ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis.

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1ß and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

Association of G84A and C276T polymorphism in neuronal nitric oxide synthase (nNOS) gene with herpes simplex encephalitis in eastern Indian population.

In this study, a hypothesis that genetic variations in neuronal nitric oxide synthase (nNOS) could influence the susceptibility and outcome of herpes simplex encephalitis was investigated. Polymorphic loci of nNOS gene, G84A and C276T were genotyped in 132 HSE cases (Age 8.2 ± 1.3yr) and 143 in healthy individuals (Age-9.2 ± 1.6yr) of the same ethnic background from Odisha. A significantly increased risk for HSVE was associated with the AG genotype (OR = 1.73, 95%CI = 1.03-2.9, P = 0.03) and AA genotype (OR = 2.96, 95%CI = 1.04-8.4, P = 0.04) of nNOS 84G →A locus. In case of nNOS 276C→T variation, HSVE risk was linked to CT genotype (OR = 1.79, 95%CI = 1.07-3.0, P = 0.03) and TT genotype (OR = 3.6, 95%CI = 1.2-10.8, P = 0.02). Patients with poor outcome either had homo or heterozygous genotype for both SNPs, but separate genotype analysis could not show significance. But combined genotype analysis of both SNPs confirmed that GG + CC was a risk factor for development of poor outcome. (OR = 6.3, CI-1.9-20.7, P = 0.0033). Haplotype analysis of both SNP did show that "at" haplotype was significantly higher and associated with HSVE cases (OR = 2.322,CI: 1.43-3.77, P = 0.00070). The result observed in this study suggested that variation at these loci of nNOS may have decreased its expression and caused low production of NO, which have resulted in risk of HSVE but provided good outcome in these patients.

Inconsistent Management of Neonatal Herpes Simplex Virus Infections.

OBJECTIVES: The incidence of neonatal herpes simplex virus (nHSV) infections is monitored periodically in the Netherlands, yet management and outcome is unknown. Comprehensive national guidelines are lacking. We aim to describe management and outcome in the last decade to explore current diagnostic and therapeutic challenges. We aim to identify possible variability in management of patients with a suspected nHSV infection. METHODS: We conducted a retrospective case series of management and outcome of nHSV infections at 2 tertiary care center locations in the Netherlands. RESULTS: An nHSV infection was diagnosed in 1% (12 of 1348) of patients in whom polymerase chain reaction for HSV was performed. Of the patients with nHSV infection, 3 of 12 died, and 4 of 9 (44%) survivors suffered neurologic sequelae. Neurologic symptoms at presentation were seen in only 2 of 8 patients with nHSV encephalitis. A cerebral spinal fluid analysis was performed in 3 of 6 patients presenting with skin lesions. Only 3 of 6 patients with neurologic symptoms received suppressive therapy. nHSV infection was diagnosed in 8 of 189 (4%) patients who were empirically treated. CONCLUSIONS: Management of nHSV infection, particularly when presented with skin lesions, is inconsistent. Many infants without a HSV infection are exposed to antiviral medication. There is substantial interhospital variation in diagnostic and therapeutic management of a suspected infection. Comprehensive guidelines need to be developed to standardize management of suspected nHSV infection.

Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis.

Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1-3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis.

Incidence and mortality of herpes simplex encephalitis in Denmark: A nationwide registry-based cohort study.

OBJECTIVES: We aimed to investigate the incidence and mortality of herpes simplex encephalitis (HSE) in a nationwide cohort. METHODS: From the Danish National Patient Registry, we identified all adults hospitalised with a first-time diagnosis of HSE in Denmark during 2004-2014. The HSE diagnoses were verified using medical records and microbiological data. Patients were followed for mortality through the Danish Civil Registry System. We estimated age-standardised incidence rates of HSE and 30-day, 60-day, and 1-year cumulative mortality. Furthermore, we assessed whether calendar year, age, gender, level of comorbidity, virus type, and department type was associated with HSE mortality. RESULTS: We identified a total of 230 cases of HSE. Median age was 60.7 years (interquartile range: 49.3-71.6). The overall incidence rate was 4.64 cases per million population per year (95% confidence interval: 4.06-5.28). The cumulative mortality within 30 days, 60 days, and 1 year of the HSE admission was 8.3%, 11.3%, and 18.6%, respectively. Advanced age and presence of comorbidity were associated with increased 60-day and 1-year mortality. CONCLUSIONS: This nationwide study of verified HSE found a higher incidence than reported in previous nationwide studies. Presence of comorbidity was identified as a novel adverse prognostic factor. Mortality rates following HSE remain high.

Can we differentiate between herpes simplex encephalitis and Japanese encephalitis?

BACKGROUND: Herpes simplex encephalitis (HSE) occurs without regional and seasonal predilections. HSE is important to differentiate from arboviral encephalitis in endemic areas because of therapeutic potential of HSE. This study evaluates clinical features, MRI and laboratory findings which may help in differentiating HSE from Japanese encephalitis (JE). METHODS: Confirmed patients with JE and HSE in last 10years were included. The presenting clinical symptoms including demographic information, seizure, behavioral abnormality, focal weakness and movement disorders were noted. Cranial MRI was done and location and nature of signal alteration were noted. Electroencephalography (EEG), cerebrospinal fluid (CSF), blood counts and serum chemistry were done. Outcome was measured by modified Rankin Scale (mRS). Death, functional outcome and neurological sequelae were noted at 3, 6 and 12months follow up, and compared between HSE and JE. Outcome was categorized as poor (mRS;>2) and good (mRS≤2). RESULTS: 97 patients with JE and 40 HSE were included. JE patients were younger than HSE and occurred in post monsoon period whereas HSE occurred throughout the year. Seizure (86% vs 40%) and behavioral abnormality (48% vs 10%) were commoner in HSE; whereas movement disorders (76% vs 0%) and focal reflex loss (42% vs 10%) were commoner in JE. CSF findings and laboratory parameters were similar in both the groups. Thalamic involvement in JE and temporal involvement in HSE were specific markers of respective encephalitis. Delta slowing on EEG was more frequent in JE than HSE. 20% JE and 30% HSE died in the hospital, and at 1year follow up JE patients showed better outcome compared to HSE (48% vs 24%). Memory loss (72% vs 22%) was the predominant sequelae in HSE. CONCLUSION: Seizure and behavioral abnormality are common features in HSE whereas focal reflex loss is commoner in JE. In a patient with acute encephalitis, thalamic lesion suggests JE and temporal lobe involvement HSE. Long term outcome in JE is better compared to HSE.

p53 Is a Host Cell Regulator during Herpes Simplex Encephalitis.

UNLABELLED: p53 is a critical host cell factor in the cellular response to a broad range of stress factors. We recently reported that p53 is required for efficient herpes simplex virus 1 (HSV-1) replication in cell culture. However, a defined role for p53 in HSV-1 replication and pathogenesis in vivo remains elusive. In this study, we examined the effects of p53 on HSV-1 infection in vivo using p53-deficient mice. Following intracranial inoculation, p53 knockout reduced viral replication in the brains of mice and led to significantly reduced rates of mortality due to herpes simplex encephalitis. These results suggest that p53 is an important host cell regulator of HSV-1 replication and pathogenesis in the central nervous system (CNS). IMPORTANCE: HSV-1 causes sporadic cases of encephalitis, which, even with antiviral therapy, can result in severe neurological defects and even death. Many host cell factors involved in the regulation of CNS HSV-1 infection have been investigated using genetically modified mice. However, most of these factors are immunological regulators and act via immunological pathways in order to restrict CNS HSV-1 infection. They therefore provide limited information on intrinsic host cell regulators that may be involved in the facilitation of CNS HSV-1 infection. Here we demonstrate that a host cell protein, p53, which has generally been considered a host cell restriction factor for various viral infections, is required for efficient HSV-1 replication and pathogenesis in the CNS of mice. This is the first report showing that p53 positively regulates viral replication and pathogenesis in vivo and provides insights into its molecular mechanism, which may suggest novel clinical treatment options for herpes simplex encephalitis.

Meningoencefalitis herpética: ¿cuándo sospecharla? / Herpetic meningoencephalitis: a review

La encefalitis herpética (EH) secundaria a la infección por el virus de herpes simple 1 (VHS1) es la causa conocida más frecuente a nivel mundial de infección viral fatal del sistema nervioso central (SNC). La agresividad de su curso clínico y la morbilidad asociada a su desarrollo obligan a todo médico generalista a mantener una alta sospecha clínica para lograr su diagnóstico. Ciertas manifestaciones clínicas como la fiebre asociada a alteraciones en el sensorio o a alteraciones en el comportamiento de un paciente o a ambas posibilidades se presentan en un porcentaje superior al 90% de los casos confirmados. La solicitud en el líquido cefalorraquídeo (LCR) de la reacción en cadena de la polimerasa (PCR) para el VHS1 es el estudio complementario de laboratorio que posee la mayor sensibilidad y especificidad para confirmar el diagnóstico de EH. A su vez, la resonancia nuclear magnética (RNM) es el estudio de imagen que posee mayor sensibilidad y especificidad para el diagnóstico de la enfermedad. La EH secundaria al VHS1 es, de las infecciones virales que afectan el SNC, la única que posee tratamiento específico. La instauración temprana de tratamiento con aciclovir disminuye la mortalidad asociada al desarrollo de la enfermedad de un 70% y sin tratamiento, hasta un 10-20%. El objetivo principal de esta revisión es señalar las diversas situaciones clínicas en las cuales se debe sospechar la EH así como guiar la correcta utilización de los estudios complementarios e instaurar de manera temprana el tratamiento para reducir al máximo la morbimortalidad. (AU)

The herpes simplex virus type 1 (HSV1) encephalitis (EH) is the most common known cause of sporadic fatal encephalitis worldwide. The fatal consequences in the development of this disease and the morbidity related to it, should alert general practitioner to be always aware of its possible diagnosis. Clinical features such as fever associated with altered mental status or disturbances in the level of consciousness are present in more than 90% of confirmed cases. The analysis of the polymerase chain reaction (PCR) for HSV1 in central nervous system (CNS) fluid is the laboratory study of choice for establishing the diagnosis with the best sensitivity and specificity. Moreover, magnetic resonance image (MRI) is the most sensitive and specific imaging study for the detection of this entity. The VHS1 EH is one of the few treatable viral infection of the central nervous system to date. Hence, early administration of adequate antiviral therapy with Acyclovir remains paramount. The early administration of empiric therapy can decrease the mortality rate from 70% without treatment to 10-20% in confirmed cases. We sought to describe the disease's clinical features, and to further discuss the accurate use of diagnostic tools and treatment strategies in order to reduce the high related morbi-mortality. (AU)

Long-term outcome of severe herpes simplex encephalitis: a population-based observational study.

INTRODUCTION: Herpes simplex encephalitis (HSE) is a rare disease with a poor prognosis. No recent evaluation of hospital incidence, acute mortality and morbidity is available. In particular, decompressive craniectomy has rarely been proposed in cases of life-threatening HSE with temporal herniation, in the absence of evidence. This study aimed to assess the hospital incidence and mortality of HSE, and to evaluate the characteristics, management, the potential value of decompressive craniectomy and the outcome of patients with HSE admitted to intensive care units (ICUs). METHODS: Epidemiological study: we used the hospital medical and administrative discharge database to identify hospital stays, deaths and ICU admissions relating to HSE in 39 hospitals, from 2010 to 2013. Retrospective monocentric cohort: all patients with HSE admitted to the ICU of the university hospital during the study were included. The use of decompressive craniectomy and long-term outcome were analyzed. The initial brain images were analyzed blind to outcome. RESULTS: The hospital incidence of HSE was 1.2/100,000 inhabitants per year, 32 % of the patients were admitted to ICUs and 17 % were mechanically ventilated. Hospital mortality was 5.5 % overall, but was as high as 11.9 % in ICUs. In the monocentric cohort, 87 % of the patients were still alive after one year but half of them had moderate to severe disability. Three patients had a high intracranial pressure (ICP) with brain herniation and eventually underwent decompressive hemicraniectomy. The one-year outcome of these patients did not seem to be different from that of the other patients. It was not possible to predict brain herniation reliably from the initial brain images. CONCLUSIONS: HSE appears to be more frequent than historically reported. The high incidence we observed probably reflects improvements in diagnostic performance (routine use of PCR). Mortality during the acute phase and long-term disability appear to be stable. High ICP and brain herniation are rare, but must be monitored carefully, as initial brain imaging is not useful for identifying high-risk patients. Decompressive craniectomy may be a useful salvage procedure in cases of intractable high ICP.

Encefalitis por virus herpes simple 1 tras extirpación de meningioma / Herpes simplex virus type 1 encephalitis after meningioma resection

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Decompressive craniectomy for encephalitis with brain herniation: case report and review of the literature.

BACKGROUND: Decompressive craniectomy (DC) has been sporadically used in cases of infectious encephalitis with brain herniation. Like for other indications of DC, evidence is lacking regarding the beneficial or detrimental effects for this pathology. METHODS: We reviewed all the cases of viral and bacterial encephalitis treated with decompressive craniectomy reported in the literature. We also present one case from our institution. These data were analyzed to determine the relation between clinical and epidemiological variables and outcome in surgically treated patients. RESULTS: Of 48 patients, 39 (81.25 %) had a favorable functional recovery and 9 (18.75 %) had a negative course. Only two patients (4 %) died after surgical treatment. A statistically significant association was found between diagnosis (viral and bacterial encephalitis) and outcome (GOS) in surgically treated patients. Viral encephalitis, usually caused by herpes simplex virus (HSV), has a more favorable outcome (92.3 % with GOS 4 or 5) than bacterial encephalitis (56.2 % with GOS 4 or 5). CONCLUSIONS: Based on this literature review, we consider that, due to the specific characteristics of infectious encephalitis, especially in case of viral infection, decompressive craniectomy is probably an effective treatment when brain stem compression threatens the course of the disease. In patients with viral encephalitis, better prognosis can be expected when surgical decompression is used than when only medical treatment is provided.

Role of IL-6 and neopterin in the pathogenesis of herpetic encephalitis.

Herpetic encephalitis (HSE) is one of the most severe infection of the central nervous system (CNS), connected with high mortality rate, even when appropriate therapy has been introduced. Better understanding of pathomechanisms responsible for neuronal injury during the course of the disease can be useful in the assessment of the risk of the occurrence of severe complications, as well as in potential introduction of additional therapeutic methods. The purpose of this study is to assess the correlation between concentration of neopterin and IL-6 in the CSF and serum, and the course of HSE. In this study, 36 patients with HSE were investigated, and the control group consisted of 32 patients in whom the infection of the CNS was excluded. We observed significantly higher concentration of neopterin and IL-6 in the CSF of patients with HSV as compared with the control group. Neopterin and IL-6 levels in the CSF correlated with the course of HSE. Higher values were connected with the risk of respiratory failure, development of permanent neurologic complications and patient death. Negative correlations between concentration of IL-6 and neopterin and patient condition assessed by Glasgow Coma Scale (GCS) were observed. Neopterin with high sensitivity and specificity allowed to predict the risk of death or severe neurological complications. Increased concentration of neopterin and IL-6 in the CSF and serum revealed reciprocal positive correlation. Assessment of the concentration of IL-6 and neopterin in the serum was not useful to predict the course of HSE.

Passively administered pooled human immunoglobulins exert IL-10 dependent anti-inflammatory effects that protect against fatal HSV encephalitis.

HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1-3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b(+) Ly6C(high) monocytes and inhibited their spontaneous degranulation in vitro. FcγRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45(+) Ly6C(low) monocytes but not for inhibiting development of Ly6C(high) monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3(+) CD4(+) T regulatory cells (Tregs) and FoxP3(-) ICOS(+) CD4(+) T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS(+) CD4(+) T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti-inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases.

[Analysis of clinical features of herpes encephalitis].

Herpes encephalitis makes up more than 20% of all viral encephalitises in countries with moderate climate. Over the period of 1971-2008, 112 inpatients with herpes encephalitis have been examined and treated. Outcomes were as follows: 90 (80%) patients recovered and 22 (20%) patients died. The diagnostic criteria were the relation with herpes simplex virus type I (HSV-1) by immunological and clinical data in the presence of clinical symptoms of viral encephalitis for recovered patients and clinical symptoms of acute encephalitis, morphological foci of necrosis in the brain, relation with HSV, the absence of other alternative diagnosis for dead patients. Based on the analysis of 112 patients, the authors present clinical symptoms of herpes encephalitis. The presentation is supported by 2 case reports.

Brainstem encephalitis: an unusual presentation of herpes simplex virus infection.

Herpes simplex virus (HSV) encephalitis has a predilection for the temporal and frontal lobes but occasionally affects the brainstem. We describe a patient who developed HSV brainstem encephalitis that progressed to quadriplegia. Using MEDLINE, we conducted a comprehensive review of other published cases of HSV brainstem encephalitis. Twenty-four published cases of HSV brainstem encephalitis met our inclusion criteria. The mean age was 41.4 years (range 18-71). HSV-1 was the etiologic agent in 79% of reported HSV brainstem encephalitis cases, and HSV-2 accounted for 21% of cases. Infection was limited to the brainstem in 29% of cases and multi-focal, including the brainstem, in 71%. Common manifestations of HSV brainstem encephalitis included neuro-ophthalmologic findings (81%), cranial nerve deficits (69%), and fever (69%). Quadriplegia, as occurred in our patient, was an unusual finding (19%). The mortality rate of HSV brainstem encephalitis was 41%. Intravenous acyclovir showed a beneficial effect on mortality (75% vs. 22%, p = 0.06). HSV brainstem encephalitis is a distinct type of HSV encephalitis. With the increasing use of HSV-PCR, more cases of HSV brainstem encephalitis may be identified. A greater recognition of this syndrome will help better define its optimal treatment and prognosis.

Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality.

BACKGROUND: Herpes simplex encephalitis (HSE) is a devastating disease. METHODS: In Sweden, a nationwide retrospective study of the incidence, morbidity, and mortality associated with HSE during the 12-year period 1990-2001 was conducted. The national inpatient register data were used, and diagnostic data from the virus laboratories were validated. RESULTS: In the study period, 638 patients hospitalized in Sweden received a primary diagnosis of HSE. Of these, 236 patients had a confirmed infection of the central nervous system due to herpes simplex virus type 1. This corresponds to an incidence of confirmed HSE due to herpes simplex virus type 1 of 2.2 cases per million population per year. Of the survivors, 87% were readmitted to the hospital. The most frequent diagnosis at readmission was epilepsy, which was found in 49 patients (21% of the 236 total patients; 24% of 203 survivors), with a median onset 9.3 months after the diagnosis of HSE. This corresponds to a 60- to 90-fold increase in risk, compared with that for the general population. Neuropsychiatric sequelae were evident in 45 (22%) of 203 surviving patients. The incidence of venous thromboembolism, including pulmonary embolism, was 5-14 times higher than that in the general population. Among patients with HSE due to herpes simplex virus type 1, the 1-year mortality was 14% (33 of 236 patients died), which was 8 times higher than expected. CONCLUSIONS: This is, to our knowledge, the first study to report long-term, nationwide follow-up data for patients with virologically confirmed HSE. There is considerable morbidity after HSE, with epilepsy being the most common diagnosis. This demonstrates the need for expanding our knowledge of the pathogenesis of HSE to direct more effective antiviral and antiinflammatory treatments.

Effects of CXCR3 signaling on development of fatal encephalitis and corneal and periocular skin disease in HSV-infected mice are mouse-strain dependent.

PURPOSE: The host inflammatory response to ocular infection with herpes simplex virus (HSV) can be either protective, with disease-free survival, or it can promote diseases such as HSV corneal disease (or herpes stromal keratitis [HSK] in humans) and encephalitis (HSE), depending on mouse strain. The role of CXCR3 chemokine signaling in HSV-induced central nervous system (CNS) inflammation and corneal disease was evaluated, and responses in genetically susceptible and resistant strains of mice were contrasted. METHODS: Resistant C57BL/6J (B6) and susceptible 129S6 (129) mice were given monoclonal antibodies (mAbs) to neutralize the CXCR3 ligands monokine induced by interferon-gamma (MIG, CXCL9) and interferon inducible protein-10 (IP-10, CXCL10) during HSV infection. In addition, the development of HSV disease was monitored in CXCR3-null mutant mice derived from resistant (B6) and susceptible (BALB/c) strains. Inflammatory cells infiltrating the cornea and brain stem were isolated and stained for flow cytometric analysis. RESULTS: MIG and IP-10 were induced in nervous system tissue after HSV inoculation by the corneal route. HSV-infected 129 mice treated with MIG- or IP-10-neutralizing mAbs showed significantly enhanced survival compared with mice treated with control isotype antibody, whereas survival of the B6 mice was unaltered. Similarly, greater survival was observed for BALB.CXCR3(-/-) mice compared with control BALB/c mice. Reduced CNS inflammation was documented that extended to the cornea, such that HSV corneal disease severity was reduced in susceptible BALB.CXCR3(-/-). In contrast, although survival of B6 and B6.CXCR3(-/-) mice was indistinguishable, B6.CXCR3(-/-) mice developed more severe corneal and periocular skin disease. CONCLUSIONS: The effects of CXCR3 signaling in HSV infection are strongly dependent on mouse strain.

Re-evaluating the diagnostic methods in herpes simplex encephalitis.

Several methods are used in clinical practice to investigate herpes simplex encephalitis (HSE), including electroencephalography (EEG) and polymerase chain reaction (PCR) of the viral genome in cerebrospinal fluid. PCR is the most sensitive and specific of the diagnostic methods currently employed. We retrospectively examined the diagnostic utility of EEG and cranial imaging within the first 24-48 h of symptom onset in patients with suspected HSE. Patients with herpes simplex-positive PCR results were compared with those with herpes simplex-negative PCR results. Periodic lateralized epileptiform discharges and/or focal temporal slowing were present in 90% of the PCR-positive patients at symptom onset compared with only 30% of the PCR-negative group. The sensitivity of EEG recordings decreased after 48 h. Although no patients had computed tomography findings suggestive of HSE, magnetic resonance imaging results were consistent with HSE in 86% of those with herpes simplex-positive PCR results obtained after 48 h from symptom onset.

[Herpetic encephalitis in adults: 23 cases]. / Encefalitis herpética en adultos: 23 casos.

OBJECTIVE: To study the clinical presentation, diagnosis, treatment and prognosis of the herpetic encephalitis in our environment. MATERIAL AND METHOD: During the past 12 years, 23 adults (age > 15 years) were treated for herpetic encephalitis in our centre. RESULTS: There were 14 males and 9 females. Ages ranged from 18 to 84 years (mean, 52.30 +/- 18.64 years). The hospital stay ranged from 5 to 64 days (mean, 26.74 +/- 15.41 days). Eleven patients were managed in the intensive care unit and nine patients required mechanical ventilation. The most frequent clinical features they were the level of conscience decrease and fever. The lymphocytic pleiocytosis was the most frequent discovery in cerebrospinal fluid. The temporal lobe lesions in the computed tomography scan appeared in 14 patients (61%). Four patients died, seven patients were asymptomatic or with minimum sequels and twelve patients developed they were disabled. CONCLUSIONS: The herpetic encephalitis is an uncommon illness. Intravenous acyclovir is recommended treatment and the corticosteroids use is controverted. The delay in the treatment beginning worsens the prognosis. Less than a third of the patients achieve the functional independence to discharge hospital.