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.     

Ungewöhnliche Manifestation eines Zoster sine herpete als unilaterales kaudales Hirnnervensyndrom

Multiple lower cranial nerve palsies are a rare complication following varicella zoster virus (VZV) reactivation, especially if typical herpetic eruptions are lacking. We report a case of a 45-year-old, immunocompetent male with unilateral involvement of the cranial nerves VIII, IX, X, and XI without skin lesions. Cerebrospinal fluid (CSF) studies revealed mononuclear pleocytosis with intrathecal antibody synthesis against VZV, while polymerase chain reaction (PCR) did not detect VZV or HSV (herpes simplex virus). The patient almost completely recovered after aciclovir administration. VZV reactivation without rash (zoster sine herpete) may lead to multiple cranial nerve palsies. PCR is a useful tool to detect VZV-DNA in CSF, but negative results do not exclude a reactivation. In case of multiple cranial nerve palsies of unknown etiology with mononuclear pleocytosis in CSF tumors of the skull base, meningitis tuberculosis, and meningeosis have to be excluded, and antiviral therapy should be discussed.     

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.     

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.     

Polymerase chain reaction analysis and oligoclonal antibody in the cerebrospinal fluid from 34 patients with varicella-zoster virus infection of the nervous system

Objective

To study cerebrospinal fluid (CSF) and serum samples from 34 consecutive patients suspected of having varicella‐zoster virus (VZV) infection of the central nervous system (CNS).

Population and methods

The patients were divided into three groups. The first group consisted of 27 patients with a rash in one to three dermatomes and clinical suspicion of meningitis and radiculitis; among them, three subgroups were distinguished according to the affected dermatome: ophthalmicus (n = 9), oticus (n = 11) and cervico‐thoraco‐lumbar zoster (n = 7). Four cases of zoster sine herpete (ZSH) were included in the second group: these patients presented with either radiculitis (n = 2) or meningoencephalitis (n = 2), without cutaneous eruption. The third group consisted of three patients with a generalised rash and encephalitis. A polymerase chain reaction (PCR) for VZV DNA and antigen‐driven immunoblots for oligoclonal anti‐VZV antibodies were carried out on all CSF samples.

Results

PCR of the CSF was positive in 44% of the patients from the first group, mainly within the first 7 days after eruption. In addition, intrathecal synthesis of anti‐VZV antibodies was detected in 37% of patients, always after an interval of 7 days (p<0.0001). Among the four patients with ZSH, a positive VZV PCR was detected in three patients and CSF‐specific oligoclonal anti‐VZV antibodies in two. PCR was also positive in the CSF of two of the three patients with generalised rash and encephalitis; local production of anti‐VZV antibodies was seen in a second CSF sample in one patient, and was also present in the third patient.

Conclusion

Amplification of VZV DNA by PCR in the CSF and antigen‐driven immunoblots have important diagnostic value in suspected VZV infection, although their presence depends on the timing of the CSF sampling. VZV is thought to be a causative agent in unexplained cases of meningitis associated with radiculitis or focal CNS symptoms, even in the absence of skin manifestations. In such patients, rapid diagnosis by this combined approach permits early antiviral treatment.Varicella‐zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox (varicella), becomes latent in the cranial nerve and dorsal root ganglia, and may reactivate decades later in 10–20% of the population to produce shingles (zoster).¹ Shingles is characterised by unilateral radicular pain and a vesicular rash that is generally limited to one to three contiguous dermatomes. The annualised incidence of shingles is about 1.5–3 cases per 1000 people, but increases to 11 cases per 1000 in the population >60 years of age.² VZV can also cause neurological complications, very rarely during the primary infection (most often a varicella cerebellitis) and more often during the reactivation phase. The main complication is post‐herpetic neuralgia, a neuropathic pain syndrome that persists after the dermatomal rash has healed. Acute neurological complications may, however, occur, and affect either the peripheral nervous system (cranial neuropathies, motor radiculopathies of the arm or the leg, bladder and bowel dysfunction) or the central nervous system (CNS; meningitis, myelitis and vasculitic encephalitis). The same neurological complications may be observed in zoster sine herpete (ZSH), which is defined by a dermatomal pain without antecedent rash.³Cerebrospinal fluid (CSF) analysis is a key tool in the diagnosis of CNS infection with VZV. The amplification of VZV DNA by polymerase chain reaction (PCR) and the detection of intrathecal synthesis (ITS) of anti‐VZV‐specific antibodies are the most reliable ways of establishing a definite diagnosis of VZV CNS infection.⁴ We present a retrospective study on CSF samples collected from 34 consecutive patients suspected of harbouring CNS VZV infection. Our population included four cases with ZSH and three with disseminated rash with meningoencephalitis. We discuss correlations between the CSF results, the timing of CSF samples and the clinical picture.     

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.     

Varicella-zoster virus meningitis coincident with bacteremia caused by liver abscess: a case report

Journal of NeuroVirology - Varicella-zoster virus (VZV) meningitis is sometimes associated with herpes zoster, which is also associated with various other infectious diseases. However, there are...     

A case of varicella-zoster myelopathy

Introduction – Early diagnosis of neurological complications of varicella-zoster virus (VZV) is important because of its treatability. We performed polymerase chain reaction (PCR) to detect VZV-DNA from the cerebrospinal fluid (CSF) of a patient with myelopathy. Patient & methods – A 69-year-old man developed sensory disturbances in the lower extremities and bladder-bowel disturbances, followed by cutaneous zoster on his left arm. Polymerase chain reaction was applied to identify the viral DNA in CSF. Results – The increased antibody index of VZV and herpes simplex virus (HSV) in the CSF suggested intrathecal synthesis of IgG antibodies to these viruses. VZV-DNA was detected in the CSF by nested PCR, but neither HSV-1 nor HSV-2 DNA was detected in CSF. He was successfully treated with acyclovir and prednisolone. Conclusion – PCR may be a useful tool for the diagnosis of VZV myelopathy.     

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.     

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.     

Fine specificities of antibodies in sera and cerebrospinal fluid in herpes virus infections of the central nervous system as detected by the antigen variable immunoblot technique

Applying the immunoblot technique a sensitive and specific method was developed for the detection of intrathecally synthesized antibodies against individual specific proteins that are antigens of various infectious agents causing encephalitis. Paired serum and cerebrospinal fluid (CSF) samples from five patients with herpes virus infections of the central nervous system (CNS) (three herpes simplex virus encephalitis, one varicella zoster virus encephalitis, one zoster ganglionitis) were investigated for the presence of locally produced IgG against the electrophoretically separated antigens of herpes simplex virus (HSV), varicella zoster virus (VZV) and human cytomegalovirus (HCMV), as well as for IgM antibodies in one case of HSV encephalitis. In two cases (HSV encephalitis and VZV encephalitis) four and one antibody, respectively, were found that were synthesized intrathecally only. In the other cases the patterns of sera and CSF antibodies were similar, the CSF antibodies showing an all-over stronger reaction, at identical IgG concentrations. In contrast to the conception of a 'limited heterogeneity' of intrathecal antibody synthesis in encephalitis, we thus found an 'expanded heterogeneity' of the intrathecally synthesized antibodies in comparison to the corresponding serum antibodies.     

Case of herpes zoster associated Guillain-Barré syndrome with a relapse of eruptions after intravenous immunoglobulin therapy]

A 77-year-old woman developed progressive dysesthesia, hypesthesia and weakness in four extremities immediately after improvement of herpes zoster in the left Th10 dermatome area. Examination of the cerebrospinal fluid (CSF) showed an increase in protein concentrations. Evidence of demyelinating polyneuropathy was demonstrated by nerve conduction studies. Her hypesthesia and weakness in the extremities were gradually improved following intravenous immunoglobulin therapy (IVIg). Varicella zoster virus (VZV) titer levels in CSF well correlated both with neurological symptoms and CSF protein concentrations. VZV DNA in the CSF was not detectable. These findings suggested autoimmune Guillain-Barré syndrome (GBS) associated with herpes zoster. An interesting finding in the present patient is that one day after the completion of IVIg, when the neurological symptoms in the extremities were apparently ameliorating, the herpes zoster eruptions again emerged in the left L3 dermatome area. By treatment with intravenous acyclovir, the vesicular eruptions were improved. We assume that IVIg might suppress the immune response against VZV and promote the recurrence of eruptions.     

Neurotropic viruses and Alzheimer''s disease: a search for varicella zoster virus DNA by the polymerase chain reaction.

BACKGROUND: In studies on the possible role of viruses in the aetiopathogenesis of Alzheimer's disease, herpes simplex virus type 1 (HSV1) DNA was detected by the polymerase chain reaction (PCR) in a high proportion of normal elderly people and of patients with Alzheimer's disease. The combination of HSV1 and a host factor, the type 4 allele of the gene for apolipoprotein E, is a strong risk factor for the disease. METHODS: Brain specimens were examined for another herpes virus, varicella zoster (VZV), which, like HSV1, is neurotropic, has a predilection for residing latently in the peripheral nervous system, and can reactivate. RESULTS: Using primers for sequences in the VZV origin of replication gene or thymidine kinase gene, VZV DNA was not found in any of 24 samples (18 HSV1 positive), from 17 patients with Alzheimer's disease, nor in 20 samples (12 HSV1 positive from 12 aged normal people. Hybridisation of the PCR products with a radiolabelled oligonucleotide probe capable of detecting less than 10 copies of the target sequence, confirmed the absence of VZV DNA. CONCLUSION: The presence of one neurotropic virus--HSV1--and the absence of another--VZV--in aged human brains is consistent with a role for HSV1 in the aetiology of Alzheimer's disease.     

Natalizumab and HSV meningitis

Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a monoclonal antibody approved for use in patients with relapsing multiple sclerosis (MS) as well as moderate to severe Crohn’s disease. We report the first case of a patient with a history of MS, on monthly natalizumab, who developed HSV-2 meningitis. We discuss the mechanism of action of natalizumab and review what is known about the reactivation of herpes infection in association with this medication. The question of herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis for patients is raised.     

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     

Case of zoster sine herpete presenting with dysphagia diagnosed by PCR analysis of VZV DNA in auricular skin exudates]

A 66-year-old woman was admitted to our hospital because of hoarseness and dysphagia after right earache and pharyngalgia. She showed right glossopharyngeal nerve and vagus nerve palsies, but no other neurological deficits. There was no skin rash within the regions of her ear, oral cavity, pharynx and larynx. Slight increase of mononuclear cells was noted in the cerebrospinal fluid. MR brain imaging was normal. We diagnosed her as zoster sine herpete (ZSH) and treated her with acyclovir, after which she almost completely recovered. The examination of antibodies and DNA of varicella zoster virus (VZV) in the serum and cerebrospinal fluid revealed a pattern of previous zoster infection without evidences of reactivation. However, VZV DNA was detected in auricular skin exudates with PCR. We conclude that PCR analysis of VZV DNA in auricular skin exudates can be a useful diagnostic tool for the diagnosis of zoster sine herpete presenting with painful glossopharyngeal nerve and vagus nerve palsies.     

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.     

Human trigeminal ganglionic explants as a model to study alphaherpesvirus reactivation

Varicella zoster virus (VZV) latency is characterized by limited virus gene expression and the absence of virus DNA replication. Investigations of VZV latency and reactivation have been hindered by the lack of an in vitro model of virus latency. Since VZV is an exclusively human pathogen, we used naturally infected human trigeminal ganglia (TG) obtained at autopsy to study virus latency. Herein, we report optimization of medium to maintain TG integrity as determined by histology and immunohistochemistry. Using the optimized culture medium, we also found that both herpes simplex virus-1 (HSV-1) and VZV DNA replicated in TG explants after 5?days in culture. The increase in HSV-1 DNA was fourfold greater than the increase in VZV DNA. Overall, we present a model for alphaherpesvirus latency in human neurons in which the key molecular events leading to virus reactivation can be studied.