Intrathecal 5-fluoro-2'-deoxyuridine (FdUrd) for the treatment of solid tumor neoplastic meningitis: an in vivo study

To evaluate the possible intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for neoplastic meningitis, its antitumor activity and neurotoxicity in vivo were assessed. FdUrd at doses in the range 5-100 microg/animal was effective against meningeal carcinomatosis using Walker 256 carcinoma cells in rats and MM46 mammary cancer cells in mice and against meningeal gliomatosis using 203 glioma cells in mice. After four intrathecal injections, FdUrd at these doses also showed minimal neurotoxicity in the C57BL/6 mouse brain. To estimate the mechanism of FdUrd efficacy, thymidine phosphorylase (TPase) and thymidine kinase (TK), key enzymes in the metabolism of FdUrd, were measured in rat, mouse and normal human brain tissue, and in human brain tumor tissues and cerebrospinal fluid (CSF) from patients with malignant brain tumors including meningeal carcinomatosis. TPase levels were lower in brain and malignant brain tumors than in other organs and their tumors. Moreover, the activity of TPase in the gray matter of human brain, which faces the cerebrospinal fluid across the cortical surface and into which malignant cells invade in meningeal carcinomatosis, was lower than that in the white matter. TK was undetectable, and TPase was detected (at very low concentrations) in only 4 of 56 patients with brain tumors or meningeal carcinomatosis. These findings indicate that brain tissue and CSF are favorable sites for FdUrd chemotherapy because the rate of conversion of FdUrd to 5-FU would be minimal. In conclusion, FdUrd is potentially useful for intrathecal treatment of neoplastic meningitis from primary brain tumors and systemic cancer.     

Multicenter evaluation of the Amplicor Enterovirus PCR test with cerebrospinal fluid from patients with aseptic meningitis. The European Union Concerted Action on Viral Meningitis and Encephalitis

The Amplicor Enterovirus PCR test was compared with viral culture for the detection of enteroviruses in cerebrospinal fluid (CSF) specimens. In a multicenter study in which nine laboratories participated, a total of 476 CSF specimens were collected from patients with suspected aseptic meningitis. Sixty-eight samples were positive by PCR (14.4%), whereas 49 samples were positive by culture (10.4%), demonstrating that the Amplicor Enterovirus PCR test was significantly more sensitive than culture (P < 0.001). After discrepancy analysis the sensitivity and specificity of the Amplicor Enterovirus PCR test obtained by using viral culture as the "gold standard" were 85.7 and 93.9%, respectively. Our results with the CSF specimens collected in different countries demonstrate that the Amplicor test is capable of detecting a large variety of enterovirus serotypes and epidemiologically unrelated isolates in CSF specimens from patients with aseptic meningitis. The Amplicor Enterovirus PCR test is a rapid assay which can be routinely performed with CSF samples and is an important improvement for the rapid diagnosis of enteroviral meningitis.     

Rapid and sensitive detection of enteroviruses in specimens from patients with aseptic meningitis

A 5-h PCR assay (Amplicor enterovirus test) was compared with viral culture for the detection of enteroviruses in cerebrospinal fluid. Of the cerebrospinal fluid specimens collected during a summer outbreak of aseptic meningitis, 34% were positive by viral culture whereas 66% were positive by the Amplicor PCR, suggesting that this technique improves the diagnosis of enteroviral meningitis.     

Impact of deltamethrin impregnated mosquito nets on the transmission of malaria in the coastal lagoon area, Benin]

Neopterin has been determined in blood as a marker of cellular immune system activation. We studied cerebrospinal fluid (CSF) neopterin levels in children with neurologic diseases, and the following results were obtained: (1) CSF neopterin levels markedly increased at the acute phase of bacterial meningitis, aseptic meningitis, and encephalitis as compared with those in patients without neurologic diseased. (2) In the CSF of patients with bacterial meningitis and aseptic meningitis, neopterin levels decreased more rapidly than the total cell count and 2'5' oligoadenylate synthetase (2-5 AS) did. (3) CSF neopterin in patients with non-infectious neurologic diseases was almost equal to that in patients without neurologic diseases. (4) There was no correlation between CSF neopterin and other CSF values, such as total cell count, mononuclear cell count, protein, and 2-5 AS. These results suggest that CSF neopterin is a useful marker of inflammatory central nervous diseases.     

Cerebrospinal fluid leukocyte aggregation in meningitis

OBJECTIVE: To evaluate whether the difference in aggregation of cerebrospinal fluid cells from patients with bacterial, viral, aseptic and partially treated meningitis can be used for diagnostic purposes. METHODS: Cerebrospinal fluid samples of 100 patients with meningitis (15 bacterial, 13 partially treated, 10 viral and 62 aseptic) were compared on the basis of the predefined leukocyte aggregation score (LAS). RESULTS: Mean LAS was 56% in the bacterial meningitis group (range, 15 to 90%), 5.8% in the partially treated meningitis group (range, 0 to 27%), 2% in the proven viral meningitis group (range, 0 to 5%) and 2% in the aseptic meningitis group (range, 0 to 15%). All patients with bacterial meningitis had a LAS of > 15%, whereas all those with viral or aseptic meningitis had a score of < 15%. Although most patients with partially treated meningitis had a low LAS, several had higher scores, which may indicate bacterial infection. There was no statistical correlation between number of cells, type of cells (mononuclear or polymorphonuclear) or cerebrospinal fluid protein and glucose concentration and degree of leukocyte aggregation for the different groups. CONCLUSION: Measurement of the LAS may contribute to the immediate differential diagnosis of bacterial or viral meningitis, especially in patients with very high pleocytosis, as sometimes seen in enteroviral meningitis. It may also serve as a guide for the likelihood of bacterial infection in cases of partially treated meningitis. Additional studies are needed to confirm these observations.     

Basic fibroblast growth factor in experimental and clinical bacterial meningitis

Basic fibroblast growth factor (bFGF), a neurotrophic factor in the CNS, is expressed at high levels in response to seizures or strokes. We examined the expression of bFGF during experimental bacterial meningitis and the levels of bFGF in the cerebrospinal fluid (CSF) of children with bacterial meningitis. For the experimental study, a mouse model of meningitis was established by intracranial injection of Streptococcus pneumoniae. Twenty-four hours after induced meningitis, the brains were sectioned and stained immunohistochemically for bFGF. Neutrophils and macrophages infiltrating the leptomeninges and the ventricles exhibited strong bFGF immunoreactivity. The neurons in the areas adjacent to the inflamed ventricles also showed enhanced bFGF expression. For the clinical study, we used an enzyme immunoassay to measure bFGF in CSF in 18 children with bacterial meningitis, 12 with aseptic meningitis, and 18 controls. The CSF levels of bFGF were twice as high in children with bacterial meningitis (medians 6.75-7.21 pg/mL) compared with those who had aseptic meningitis (2.9 pg/mL) or in control subjects (2.65 pg/mL, p < 0.0001, respectively). In patients with bacterial meningitis who survived, CSF bFGF decreased significantly after 24-50 h of antibiotic therapy (p < 0.0005). Patients who developed major sequelae or died had much higher levels of CSF bFGF than those without (134.9 pg/mL versus 7.38 pg/mL, p < 0.05). These findings of enhanced immunoreactivity of bFGF in experimental bacterial meningitis and an association of CSF levels of bFGF with disease severity in childhood bacterial meningitis suggest a biologic role for this neurotrophic factor in the pathophysiology of bacterial meningitis.     

Increased creatine kinase brain isoenzyme concentration in cerebrospinal fluid with meningitis

CPK-BB (CK-BB) isoenzyme is an intracellular enzyme released in various neurologic conditions, including central nervous system (CNS) infections. Activity of CK-BB in cerebrospinal fluid (CSF) was determined in 80 children by electrophoresis and densitometry. The possible correlation between CNS infection and CK concentrations was assessed. Significantly elevated concentrations of CK activity (P < 0.01) in the CSF were found in children with bacterial meningitis as compared with children with either aseptic meningitis or normal CSF findings. The data suggest the possibility of utilizing CSF CK activity to differentiate between bacterial and viral meningitis in situations where a routine CSF examination is inconclusive.     

Diagnostic imaging of neurotuberculosis

Neurotuberculosis is represented by different and possibly concomitant forms, of which the most frequent are tuberculous meningitis and parenchymal tuberculosis followed by cerebral miliary tuberculosis and the extremely rare tuberculous abscesses. Tuberculous meningitis is characterized by the presence of inflammatory meningeal exudate involving meningeal surfaces and CSF spaces with involvement of relative vascular and nervous structures. Most frequent complications are parenchymal infarction, hydrocephalus and mycotic aneurysms. Inflammatory meningeal exudate shows intense contrast enhancement. Parenchymal tuberculosis may directly involve the cerebral and/or medullary parenchyma as areas of cerebritis/myelitis with solid nodular lesions (tuberculomas) with a central area of caseating necrosis. Tuberculomas are characterized by intense nodular or ring enhancement.     

Cerebrospinal fluid pleocytosis in children with pneumonia but lacking evidence of meningitis

Headache, nuchal rigidity, positive Kernig's sign, and even convulsions may be observed during severe bacterial infections such as pneumonia, pyelonephritis, typhoid fever, and bacillary dysentery. In such cases, meningitis can be excluded only by documentation of normal cerebrospinal fluid (CSF). The authors describe four children with lobar pneumonia in whom the clinical signs of meningeal irritation were associated with a mild increase in the white blood cell count in the CSF (pleocytosis) although there was no other evidence of meningeal infection.     

The aseptic meningitis syndrome: a complication of posterior fossa surgery

The syndrome of aseptic meningitis is characterized by spiking fever and meningismus. CSF analysis generally shows increased pleocytosis, hypoglycorrhachia, elevated protein and negative cultures. In an earlier series, 70% of children with posterior fossa operations developed the syndrome. In a new review the incidence was slightly more than 30%. The incidence of aseptic meningitis following operation for structural lesions was 44%, which was higher than the tumor group, where the meningitic syndrome was seen in 25% of the children. It is the purpose of this paper to reexamine the impact that steroids have made on the prevalence of the aseptic meningitis syndrome, and to review recent studies that have attempted to distinguish between aseptic and bacterial meningitis.     

The arthroscopic treatment of avascular necrosis of the proximal pole following scaphoid nonunion

To investigate the clinical character of an outbreak of aseptic meningitis in Iwamizawa 1997 caused by echovirus 30, and to investigate the spreading of the outbreak, we analyzed clinical character of 75 hospitalized patients in our hospital, and mapped the patients' distribution in Iwamizawa City each week. We detected in our hospital an epidemic outbreak of acute enteroviral meningitis caused by echovirus type 30 in Iwamizawa, from September to December, 1997. Regarding the patients, there was little prevalence in males, with an average age of 6 years and a range of 0 to 13 years of age. The most constant symptoms were three major one such as headache (90%), fever up (89%), vomiting/nausea (87%), sometimes sorethroat (30%) and abdominal pain (15%). One case had a febrile convulsion temporally, and two cases had acute meningoencephalopathy and- encephalitis. In the cereblospinal fluid (CSF), we found no predominance of mononuclear cell (MNC) (58%) in the differential cell count. The mean of the peak of CSF cell counts was 654/3. White blood cell (WBC) was 8940/microliters, and CRP 1.4 mg/dl. None of them was detected in the bacterial culture of the CSF. Viral cultures were performed on CSF in 26 cases. Echovirus type 30 was isolated in 4 cases of hospitalized patients, and in one case with meningismus without pleocytosis. The beginning of the outbreak was observed in two kindergarten and one elementary school side by side. The peak of the whole outbreak was detected in the 3rd to 6th week, however the school spreading peak was detected in the 3rd and 4th week, and spreading was going in the whole city.     

Clinical and immunologic responses of vaccinated and unvaccinated calves to infection with a virulent type-II isolate of bovine viral diarrhea virus

OBJECTIVE: To determine efficacy of a modified-live type-I isolate of bovine viral diarrhea virus (BVDV) vaccine in protecting calves from infection with a virulent type-II isolate, and to determine which type of immune response (i.e., humoral or cellular) correlates with protection. DESIGN: Prospective study. ANIMALS: 28 neonatal Holstein and Holstein-cross calves. PROCEDURE: Within 18 hours of birth, calves received maternal colostrum or were fed pooled colostrum. On days 7 to 10 after birth, calves were determined to be seropositive (n = 16) or seronegative (12) for antibodies to BVDV on the basis of ELISA and virus neutralization test results. Seropositive and seronegative 10- to 14-day-old calves were then given a combined vaccine that contained a modified-live type-I isolate of BVDV or a similar vaccine that lacked protection against bovine viral diarrhea. All calves were inoculated intranasally approximately 21 days after vaccination with a virulent type-II isolate of BVDV. Clinical and immunologic variables, including clinical scores, rectal temperatures, results of CBC with lymphocyte subset analysis, antibody responses, and cell-mediated immune responses, were monitored for 14 days after inoculation. RESULTS: Seronegative-unvaccinated calves developed severe disease and required euthanasia. Vaccination of seronegative calves with a modified-live type-I isolate had a disease-sparing effect as did passive transfer of colostral antibodies to BVDV. Clinical scores were not significantly different between seropositive-vaccinated and seropositive-unvaccinated calves after viral inoculation. CLINICAL IMPLICATIONS: A single dose of a modified-live type-I isolate of BVDV vaccine protects young calves from clinical signs of disease associated with type-II isolates.     

Meningeal carcinomatosis

An anatomopathologic study of 18 cases of pure meningeal carcinomatosis is presented. In five of these cases, the brain, spinal cord, choroid plexuses, cerebral vessels, and prevertebral soft tissues, including the lumbosacral nerve plexuses and ganglia, were examined microscopically in an attmept to determine the routes of tumor spread. Our results suggest that the malignant cells reach the cerebrospinal leptomeninges via perineural, endoneural, and perivascular lymphatics and sheaths through the intervertebral and possibly cranial foramina. Involvement of the choroid plexuses appears to be secondary to, rather than the avenue for, leptomeningeal carcinomatosis, with the tumor cells reaching the choroid plexuses via the perivascular sheaths of choroidal vessels. Leptomeningeal carcinomatosis was the only manifestation of metastatic spread beyond regional lymph nodes in about 40% of all reported cases in which this information is available. This implies that radiation or other forms of local therapy to the cerebrospinal leptomeninges may provide an effective means of palliation in many of these cases.     

Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen

BACKGROUND: This retrospective study evaluates the results of a regimen of high-dose intrathecal methotrexate and the prognostic factors for the response in patients with meningeal from breast carcinoma. METHODS: From 1979 to 1994, 68 breast carcinoma patients were diagnosed with meningeal carcinomatosis at a mean age of 52 years. All but two had previous metastatic involvement. The proportion of lobular and ductal carcinomas was balanced. Malignant cells were present in cerebrospinal fluid (CSF) samples from 61 patients, whereas the 7 remaining patients had increased CSF protein associated with computerized tomographic scan evidence of meningeal metastases. From 1989, 41 of the patients received a regimen of high-dose intrathecal methotrexate with systemic folinic acid rescue (HD-MTX+FA): intrathecal MTX, 15 mg daily x 5 days, repeated every 2 weeks, and intrathecal hydrocortisone acetate, 125 mg on Day 1, and folinic acid, 10 mg intramuscularly 12 hours after each MTX injection. Systemic treatment and radiation therapy were usually associated. Patients treated before 1988 received intrathecal MTX in conventional doses (15 mg once a week). RESULTS: Clinical objective response, defined as a neurological improvement for at least one month, was achieved in 17 patients (41%) and stabilization in 14 (34%) treated with the HD-MTX+FA regimen. The response rate was significantly higher compared with that of the group treated with the conventional doses (P = 0.03). Median survival was 14 weeks for patients treated with the HD-MTX+FA regimen, compared with 7 weeks for patients who received conventional doses of MTX (P = 0.01). Grade 3 or 4 neutropenia was the main toxicity that occurred in 16 16 patients (39%) treated with the HD-MTX+FA regimen, and in 7 patients (33%) treated with conventional doses of MTX. In a univariate analysis, three parameters were singled out as having a favorable prognostic value for response to therapy; controlled systemic disease at diagnosis (P < 0.05), low initial CSF protein level (P < 0.05), and concomitant systemic chemotherapy during intrathecal therapy (P < 0.02). Multivariate analysis was not performed because the sample size was too small. CONCLUSIONS: Although this study was retrospective, the intrathecal HD-MTX+FA regimen appears to be a more efficient strategy than conventional doses of MTX to induce neurologic improvement and perhaps better survival. It should be recommended in combination with systemic chemotherapy for selected patients with meningeal carcinomatosis from breast carcinoma who are likely to benefit from intensive therapy, i.e., patients with a CSF protein level less than 5 g/L and in whom systemic disease has been controlled.     

Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation

This article describes the modulation, by extracellular collagen, of DNA and proteoglycan synthesis in articular chondrocytes stimulated with transforming growth factor-beta 1. Type-I and type-II collagen, heat-denatured type-II collagen, and bovine serum albumin were each incorporated into alginate in increasing concentrations. Bovine articular chondrocytes were isolated and were resuspended in the alginate, yielding alginate beads with final extracellular protein concentrations of 0-1.5% (wt/vol) for the collagens and 0-2.5% (wt/vol) for bovine serum albumin. Cultures of beads were maintained for 7 days in basal Dulbecco's modified Eagle medium or in medium supplemented with 10 ng/ml transforming growth factor-beta 1. Subsequently, the synthesis of DNA and proteoglycan was measured by radiolabel-incorporation methods with [35S]sulfate and [3H]thymidine, and the values were normalized to the DNA content. Transforming growth factor-beta 1 stimulated the synthesis of both DNA and proteoglycan in a bimodal fashion. The presence of extracellular type-II collagen increased the rate of DNA and proteoglycan synthesis in a dose-dependent fashion in cultures stimulated by transforming growth factor-beta 1, whereas heat-inactivated type-II collagen abrogated the effects observed with type-II collagen for synthesis of both DNA and proteoglycan. In contrast, the presence of extracellular type-I collagen caused a dose-dependent inhibition of synthesis of both DNA and proteoglycan in cultures stimulated with transforming growth factor-beta 1. Extracellular bovine serum albumin brought about a limited increase in synthesis rates, presumably by blocking nonspecific cytokine binding. These results suggest that type-II collagen has a specific role in chondrocyte regulation and serves to mediate the response of chondrocytes to transforming growth factor-beta 1.     

Rapid diagnosis of tuberculous meningitis by polymerase chain reaction assay of cerebrospinal fluid

A polymerase chain reaction (PCR) method for the rapid diagnosis of tuberculous meningitis (TBM) was used to study prospectively 47 cerebrospinal fluid (CSF) samples from 45 patients. Twenty CSF samples were from patients with clinically suspected TBM and another 27 samples came from patients without clinically suspected TBM. Mycobacterial DNA was detected in 15 CSF samples (14 from patients with clinically suspected TBM and 1 from a patient not suspected of having TBM). Of the PCR-positive samples, 4 were also positive for mycobacterial culture. However, 32 PCR-negative samples were all culture-negative. All samples were negative for the acid-fast bacillus by direct smear. The single PCR-positive patient in the clinically unsuspected TBM group was initially diagnosed as suffering from aseptic meningitis on the basis of his clinical features. The mycobacterial culture of his CSF specimen was also positive and a revised diagnosis of an aseptic type of TBM was made. The estimations of specificity and sensitivity in this study were 100% and 70% respectively. The results showed that using a PCR to detect mycobacterial DNA in CSF for the early diagnosis of TBM is not only a rapid but also an accurate method.     

Effects of contrast on attraction of the housefly, Musca domestica, to visual targets

There is evidence that the treatment of bacterial meningitis with antibiotics liberates harmful bacterial products in the subarachnoid space (SAS). This enhances meningeal inflammation and in particular the recruitment of leukocytes into the cerebrospinal fluid (CSF), which has been shown to be more harmful than beneficial in this disease. In this study, we used a rabbit meningitis model based on intracisternal injection of live Streptococcus pneumoniae. Ampicillin (40 mg/kg of body weight given intravenously [i.v.] 16 h after induction of meningitis) caused a fivefold increase in CSF leukocytes over a 4-h period. Inhibition of leukocyte rolling by treatment with the polysaccharide fucoidin (10 mg/kg, i.v.) prevented the enhanced leukocyte extravasation into the SAS and attenuated the leakage of plasma proteins over the blood-brain barrier. These results suggest that certain polysaccharides that block leukocyte rolling have the potential to reduce leukocyte-dependent central nervous system damage in bacterial meningitis.