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OBJECTIVE: To characterize differences between Herpes Simplex virus encephalitis and Varicella-Zoster virus encephalitis (HSVE and VZVE) and other aetiologies of infectious encephalitis (IE), and to investigate the impact of time-to-aciclovir (ACV) start, ACV dose and duration on outcome.
METHODS: We compared 132 HSVE, 65 VZVE and 297 other IE enrolled in a prospective cohort (ENCEIF). We estimated associations between time-to-ACV start, dose or duration and outcome through adjusted odds ratio (aOR) using logistic regression analysis.
RESULTS: Prevalence of immunodepression differed among aetiologies: 15/65 (23%) for VZVE, 13/132 (10%) for HSVE and 30/297 (10%) for other IE (p <0.05), as was presence of seizure at admission: 27/132 (20%) for HSVE, 4/65 (6%) for VZVE and 43/297 (14%) for other IE (p <0.05). Poor outcome at hospital discharge (Glasgow outcome scale ≤3) differed among the three groups: 40/127 (31%) for HSVE, 12/65 (18%) for VZVE and 38/290 (13%) for other IE (p <0.05). Time-to-ACV start was associated with outcome in HSVE (aOR 3.61 [1.25-10.40]), but not in VZVE (aOR 0.84 [0.18-3.85]). Increased ACV dose was not associated with outcome among HSVE (aOR 1.25 [0.44-3.64]) nor VZVE (aOR 1.16 [0.24-5.73]).
CONCLUSIONS: HSVE and VZVE are distinct in clinical presentation, outcome and prognostic factors. The impact of early ACV initiation was more apparent for HSVE than for VZVE; however, this could be because of VZVE\'s smaller sample size and lower outcome rate leading to low statistical power or because of potential distinct IE pathophysiology.

Encephalitis is inflammation of the brain parenchyma, most often caused by viruses. Historically, data have shown herpes simplex virus 1 and 2 to be the most common causes of viral encephalitis, with cases due to varicella zoster virus (VZV) more often seen in older age and immunocompromised states. However, emerging data show VZV as an increasingly common culprit of encephalitis in young, immunocompetent patients. PCR analysis of the cerebrospinal fluid is the most accurate diagnostic modality for viral encephalitis. Appropriate and complete treatment hinges on accurate identification of the cause of encephalitis, underscoring the need for comprehensive testing. We present a case of VZV encephalitis in an immunocompetent male patient in his 40s.

Acute Varicella Zoster viral encephalitis in immunocompetent adult patients without cutaneous herpes has rarely been reported. A 24-year-old female was hospitalized for a headache with a fever but without other obvious symptoms. Multiple routine examinations showed no abnormalities. Lumbar puncture indicated intracranial hypertension. The examination of cerebrospinal fluid by metagenomic next-generation sequencing demonstrated acute Varicella Zoster viral encephalitis. The patient\'s condition improved by treatment with acyclovir for antiviral therapy and mannitol dehydration to lower cranial pressure. Central Varicella Zoster viral infection should be emphasized as it is easily misdiagnosed and rare in clinical settings. Metagenomic next-generation sequencing of cerebrospinal fluid has significant advantages in the diagnosis of Varicella Zoster viral encephalitis.

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OBJECTIVE: Varicella-zoster virus (VZV) is one of the most common etiologies of viral meningitis/encephalitis. The early clinical manifestations and cerebrospinal fluid (CSF) changes of VZV meningitis/encephalitis lack specificity, and it is easy to be misdiagnosed as other viral encephalitides or tuberculous meningitis. This study aims to investigate whether the clinical characteristics, CSF analysis findings, and CSF cytokine levels could distinguish VZV meningitis/encephalitis from central nervous system (CNS) herpes simplex virus (HSV) and Mycobacterium tuberculosis (MTB) infections.
METHODS: The medical records from 157 CNS infections, including 49 HSV (45 HSV-1, 4 HSV-2), 55 VZV, and 53 MTB infections between January 2018 and June 2021 in the Cytology Laboratory, Department of Neurology, Third Xiangya Hospital of Central South University were retrospectively reviewed. The data of 3 groups included demographic characteristics, laboratory results, radiographic findings, and outcomes. The levels of 12 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-γ, IFN-α, and TNF-α) in the CSF of 68 patients (13 HSV, 22 VZV, and 33 MTB infection cases) were quantified. Clinical and laboratory data were compared among the 3 groups.
RESULTS: The most common clinical manifestations in the 3 groups were fever, headache, vomiting, and neck stiffness. The clinical manifestations of HSV and VZV CNS disease were similar, although fever and altered consciousness were less common in the VZV group than those in the HSV and MTB groups (63.6% vs 87.8% vs 96.2%, P<0.001, and 14.5% vs 26.5% vs 47.2%, P=0.004, respectively). Seven patients (7/55, 12.7%) presented cutaneous zoster in the VZV group. CSF leukocyte count was significantly higher in the VZV group (230×106 cells/mL) and MTB groups (276×106 cells/mL) than that in the HSV group (87×106 cells/mL, P=0.002). CSF protein level was significantly higher in the VZV than that in the HSV group (1 034 mg/L vs 694 mg/L, P=0.011) but lower than that in the MTB group (1 744 mg/L, P<0.001). IL-6 (VZV vs HSV vs MTB: 2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL, P=0.029) and IL-8 (VZV vs HSV vs MTB: 4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL, P=0.046) levels were significantly different among the 3 groups and were elevated in the VZV group.Post hoc analysis revealed that IL-6 and IL-8 were significantly higher in the VZV group than those in the MTB group (P=0.002 and P=0.035, respectively), but not in the HSV group (P>0.05).
CONCLUSIONS: VZV meningitis/encephalitis presents with CSF hypercellularity and proteinemia, challenging the classical view of CSF profiles in viral encephalitis. CSF IL-6 and IL-8 levels are elevated in patients with VZV meningitis/encephalitis, indicating a more intense inflammatory response in these patients.
目的: 水痘-带状疱疹病毒(varicella-zoster virus，VZV)是最常见引起病毒性脑膜炎/脑炎的致病菌之一.VZV脑膜炎/脑炎早期临床表现和脑脊液(cerebrospinal fluid，CSF)变化缺乏特异性，容易被误诊为其他病毒性脑炎或结核性脑膜炎。因此本研究探讨VZV脑膜炎/脑炎与中枢神经系统(central nervous system，CNS)单纯疱疹病毒(herpes simplex virus，HSV)、结核分枝杆菌(Mycobacteriumtuberculosis，MTB)感染的临床特征、CSF结果及CSF细胞因子水平的区别。方法: 回顾性研究2018年1月至2021年6月中南大学湘雅三医院神经内科细胞学实验室确诊的157例CNS感染患者的医疗记录，其中感染HSV 49例(HSV-1 45例，HSV-2 4例)，VZV 55例，MTB 53例。收集的3组数据，包括人口学特征、实验室结果、影像学结果和疾病结局。对68例(13例HSV，22例VZV和33例MTB)患者CSF中的12个细胞因子(IL-1β，IL-2，IL-4，IL-5，IL-6，IL-8，IL-10，IL-12p70，IL-17，IFN-γ，IFN-α，TNF-α)水平进行检测。比较3组患者的临床和实验室资料。结果: 3组患者最常见的临床表现是发热、头痛、呕吐和颈部僵硬。HSV和VZV CNS疾病的临床表现相似。与HSV和MTB组相比，VZV组发热(63.6% vs 87.8% vs 96.2%，P<0.001)和意识改变(14.5% vs 26.5% vs 47.2%，P=0.004)更少见。VZV组有7例(12.7%)患者出现皮肤带状疱疹。VZV组(230×106/mL)和MTB组(276×106/mL)CSF白细胞计数显著高于HSV组(87×106/mL，P=0.002)，此外，VZV组CSF蛋白水平显著高于HSV组(1 034 mg/L vs 694 mg/L，P=0.011)，但低于MTB组(1 744 mg/L，P<0.001)。所测细胞因子中，3组IL-6(VZV vs HSV vs MTB：2 855.93 pg/mL vs 2 128.26 pg/mL vs 354.77 pg/mL，P=0.029)、IL-8(VZV vs HSV vs MTB：4 001.46 pg/mL vs 1 578.11 pg/mL vs 1 023.25 pg/mL，P=0.046)水平比较差异有统计学意义，其中VZV组IL-6和IL-8水平显著升高。事后分析显示：VZV组的IL-6和IL-8明显高于MTB组(分别为P=0.002和P=0.035)，但与HSV组相比差异无统计学意义(P>0.05)。结论: VZV脑膜炎/脑炎表现为CSF高细胞数和高蛋白质，这改变了我们对病毒性脑炎CSF谱的传统认识。VZV脑膜炎/脑炎患者CSF IL-6和IL-8水平升高，提示这些患者的炎症反应更为强烈。.

BACKGROUND The outcomes of varicella zoster virus (VZV) encephalitis/meningitis vary from complete recovery to severe complications. This study aimed to investigate the predictive factors of encephalitis and meningitis caused by VZV reactivation. MATERIAL AND METHODS VZV encephalitis/meningitis patients (n=39) who were treated between January 2019 and December 2021 were included. Patients were followed up for 3 months after discharge and divided into a favorable outcome group (FO, n=18; 46.2%) and an unfavorable outcome group (UO, n=21; 53.8%) according to whether it affects quality of life. The clinical data were retrospectively analyzed and compared between groups. RESULTS As compared to the FO group, patients in the UO group were more likely to have higher body temperature (>38°C) at admission, longer interval from onset of CNS symptoms to initial of antiviral therapy, higher white blood cells (WBC) and adenosine deaminase (ADA) in the cerebrospinal fluid (CSF) and higher CRP in the blood (P<0.05 or P<0.01). Univariate logistic regression analysis showed CSF ADA (OR=1.279, 95% CI: 0.996~1.642) and interval from onset of CNS symptoms to initial of antiviral therapy (OR=1.299, 95% CI: 1.011~1.669) were independent risk factors for unfavorable outcomes (P<0.05). The sensitivity and specificity of combined CSF ADA and time interval from onset of CNS symptoms to initial of antiviral therapy were 78.8% and 95.2%, respectively, in predicting outcomes. CONCLUSIONS Higher CSF ADA and longer interval from onset of CNS symptoms to initial of antiviral therapy predict an unfavorable outcome, and the combination of both factors can achieve better performance.