Countercurrent immunoelectrophoresis in the diagnosis of viral infections of the central nervous system.

Countercurrent immunoelectrophoresis was utilized in the study of 621 specimens of cerebrospinal fluid to determine the correlation of detection of viral antigens with the clinical diagnosis of aseptic meningitis and related viral infections. A panel of viral antisera was immunoelectrophoresed against 119 specimens from patients with suspected viral infections of the central nervous system (group I), 32 from patients with bacterial meningitis (group 2), and 470 from patients with no suspected infection of the nervous system (group 3). One or more precipitin bands were detected in 79% of specimens from group 1, 19% from group 2, and 4% from group 3. Paired acute- and convalescent-phase sera from 32 (78%) of 41 patients with precipitin bands detected by countercurrent immunoelectrophoresis demonstrated a fourfold or greater change in complement-fixing antibodies to the detected antigen. With refinements in antisera, countercurrent immunoelectrophoresis may become useful in the rapid laboratory diagnosis of viral infection of the central nervous system.     

Laboratory diagnosis of central nervous system infections.

The laboratory diagnosis of CNS infection is essential for optimal therapy. Acute infection requires rapid turn-around testing with high predictive values, that is, the ability of a test to accurately identify those patients who do or do not have disease caused by a specific etiology. The Gram's stain, fungal stains of direct smears, antigen testing for C. neoformans, and culture of bacteria, fungi, mycobacteria, and some viruses are important tests for the diagnosis of acute infection. The laboratory diagnosis of chronic infection necessitates discussion between the clinician and laboratory technician to allow triaging of testing. Antigen tests for bacteria, fungi, and viruses; antibody tests for multiple microorganisms; and PCR testing for bacteria, M. tuberculosis, and many viruses are all important in limited clinical situations. All testing for acute or chronic disease depends on sufficient specimen that is transported to the laboratory in a manner that will not compromise viability or chemical integrity. Sterile containers that maintain moisture content, exclude oxygen for anaerobic requests, and are stored at proper temperatures (22 degrees C room, 4 degrees C refrigeration, or -20 degrees C freezer depending on pathogen and test) are mandatory. Many laboratory issues addressing the diagnosis of CNS infection are changing or evolving. Most important is the recognition that bacterial antigen testing for the diagnosis of acute bacterial meningitis rarely impacts patient management and is not routinely needed, CSF shunt infections differ from usual meningeal infections and require rapid diagnosis, and TB meningitis remains a difficult disease to diagnosis but may be confirmed first by PCR testing of CSF. In addition, Whipple's disease of the CNS can be confirmed using PCR with CSF; CJD has a marker protein, referred to as 14-3-3 antigen, that can be detected in CSF, and the diagnosis of fungal CNS disease requires careful interpretation of direct smears, antigen and antibody testing, and culture. Most difficult to diagnose among the CNS infections are viral meningitis and encephalitis. The appearance of new etiologies, such as West Nile virus, and the common use of PCR for the herpes viruses and enteroviruses represent important advances. Evolving methods for the laboratory diagnosis of CNS infection represent significant improvements over previous testing; however, the array of tests available demands more attention for appropriate selection, is significantly more expensive, and requires new skills for performance and interpretation. The responsibility for proper use of laboratory testing lies both with the clinician and laboratory technician.     

Molecular diagnosis of the central nervous system (CNS) infections

Central nervous system (CNS) infections such as meningitis and encephalitis are medical emergencies that require rapid diagnosis of the causative pathogen to guide early and adequate treatment since a delay in implementing an adequate antimicrobial therapy can lead to death. The current microbiological diagnostic methods based on culture or antigen detection have important limitations in their capacity to accurately identify the different potential pathogens causing CNS and, in the time, to obtaining results. Rapid syndromic molecular arrays have been developed. The main advantage of using a meningoencephalitis panel based in a multiplex test is that includes bacteria, viruses and fungi, covering the most prevalent microorganisms causing meningitis and encephalitis and the turn-around time is circa 1 h. The use of these multiplex-PCR based tools is reviewed and the advantages and disadvantages of this technique are discussed.     

Herpesvirus infections of the central nervous system

In recent years, advances in the diagnosis and treatment of herpes simplex encephalitis (HSE) have been achieved due to the prevalence of antiviral drugs and the introduction of the polymerase chain reaction (PCR) to test the cerebrospinal fluid. The several clinical forms of herpes simplex virus type 1 (HSV-1) infections of the central nervous system (CNS), including acute disseminated encephalomyelitis and brainstem encephalitis, have been clarified. However, fatal, prolonged, or relapsed cases are still observed, and early detection and appropriate treatment is necessary to lead to a good prognosis for these intractable HSE cases. In adult HSV-2 infections, meningitis and myelitis associated with genital herpes are common. In the past, HSV-2 myelitis has been reported as a form of fatal necrotizing myelopathy; however, using PCR and magnetic resonance imaging studies, mild surviving cases are increasingly likely to be identified. Meanwhile, various CNS syndromes resulting from the herpes group viruses, including varicella-zoster virus and Epstein-Barr virus have also been reported. These herpesviruses have several characteristics in common, e.g., they exist in the latent state and they occur in both mucocutaneous and CNS infections. Adult HSV-1 and -2 infections of the CNS are discussed together with other herpes group virus infections of the CNS.     

小胶质细胞在病毒性中枢神经系统感染中的作用

小胶质细胞是中枢神经系统中的免疫细胞,是中枢神经系统抵抗病原体入侵的第一道防线。当病原微生物进入脑组织后,小胶质细胞迅速做出反应,识别、吞噬病原微生物,呈递抗原和分泌多种生物活性物质。但是,小胶质细胞的过度活化又可诱发中枢神经系统免疫病理损伤或神经退行性病变。因而,具有生理和病理双重作用。本文就小胶质细胞在病毒感染性中枢神经系统疾病中的作用及其机制进行综述。     

Antibacterial agents in infections of the central nervous system

Experimental animal models have provided information applicable to antimicrobial therapy of infections of the central nervous system. The efficacy of an antimicrobial agent in the therapy of bacterial meningitis depends on its ability to penetrate the blood-brain barrier, its activity in purulent cerebrospinal fluid, and a demonstration of rapid bactericidal activity against the offending pathogen. The recent emergence of resistant pathogens is challenging the therapy for bacterial meningitis. Various strategies for treating resistant pathogens have been evaluated in experimental animal models. Encouraging results have led to clinical trials to evaluate the efficacy of newer agents, alone or in combination with standard regimens.     

Epstein-Barr virus infections of the central nervous system

OBJECTIVE: Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. RESULTS: Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. CONCLUSION: Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.     

Effective use of polymerase chain reaction for diagnosis of central nervous system infections.

Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) specimens has become standard for confirmatory diagnosis of central nervous system (CNS) infections; however, these tests increase health care costs. We reviewed 3-year data from 974 consecutive CSF specimens submitted for detection of seven pathogens by PCR. In 1997, 237 of 367 specimens (64.6%) were submitted for multiple tests, compared with 203 of 522 (38.9%) in 1996 and 18 of 85 (21.2%) in 1995. In each year the arrival of new house officers coincided with a peak in multiple testing. Among 732 specimens submitted for herpesvirus detection, results were positive for 24 (4.6%) of 523 specimens with increased leukocyte counts or protein levels. None of 209 specimens with normal leukocyte and protein levels were positive for herpesviruses. None of 471 CSF specimens submitted for Borrelia burgdorferi detection were PCR-positive. Use of protein and leukocytes to screen CSF specimens before employing PCR for herpesvirus detection would save almost one-third of costs without reducing sensitivity.     

Use of antibacterial agents in infections of the central nervous system

The movement of drugs from the systemic circulation into the central nervous system is restricted by several factors, including the blood-brain and blood-CSF barriers, an active transport system that affects primarily the beta-lactam antibiotics, and the high degree of serum protein binding of certain agents. The functions of the blood-brain and blood-CSF barriers and of the active transport system are reduced but not abolished by inflammation. For most antimicrobial agents, the major determinant of passage aside from serum protein binding is the degree of lipid-solubility of the drug. The beta-lactam and aminoglycoside antibiotics and vancomycin penetrate the central nervous system relatively poorly, whereas chloramphenicol, metronidazole, the fluoroquinolones and trimethoprim-sulfamethoxazole fare better. Knowledge of the relative capacity of various drugs to penetrate the central nervous system after systemic administration may help the physician to choose an optimum regimen for the treatment of bacterial meningitis and brain abscess.     

Dual infections of the central nervous system with Epstein-Barr virus

We describe clinical and laboratory characteristics of 16 patients with central nervous system (CNS) infection caused by Epstein-Barr virus (EBV) and another pathogen. Seven of 10 immunocompromised patients had coinfection with viruses (3 with cytomegalovirus, 2 with JC virus, and 2 with varicella zoster virus) and 3 with nonviral pathogens (2 with pneumococcus and 1 with Cryptococcus species). Three of 6 immunocompetent patients had coinfections with viruses (1 each with herpes simplex virus, varicella zoster virus, and West Nile virus), and 3 had coinfections with nonviral pathogens (2 with Ehrlichia chaffeensis and 1 with Mycoplasma pneumoniae). The EBV load was similar in immunocompromised and immunocompetent patients and in patients with viral and nonviral coinfections. EBV lytic-cycle mRNA was detected in the cerebrospinal fluid of 5 of 6 tested samples, indicating EBV replication in the CNS during coinfection.     

Listerial infections of the central nervous system in the previously healthy adult

Summary Four cases of central nervous system (CNS) infection caused byListeria monocytogenes are reported. All occurred in adult patients previously well before the onset of symptoms. Three had evidence of encephalitis, predominantly affecting the brainstem in two, and one had meningitis. Of the three patients with encephalitis, two had clinical signs of meningeal involvement. Initial examination of the cerebrospinal fluid (CSF) demonstrated between 110 and 680 white cells/mm³ predominantly consisting of either lymphocytes or neutrophils. Protein estimation varied from 25 mg/dl to 400 mg/dl and glucose concentration from 10 mg/dl to 100 mg/dl.Listeria monocytogenes was isolated from the blood in the two cases of brainstem infection and from the CSF in the others. All strains were of serogroup 4 and susceptiblein vitro to penicillin, ampicillin, gentamicin and chloramphenicol. In one patient the diagnosis was made post-mortem. Of the other patients, two survived without neurological sequelae but the third had severe brain damage. The clinical features, diagnosis and treatment of listerial CNS infections are discussed.

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Listeriose-Infektion des Zentralnervensystems bei vorher gesunden Erwachsenen

Zusammenfassung Es wird überListeria monocytogenes-Infektionen des Zentralnervensystems (ZNS) bei vier vorher gesunden Erwachsenen berichtet. Bei drei Patienten lagen Zeichen einer Encephalitis vor, bei zweien von ihnen war vorwiegend der Hirnstamm befallen, ein Patient hatte eine Meningitis. Klinische Zeichen einer Meningenbeteiligung boten zwei der drei Encephalitis-Patienten. Im Liquor cerebrospinalis fanden sich bei der ersten Untersuchung zwischen 110 und 680 Leukozyten/mm³, dabei überwogen entweder Lymphozyten oder neutrophile Granulozyten. Die Eiweißkonzentrationen im Liquor schwankten zwischen 25 mg/dl und 400 mg/dl, die Glukosekonzentrationen zwischen 10 mg/dl und 100 mg/dl.Listeria monocytogenes wurde in zwei Fällen mit Hirnstammbefall aus dem Blut isoliert und in den anderen Fällen aus dem Liquor cerebrospinalis. Alle Stämme gehörten der Serogruppe 4 an und warenin vitro gegenüber Penicillin, Ampicillin, Gentamicin und Chloramphenicol empfindlich. In einem Fall wurde die Diagnose post mortem gestellt. Von den anderen Patienten überlebten zwei ohne neurologische Folgeerscheinungen, der dritte hingegen hatte eine schwere Hirnschädigung. Die klinischen Charakteristika, Diagnose und Behandlung der Listeria-Infektionen des Zentralnervensystems werden diskutiert.

     

Neurocritical care of patients with central nervous system infections

Bacterial meningitis and viral encephalitis are life-threatening infections with high mortality rates. Patients who survive these infections often remain permanently disabled. Potential neurologic complications requiring careful attention include impaired consciousness, elevated intracranial pressure, hydrocephalus, stroke, and seizures. Systemic complications are also common and are frequently the immediate cause of death. Critical care of these patients should focus not only on treatment of the underlying infection and its immediate complications but also on minimizing secondary brain injury. Given the increasing complexity of the diagnostic and therapeutic modalities available in managing central nervous system infections, the involvement of neurocritical care units and neurointensivists may be particularly helpful in improving outcomes.     

Linezolid for the treatment of central nervous system infections in neurosurgical patients

We report our experience with linezolid in the treatment of 5 patients with central nervous system infections subsequent to neurosurgical interventions. In all cases, initial antimicrobial treatment regimens, including a glycopeptide, either failed or were associated with significant adverse events. The good clinical outcome and the absence of significant side-effects associated with linezolid suggest that it may be an attractive alternative for the treatment of central nervous system infections, particularly in settings characterized by a high incidence of multiresistant Gram-positive pathogens.