Varicella zoster virus (VZV) reactivation results in zoster, which may be complicated by postherpetic neuralgia, myelitis, meningoencephalitis, and VZV vasculopathy. This review highlights the ...clinical features, laboratory abnormalities, imaging changes, and optimal treatment of each of those conditions. Because all of these neurological disorders produced by VZV reactivation can occur in the absence of rash, the virological tests proving that VZV caused disease are discussed.
After primary infection, VZV becomes latent in ganglionic neurons along the entire neuraxis. With a decline in VZV-specific cell-mediated immunity, VZV reactivates from ganglia and travels anterograde to the skin to cause zoster, which is often complicated by postherpetic neuralgia. VZV can also travel retrograde to produce meningoencephalitis, myelitis, and stroke. When these complications occur without rash, VZV-induced disease can be diagnosed by detection of VZV DNA or anti-VZV antibody in cerebrospinal fluid and treated with intravenous acyclovir.
Awareness of the expanding spectrum of neurological complications caused by VZV reactivation with and without rash will improve diagnosis and treatment.
Background Varicella zoster virus (VZV) is a neurotropic, exclusively human herpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons ...along the entire neuraxis. As cell-mediated immunity to VZV declines with advancing age and immunosuppression, VZV reactivates to produce zoster (shingles). One of the most serious complications of zoster is VZV vasculopathy. Methods We reviewed recent studies of stroke associated with varicella and zoster, how VZV vasculopathy is verified virologically, vaccination to prevent varicella and immunization to prevent zoster, and VZV in giant cell arteritis (GCA). Findings We report recent epidemiological studies revealing an increased risk of stroke after zoster; the clinical, laboratory, and imaging features of VZV vasculopathy; that VZV vasculopathy is confirmed by the presence of either VZV DNA or anti-VZV IgG antibody in cerebrospinal fluid; special features of VZV vasculopathy in children; vaccination to prevent varicella and immunization to prevent zoster; and the latest evidence linking VZV to GCA. Conclusion In children and adults, VZV is a common cause of stroke.
Summary 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). 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. VZV vasculopathy in immunocompetent or immunocompromised individuals can be unifocal or multifocal with deep-seated and superficial infarctions. Lesions at the grey–white matter junction on brain imaging are a clue to diagnosis. Involvement of both large and small arteries is more common than that of either alone. Most patients have a mononuclear cerebrospinal fluid pleocytosis, often with red blood cells. Cerebrospinal fluid pleocytosis and rash are absent in about a third of cases. Anti-VZV IgG antibody in the cerebrospinal fluid is found more frequently than VZV DNA. In recent years, the number of recognised VZV vasculopathies has grown, and accurate diagnosis is important for the effective treatment of these disorders.
Objective
The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO‐IgGs) directed against the aquaporin‐4 (AQP4) water channel located on astrocyte foot processes in the ...perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO‐IgGs and their role in disease pathogenesis.
Methods
Fluorescence‐activated cell sorting and single‐cell reverse transcriptase polymerase chain reaction were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE).
Results
Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen‐targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4‐specific rAbs recognized conformational epitopes and mediated both AQP4‐directed antibody‐dependent cellular cytotoxicity and complement‐mediated lysis. When administered to rats with EAE, an AQP4‐specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis, and complement and Ig deposition.
Interpretation
Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4‐specfic Ig is synthesized intrathecally at disease onset and directly contributes to CNS pathology. AQP4 is now the first confirmed antigenic target in human demyelinating disease. Ann Neurol 2009;66:617–629
Abstract Contrast-enhanced vessel wall imaging high-resolution MRI (HRMR) has revealed vessel wall thickening and enhancement in multiple intracranial vasculopathies, including varicella zoster virus ...(VZV) vasculopathy. We retrospectively reviewed a database of patients with virologically-verified VZV vasculopathy, who underwent initial and follow-up HRMR between April 2011 and May 2014. Six patients were identified. Baseline demographic and clinical characteristics were collected, including stroke risk factors, history of VZV-related disorders, neurological presentation, course and antiviral treatment. Initial HRMR in patients with VZV vasculopathy demonstrated various patterns of stenosis, vessel wall thickening and enhancement, predominantly in terminal internal carotid artery segments and the M1 segment of the middle cerebral arteries. Follow-up HRMR showed improvement of stenosis, with reduced vessel wall thickening and enhancement at multiple times after treatment. HRMR has the potential to assist in diagnosis and treatment of VZV vasculopathy.
To assess the risk of stroke and myocardial infarction (MI) after herpes zoster in a US community population of older adults.
We performed a community cohort study (January 1, 1986, to October 1, ...2011) comparing the risk of stroke and MI in 4862 adult residents of Olmsted County, Minnesota, 50 years and older with and without herpes zoster and 19,433 sex- and age-matched individuals with no history of herpes zoster. Odds ratios are presented for MI and stroke at 3, 6, 12, and 36 months after index herpes zoster plus hazard ratios for long-term risk (up to 28.6 years).
Individuals with herpes zoster had more risk or confounding factors for MI and stroke, suggesting that they had worse health status overall. When controlling for the multiple risk factors, those with herpes zoster were at increased risk for stroke at 3 months after herpes zoster compared with those without a history of herpes zoster (odds ratio, 1.53; 95% CI, 1.10-2.33; P=.04). The association between herpes zoster and MI at 3 months was not robust across analytic methods. Herpes zoster was not associated with an increased risk of stroke or MI at any point beyond 3 months.
Herpes zoster was associated with only a short-term increased risk of stroke, which may be preventable with the prevention of herpes zoster.
Varicella zoster virus (VZV) infects >95 % of the world population. Typically, varicella (chickenpox) results from primary infection. The virus then becomes latent in ganglionic neurons along the ...entire neuraxis. In immunocompromised individuals, VZV reactivates and causes herpes zoster (shingles), pain, and rash in 1–2 dermatomes. Multiple case reports showed a link between stroke and zoster, and recent studies have emerged which reveal that VZV infection of the cerebral arteries directly causes pathological vascular remodeling and stroke (VZV vasculopathy). In the past few years, several large epidemiological studies in Taiwan, Denmark, and the U.K. demonstrated that zoster is a risk factor for stroke and that antiviral therapy may reduce this risk. Herein, the history, clinical features, and putative mechanisms of VZV vasculopathy, as well as recent epidemiological studies demonstrating that zoster increases the risk of stroke, are discussed.
IMPORTANCE: Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often ...negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV). OBJECTIVE: To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years. MAIN OUTCOMES AND MEASURES: Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers. RESULTS: Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk RR = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs. CONCLUSIONS AND RELEVANCE: In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.
Varicella-zoster virus (VZV) infection causes varicella, after which the virus becomes latent in ganglionic neurons. In tissue culture, VZV-infected human neurons remain viable at 2 weeks, whereas ...fibroblasts develop cytopathology. Next-generation RNA sequencing was used to compare VZV transcriptomes in neurons and fibroblasts and identified only 12 differentially transcribed genes of the 70 annotated VZV open reading frames (ORFs), suggesting that defective virus transcription does not account for the lack of cell death in VZV-infected neurons in vitro.
Opinion statement
Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which virus becomes latent in ganglionic ...neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines and virus reactivates to cause zoster (shingles), which can occur anywhere on the body. Skin lesions resolve within 1–2 weeks, while complete cessation of pain usually takes 4–6 weeks. Zoster can be followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, meningoencephalitis, cerebellitis, myelopathy, multiple ocular disorders and vasculopathy that can mimic giant cell arteritis. All of the neurological and ocular disorders listed above may also develop without rash. Diagnosis of VZV-induced neurological disease may require examination of cerebrospinal fluid (CSF), serum and/ or ocular fluids. In the absence of rash in a patient with neurological disease potentially due to VZV, CSF should be examined for VZV DNA by PCR and for anti-VZV IgG and IgM. Detection of VZV IgG antibody in CSF is superior to detection of VZV DNA in CSF to diagnose vasculopathy, recurrent myelopathy, and brainstem encephalitis. Oral antiviral drugs speed healing of rash and shorten acute pain. Immunocompromised patients require intravenous acyclovir. First-line treatments for post-herpetic neuralgia include tricyclic antidepressants, gabapentin, pregabalin, and topical lidocaine patches. VZV vasculopathy, meningoencephalitis, and myelitis are all treated with intravenous acyclovir.
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