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

Journal of NeuroVirology - 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...     

Changes in vascular permeability of the central nervous system by experimental herpes simplex and vaccinia virus infections

Summary A study was made to examine the occurrence and distribution of changes in vascular permeability in viral infections of the CNS in mice. Vascular permeability was demonstrated by fluorescent microscopic tracing of intravasally introduced serum albumin labeled with Evans blue. Viruses—Herpes simplex and different strains of vaccinia—were used, which produce contrasting clinical pictures and morphological changes following intracerebral inoculation. Immunofluorescent technique was employed for the localization of viral antigen. The principal findings were as follows:Infection with neurovirulent strains of vaccinia was followed by widespread lesions of the vascular permeability with exudation of albumin in the leptomeninges and diffusion in the neuropil of the cerebral and cerebellar cortex. Unless very large doses of a non-neuroadapted vaccinia strain were injected i.c., no clinical sings of disease appeared and no changes of the vascular permeability were detected in spite of virus multiplication.Following infection with Herpes simplex, changes of the vascular permeability were seen mainly in the hippocampal regions, in areas bordering on the ventricles and in the olfactory bulbs.The significance of the increased vascular permeability for the clinical picture is discussed, as is the relationship between the oedema and the reactions of the neuroectodermal cells.This study was supported by a grant, B69-12X-82-05, from the Swedish Medical Research Council. The authors wish to express their gratitude to Drs.E. Lycke, L. Lindholm, andY. Olsson for valuable criticism and advice and to Mrs.Gun Lundblad for skilful technical assistance.     

Beta-2-microglobulin in the cerebrospinal fluid of patients with infections of the central nervous system

Beta-2-microglobulin was determined in 147 patients admitted to hospital because of suspicion of CNS disease. Patients with meningism were chosen as control group. The concentration of beta-2-microglobulin in the spinal fluid of control patients was correlated with age. Reference values for 0-40 years were 0.34-1.58 mg/l. Above 40 years of age the values were 0.46-3.14 mg/l. CSF beta-2-microglobulin levels of patients with meningism, aseptic and bacterial meningitis overlap too much to be relevant in distinguishing between these entities. Five patients with herpes simplex encephalitis had markedly elevated levels ranging from 4.4 to 9.0 mg/l. Ten patients with herpes zoster-associated encephalitis had values from 1.1 to 6.1 mg/l. In the patient groups with CNS infections, the ratio of serum to spinal fluid beta-2-microglobulin was significantly more frequently less than 1 as compared with the meningism group, indicating intrathecal production of the protein. Further studies on the clinical relevance of CSF beta-2-microglobulin in the diagnosis of encephalitis seem warranted.     

Diagnosis of Epstein-Barr virus–induced central nervous system infections by DNA amplification from cerebrospinal fluid

A nested polymerase chain reaction was used for the detection of Epstein-Barr virus DNA in 1 patient with encephalitis, and in 1 patient with myelitis. Epstein-Barr virus DNA was detected in cerebrospinal fluid samples obtained at the onset of neurological symptoms in both patients, and serological findings indicated ongoing Epstein-Barr virus infection. In the patient with encephalitis, herpes simplex virus type 1 DNA was transiently detected in the cerebrospinal fluid, while Epstein-Barr virus DNA was still present on day 44 after admittance. Single-photon emission computed tomography in this patient indicated a frontal bilateral hypoperfusion. The diagnostic value of polymerase chain reaction on cerebrospinal fluid and serum samples for Epstein-Barr virus infections of the central nervous system is emphasized.     

Detecting infectious agents in central nervous system inflammation by cerebrospinal fluid analysis

Cerebrospinal fluid analysis is the method of choice in CNS infection and provides the basis for appropriate treatment. Due to the proximity of CSF and CNS, the infectious agent may be detected directly by microscopy or antigen or nucleic acid detection--the latter by polymerase chain reaction--in native CSF or after culture. Furthermore, intrathecal antibody synthesis against the infectious agent may identify the cause of infection. This indirect antigen detection method requires correction for a systemic antibody response and a blood-CSF barrier disturbance. The following text gives an overview of appropriate detection methods and their relevance to the most important CNS infections.     

Immunoglobulin G antibodies to herpes simplex type 1 virus detected by radioimmunoassay in serum and cerebrospinal fluid of patients with schizophrenia.

Serum and CSF specimens from 16 schizophrenic patients and 18 nonpsychiatric controls were tested by radioimmunoassay for immunoglobulin G antibody of capsid, envelope and excreted antigens of herpes simplex type 1 virus. There were no significant differences in the antibody levels between the schizophrenic patients and the controls. The etiological role of viruses and virus-like agents in schizophrenia and some methodological aspects are discussed.     

Diagnostic value of cerebrospinal fluid antibodies in herpes simplex virus encephalitis.

Antibodies to different viruses and bacteria were measured in the cerebrospinal fluid (CSF) of six patients with herpes simplex virus encephalitis proven by brain biopsy and in five others with a presumptive diagnosis. Antibodies to herpes simplex virus but not to other organisms appeared in the CSF of all patients after the first weeks of the illness. Herpes simplex virus antibodies were not found in control CSF. The antibodies persisted in the CSF and the serum/CSF antibody ratio remained altered, 32:1 to less than 1:1, in all cases during the follow-up to 29 months or until death. The CSF albumin level was normal and the IgG index (formula: see text) elevated in four proven and three presumptive cases indicating a local antibody production; in four patients the findings were inconsistent. These results suggest that prolonged antigen stimulation is present in the central nervous system after acute herpes simplex encephalitis and that serological measurements combined with immunoglobulin and albumin determinations may provide a tentative but not definite diagnosis in some cases after the acute phase of encephalitis together with a method for follow-up of patients.     

脑脊液循环动力学的初步计算机建模分析

目的 应用磁共振相位对比法和计算流体力学软件对脑脊液循环系统进行数值模拟,分析脑脊液循环的动力学特性,并与临床实际相比较.方法 用磁共振相位对比法测定2例正常人的中脑导水管脑脊液流速,并利用临床磁共振扫描图像建市脑脊液循环系统的数值模型,用Matlab软件及Enguage软件提取脑脊液循环系统的轮廓并进行网格划分,然后应用COMSOL Muhiphysics软件进行脑脊液循环系统数值模拟及脑脊液动力学分析.结果 通过模拟软件能模拟脑脊液循环存在的与心动周期相关的有规律的双向流动,表现为心脏收缩期向足侧流动,舒张期向头侧流动,各时相期计算出的速度与我们用磁共振相位对比法测定的在体速度相一致.同时脑脊液循环系统的数值模型能够计算得到颅内压力梯度、脑和脊髓组织固体应力等.结论 脑脊液循环系统的计算机建模分析能无创性得到脑脊液循环的各项动力学量化指标,计算所得与临床实际相符合.本模型为进一步研究一些中枢系统疾病如交通性脑积水、Chiari畸形、脊髓空洞症等的脑脊液动力学机制奠定了基础.     

Adenylate kinase activity of cerebrospinal fluid in central nervous system disorders

Adenylate kinase activity was measured in 41 samples of cerebrospinal fluid in 34 patients with various neurological disorders or psychiatric symptomatologies. Activities of the enzyme showed to be linked to clinically estimated acuteness or progression of the changes in the central nervous system at the time of specimen collection. The findings suggest the conclusion that determination of adenylate kinase activity in cerebrospinal fluid is a meaningful tool for the evaluation of progression and/or acuteness of central nervous system disorders.     

Clinical applications of new cerebrospinal fluid analytic techniques for the diagnosis and treatment of central nervous system infections

Advances in molecular biology and immunology provide new, highly sensitive and specific techniques that can be applied to analysis of cerebrospinal fluid to enhance the diagnosis and treatment of central nervous system (CNS) infections. In addition to improved accuracy and speed of diagnosis, these modalities may offer improved means of monitoring treatment efficacy, establishing prognosis, detecting organism resistance, and tracking epidemic sources. This brief review discusses a number of recent papers applying these methods, in order to illustrate their value and significance for clinical neurologic practice. Some of these applications are commonly available, whereas others are likely to enter the physician’s armamentarium in the near future. As they do, they can be expected to improve the treatment of CNS infections.     

Neopterin,biopterin, and nitric oxide concentrations in the cerebrospinal fluid of children with central nervous system infections

We measured neopterin, biopterin and nitric oxide (NO) concentrations in the cerebrospinal fluid of pediatric patients with central nervous system (CNS) infectious diseases. The nitric oxide and neopterin concentrations were significantly elevated in encephalitis patients, especially in two cases with serious neurological sequelae, while the biopterin levels were not elevated. The bacterial meningitis patients, on the contrary, had high cerebrospinal fluid concentrations of neopterin and biopterin, but not of NO. Although these findings are preliminary, it may suggest that cerebrospinal fluids nitric oxide would be a useful marker to prospect neurological prognoses in the CNS infections.     

Paraneoplastic antibodies detected by isoelectric focusing of cerebrospinal fluid and serum

Patients with paraneoplastic neurological syndromes often produce intrathecal antibodies. We have employed isoelectric focusing and peroxidase-labeled anti-IgG or 35S-labeled Hu or Yo antigens to identify oligoclonal bands (OCB) representing either total IgG or Hu or Yo antibodies in serum and CSF of patients with paraneoplastic encephalomyelitis (PEM) or paraneoplastic cerebellar degeneration (PCD). OCBs representing paraneoplastic antibodies were found in all CSF, but in only three sera. Yo antibodies represented the majority of IgG bands in PCD-CSF, which may reflect a limited immune response, whereas in PEM/SN, there were numerous additonal IgG bands of unknown specificity, indicating a broader immune response in these patients.     

中枢神经系统感染性疾病脑脊液检查的临床应用

目前,对于中枢神经系统感染性疾病的诊断仍需依赖脑脊液检查结果,尤其是病原微生物的检查结果。不同炎症反应(包括细菌性、病毒性、肉芽肿性)脑脊液成分特点不同。一般病原微生物培养最具特异性但敏感性较低,实际上,大多数病毒、寄生虫、真菌和慢性细菌性中枢神经系统感染其脑脊液培养常为阴性。血清病原抗体阳性仅能证明体内     

Detection and identification of virus-specific, oligoclonal IgG in unconcentrated cerebrospinal fluid by immunoblot technique

A technique is described which allows the detection of virus-specific oligoclonal IgG in unconcentrated cerebrospinal fluid (CSF) from patients with virus infections of the central nervous system. CSF is isoelectrically focused in agarose gels and immunoglobulins are blotted to nitrocellulose filters, passively loaded with either anti-human IgG or viral antigen. Transferred total IgG, as well as virus-specific IgG, is identified by the use of peroxidase-labelled anti-human IgG and 4-chloro-1-naphthol as a precipitating peroxidase substrate. Application of this assay in cases of SSPE, mumps meningitis and herpes simplex encephalitis demonstrates sensitivity and possible suitability of this technique for use in diagnosis of virus infections of the CNS.     

Function of purification drainage of the central nervous system through the cerebrospinal fluid

It has long been known that the cerebrospinal fluid can not be the nervous system lymph, and Mestrezat, in his authoritative book of the year 1912, demonstrated it plainly. Davson has undertaken this subject and suggested the hypothesis of a sink action of cerebrospinal fluid, allowing a slow leakage of solutes from nervous tissue extracellular space. In order to test this hypothesis, Oldendorf and Davson performed a series of animal experiments and they demonstrated that there was leakage of the solute into cerebrospinal fluid. Based on the idea of this sink action of cerebrospinal fluid, some possible physiological implications were considered such as the mechanism of origin of the ventricle-subarachnoid cerebrospinal fluid protein gradient; the mechanism of protection of the central nervous system against the harmful substances of the blood stream; and the homeostatic mechanism whereby the concentration of some ions of the fluid remains constant. Also, it is considered the possibility of a sink action of cerebrospinal fluid in the resolution of brain edema in water intoxication and other types of central nervous system edema.     

Vessel wall enhancement in herpes simplex virus central nervous system vasculitis

Infection is a well-known cause of cerebral vasculopathy and vasculitis. We report a 36-year-old woman with cerebral vasculitis and ischemic stroke secondary to herpes simplex virus (HSV). MRI studies revealed a pontine stroke with basilar artery stenosis and vessel wall gadolinium enhancement. This case demonstrates the ability of HSV to cause a focal brainstem vasculitis and the utility of enhanced MRI in the diagnosis of stroke related to HSV central nervous system vasculitis.     

Quantitative CSF PCR in Epstein-Barr virus infections of the central nervous system

Acute Epstein-Barr virus (EBV) infection of the central nervous system (CNS) is associated with meningoencephalitis and other neurological syndromes and with CNS lymphomas (CNSLs). Diagnosis is based on serological studies and more recently on detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR). We measured EBV DNA by quantitative PCR and EBV mRNA by RT-PCR in the CSF in patients with EBV-associated neurological disorders. EBV was identified as the cause of CNS infection in 28 patients: 14 with CNSL, 10 with encephalitis, and 4 with postinfectious neurological complications. CSF analysis showed that patients with CNSL had high EBV load (mean +/- standard error of 4.8 +/- 0.2 log(10) DNA copies/ml) and low leukocyte counts (22 +/- 7 cells/microl); encephalitis was characterized by high EBV load (4.2 +/- 0.3 log(10) DNA copies/ml) and high leukocyte counts (143 +/- 62 cells/microl); and patients with postinfectious complications showed low EBV load (3.0 +/- 0.2 log(10) DNA copies/ml) with high leukocyte counts (88 +/- 57 cells/microl). Lytic cycle EBV mRNA, a marker of viral replication, was identified in 10 CSF samples from patients with CNSL and encephalitis. These studies demonstrate the utility of quantitative CSF PCR and establish the presence of lytic cycle EBV mRNA in CSF of patients with EBV-associated neurological disease.     

Serum and cerebrospinal fluid levels of interleukin-18 in human immunodeficiency virus type 1-associated central nervous system disease

Interleukin-18 (IL-18) is a proinflammatory cytokine released by macrophages that strongly stimulates the production of interferon-gamma, thereby linking innate and acquired immunity. Its role in human immunodeficiency virus (HIV) pathogenesis is under debate and little is known about its role in neuro-AIDS (acquired immunodeficiency syndrome). Serum and cerebrospinal fluid (CSF) levels of IL-18 were determined by a commercially available enzyme-linked immunosorbent assay (ELISA) in 22 HIV-seropositive patients without neurological symptoms (HIV+), 21 patients with AIDS dementia complex (ADC), and 31 patients with AIDS-defining opportunistic infections (OIs) of the brain. Thirty-two HIV seronegative patients (HIV-) served as controls. Compared to HIV- controls, serum IL-18 levels were increased in HIV+ and ADC but not in OI patients. In contrast, CSF IL-18 levels were elevated in OI patients whereas HIV+ and ADC patients were not different from HIV- controls. We provide evidence for an significantly increased IL-18 level in the CSF of HIV+ patients with cerebral OIs, suggestive of a role for IL-18 in the intrathecal host response to OIs.