Time course of chemokines in the cerebrospinal fluid and serum during herpes simplex type 1 encephalitis

https://doi.org/10.1016/S0022-510X(98)00061-6Get rights and content

Abstract

Chemokines (chemoattractant cytokines) attract and activate specific leukocyte subsets. With regard to their expression by brain parenchymal cells, they may represent the key molecules that control leukocyte entry into the subarachnoid space. In order to evaluate the contribution of chemokines in vivo, we determined the levels of MCP-1, MIP-1α, RANTES, IL-8, as well as of the sIL-2R in three patients with proven herpes simplex encephalitis type 1 (HSE-1). CSF samples were drawn by a subarachnoid catheter system throughout the time course of hospitalisation. Results were compared to chemokine levels in serum drawn in parallel. The clinical status was documented by the Modified Barthel Index and correlated with chemokine levels in the CSF. The results were compared with the chemokine levels in the CSF of 17 control patients with normal CSF routine parameters. High chemokine levels were detectable in the CSF of all HSE-patients. MCP-1 peak levels were found at the time of admission, while maximal IL-8 levels occurred 4 to 8 h later. The levels of MIP-1α and RANTES were lower than those of MCP-1 with a maximum at the time of admission. In all patients the levels of the sIL-2R increased later in the time course, at 14 to 20 h after admission. When the levels of MCP-1 were compared with the clinical status by Modified Barthel Index, we found a high reciprocal correlation (r=−0.82). Routine CSF parameters, such as leukocytes, albumin and immunoglobulins did not correlate with the clinical status. Chemokine levels in serum were found to be close to the detection limits of the ELISA systems. Our data suggest that chemokines play an important role in the pathogenesis of HSE. They may be useful parameters to monitor the stage and severity of the disease. The late increase of sIL2-R levels may indicate the beginning of the reconstitution phase.

Introduction

Herpes simplex virus is a common etiologic agent of non-epidemic sporadic acute focal encephalitis with an approximate incidence of 1 in 250 000 [18]. In the absence of antiviral therapy, only a minority of 2.5% of the patients regain normal function [35]. After treatment with aciclovir was established, mortality was decreased from 70% to 28% after 18 months [30]. However, in the long term, only 38% were judged to be normal or to have mild deficits [35], indicating the need to further improve early sensitive diagnostic parameters and therapy.

In the early phase of HSE, analysis of the CSF, EEG and MRI provides means of diagnostic value which has to be confirmed by a positive HSE antibody detection and PCR [1]. Despite pathological findings in 95% of CSF samples from the first lumbar puncture [35], changes are not pathognomonic for HSE and vary greatly [18]. CSF analysis typically shows elevated protein levels with an average of 81 mg/dl [9]and a predominantly lymphocytic pleocytosis of 50 to 100 cells/mm3, although in early stages polymorphonuclear cells (PMN) are visible.

As in other inflammatory diseases of the central nervous system, the mechanisms of leukocyte immigration into the CSF are not completely understood. Cytokines are regarded as playing an important role in the initial step of the directed migration of leukocytes to the site of the inflammatory process within the CNS 15, 22. Proinflammatory cytokines such as IL-1 and TNF α do not directly stimulate leukocyte chemotaxis 24, 32. Therefore we focused this study on chemoattractant cytokines (chemokines) because of their ability to attract specific leukocyte subsets leading to accumulation in the inflamed tissue.

Alpha or CXC-chemokines preferentially attract and activate PMN, whereas beta or CC-chemokines predominantly chemoattract mononuclear cells 2, 3. Today, only few clinical data are available on chemokines in the cerebrospinal fluid 27, 19, 31. In more recent studies only one specimen per patient was investigated. To analyse the spectrum, quantity and time course of CSF chemokines in a well defined inflammatory disease of the CNS, paired CSF and serum concentrations of MCP-1, RANTES, MIP-1α, and IL-8 were determined in a series of patients with HSE. In addition, we monitored the soluble IL-2 receptor, indicative of the presence of activated mononuclear cells, and standard CSF parameters in these patients during hospitalisation. Results were related to the clinical course and compared with the chemokine levels in the CSF and serum of 17 control patients with normal CSF parameters.

Section snippets

Patients and sample collection

A prospective study was performed on three patients hospitalized for early signs of encephalitis. HSE was proven by a positive PCR analysis on days 1 to 2 in all patients. A nested PCR-analysis was essentially performed as described in detail by Aurelius et al. [1].

Subsequent seroconversion of herpes simplex type 1 antibody titers was found in patients 1 and 2 after the second week of illness (Enzygnost, Behring, Marburg, Germany). Patient 3 did not develop detectable antibody titers during the

Routine parameters

The results of the routinely determined parameters in CSF such as leukocytes, albumin ratio and immunoglobulin ratio (CSF/serum) are summarized in Table 1–3. The maximum cell count showed different intraindividual peaks and reduced to 10 to 30% of the maximum by the day of discharge (Table 1). The differential cell count was dominated by lympho- and monocytes. The proportion of granulocytes decreased from 5 to 27% at admission to 0 to 2% at the time of discharge. The albumin ratio (CSF/serum),

Discussion

The immigration of leukocytes into the subarachnoid space is a hallmark of meningitis and encephalitis.

Acute inflammations of the CSF are associated with higher CSF-levels of chemokines than chronic inflammations such as multiple sclerosis [19].

Besides an inflammation induced upregulation of cellular adhesion molecules, which leads to attachment of leukocytes to endothelial cells, chemokines appear to be essentially involved in the regulation of leukocyte migration into the CNS by attracting

Acknowledgements

We gratefully acknowledge Willi Brindöpke and Annette Hehenkamp for their excellent technical assistance. This work was supported by a grant of the Deutsche Forschungsgemeinschaft (Sp 395/2-2).

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