[Varicella-zoster meningoencephalitis and vasculitis after treatment with amenamevir to herpes zoster in the trigeminal nerve area].

A 78-year-old woman was diagnosed with herpes zoster in the first branch of the trigeminal nerve and was treated with amenamevir. Subsequently, she was hospitalized for postherpetic neuralgia. Fever and unconsciousness were observed, and a diagnosis of varicella-zoster virus meningoencephalitis and vasculitis was made. In addition to the antithrombotic therapy, she was treated with intravenous acyclovir and steroid pulse therapy; however, her unconsciousness persisted. Amenamevir was not transferrable to the spinal fluid and resulted in an incomplete treatment of herpes zoster in the cerebral nerve region, suggesting that this case may be related to the severe course of the disease.

Human Herpesvirus 6 Encephalitis in Immunocompetent and Immunocompromised Hosts.

OBJECTIVE: The aim of this study was to analyze the clinical, radiologic, and biological features associated with human herpesvirus 6 (HHV-6) encephalitis in immunocompetent and immunocompromised hosts to establish which clinical settings should prompt HHV-6 testing. METHODS: We performed a retrospective research in the virology database of Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) for all patients who tested positive for HHV-6 DNA in the CSF and/or in blood from January 2008 to September 2018 and separately assessed the number of patients meeting the criteria for HHV-6 encephalitis in the group of immunocompetent and immunocompromised hosts. RESULTS: Of the 926 patients tested for HHV-6 during the period of interest, 45 met the study criteria. Among immunocompetent hosts (n = 17), HHV-6 encephalitis was diagnosed to 4 infants or children presenting with seizures or mild encephalopathy during primary HHV-6 infection (CSF/blood replication ratio <<1 in all cases). Among immunocompromised hosts (n = 28), HHV-6 encephalitis was diagnosed to 7 adolescents/adults with hematologic conditions presenting with altered mental status (7/7), seizures (3/7), vigilance impairment (3/7), behavioral changes (2/7), hyponatremia (2/7), and anterograde amnesia (1/7). Initial brain MRI was altered only in 2 patients, but 6 of the 7 had a CSF/blood replication ratio >1. CONCLUSIONS: The detection of a CSF/blood replication ratio >1 represented a specific feature of immunocompromised patients with HHV-6 encephalitis and could be of special help to establish a diagnosis of HHV-6 encephalitis in hematopoietic stem cell transplant recipients lacking radiologic evidence of limbic involvement.

An unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNS infection: a prospective observational study.

BACKGROUND: Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood-brain barrier (BBB) in acute CNS infection may be of interest. OBJECTIVES: To investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS. METHODS: We investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS. RESULTS: Increased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration. CONCLUSIONS: In patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS.

Maintaining Concentration of Ribavirin in Cerebrospinal Fluid by a New Dosage Method; 3 Cases of Subacute Sclerosing Panencephalitis Treated Using a Subcutaneous Continuous Infusion Pump.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a slow virus infectious disease resulting from persistent infection with mutant measles virus. At present, there is no effective treatment for SSPE. Interferon-α and inosine pranobex have both been used for the treatment of SSPE, and partial success has been reported for the antiviral drug, ribavirin (RBV). The standardization of dosage method is necessary to carry out treatment with RBV more safely and effectively. In this study, RBV concentrations in cerebrospinal fluid (CSF) were monitored during the intraventricular administration using a subcutaneous continuous infusion pump. METHODS: Three patients with new-onset SSPE were treated with RBV using a subcutaneous continuous infusion pump. On days 3-10 after the start of RBV infusion, CSFs were obtained by lumbar tap, and the concentration of RBV in the CSF was measured using high-performance liquid chromatography. RESULTS: RBV concentration increased in a dose-dependent manner in all 3 patients, and the target concentration could be generally maintained without any severe side effects. We observed that the clinical symptoms were temporarily relieved in each case. In the 2 cases for whom treatment is continuing, the patients remain in stage III, while the patient who discontinued the therapy progressed to stage IV. CONCLUSION: The target RBV concentration in the CSF could be maintained continuously by intraventricular administration using a subcutaneous continuous infusion pump. The accumulation of further cases is necessary to confirm the safety and efficacy of this medical treatment.

Trials of antivirals in the treatment of multiple sclerosis.

There is increasing evidence that human herpes viruses and human endogenous retroviruses (HERV) are involved in the aetiology and pathogenesis of multiple sclerosis (MS). In order to acquire the ultimate evidence to confirm such a relationship, it is probably required to use specific antiviral drugs in clinical trials of MS. The results of published antiviral clinical trials in patients with MS are summarized in this review. None of them showed statistically significant effects on primary outcomes of disease activity or on disability development. However, given their small sample sizes, the strong trends and effects observed in subgroup analysis of antiherpes virus treatment in patients with MS warrant further studies. The possible involvement of HERV in MS is intriguing, and drugs have been developed that could reduce the impact of HERV in MS. However, larger studies are needed as the phase I and II trials were not designed to show clinical efficacy in MS.

Successful treatment and FDG-PET/CT monitoring of HHV-6 encephalitis in a non-neutropenic patient: case report and literature review.

Human herpesvirus (HHV)-6 reactivation is associated with severe forms of encephalitis among patients undergoing hematopoietic stem cell transplantation. Cases in non-neutropenic patients are uncommon. The efficacy of ganciclovir and other compounds that are used for the treatment of HHV-6 encephalitis remains suboptimal and linked to toxicity. Valganciclovir, the oral prodrug of ganciclovir, could be practical to treat outpatients, but it is not commonly used for severe cases. We report a case of HHV-6 encephalitis in a non-neutropenic patient successfully treated with valganciclovir and undergoing therapeutic drug monitoring in plasma and in the cerebrospinal fluid. Resolution of infectious foci was documented by cerebral MRI and F18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). A review of the literature on HHV-6 encephalitis is also reported.

Metabolomics of cerebrospinal fluid from humans treated for rabies.

Rabies is a rapidly progressive lyssavirus encephalitis that is statistically 100% fatal. There are no clinically effective antiviral drugs for rabies. An immunologically naïve teenager survived rabies in 2004 through improvised supportive care; since then, 5 additional survivors have been associated with use of the so-called Milwaukee Protocol (MP). The MP applies critical care focused on the altered metabolic and physiologic states associated with rabies. The aim of this study was to examine the metabolic profile of cerebrospinal fluid (CSF) from rabies patients during clinical progression of rabies encephalitis in survivors and nonsurvivors and to compare these samples with control CSF samples. Unsupervised clustering algorithms distinguished three stages of rabies disease and identified several metabolites that differentiated rabies survivors from those who subsequently died, in particular, metabolites related to energy metabolism and cell volume control. Moreover, for those patients who survived, the trajectory of their metabolic profile tracked toward the control profile and away from the rabies profile. NMR metabolomics of human rabies CSF provide new insights into the mechanisms of rabies pathogenesis, which may guide future therapy of this disease.

Absence of central nervous system and hypothermic effects after single oral administration of high doses of oseltamivir in the rat.

Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical study in rodents suggested a hypothermic effect of oseltamivir. The current studies investigated the CNS effects, body temperature effect and toxicokinetic profile of oseltamivir in rats. The CNS/temperature study included three groups receiving oseltamivir (500, 763 and 1000 mg/kg free base by oral gavage), one vehicle/control group and one reference group (D-amphetamine, 10 mg/kg). CNS parameters (behaviour, motor activity and co-ordination and sensory/motor reflex responses) and rectal temperature were measured at baseline and at five intervals until 8 hr after dosing. In the toxicokinetic study, rats received oseltamivir by oral gavage at 763 or 1000 mg/kg free base. Plasma, cerebrospinal fluid (CSF) and perfused brain concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured until 8 hr after dosing. Median scores for CNS parameters were similar in controls and animals receiving oseltamivir at all time points. Oseltamivir had no physiologically relevant effect on body temperature, but induced a short-lived and small dose-independent decrease in temperature in all active treatment groups at 1 hr after dosing only. Plasma concentrations of OC were higher than of oseltamivir, but the reverse was true in CSF and brain. CNS penetration was low for both moieties. In rats, oseltamivir at supratherapeutic doses up to 1000 mg/kg free base did not exert any effects on CNS function or hypothermic effects and led to limited CNS exposure, resulting in large safety margins.

Valacyclovir for herpes simplex encephalitis.

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.

Acyclovir resistance in herpes simplex encephalitis.

Herpes simplex virus type 1 is a common cause of severe sporadic encephalitis. Treatment with acyclovir is highly effective in this disease. We report the case of a 27-year-old, immunocompetent woman with acyclovir-resistant herpes simplex encephalitis. Although she had not been treated before, herpes simplex virus type 1 DNA from the cerebrospinal fluid showed a non-synonymous mutation in the thymidine kinase gene, which is likely to have caused resistance to acyclovir. Herpes simplex encephalitis resolved after treatment with foscarnet. To our knowledge, this is the first report of acyclovir-resistant herpes simplex virus encephalitis in an immunocompetent, previously therapy-naive adult.

Multiple oral dosing of valacyclovir in horses and ponies.

The aim of the current study was to investigate whether multiple oral dosing of valacyclovir could result in plasma concentrations exceeding the EC(50)-value of acyclovir against equine herpesvirus 1 (EHV1) during the majority of the treatment period. Additionally, we wanted to determine the concentration of acyclovir in nasal mucus and cerebrospinal fluid (CSF). Valacyclovir was administered to four horses and two ponies, three times daily, at a dosage of 40 mg/kg, for four consecutive days. Blood was collected prior to each administration and 1 h after dosing. Nasal mucus samples and CSF were collected once during treatment; 1 h after the last administration. This dosage regimen resulted in plasma concentrations that were higher than the EC(50)-value of 1.7 microg/mL, i.e. EC(50) of an isolate highly susceptible to acyclovir, for 80% of the treatment period; and higher than the EC(50)-value of 3.0 microg/mL, i.e. EC(50) of an isolate less susceptible to acyclovir, for 60% of the treatment period. Concentration in nasal mucus samples and CSF was 0.36-1.17 microg/mL and 0.11-0.23 microg/mL, respectively. This study illustrates that multiple dosing of valacyclovir may result in a therapeutic benefit as plasma concentrations could be maintained above the EC(50)-value of acyclovir against EHV1 for more than 50% of the treatment period. Acyclovir could be detected in both nasal mucus samples and CSF. However, these concentrations were lower than the EC(50).

Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers.

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C(max)], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C(max), 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C(max) CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.

[Gamma interferon testing in blood and cerebrospinal fluid--rapid method for the diagnosis of tuberculous meningitis]. / Dozarea gama-interferonului în sânge si în lichid cefalorahidian--metoda rapida de diagnostic a meningitei tuberculoase.

AIM: To evaluate the benefit of this early method of diagnosis of tuberculous meningitis, gamma-interferon levels comparatively in blood and cerebrospinal fluid (CSF). MATERIAL AND METHOD: We have studied 50 patients with tuberculous meningitis admitted in the Clinic of Infectious Diseases Iasi between 2006-2007, from the epidemiological, clinical, diagnosis and therapeutical points of view. RESULTS: Tuberculous meningitis was more frequent in males, with a mean ration of 2.5. The age of patients varied between 2 and 78 years of age, with a mean value of 30.5 years. 35.6% of patients were children. In 32 cases the meningeal infection was secondary, disseminated from a primary site, most frequently from the lungs (68,7%). The bacteriologic confirmation was through culture in 13.3%, with an average of 23.4 days of incubation. In whole blood the sensitivity Quantiferon TB Gold assay (QTF) was 78.57%. In CSF the specificity was higher than in blood (96.1 vs. 88.4%), having a positive prediction value over 90%. Antituberculous therapy prior to QTF testing had a negative impact, 50 to 6 cases having negative QTF results. CONCLUSION: The performance indicators of TB Gold Quantiferon Test in serum or CSF are high, being more sensitive and rapid than the direct exam of CSF or BK culture.

Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys.

Beta-D-dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h(-1); fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

Effects of acute renal failure and ganciclovir on the pharmacodynamics of levofloxacin-induced seizures in rats.

Seizures have been reported in patients receiving fluoroquinolones, including levofloxacin (LVFX). In the present study, we investigated the effects of experimental renal failure and the concomitant treatment with ganciclovir on the pharmacodynamics of LVFX-induced seizures to identify whether these factors can alter the pharmacokinetics or the pharmacodynamics of LVFX. Male Wistar rats received an intravenous infusion of LVFX at 250, 500, or 1000 mg/h/rat until the onset of seizures, and samples of serum, brain, and cerebrospinal fluid (CSF) were obtained. The concentration of LVFX in CSF at the onset of seizures was not affected by the infusion rate, whereas that in serum and brain increased with increasing infusion rate. This suggests that the concentration of LVFX in CSF is an appropriate index of the drug concentration at the site of action. The concentration of LVFX in CSF at the onset of seizures was significantly lower in rats with renal failure than in the control rats. Pretreatment with methylguanidine, an uremic toxin, at 600 mg/h/rat for 8 min reduced the concentration of LVFX in CSF at the onset of seizures and the total body clearance of LVFX after the intravenous injection. In rats pretreated with ganciclovir at 500 mg/h/rat for 1 h, the concentration of LVFX in CSF at the onset of seizures was significantly lower than the control rats. These results suggest that renal failure and ganciclovir can be the risk factors for LVFX-induced seizures, and that they increase the sensitivity of the central nervous system to LVFX-induced seizures.

Factors affecting delivery of antiviral drugs to the brain.

Although the CNS is in part protected from peripheral insults by the blood-brain barrier and the blood-cerebrospinal fluid barrier, a number of human viruses gain access to the brain, replicate within this organ, or sustain latent infection. The efficacy of antiviral drugs towards the cerebral viral load is often limited as both blood-brain interfaces impede their cerebral distribution. For polar compounds, the major factor restricting their entry lies in the tight junctions that occlude the paracellular pathway across these barriers. For compounds with more favourable lipid solubility properties, CNS penetration will be function of a number of physicochemical factors that include the degree of lipophilicity, size and ability to bind to protein or red blood cells, as well as other factors inherent to the vascular and choroidal systems, such as the local cerebral blood flow and the surface area available for exchange. In addition, influx and efflux transport systems, or metabolic processes active in both capillary endothelial cells and choroid plexus epithelial cells, can greatly change the bioavailability of a drug in one or several compartments of the CNS. The relative importance of these various factors with respect to the CNS delivery of the different classes of antiviral drugs is illustrated and discussed.

Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir.

The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean +/- standard deviation [SD], 27.1 +/- 5.6 micro M), and the minimum concentration in serum was 3.1 +/- 1.1 micro M (mean +/- SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean +/- SD levels being 2.5 +/- 0.9 and 2.3 +/- 0.7 micro M, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.

High-dose intravenous ribavirin therapy for subacute sclerosing panencephalitis.

Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo.