Virus Central Nervous System Disease Research Articles

Acyclovir-induced neurotoxicity with a positive cerebrospinal fluid varicella zoster PCR result creating a management dilemma: a case report

BackgroundVaricella zoster virus central nervous system infections can present as aseptic meningitis, encephalitis, myelitis, and vasculopathy. Diagnosis is based on identification of varicella zoster virus deoxyribonucleic acid (DNA) in the cerebrospinal fluid by polymerase chain reaction. Therapy for these infections is acyclovir or valacyclovir. However, acyclovir can have neurotoxic effects that can mimic the presentation of varicella zoster virus central nervous system disease. We present a rare presentation of a patient who had acyclovir-induced neurotoxicity who also had a false-positive cerebrospinal fluid varicella zoster virus polymerase chain reaction result, creating a management dilemma. We review the clinical characteristics of acyclovir-induced neurotoxicity. In addition, we present the diagnostic characteristics of the cerebrospinal fluid viral polymerase chain reaction and alternative methods to diagnose central nervous system varicella zoster virus disease.Case presentationA 68-year-old Hispanic man with end-stage renal disease was diagnosed with cutaneous zoster at an outside facility and was started on acyclovir 4 days prior to admission. His family noted worsening confusion, agitation, speech difficulty, and hallucinations, leading them to bring him to the emergency department. His cerebrospinal fluid varicella zoster virus polymerase chain reaction result was positive, indicating the presence of varicella zoster virus deoxyribonucleic acid in the cerebrospinal fluid; however, he did not have cerebrospinal fluid pleocytosis typical of varicella zoster virus meningoencephalitis. Pharmacy records from the outside hospital revealed supratherapeutic acyclovir dosing. This led to a diagnostic dilemma over whether this patient had varicella zoster virus encephalitis or acyclovir-induced neurotoxicity. Acyclovir was discontinued, and the patient underwent two sessions of hemodialysis to remove acyclovir, which led to a full neurologic recovery.ConclusionsVaricella zoster virus encephalitis and acyclovir-induced neurotoxicity can have similar presentations. Varicella zoster virus deoxyribonucleic acid can be present in the cerebrospinal fluid during active cutaneous zoster in the absence of central nervous system disease. If concern for central nervous system varicella zoster virus disease remains high, additional testing with cerebrospinal fluid serology can be performed. Compared with central nervous system varicella zoster virus disease, acyclovir-induced neurotoxicity has a more predictable clinical resolution once drug therapy is discontinued or the patient undergoes hemodialysis, which can aid in making the diagnosis. Clinicians should be aware of this rare and dangerous complication of acyclovir. In addition, clinicians should have an understanding of the diagnostic limitations of cerebrospinal fluid viral polymerase chain reaction and have alternative approaches available to diagnose central nervous system varicella zoster virus disease when it is suspected.

Clinical and Laboratory Findings That Differentiate Herpes Simplex Virus Central Nervous System Disease from Enteroviral Meningitis.

Background. It can be difficult for clinicians to distinguish between the relatively benign enteroviral (EnV) meningitis and potentially lethal herpes simplex virus (HSV) central nervous system (CNS) disease. Very limited evidence currently exists to guide them. Objective. This study sought to identify clinical features and cerebrospinal fluid (CSF) findings associated with HSV CNS disease. Methods. Given that PCR testing often is not immediately available, this chart review study sought to identify clinical and cerebrospinal fluid (CSF) findings associated with HSV meningitis over a 6-year period. In cases where PCR was not performed, HSV and EnV were assigned based on clinical criteria. Results. We enrolled 166 consecutive patients: 40 HSV and 126 EnV patients. HSV patients had a mean 40.4 versus 31.3 years for EnV, p = 0.005, seizures 21.1% versus 1.6% for EnV, p < 0.001, altered mental status 46.2% versus 3.2% for EnV, p < 0.001, or neurological deficits 44.7% versus 3.9% for EnV, p < 0.001. CSF neutrophils were lower in HSV (median 3.0% versus 9.5%, p = 0.0002); median lymphocytes (87.0% versus 67.0%, p = 0.0004) and protein (0.9 g/L versus 0.6 g/L, p = 0.0005) were elevated. Conclusion. Our study found that HSV patients were older and more likely to have seizure, altered mental status, or neurological deficits than patients with benign EnV meningitis. HSV cases had lower CSF neutrophils, higher lymphocytes, and higher protein levels.

Varicella zoster virus pneumonitis and brainstem encephalitis without skin rash in an immunocompetent adult.

Varicella zoster virus (VZV) pneumonitis and brainstem encephalitis developed in an immunocompetent adult without rash. Chest computed tomography exhibited nodularity; lung biopsy revealed multinucleated giant cells, Cowdry A inclusions, VZV antigen, and DNA. Varicella zoster virus central nervous system disease was verified by cerebrospinal fluid (CSF) anti-VZV IgG antibody with reduced serum/CSF ratios.

Current developments in understanding of West Nile virus central nervous system disease.

West Nile virus (WNV) is the most important cause of epidemic encephalitis in the United States. We review articles published in the last 18 months related to the epidemiology, immunology, clinical features, and treatment of this disease. There was a resurgence in WNV disease in the United States in 2012. The WNV strain now predominant in the United States (NA/WN02) differs from the initial emergent isolate in 1999 (NY99). However, differences in the genetics of currently circulating United States WNV strains do not explain variations in epidemic magnitude or disease severity. Innate and acquired immunity are critical in control of WNV, and in some cases pathways are central nervous system specific. The clinical features of infection are now well understood, although nonconfirmed observations of chronic viral excretion in urine remain controversial. There is no specific antiviral therapy for WNV, but studies of antivirals specific for other flaviviruses may identify agents with promise against WNV. Phase I and II human WNV vaccine clinical trials have established that well tolerated and immunogenic WNV vaccines can be developed. WNV remains an important public health problem. Although recent studies have significantly increased our understanding of host immune and genetic factors involved in control of WNV infection, no specific therapy is yet available. Development of a well tolerated, immunogenic, and effective vaccine against WNV is almost certainly feasible, but economic factors and the lack of predictability of the magnitude and location of outbreaks are problematic for designing phase III trials and ultimate licensure.

Varicella-zoster virus CNS disease—Viral load, clinical manifestations and sequels

Background Real-time polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) samples has improved the diagnosis of varicella-zoster virus (VZV) infection of the central nervous system (CNS). The VZV viral load in the CSF obtained from VZV-related neurological syndromes is not known. Objectives To investigate VZV viral loads associated with VZV-related neurological syndromes, and to describe the clinical manifestations and sequels in patients with VZV DNA in the CSF. Study Design Patients in the Western Gotaland region of Sweden with CNS symptoms and VZV DNA in the CSF, during 1995–2006 were retrospectively identified. The diagnoses, laboratory tests (including virus quantity), antiviral treatment, and neurological complications were studied. Results Ninety-seven patients with VZV DNA in the CSF detected by PCR were identified. In 66 patients in whom VZV DNA levels were determined, significantly higher viral loads were found in those with encephalitis and acute aseptic meningitis compared to patients with cranial nerve affection (including Ramsay Hunt syndrome). Fifty patients had a follow-up; 34 (68%) had neurological symptoms 1 month after acute disease and 25 (50%) had neurological complications 3 months after discharge. A minimum yearly incidence of 1.8 per 100,000 of PCR diagnosed VZV CNS infections was estimated. Conclusions VZV was the most common α-herpesvirus detected in CSF samples from patients with CNS symptoms in the Western Gotaland region of Sweden. CSF viral loads were higher in patients with encephalitis and acute aseptic meningitis than in other CNS syndromes caused by VZV. A majority of the patients that were seen in follow-up had neurological symptoms and sequels.

Long-term Follow-up of HCV Infected Patients; Updated Results of the EBMT Prospective Study

Long-term Follow-up of HCV Infected Patients; Updated Results of the EBMT Prospective Study

Quantitative real-time PCR in paediatric patients with herpes simplex infections of the central nervous system

The aim of this study was to evaluate viral DNA load in paediatric patients with herpes simplex infections of the central nervous system. A real-time PCR assay for herpes simplex types 1 and 2 was developed for this 8-year retrospective study that included children with herpes simplex infection of the central nervous system (CNS) admitted to a paediatric hospital in Barcelona. Ten patients were diagnosed with herpes simplex CNS disease, 9 with herpes simplex encephalitis and 1 with neonatal herpes. The rate of the annual incidence of disease was stable during the study period, with a mean rate of 0.8 episodes per 100,000 children per year. Viral load was correlated with the increase in patient age (p<0.05) and with levels of more than 100leukocytes/mm3 in CSF p=0.02. Viral load was correlated with timing of the test in relation to the onset of clinical illness: 1.5×104GE/ml when the test was carried out in the first 72h versus 7.7×106GE/ml when test was carried out after 5 days of symptoms, p=0.01. In conclusion, quantitative real-time PCR provides a rapid, easy and accurate diagnosis of herpes virus CNS disease including viral load as supplementary information. Further studies are needed to confirm the relationship between viral load and other clinical, pathological, and genetic variables.

A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a Broader Spectrum of Disease?

The purpose of this study was to review the experience with herpes simplex encephalitis at the Hospital for Sick Children over the past 12 years. All patients who were admitted to our institution with acute encephalitis between January 1994 and December 2005 were enrolled prospectively in an encephalitis registry. Children from the registry with herpes simplex encephalitis were included in this study; we detailed the clinical presentations, laboratory findings, electroencephalographic findings, diagnostic imaging findings, treatments, and outcomes for all cases. Of 322 cases of acute encephalitis, 5% were caused by herpes simplex virus. Initially negative herpes simplex virus cerebrospinal fluid polymerase chain reaction results were found in 2 cases (13%), but results became positive in repeat cerebrospinal fluid analyses. Classic clinical presentations were seen in 75% of cases, cerebrospinal fluid pleocytosis was found in 94%, elevated cerebrospinal fluid protein levels were found in 50%, electroencephalographic changes were observed in 94%, and diagnostic imaging abnormalities were noted in 88%. All patients were treated with intravenous acyclovir. Neurologic sequelae occurred in 63% of cases, including seizures in 44% and developmental delays in 25%. There were no deaths in this study group. Herpes simplex encephalitis continues to be associated with poor long-term neurologic outcomes despite appropriate therapy. Cerebrospinal fluid polymerase chain reaction results may be negative early in the course of herpes simplex encephalitis; therefore, repeat cerebrospinal fluid analysis should be considered if herpes simplex encephalitis is suspected. Atypical forms of herpes simplex virus central nervous system disease may occur in children.

Sequence variation in the CC-chemokine ligand 2 promoter of pigtailed macaques is not associated with the incidence or severity of neuropathology in a simian immunodeficiency virus model of human immunodeficiency virus central nervous system disease

Increased expression of CC-chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and brain is consistently observed in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) central nervous system (CNS) disease. The molecular basis for the correlation between increased expression of CCL2 and HIV neuropathogenesis has been linked to a polymorphism at -2578 in the promoter of human CCL2, which was reported to influence the rate of progression to acquired immunodeficiency syndrome (AIDS) and the predisposition of HIV-infected individuals to develop HIV-associated dementia. However, because the rate of neurological deterioration essentially parallels the progression of immunosuppression, it is inherently difficult to uncouple the influence of this polymorphism on increased progression to AIDS from increased propensity to develop CNS complications. To further investigate the correlation between CCL2 and HIV/SIV CNS disease, the authors sequenced the CCL2 promoter of 29 pigtailed macaques examined in their accelerated and consistent SIV model in which all infected macaques develop AIDS but only 69% developed moderate/severe CNS lesions. Sequence analysis identified 39 sites of nucleotide variation in the pigtailed macaque CCL2 promoter/enhancer regions, with the resulting consensus sequence aligning with 94.7% homology to the human CCL2 promoter. After genetic analyses, no variation was found to correlate with the incidence or severity of CNS lesions or with levels of CCL2 in plasma or CSF. These findings suggest that the determinants of neuropathogenesis in this SIV model are distinct from variation in these regions of the CCL2 promoter.

Platelet decline: An early predictive hematologic marker of simian immunodeficiency virus central nervous system disease

As the prevalence of human immunodeficiency virus (HIV)-induced central nervous system (CNS) disease has increased with antiretroviral treatment, there is a critical need for identifying biomarkers that predict HIV CNS disease. To identify novel hematologic markers that precede and predict CNS disease, the authors examined longitudinal hematology data from 47 simian immunodeficiency virus (SIV)-infected macaques. This study demonstrated that the magnitude of decline in circulating platelet counts beginning at day 28 post infection, during asymptomatic SIV infection, predicted the eventual development of SIV encephalitis. Univariate analysis performed on platelet values obtained day 56 post inoculation demonstrated that SIV-infected macaques with the greatest decline in platelet numbers were 18 times more likely to develop SIV CNS disease than SIV-infected animals with minimal to no decline in circulating platelet counts. Decline in platelet number was a more robust marker than decline in hemoglobin levels, a previously identified marker of HIV CNS disease. The identification of an association between decline in platelets and the development of encephalitis demonstrates that monitoring platelet decline in HIV-infected individuals may serve as a predictive marker for clinical progression to HIV-induced CNS disease. Identifying those HIV-infected individuals at risk for CNS disease during asymptomatic stages of infection would promote early interventive, neuroprotective therapy to prevent neuronal damage and loss.

Searching for clues: tracking the pathogenesis of human immunodeficiency virus central nervous system disease by use of an accelerated, consistent simian immunodeficiency virus macaque model.

An accelerated model of human immunodeficiency virus central nervous system disease was developed in which more than 90% of infected macaques develop typical simian immunodeficiency virus (SIV) encephalitis with neuronal dysfunction by postinoculation (pi) day 84. Infected macaques had replicating virus and microglial activation in the brain 10 days after inoculation; viral replication and microglial activation were suppressed at pi day 21. By pi day 56, viral recrudescence in the brain was detected in 2 of 6 infected macaques. CD4 cells were the predominant lymphocytes in the brain during acute and asymptomatic infection; cytotoxic T lymphocytes and NK cells predominated in macaques with encephalitis. Low levels of peripheral blood NK lytic activity at pi day 10, elevated cerebrospinal fluid (CSF) monocyte chemoattractant protein-1 after 28 days, and high CSF viral RNA after 42 days predicted SIV encephalitis. This model is ideal to track the viral, cellular, and immunologic changes in the brain during acute and asymptomatic infection and during viral recrudescence and SIV encephalitis.

A novel simian immunodeficiency virus model that provides insight into mechanisms of human immunodeficiency virus central nervous system disease.

Although highly active antiretroviral therapy (HAART) has reduced the incidence of dementia, a significant proportion of HIV-infected individuals cease therapy because of unacceptable side effects. Further, HAART is not available to the majority of HIV-infected people worldwide. Thus, animal models remain an important means by which to investigate the pathogenesis of HIV-induced CNS disease, particularly events during acute infection. We have developed an accelerated, consistent SIV/macaque model of HIV infection in which over 90 percent of inoculated macaques develop SIV encephalitis and behavioral changes by three months post-inoculation (p.i.). Viral load in the CSF during terminal infection and the ratio of MCP-1 in CSF:plasma are strong predictors of the severity of encephalitis at necropsy. The high incidence of CNS disease in this model provides an opportunity to correlate host and viral events in the CNS during acute infection with the later development of CNS disease. Using this model, we have demonstrated that viral DNA persists in the brain throughout asymptomatic infection despite significant suppression of active virus replication. We have further demonstrated that encephalitis is associated with the selective replication of macrophage-tropic, neurovirulent viral strains, and that recrudescence of virus replication during terminal infection occurs by reactivation of preexisting viral strains in the brain.

Nested PCR for rapid detection of mumps virus in cerebrospinal fluid from patients with neurological diseases.

In this study, we have developed a reverse transcription (RT)-nested polymerase chain reaction (n-PCR) for the detection of mumps virus RNA in cerebrospinal fluid (CSF) from patients with neurological infections. A specific 112-bp fragment was amplified by this method with primers from the nucleoprotein of the mumps virus genome. The mumps virus RT-n-PCR was capable of detecting 0.001 PFU/ml and 0.005 50% tissue culture infective dose/ml. This method was found to be specific, since no PCR product was detected in each of the CSF samples from patients with proven non-mumps virus-related meningitis or encephalitis. Mumps virus RNA was detected in all 18 CSF samples confirmed by culture to be infected with mumps virus. Positive PCR results were obtained for the CSF of 26 of 28 patients that were positive for signs of mumps virus infection (i.e., cultivable virus from urine or oropharyngeal samples or positivity for anti-mumps virus immunoglobulin M) but without cultivable virus in their CSF. Overall, mumps virus RNA was detected in CSF of 96% of the patients with a clinical diagnosis of viral central nervous system (CNS) disease and confirmed mumps virus infection, while mumps virus was isolated in CSF of only 39% of the patients. Furthermore, in a retrospective study, we were able to detect mumps virus RNA in 25 of 55 (46%) CSF samples from patients with a clinical diagnosis of viral CNS disease and negative laboratory evidence of viral infection including mumps virus infection. The 25 patients represent 12% of the 236 patients who had a clinical diagnosis of viral CNS infections and whose CSF was examined at our laboratory for a 2-year period. The findings confirm the importance of mumps virus as a causative agent of CNS infections in countries with low vaccine coverage rates. In summary, our study demonstrates the usefulness of the mumps virus RT-n-PCR for the diagnosis of mumps virus CNS disease and suggests that this assay may soon become the "gold standard" test for the diagnosis of mumps virus CNS infection.