The protean manifestations of varicella-zoster virus vasculopathy

Varicella-zoster virus (VZV) vasculopathy in the central nervous system (CNS) affects large and small cerebral vessels. Large-vessel disease is most common in immunocompetent individuals, whereas small-vessel disease usually develops in immunocompromised patients. In some patients, both large and small vessels are involved. Neurological features are protean. Neurological disease often occurs months after zoster and sometimes without any history of zoster rash. Magnetic resonance imaging (MRI) scanning, cerebral angiography, and examination of cerebrospinal fluid (CSF) with virological analysis are needed to confirm the diagnosis. VZV vasculopathy patients do not always have VZV DNA in CSF, but diagnosis can be confirmed by finding anti-VZV antibody in CSF, along with reduced serum/CSF ratios of VZV immunoglobulin G (IgG) compared to albumin or total IgG. When VZV vasculopathy develops months after zoster, antiviral treatment is often effective.     

Varicella zoster virus vasculopathy: clinical features and pathogenesis

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. VZV vasculopathy occurs in immunocompetent and immunocompromised individuals and involves both large and small vessels. MRI abnormalities include more deep-seated than superficial lesions, particularly at gray–white matter junctions, and lesions may enhance. Diagnosis is challenging, since stroke can occur months after zoster rash and in the absence of rash or CSF pleocytosis. The best virological test for diagnosis is detection of anti-VZV IgG antibody in the CSF. Pathological studies of VZV-infected arteries from patients with VZV vasculopathy reveal that the arterial adventitia is the initial site of infection, after which virus spreads transmuraly towards the lumen. Histological and immunohistochemical studies of VZV-infected arteries show a thickened intima, disrupted internal elastic lamina, and loss of smooth muscle cells, that likely contribute to weakening of the vessel wall and occlusion. Early in disease, VZV-infected arteries contain CD4+ and CD8+ T cells, macrophages, and rare B cells, in addition to abundant neutrophils in early disease. Importantly, perivascular inflammatory cells underlie the areas of thickened intima, raising the possibility that soluble factors secreted by these cells contribute to arterial remodeling. This review discusses the clinical features of VZV vasculopathy and potential mechanisms of VZV-induced cerebrovascular remodeling and stroke.     

VZV vasculopathy and postherpetic neuralgia: progress and perspective on antiviral therapy

Two serious complications of varicella-zoster virus (VZV) reactivation are vasculopathy and postherpetic neuralgia (PHN). Clinical-virologic analyses have proven that VZV vasculopathy is caused by chronic active virus infection in cerebral arteries. Conclusive evidence that PHN is caused by persistent or productive VZV infection is less compelling because human ganglia are not accessible during life for pathologic and virologic examination. However, the notion that PHN may reflect a smoldering VZV ganglionitis is supported by 1) the detection of VZV DNA and proteins in peripheral blood mononuclear cells of many patients with PHN; 2) studies of multiple patients with zoster sine herpete, which indicate a productive VZV ganglionitis; and 3) a favorable response of some patients with zoster sine herpete and PHN to antiviral treatment. Few studies have used antiviral therapy to manage PHN with conflicting results. Larger, double-blind studies, which give IV antiviral drug, are needed.     

Search for varicella zoster virus and herpes simplex virus-1 in normal human cerebral arteries

Virological confirmation of varicella zoster virus (VZV) vasculopathy is provided by presence of virus in the cerebral arteries, frequently associated with inflammation. Yet, cerebral arteries from normal subjects have never been studied for VZV DNA or antigen. We analyzed 63 human cerebral arteries from 45 subjects for VZV DNA and antigen, control herpes simplex virus (HSV)-1 DNA and antigen, and leukocyte-specific CD45 antigen. No cerebral arteries contained VZV or HSV-1 DNA or antigen; eight arteries from seven subjects contained leukocytes expressing CD45. Thus, the presence of VZV antigen in cerebral arteries of patients with stroke is likely to be clinically significant.     

Neurologic manifestations of varicella zoster virus infections

Varicella zoster virus (VZV) causes acute viral exanthema in childhood, becomes latent, and can reactivate years later to produce neurologic disease. Primary VZV infection is associated with acute cerebellitis and stroke, particularly in childhood. VZV reactivation may result in neuropathy, myelitis, stroke, and encephalitis, the latter two syndromes the result of small and large vessel vasculopathy. Prompt diagnosis and treatment are critical to minimize morbidity in herpes zoster as well as morbidity and death in VZV vasculitis and encephalitis. Detection of anti-VZV antibodies in cerebrospinal fluid is the most sensitive method of diagnosing varicella infection of the nervous system. Despite the advent of the VZV vaccine, varicella remains a significant cause of neurologic morbidity.     

Varicella-zoster virus at relapses of multiple sclerosis

Abstract The possible participation of different herpes viruses was studied during exacerbations of multiple sclerosis (MS). We searched for the presence of DNA from the following herpes viruses: varicella zoster virus (VZV), herpes-simplex viruses 1 and 2; Epstein-Barr virus (EBV) and human herpes-virus-6 (HHV6) in mononuclear cells from patients with MS during relapse (n = 40), MS during remission (n = 131) and controls (n = 125). Additionally, immune cells containing viral antigens were quantified by flow cytometry, and VZV load was determined by real time PCR in 2 MS patients at various times during relapse and remission. DNA from VZV was found in 95% of MS patients during relapse and in 17% during remission; all controls were negative; by contrast, DNA from HHV6 was found in 24% of MS patients during relapse and in 2% during remission; DNA from herpes simplex viruses was not found in any subject; and DNA from EBV was found in a similar percentage of subjects from all groups. Sequential quantification of VZV-load showed a curve that increased during relapse and disappeared at remission. Also, VZV antigens were found inside a large number of immune cells from MS patients during relapse as compared with MS patients on remission and controls. In the typical forms of VZV infection, varicella and herpes-zoster, DNA from VZV is found in mononuclear cells exclusively during brief periods at the beginning of the active infection, but not during latency; thus, the conspicuous presence of VZV during relapses of MS may indicate a period of active infection and suggests the participation of VZV in the pathogenesis of MS.     

Neurovirulence of varicella and the live attenuated varicella vaccine virus

Varicella-zoster virus (VZV) is a neurotropic herpesvirus, which can cause a variety of complications during varicella infections. These range from meningoencephalitis to polyneuritis to retinitis. After primary VZV infection, VZV enters the dorsal root ganglia in a latent state. Reactivation from latency leads to zoster. The velocity of VZV is 13 cm per day, as the virus travels from ganglion to skin. The live attenuated varicella vaccine virus is markedly less neurovirulent than the wild-type virus. Nevertheless, a few cases of herpes zoster due to the vaccine virus have been documented. Usually, herpes zoster occurs in the same arm as the vaccination, often 3 or more years after vaccination. Thus, herpes zoster in a vaccinee often represents a reactivation of vaccine virus that was carried to the cervical dorsal root ganglia from a site of local replication in the arm. Finally, the role of autophagy during VZV infection is discussed. Autophagosome formation is a prominent feature in the skin vesicles during both varicella and herpes zoster. Therefore, autophagy is one of the innate immune mechanisms associated with VZV infection in humans.     

Recurrent hemiplegia associated with cerebral vasculopathy following third trimester maternal herpes zoster infection

The chickenpox virus (varicella zoster virus; VZV) is known to cause large and small vessel central nervous system vasculopathies that may be associated with strokes in both adults and children. We present the case of a female aged 2 years 6 months who developed a chronic progressive small-vessel vasculopathy with radiological features of moyamoya disease as a manifestation of congenital varicella syndrome. Clinically, the condition was characterized by recurrent ischaemic strokes, which were brought under control using intravenous acyclovir. The case is unique in that it is the first report of congenital varicella syndrome to occur after a maternal herpes zoster infection. Furthermore, it is the first case of symptomatic VZV infection in a child to occur after a maternal infection occurring in the third trimester of pregnancy.     

Subclinical reactivation of varicella zoster virus in all stages of HIV infection

Analysis of 200 paired serum and cerebrospinal fluid (CSF) samples from 180 HIV-positive individuals, 136 of whom had AIDS, revealed intrathecal synthesis of antibodies specific for varicella zoster virus (VZV) in 28 (16%) individuals, measles virus in 15 (8%), herpes simplex virus-1 (HSV-1) in 1 (0.6%), and HSV-2 in none. Of the 28 subjects with a positive VZV antibody specificity index, only 1 had zoster rash at the time of serum and CSF sampling; of the total 180 HIV-positive subjects, 146 (81%) had no history of zoster. Based on an estimated 33.4 million HIV-positive individuals worldwide, subclinical reactivation of VZV in even less than 16% of HIV-positive people suggests the possibility that millions of people have active VZV infection of the central nervous system. In cases of VZV vasculopathy, myelopathy and even zoster sine herpete, the CSF is often positive for anti-VZV antibody, but negative for VZV DNA. To rule out VZV infection of the nervous system, CSF must be tested for VZV DNA and anti-VZV IgG and IgM antibody.     

Cerebral vasculopathy associated with primary varicella infection

A previously healthy 5-year-old boy developed cerebral vasculopathy, presenting as two episodes of acute hemiparesis 3 and 9 months, respectively, after a primary varicella infection (chickenpox). This association has not been reported before, to our knowledge, although cerebral vasculopathy is a well-known complication of herpes zoster ophthalmicus. The diagnosis was based on the presence of oligoclonal varicella-specific IgG in the cerebrospinal fluid and angiographic findings. Clinical and angiographic follow-up, and serial thymidine kinase activity levels in the cerebrospinal fluid suggested a self-limiting course of the virus-induced vasculopathy. Varicella zoster virus seems to be another potential causative agent to be considered in acute childhood hemiplegia.     

Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash

The authors report three patients with acute, chronic, and recurrent neuropathy associated with varicella zoster virus (VZV) infection but without zoster rash. CSF of all three patients contained VZV immunoglobulin G antibody, but not herpes simplex virus. In two patients, serum/CSF ratios of VZV immunoglobulin G were reduced compared to normal ratios for immunoglobulin G and albumin, and one patient also had VZV immunoglobulin M in CSF. All three patients received antiviral therapy and improved. The diagnosis of nervous system infection by VZV may be confirmed by the presence of antibody to VZV in CSF even without detectable VZV DNA.     

Herpes zoster ophthalmicus and delayed contralateral hemiparesis caused by cerebral angiitis: Diagnosis and management approaches

Four patients with herpes zoster ophthalmicus and delayed contralateral hemiparesis are described, and their findings are compared with those in patients previously reported in the English language literature. The current patients evidenced multifocal ipsilateral cerebral angiitis by angiography and multifocal infarcts in the distribution of the ipsilateral middle cerebral artery by computed tomographic scanning. Cerebrospinal fluid showed mononuclear pleocytosis, positive oligoclonal bands, and an elevated immunoglobulin G index. Two patients were treated with corticosteroids and acyclovir, and 1 with corticosteroids alone, all without apparent response. Necrotizing angiitis ipsilateral to the herpes zoster ophthalmicus was demonstrated postmortem in 1 patient with multifocal cerebral infarction and progressive leukoencephalopathy. Neither herpes varicella zoster immunocytochemical reactivity nor viral inclusions were seen. The leukoencephalopathy associated with herpes varicella zoster either may be caused by cerebral angiitis or, as previously reported, may be a temporally remote manifestation of persistent herpes varicella zoster infection. The cerebral angiitis associated with herpes varicella zoster is histologically similar to granulomatous angiitis, and both may be related to herpes varicella zoster infection of the cerebral vasculature.     

Issues in the Treatment of Neurological Conditions Caused by Reactivation of Varicella Zoster Virus (VZV)

Varicella zoster virus (VZV) is a ubiquitous neurotropic human herpesvirus. Primary infection usually causes varicella (chicken pox), after which virus becomes latent in ganglia along the entire neuraxis. Decades later, virus reactivates to produce herpes zoster (shingles), a painful dermatomally distributed vesicular eruption. Zoster may be further complicated by postherpetic neuralgia, VZV vasculopathy, myelitis, and segmental motor weakness. VZV reactivation has also been associated with giant cell arteritis. This overview discusses treatment of various conditions that often require both corticosteroids and antiviral drugs. Treatment for VZV-associated disease is often based on case reports and small studies rather than large-scale clinical trials. Issues that require resolution include the optimal duration of such combined therapy, more effective treatment for postherpetic neuralgia, whether some treatments should be given orally or intravenously, the widening spectrum of zoster sine herpete, and the role of antiviral therapy in giant cell arteritis.     

Detection of varicella-zoster virus DNA by polymerase chain reaction in cerebrospinal fluid of patients with herpes zoster meningitis

Summary In three of five patients with herpes zoster meningitis, varicella-zoster virus (VZV) DNA was detected by the polymerase chain reaction (PCR) in the initial samples of cerebrospinal fluid. DNA fragments of group A or B, following classification of VZV strains by the size of the variable region IV of VZV genome, were found at the 7th, 10th and 24th illness day in the three positive cases: one of these cases did not have skin lesions. These results suggest that the detection of VZV DNA by PCR is useful for the diagnosis of herpes zoster meningitis, as well as for its molecular epidemiology.     

疱疹后遗神经痛病人的神经损伤与水痘-带状疱疹病毒持续激活和复制的关系

目的　研究带状疱疹后遗神经痛 (PHN)患者的水痘 带状疱疹病毒 (VZV)持续激活、复制对感觉神经系统损伤的影响。方法　用感觉定量分析仪 (TSA 2 0 0 1)对 2 5例PHN患者和 38例带状疱疹患者的疼痛区及对侧镜像区进行感觉定量测量 ,同时用PCR和SouthernBlot方法对其外周血单核细胞 (PBMC)进行VZV检测。结果　带状疱疹急性期和PHN病人疼痛区的各感觉阈值均大于对侧镜像区 ,而愈后无PHN的带状疱疹病人两者间未见显著性差异 ;PHN病人的感觉缺失值大于带状疱疹急性期病人 ;PHN患者的VZV检出率为 32 % ,而在愈后无PHN患者却未检测到。结论　VZV在带状疱疹患者的背根神经节内长久复制和激活会引起神经系统严重的、甚至是不可逆的损伤 ,这对PHN的形成起着重要作用     

Incidence of varicella zoster virus infections of the central nervous system in the elderly: a large tertiary hospital-based series (2007–2014)

The aim of the study was to describe the clinical and epidemiological characteristics of the central nervous system (CNS) infection by varicella zoster virus (VZV) in patients older than 65 years in a tertiary community hospital. We retrospectively analysed the results of cerebrospinal fluid (CSF) testing in patients older than 65 years between 2007 and 2014 with clinically suspected VZV infection with CNS involvement. Patients whose CSF samples were positive for VZV DNA were included, as were those with negative results who simultaneously presented herpes zoster and CSF or magnetic resonance imaging findings suggestive of CNS infection, and in whom other possible aetiologies had been ruled out. The study included 280 patients. The disease was considered to be caused by a VZV infection in 32 patients (11.4%), of which 23 cases were virologically confirmed (detection of VZV DNA in CSF). The most frequent diagnosis of the patients with VZV CNS infection was encephalitis (83.3%), followed by meningitis (13.3%) and cerebellitis (3.3%). The mean annual incidence of VZV CNS infection was 3.0 cases per 100,000 inhabitants. VZV was the most common cause of encephalitis and viral meningitis, ahead of herpes simplex virus (n = 9). At the time of discharge, 12 (40%) patients showed neurological sequelae. Five patients (20%) died during hospitalization, all with encephalitis. Patients with a fatal outcome had significantly higher median age and longer delay before initiating acyclovir. In conclusion, VZV was the first cause of encephalitis in our elderly population. Despite acyclovir treatment, there was a high rate of case fatality and sequelae at discharge.     

Multifocal varicella-zoster virus leukoencephalitis temporally remote from herpes zoster

Two patients with cancer, one with Hodgkin's disease and the other with a granulosa cell tumor of the ovary, developed a progressive, eventually fatal infection of the central nervous system exhibiting multifocal symptoms and signs. Pathologically, gross abnormalities of the brain resembled those in progressive multifocal leukoencephalopathy (PML), with discrete and confluent plaque-like lesions concentrated in the white matter, particularly along the gray-white junction. Microscopically, pathological changes differed distinctly from those associated with PML; in addition to confluent foci of white matter injury characterized by early demyelination and subsequent necrosis, prominent Cowdry type A eosinophilic intranuclear inclusions were noted in oligodendrocytes, astrocytes, and neurons. By electron microscopy, intranuclear spherical particles consistent in size and appearance with herpesvirus nucleocapsids were found within the lesions. Immunoperoxidase studies detected varicella-zoster virus (VZV) antigens in infected cells, implicating this virus as the responsible agent despite a lapse of many months between the cutaneous herpes zoster and onset of cerebral symptoms in both patients.     

A case of delayed cerebral infarction occurring in puerperium preceded by herpes zoster ophthalmicus in late pregnancy]

Delayed central neurological symptoms following herpes zoster ophthalmicus (HZO) such as "herpes zoster ophthalmicus and delayed contralateral hemiparesis" are considered to be due to ipsilateral intracranial vasculopathy. We experienced a rare case with cerebral infarction occurred in puerperium following HZO in late pregnancy. A healthy 30-year-old woman had left HZO at weeks 35 of gestation. She was given acyclovir (ACV) for external use and improved with small pigmentation on the left eye-lid. Seven weeks after the onset of HZO, she suddenly developed aphasia and right hemiparesis. Cerebral angiogram showed narrowing on M 1 segment of the ipsilateral middle cerebral artery. The occlusion was seen on peripheral portion of the angular artery on the same side. In cerebrospinal fluid (CSF), cell count was slightly elevated, but concentration of protein and sugar were normal. Varicella-zoster titer was increased in both serum and CSF. She was treated with intravenous ACV (1500 mg/day) for 10 days. On the next day after the treatment, the cell count was normalized and on 18th day, varicella-zoster titer was decreased in CSF. Higher brain function improved and no relapses occurred. This is a first case of delayed cerebral infarction occurring in puerperium preceded by herpes zoster ophthalmicus in late pregnancy, as far as we searched. We should treat carefully pregnant or lactating patients with HZO, considering delayed cerebral infarction.     

Interleukin-6 in the cerebrospinal fluid of two patients with herpes zoster meningitis

Interleukin-6 (IL-6) levels in the cerebrospinal fluid (CSF) and serum were measured in two immuno-competent children with herpes zoster meningitis, who had vesicles, fever, headache and vomiting before admission. The causative agent was identified as varicella zoster virus (VZV) by detecting an increased antibody index in the serum and specific DNA (by polymerase chain reaction) in the CSF. Both patients fully recovered after treatment with acyclovir. The CSF IL-6 levels were high (260.1 pg/ml, 106.1 pg/ml) at the acute stage and thereafter showed a rapid recovery. The serum IL-6 levels were normal. The increased IL-6 level in the CSF may reflect intrathecal inflammatory response following invasion of VZV into the central nervous system.