Varicella-zoster Virus DNA In Cerebrospinal Fluid Research Articles

Acyclovir treatment of varicella-zoster virus meningeal infections and acute kidney injury: a multicentre case series study

Background Systematic treatment with intravenous acyclovir is usually given when varicella zoster virus (VZV) DNA is isolated in cerebrospinal fluid (CSF), indicating central nervous system (CNS) involvement. Our study aimed to describe therapeutic management and acute kidney injury (AKI) occurrence during acyclovir treatment of VZV infection with CNS involvement. Methods Multicentre, retrospective study including all patients from 2010 to 2022 with VZV DNA in CSF. Patient management and outcomes were compared according to clinical presentation and indications for intravenous acyclovir: i) definite (encephalitis, myelitis or stroke, peripheral nervous system (PNS) with ≥ 2 roots, herpes zoster ≥ 3 dermatomes, immunosuppression), ii) questionable (1 or 2 dermatomes) or iii) no indication (other situations). Results 154 patients were included (median age 66 (interquartile range 43–77), 87 (56%) males); 60 (39%) had encephalitis, myelitis or stroke, 35 (23%) had PNS involvement, 37 (24%) had isolated meningitis, 14 (9%) had isolated cutaneous presentation, and 8 (5%) had other presentations. Overall, 128 (83%) received intravenous acyclovir for more than 72 h. AKI occurred in 57 (37%) patients. Finally, 42 (27%) and 25 (16%) patients had respectively no or a questionable indication for intravenous acyclovir, while 29 (69%) and 23 (92%) of them received it for more than 72 h, with AKI in 13 (35%) and 13 (52%) patients, respectively. In-hospital mortality was 12% (n = 18), and no deaths were reported in isolated meningitis. Conclusions Intravenous acyclovir is widely prescribed when VZV DNA is isolated in CSF, regardless of the clinical presentation, with a high rate of AKI. Further studies are needed to better define the value of intravenous acyclovir in isolated VZV meningitis.

Cognitive impairment without altered levels of cerebrospinal fluid biomarkers in patients with encephalitis caused by varicella-zoster virus: a pilot study

Varicella-zoster virus (VZV) is one of the most common agents causing viral infections of the central nervous system (CNS). VZV encephalitis is associated with severe neurological sequelae, despite antiviral treatment. Cognitive impairment has been reported and VZV has been associated with dementia. Our aim was to investigate the cognitive impairment and cerebrospinal fluid biomarkers in a follow-up study of patients with VZV encephalitis. Thirteen patients with VZV encephalitis, diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF) by PCR and concomitant symptoms of encephalitis, were included. Neuropsychological assessment in parallel with a lumbar puncture to obtain CSF was performed 1.5–7 years after acute disease. The CSF biomarkers neurofilament light chain (NFL), S100B, glial fibrillary acidic protein (GFAP), amyloid-β (Aβ) 40 and Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) were analysed and compared to controls (n = 24). Cognitive impairment was shown in the domains of executive functions and speed/attention and to a minor degree in the domains of learning/memory and language, indicated by a significantly poorer performance on seven neuropsychological test variables. No convincing evidence of alterations in concentrations of biomarkers in the CSF were shown. Our results indicate that patients with VZV encephalitis suffer from cognitive impairment long time after acute disease. Importantly, these impairments do not seem to be accompanied by biomarker evidence of ongoing neuronal or astrocytic injury/activation or induction of dementia-related brain pathologies by the infection.

Serum and cerebrospinal fluid neurofilament light chain in patients with central nervous system infections caused by varicella-zoster virus

Varicella-zoster virus (VZV) is a common cause of viral central nervous system (CNS) infection, and patients may suffer from severe neurological sequelae. The biomarker neurofilament light chain (NFL) is used for assessment of neuronal damage and is normally measured in cerebrospinal fluid (CSF). Novel methods have given the possibility to measure NFL in serum instead, which could be a convenient tool to estimate severity of disease and prognosis in VZV CNS infections. Here, we investigate the correlation of serum and CSF NFL in patients with VZV CNS infection and the association of NFL levels in serum and CSF with different VZV CNS entities. NFL in serum and CSF was measured in 61 patients who were retrospectively identified with neurological symptoms and VZV DNA in CSF detected by PCR. Thirty-three herpes zoster patients and 40 healthy blood donors served as control groups. NFL levels in serum and CSF correlated strongly in the patients with VZV CNS infection. Encephalitis was associated with significantly higher levels of NFL in both serum and CSF compared with meningitis and Ramsay Hunt syndrome. Surprisingly, herpes zoster controls had very high serum NFL levels, comparable with those shown in encephalitis patients. We show that analysis of serum NFL can be used instead of CSF NFL for estimation of neuronal injury in patients with VZV CNS infection. However, high levels of serum NFL also in patients with herpes zoster, without signs of CNS involvement, may complicate the interpretation.

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 65years in a tertiary community hospital. We retrospectively analysed the results of cerebrospinal fluid (CSF) testing in patients older than 65years 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.

Varicella-zoster virus (VZV) DNA in serum of patients with VZV central nervous system infections

Varicella-zoster virus (VZV) is a common viral agent causing central nervous system (CNS) infections, normally diagnosed by detection of VZV DNA in cerebrospinal fluid (CSF). Our aim was to investigate trends in VZV DNAemia in VZV CNS infections, which could potentially contribute to diagnosis and secondly, correlate the amount of VZV DNA in serum to severity of disease. Seventy-two patients with VZV CNS infections diagnosed by detection of VZV DNA in CSF and concomitant neurological symptoms were included. The amount of VZV DNA was measured by real-time PCR in paired serum and CSF samples and compared to a control group of herpes zoster (n=36). An increased amount of VZV DNA was detected in serum in patients with encephalitis compared to patients with meningitis or Ramsay-Hunt syndrome, respectively (p=0.003 and p=0.024). A greater proportion of patients with VZV CNS infections and detectable VZV DNA in serum had ongoing rash compared to those without detectable VZV DNA in serum (p≤0.001). The viral load in serum of patients with neurological symptoms was lower compared to in patients with herpes zoster without neurological symptoms (p≤0.001) and only 32/72 of the patients with VZV CNS disease had VZV DNA detected in serum. Increased amount of VZV DNA in serum of patients with VZV CNS infections seems associated with encephalitis and ongoing rash. Additionally, viral DNA analysis by PCR in serum may be a helpful diagnostic tool although viral DNA analysis by PCR in CSF is the method of choice for diagnosis.

Cerebrospinal fluid biomarkers in facial nerve palsy caused by Varicella Zoster virus

No: 1680 Presentation at ESCV 2015: Poster 1 Cerebrospinal fluid biomarkers in facial nerve palsy caused by Varicella Zoster virus J. Lindstrom1,∗, A. Grahn1, H. Zetterberg2, M. Studahl1 1 Department of Infectious Diseases, Sahlgrenska University Hospital, Ostra, Goteborg, Sweden 2 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sweden Background: Reactivation of Varicella Zoster virus (VZV) can cause facial nerve palsy with neurological sequels despite treatment with aciclovir and/or corticosteroids. Associated symptoms such as vertigo and loss of hearing are frequent. Facial nerve palsy caused by VZV manifest as Ramsay Hunt syndrome when blisters are present, or as zoster sine herpete without blisters. Neurofilament light protein (NFL), glial fibrillary acidic protein (GFAp) and S-100 are cerebrospinal fluid (CSF) biomarkers that have been used to estimate severity of neuronal damage and prognosis in various CNS diseases. One previous study has been performed on VZV in the central nervous system (CNS), but patients with facial palsy have not been specifically studied. Methods: 28 patientswith VZV facial palsy, diagnosed by detection of VZV DNA in CSF by PCR, were retrospectively identified. GFAp, NFL and S-100 were measured in stored CSF samples and compared with a control group (n=52). Medical records were studied for relevant patient data such as severity of symptoms, treatment and laboratory parameters. Results: CSF concentrations of NFL and GFAp were significantly elevated compared to controls (p<0.01 and p<0.05) and S-100 concentrations were reduced. Additionally, NFL kinetics indicated slightly increasing concentrations in CSF samples drawn more than seven days after onset of neurological symptoms. Viral load (VZV DNA copies/ml) correlated with both NFL (Spearman r=0.51; p<0.01) and GFAp (Spearman r=0.54; p<0.01). No correlations were found between biomarkers and severity of symptoms, clinical outcome at follow-up, or treatment with aciclovir prior to CSF sampling in this small study. Conclusion: In this first study on biomarkers in facial palsy caused by VZV, we identified a pattern of elevated NFL, elevated GFAp and decreased S-100 compared to controls. Increased NFL levels reflect axonal damage, and elevated levels of GFAp, in combination with decreased concentrations of S-100 , indicate astrogliosis rather than damage to the astroglial cell membrane. Biomarkers of neuron and glial cell damage can be used to understand pathogenesis, and in future studies assessment of these biomarkers in relation to treatment and clinical outcome should be explored. http://dx.doi.org/10.1016/j.jcv.2015.07.137 Abstract No: 1682 Presentation at ESCV 2015: Poster 1 False negative influenza A virus subtype H3N2 in Prodesse GenProbe ProFlu+ PCR assay in season 2014–2015 N. Kirkby1,∗, T.N. Thomsen1, R. Trebbien2, K. Vorborg2, J. Ronn2, T.K. Fischer2, C.B. Christiansen1 1 Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark 2 National Influenza Center, Virological Surveillance and Research Department of Microbiological

Manifestations neurologiques associées à la varicelle : apport de l’amplification génique dans le liquide céphalo-rachidien

Varicella-zoster virus (VZV) is, like other alphaherpes viruses, neurotropic. Of the admissions to hospital for varicella, 7.6-25% are due to neurologic manifestations. Most of the time, the concomitant skin lesions facilitate the diagnosis. The justification of qualitative PCR (polymerase chain reaction) for VZV DNA in cerebrospinal fluid in the management of these patients is not clear. The aim of this study was to evaluate the prognostic value of qualitative PCR for VZV DNA in cerebrospinal fluid and to assess its impact on patient management. We conducted a retrospective monocentric study in Versailles Hospital (France). It included every child admitted for neurologic manifestations associated with varicella and compared the patients with positive PCR for VZV DNA to those with a negative PCR in the cerebrospinal fluid. Seven patients with positive PCR and 16 patients with negative PCR were included. The median age of the children included was 3 years (range, 1.6-12 years) and 2 years (range, 0.6-5 years), respectively. In the positive PCR group, 86% of the children had fever on first examination and the average time between the onset of skin lesions and neurological signs was +1.28 days (range, -2 to +5 days). In comparison, in the negative PCR group, 81% of the children had fever and the average time delay was +1.75 days (-2 to +7 days). There was no significant difference in terms of length of hospitalization; 3 days (range, 0-6 days) and 3 days (range, 2-7 days), respectively. All patients discharged from our department went home. In addition, there was no significant difference between the two groups in terms of treatment with acyclovir; two children (28.5%) were treated in the positive PCR group versus four (25%) in the negative PCR group. Our study showed no prognostic value for qualitative PCR for VZV DNA in the cerebrospinal fluid of patients with neurologic manifestations of varicella. Therefore, its relevance can be questioned in clinical practice. However, in case of encephalitis and meningitis during primary infection with VZV, quantitative PCR for VZV DNA might have a prognostic value and therefore requires further study.

Association between viral load of varicella zoster virus in cerebrospinal fluid and the clinical course of central nervous system infection

Varicella zoster virus (VZV) like other alphaherpes viruses stays latent after its primary infection. During its reactivation, it can infect the central nervous system (CNS) causing a variety of clinical presentations. Using polymerase chain reaction (PCR) for detection of VZV DNA in cerebrospinal fluid (CSF), it is now recognized in some series as the most common causative agent of viral CNS infection. We aimed to investigate in our study the correlation between VZV viral load in the CSF and the clinical course of its infection, using quantitative real-time PCR. For this purpose, we examined 56 specimens of consecutive patients with positive CSF for VZV DNA in a qualitative test, with a clinical picture of meningitis or encephalitis collected over 10years in Rambam medical center. We found a significant correlation between VZV viral load and the severity and duration of neurological disease. We believe that using quantitative measurement of VZV DNA in the CSF, could serve as a prognostic marker which would influence treatment decisions.

Editorial Commentary: Strokes and Infection With Varicella Zoster Virus

It was long assumed, before recent developments proved otherwise, that the presence of an infection with varicella zoster virus (VZV) was inevitably associated with a rash. We now know, due to the use of polymerase chain reaction (PCR) and other methods that have improved diagnosis, that patients can harbor infections with VZV even in the absence of cutaneous manifestations Such “occult” VZV infections often affect the nervous and gastrointestinal systems. Central nervous system (CNS) VZV infections without rash were initially identified at autopsy [1] and subsequently in patients with meningitis through the PCR detection of VZV DNA in cerebrospinal fluid (CSF) [2]. Although there appears to be a relationship between VZV infection and arterial ischemic stroke (AIS) [3], these patients also do not display a rash when they develop symptoms involving the CNS. In the current issue of Clinical Infectious Diseases, Thomas et al describe the connection between varicella and subsequent AIS in children. They used 4 large databases and a self-controlled case series, analyzing data from strokes in the varicella cases. Data were analyzed 0–6 months after an episode of varicella and again at a later time. This method avoids confounding factors and is efficient at relating a rare condition, such as stroke in childhood, to a common infection, varicella, although it does not provide information on the absolute risk of postvaricella stroke. Thomas et al’s study revealed that in the 6 months following varicella, the incidence of childhood stroke is increased by a factor of approximately 4. There was no significant increase in strokes in adults after varicella, nor was there any increase in strokes 7– 12 months after varicella in children. The pathogenesis of postvaricella stroke is not known, but VZV can infect cerebral arteries, which provokes inflammatory responses that damage the infected arteries and may lead to aneurysms [4–6]. Because the interval between an episode of varicella and a stroke can be as long as 6 months, reactivation of latent VZV acquired during varicella, rather than a smoldering persistent infection in arteries, seems more likely to cause AIS, although either possibility remains plausible. The VZV that infects arteries could be delivered from sensory neurons in which VZV reactivates or as a result of a viremia. It may well be that most strokes following varicella are, in reality, strokes following zoster without rash. When one such stroke develops, there may be recurrences [7]. Strokes may also follow classic zoster, particularly when the ophthalmic branch of the trigeminal nerve is involved. It is conceivable that AIS after varicella in children is a manifestation of a rare defect in innate immunity described in certain severe alpha herpesvirus infections [8–12]. One mystery is why VZV would be at increased risk for reactivation soon after varicella. This timing may reflect the putative immunologic predisposition. Clearly, additional knowledge of the state of VZV prior to infection of cerebral arteries, as well as the immunologic status of the host who has experienced a VZV-induced stroke, is needed. A relationship between zoster and stroke was appreciated before postvaricella stroke was recognized. At first termed giant cell arteritis, it now appears that this vasculitis syndrome is similar to what is termed VZV vasculopathy [13]. VZV vasculopathy may be a subset of giant cell arteritis. It was recognized historically that in the months following zoster, patients (usually adults) might manifest symptoms of stroke ipsilateral to the side of the body where zoster occurred. Because strokes in children are unusual or rare, this increase in CNS disease from varicella, albeit serious to individuals, is not a major public health problem. The morbidity (which may be long-lasting) Received 16 September 2013; accepted 18 September 2013; electronically published 2 October 2013. Correspondence: Anne A. Gershon, MD, Department of Pediatrics, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 19-110, New York, NY 10032 (aag1@columbia.edu). Clinical Infectious Diseases 2014;58(1):69–71 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit663

Complications of varicella zoster virus reactivation.

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.

Acute meningoencephalomyelitis due to varicella-zoster virus in an AIDS patient: report of a case and review of the literature

Varicella-zoster virus (VZV) meningoencephalomyelitis is a rare but severe neurological complication of VZV reactivation in immunocompromised patients. We report the case of an HIV-infected individual who developed an acute and severe meningoencephalomyelitis accompanied by a disseminated cutaneous eruption due to VZV. The presence of VZV DNA in cerebrospinal fluid was confirmed by polymerase chain reaction (PCR) technique. The patient started undergoing an intravenous acyclovir therapy with a mild recovery of neurological manifestations. Varicella-zoster virus should be included as a cause of acute meningoencephalomyelitis in patients with AIDS. Early diagnosis followed by specific therapy should modify the rapid and fulminant course for this kind of patients.

The History and Mystery of VZV in Saliva

The History and Mystery of VZV in Saliva

Quantitative real time PCR detection of Varicella-zoster virus DNA in cerebrospinal fluid in patients with neurological disease.

Varicella-zoster virus (VZV) reactivation can lead to the development of neurological disease. Diagnosis has been based on the detection of VZV DNA in cerebrospinal fluid (CSF) by PCR-based methods. The aim of this study was to determine whether the VZV DNA copy number in the CSF correlates with the course of the disease and to determine its prognostic relevance. VZV DNA was quantified in CSF samples obtained from 30 patients with neurological disease due to VZV reactivation using real time PCR, and the VZV DNA copy number was correlated to the clinical and laboratory findings for each case. Viral loads ranged from 50 copies/ml to 2.6 x 10(8) copies/ml. Significantly higher viral loads [geometric mean (GM): 7.2 x 10(4) copies/ml] were found in patients with encephalitis compared to patients with meningitis (GM: 4.1 x 10(3) copies/ml) (P=0.01, Mann-Whitney U test). In eight patients without zoster dermal lesions no significant difference in viral load (GM: 4.6 x 10(3)) was detected compared to patients exhibiting dermal lesions (GM: 2.2 x 10(4)) (P=0.14). High copy numbers of VZV DNA in CSF were clearly associated with the severity of neurological disease and none of the patients with a VZV viral load below 10(4) copies had a disease course which required intensive care.

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.

Detection of Varicella-Zoster Virus DNA by Nested PCR in CSF from HIV-Infected Patients

The aim of this prospective study was to determine the frequency and clinical significance of detection of varicella-zoster virus (VZV) DNA in cerebrospinal fluid (CSF) from 120 HIV-infected individuals. Six of 8 CSF samples from patients with recent (up to 8 months previously) or concurrent cutaneous zoster contained detectable VZV DNA using the polymerase chain reaction. No detectable CSF VZV DNA was present in two patients who had an encephalopathy complicating cutaneous zoster or in 112 other patients without a history of recent of concurrent zoster. In conclusion, VZV DNA may be detected in CSF of patients with neurological disease and concurrent or recent zoster. However, the absence of detectable VZV DNA in CSF does not preclude the possibility of VZV associated neurological complications.