidly evolving situation. A recent study to identify mechanisms contributing to the persistence of inflammatory cells in VZV-infected arteries months after disease onset focused on the dysregulated expression of programmed death ligand-1 (PD-L1) during VZV infection of primary vascular cells in vitro [44].  |  Nagel MA, Choe A, Rempel A, Wyborny A, Stenmark K, Gilden D. Ferry G, Lonchampt M, Pennel L, de Nanteuil G, Canet E, Tucker GC. The presence of neutrophils in the arterial adventitia in early VZV vasculopathy is consistent with their presence in the CSF of patients with neurological disease due to VZV [31–33]. Primary infection produces varicella, followed by establishment of virus latency in cranial nerve, dorsal root, and autonomic ganglionic neurons [1]. Varicella Zoster Virus: A Common Cause of Stroke in Children and Adults. The cause of GCA was not clear but activation of vascular dendritic cells in the artery wall by an unknown antigen in the adventitia was proposed as an early step in disease progression [13]. Vasculopathy caused by HZ is associated with significant morbidity and mortality, affecting structures such as the brain, which can lead to stroke. Furthermore, TA biopsies of patients with herpes zoster ophthalmicus with delayed arteritis also revealed GCA pathology [17]. Historically, VZV vasculopathy was characterized as involving intracranial arteries and presented as transient ischemic attacks and ischemic or hemorrhagic strokes. Disseminated zoster. A single case report raised the possibility of VZV infection in Takayasu arteritis [28]. VZV vasculopathy has also been associated with cerebral amyloid angiopathy and moyamoya syndrome. Authors Maria A Nagel 1 , Don Gilden. Recently, the live attenuated varicella vaccine strain was shown to cause VZV vasculopathy in an immunodeficient child [9], confirming the need for caution in vaccinating potentially immunocompromised children. Objective: Varicella zoster virus (VZV) is an under-recognized yet treatable cause of stroke. Varicella zoster virus (VZV) is a highly neurotropic human herpesvirus. Similarly, Procop and colleagues failed to find VZV DNA in 5 snap-frozen GCA-positive TA biopsies [22], which is most likely due to the low abundance of viral antigen in skip lesions. Given our increasing aging population and recognition that VZV reactivation manifesting as zoster is a risk factor for stroke and myocardial infarction, recognition of VZV as a potential cause of vascular disease with or without associated zoster rash is essential to decrease associated morbidity and mortality because VZV vasculopathy can be treated with antiviral therapy. Flores Rosario K, Michelis KC, Bjorkman C, Araj FG. Please enable it to take advantage of the complete set of features! J Stroke Cerebrovasc Dis. Because granulomatous arteritis of the aorta has similar pathology to VZV vasculopathy and GCA, a smaller study similar to the GCA study by Gilden and colleagues [19] was conducted, which showed VZV antigen in 11 of 11 aortas with pathologically verified granulomatous arteritis, in 1 of 1 cases of nongranulomatous arteritis, and in 5 of 18 control aortas (28%) obtained at autopsy, again most likely due to subclinical reactivation or early disease [27]. VZV vasculopathy was first described in 1896 [2] and included cases of varicella or zoster that were temporally associated with stroke, particularly when zoster occurred in the ophthalmic division of the trigeminal nerve. eCollection 2019 Nov. Mayo Clin Proc. Pathological and virological analysis of affected arteries from cases of clinically unifocal vasculopathy after zoster or varicella reveal multinucleated giant cells, Cowdry type A inclusion bodies, and herpesvirus particles as well as VZV DNA antigen in affected vessels 3,6. VZV vasculopathy is a potentially treatable cause of vascular disease and should be suspected in patients with zoster or varicella followed by transient ischemic attacks, ischemic and hemorrhagic stroke, aneurysm, sinus thrombosis and giant … Thus, it is not surprising that Muratore and colleagues [21] did not detect VZV antigen in GCA-positive TAs when they stained 1 slide compared to 50 slides/TA of 34 GCA-positive TA biopsies and then an additional 30 slides/TA in a subset of these GCA-positive TA biopsies (n = 10); this group immunostained a total of 334 slides compared to 5200 in the Gilden study. Y1 - 1988/1/1. The protean clinical manifestations of varicella zoster virus (VZV) vasculopathy are being fully recognized as a treatable cause of stroke. Finally, a thickened intima was associated with inflammation in vasa vasorum vessels in early VZV vasculopathy, consistent with the notion that inflammatory cells secrete soluble factors that contribute to pathological vascular wall remodeling [42, 43]. Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus that produces varicella then becomes latent in ganglionic neurons. Nagel MA, Khmeleva N, Boyer PJ, Choe A, Bert R, Gilden D. Gilden D, White T, Khmeleva N, Boyer PJ, Nagel MA. The authors thank Marina Hoffman for editorial review and Cathy Allen for manuscript preparation. PD-L1 is a 40-kDa type 1 transmembrane protein in the B7 immunoglobulin family that can be expressed on virtually all nucleated cells. In children, postvaricella stroke is usually monophasic, typically presenting as an acute hemiparesis at, on average, 4 months after varicella [8]. Published by Oxford University Press for the Infectious Diseases Society of America. Recent studies failed to detect VZV in GCA-positive TAs at the frequency of the aforementioned studies. 2017 Jul 15;308:112-117. doi: 10.1016/j.jneuroim.2017.03.014. Learn about the other conditions caused by herpes zoster, also called varicella zoster, that can be more dangerous than chicken pox or shingles. Long-term antiviral drugs are far less risky than long-term corticosteroids. Varicella zoster virus (VZV) is a ubiquitous, exclusively human alphaherpesvirus that produces varicella then becomes latent in ganglionic neurons. Oxford University Press is a department of the University of Oxford.  |  Soluble factors secreted by inflammatory cells further contribute to vascular smooth muscle death and accumulation of myofibroblasts in the thickened intima, potentially leading to occlusion of blood flow and ischemic stroke. A more extensive study reported VZV antigen in 12% of GCA-positive TA biopsies rather than 70%; the researchers stained between 10 and 40 sections/TA at varying sites in 25 patients (250–1000 total slides) [23]; VZV DNA was not measured in this study. VZV vasculopathy can cause ischaemic infarction of the brain and spinal cord, as well as aneurysm, subarachnoid and cerebral haemorrhage, carotid dissection, and, rarely, peripheral arterial disease. Future studies on patient arteries infected with VZV are needed to confirm these in vitro findings. Finally, two-thirds of the VZV vasculopathy patients stabilized or improved with antiviral therapy. All rights reserved. [ Links ] 35 Nagel MA, Gilden D. Update on varicella zoster virus vasculopathy. Herpes zoster (HZ) corresponds to the reactivation of varicella zoster virus (VZV). AU - Price, R. W. AU - Petito, C. K. PY - 1988/1/1. © The Author(s) 2018. Li J, Li W, Su J, Liu W, Altura BT, Altura BM. In virologically verified intracerebral VZV vasculopathy and GCA, VZV-infected vascular cells produce significantly elevated levels of IL-6, as well as other proinflammatory cytokines [25, 26]; so while IL-6 activity can be blocked and inflammation-mediated damage mollified by tocilizumab and corticosteroids, treatment of underlying VZV infection is essential, particularly because corticosteroids alone can potentiate VZV replication. Acyclovir treatment led to dramatic clinical improvement with the patient able to leave hospice care. eCollection 2020. While there have been single-case reports of GCA patients whose TAs contain VZV responding favorably to antiviral therapy, larger prospective studies still need to be undertaken to determine the effectiveness of antiviral therapy with or without corticosteroids in cases of GCA associated with VZV infection; however, it is established that intracerebral cases of VZV vasculopathy improve or stabilize with antiviral therapy [7]. Clinical, imaging, and CSF features of VZV vasculopathy, its development in the absence of rash, and the value of anti-VZV antibody in … Due to the protracted nature of disease, VZV DNA was detected in only 30% of CSF samples whereas anti-VZV IgG antibody was found in 93% of CSF samples, including a reduced serum/CSF ratio of anti-VZV IgG that confirmed intrathecal synthesis of anti-VZV IgG. VZV reactivates to produce zoster, as well as VZV vasculopathy. Open Forum Infect Dis. Thus, we determined if VZV central nervous system infection produces amyloid. AU - Morgello, S. AU - Block, G. A. Varicella-zoster virus (VZV) was once thought to be a fairly innocuous pathogen. Al-Abdulla NA, Rismondo V, Minkowski JS, Miller NR. In the future, rigorous prospective studies are still needed to determine whether oral antiviral agents and corticosteroids are as effective as intravenous acyclovir and corticosteroids, as well as appropriate dosage and duration of treatment. VZV vasculopathy should be suspected in individuals, particularly if immunocompromised, who have had a stroke or aneurysm with: (1) a recent history of varicella or zoster, (2) recurrence of unclear cause with or without rash, or (3) unclear etiology and absence of stroke risk factors. Varicella–Zoster Virus Vasculopathy and Infarction in Patient 1. Rarely, aseptic meningitis, myelitis, peripheral motor neuropathy, cerebellar syndromes, and stroke syndromes due to involvement of cerebral arteries (varicella zoster virus vasculopathy) can occur. Most individuals with herpes zoster will … Vasculopathies caused by varicella zoster virus (VZV) are indicative of a productive virus infection in cerebral arteries after either reactivation of VZV (shingles) or primary infection (chickenpox). NLM 2020 Aug 12;11:1862. doi: 10.3389/fmicb.2020.01862. 2014 Jun;27(3):356-60. doi: 10.1097/WCO.0000000000000092. Nagel MA, Traktinskiy I, Azarkh Y, et al. As positive controls for CNS inflammatory disease, CSF from 30 patients with multiple sclerosis (MS) was studied, along with CSF from 20 healthy individuals to serve as negative controls. The burden of disease is significant given that 50% of individuals reactivate and develop zoster by 85 years of age. Search for other works by this author on: Distribution of herpes simplex virus type 1 and varicella zoster virus in ganglia of the human head and neck, Varicella zoster virus, a cause of waxing and waning vasculitis: the New England Journal of Medicine case 5-1995 revisited, Herpes zoster and the risk of ischemic and hemorrhagic stroke: a systematic review and meta-analysis, Risk of stroke following herpes zoster: a self-controlled case-series study, Acute cardiovascular events after herpes zoster: a self-controlled case series analysis in vaccinated and unvaccinated older residents of the United States, The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features, Stroke after varicella-zoster infection: report of a case and review of the literature, Vaccine strain varicella-zoster virus-induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency, Rapid development of 9 cerebral aneurysms in varicella-zoster virus vasculopathy, Cerebral venous sinus thrombosis: association with primary varicella zoster virus infection, AST Infectious Diseases Community of Practice, Herpes simplex virus in solid organ transplantation, Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis, Herpes zoster vasculitis presenting as giant cell arteritis with bilateral internuclear ophthalmoplegia, Herpes zoster vasculitis presenting as giant cell arteritis with choroidal infarction, Varicella zoster virus in the temporal artery of a patient with giant cell arteritis, Temporal artery biopsy in herpes zoster ophthalmicus with delayed arteritis, Multifocal VZV vasculopathy with temporal artery infection mimics giant cell arteritis, Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis, VZV in biopsy-positive and -negative giant cell arteritis: analysis of 100+ temporal arteries, No detection of varicella-zoster virus in temporal arteries of patients with giant cell arteritis, Varicella zoster virus and large vessel vasculitis, the absence of an association, Identification of herpes zoster-associated temporal arteritis among cases of giant cell arteritis, Trial of tocilizumab in giant-cell arteritis, Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy, Varicella zoster virus-infected cerebrovascular cells produce a proinflammatory environment, Varicella zoster virus infection in granulomatous arteritis of the aorta, Successful antiviral treatment of giant cell arteritis and Takayasu arteritis, Varicella zoster virus vasculopathy: analysis of virus-infected arteries, Varicella-zoster virus vasculopathy: immune characteristics of virus-infected arteries, Recurrent polymorphonuclear pleocytosis with increased red blood cells caused by varicella zoster virus infection of the central nervous system: case report and review of the literature, Cellular events in zoster vesicles: relation to clinical course and immune parameters, Xanthine oxidase-derived ROS upregulate Egr-a via ERK1/2 in PA smooth muscle cells; model to test impact of extracellular ROS in chronic hypoxia, Phosphoinositide-dependent kinase 1 and p21-activated protein kinase mediate reactive oxygen species-dependent regulation of platelet-derived growth factor-induced smooth muscle cell migration, Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells, Hydrogen peroxide induces apoptosis in cerebral vascular smooth muscle cells: possible relation to neurodegenerative diseases and strokes, Differential regulation of matrix metalloproteinases in varicella zoster virus-infected human brain vascular adventitial fibroblasts, Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injury, Preferential inactivation of tissue inhibitor of metalloproteinases-1 that is bound to the precursor of matrix metalloproteinase 9 (progelatinase B) by human neutrophil elastase, Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G, Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, Targeting the adventitial microenvironment in pulmonary hypertension: a potential approach to therapy that considers epigenetic change, Varicella-zoster virus downregulates programmed death ligand 1 and major histocompatibility complex class I in human brain vascular adventitial fibroblasts, perineurial cells, and lung fibroblasts. Recently, several studies emerged indicating that VZV vasculopathy can also affect the extracranial circulation, including temporal arteries (TAs) from patients with giant cell arteritis (GCA).

varicella zoster vasculopathy

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