A case of idiopathic hypertrophic pachymeningitis with high adenosine deaminase in cerebrospinal fluid.

Adenosine deaminase (ADA) in cerebrospinal fluid (CSF) has been reported as useful to diagnose tuberculous meningitis and hypertrophic pachymeningitis (HP). The case of a 59-year-old woman with impaired vision and an auditory disturbance due to massive intracranial HP is presented. Although acid-fast bacillus cultures and polymerase chain reaction tests for Mycobacterium tuberculosis in the CSF were negative, tuberculous HP was diagnosed clinically because of the high ADA in CSF, and anti-tuberculosis drugs were administered with prednisolone because idiopathic HP (IHP) could not be ruled out. Since the impaired vision worsened with prednisolone reduction despite the continuation of anti-tuberculosis drugs, a dural biopsy was performed, and the patient was diagnosed with IHP. ADA is associated with lymphocyte proliferation and differentiation and increased by activation of cell-mediated immunity. Elevated CSF-ADA might be caused by lymphocyte infiltration in the thickened dura mater.

Hypertrophic pachymeningitis: significance of myeloperoxidase anti-neutrophil cytoplasmic antibody.

The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Evaluation of cerebrospinal fluid adenosine deaminase activity for the differential diagnosis of tuberculous and nontuberculous meningitis.

INTRODUCTION: The diagnosis value of adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of tuberculous meningitis (TBM) has been well documented. However, the cutoff point of CSF ADA has not been fully assessed. In the current study, the authors set to calculate the cutoff points of ADA and monitor the changes of CSF ADA activities in patients with TBM after antitubercular therapy. METHODS: CSF ADA activity in patients with different types of meningitis was measured by Trinder enzyme-coupled assay. RESULTS: The mean CSF ADA values in the patients with TBM, bacterial meningitis, viral meningitis, cryptococcal meningitis and noninfectious neurologic disorders were 14.1 ± 5.4, 9.6 ± 5.5, 4.3 ± 2.5, 7.8 ± 3.4 and 2.6 ± 1.3 U/L, respectively. CSF ADA activity was significantly higher in TBM compared with patients with non-TBM (P < 0.05). Moreover, the best cutoff point for differentiating between TBM and non-TBM was 9.5 U/L. In addition, CSF ADA activity was decreased in patients with TBM after antitubercular therapy in a time-dependent manner. CONCLUSIONS: The determination of ADA with a cutoff value of 9.5 U/L in CSF is a useful aid for the differential diagnosis of TBM and non-TBM. Moreover, dynamic monitoring of CSF ADA activity may be an indicator for evaluating antitubercular therapy in TBM.

Matrix metalloproteinase-12 leads to elastin degradation in BALB/c mice with eosinophilic meningitis caused by Angiostrongylus cantonensis.

The rat lugworm Angiostrongylus cantonensis can cause eosinophilic meningitis. The purpose of this study was to determine whether matrix metalloproteinase (MMP)-12 and its substrate elastin participate in this inflammatory response. We showed that the MMP-12/tissue inhibitor of metalloproteinase-1 ratio was significantly increased in the CSF of A. cantonensis-infected mice from day 10 p.i., and reached high levels on days 20 and 25 p.i. MMP-12 production was correlated with elastin degradation, eosinophil count, blood-CSF barrier permeability and pathological changes in the subarachnoid space. Also, MMP-12 might contribute to elastin degradation in the meningeal vessel of the subarachnoid space. Simultaneous administration of albendazole and doxycycline significantly reduced the levels of MMP-12, elastin and Evans blue in mice with meningitis. These results imply that MMP-12 contributes to the elastin degradation that occurs in angiostrongyliasis meningitis, and doxycycline can reverse related inflammatory events by inhibition of MMP-12.

Expression of matrix metalloproteinases and their tissue inhibitors in the serum and cerebrospinal fluid of patients with meningitis.

Meningitis is associated with an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMP (TIMPs). Serum and CSF were collected prospectively from all patients with meningitis between January 2008 and December 2008 to measure the concentrations of MMP/TIMP in those patients who underwent a lumbar puncture for a presumptive diagnosis of meningitis. A total of 199 patients were enrolled into the study. The concentrations of CSF MMP-9 and TIMP-1 were significantly higher in the meningitis group compared with the control group (p 0.032 and p <0.001, respectively). However, the CSF TIMP-4 levels were significantly lower in the meningitis groups compared with the control groups (p <0.001). Patients with bacterial meningitis had higher CSF MMP-9 and TIMP-1 levels than those who had aseptic meningitis and controls. Patients with various infectious meningitis etiologies tended to have higher CSF MMP-9 expression by gelatin zymography when compared with the controls. In conclusion, MMP/TIMP system dysregulation was found in patients with meningitis, and CSF MMP and TIMP might act as novel indicators in patients with meningitis.

Cerebrospinal fluid u-plasminogen activator and matrix metalloproteinase-9 levels in human eosinophilic meningitis associated with angiostrongyliasis.

Cerebrospinal fluid (CSF) urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) levels were measured in patients with eosinophilic meningitis associated with angiostrongyliasis (EOMA) by quantitative sandwich enzyme immunoassays. The CSF concentrations of uPA and MMP-9 were evaluated in 30 EOMA patients and 10 controls. The CSF uPA and MMP-9 levels of the EOMA patients were significantly higher than those of the controls (p<0.001). The positive detection values were 73% (22/30) and 86.7% (26/30) for uPA and MMP-9, respectively. The uPA detection was in correlation with headache duration (p=0.008) and stiff neck (p=0.048), while the MMP-9 was in correlation with CSF total protein (p=0.006), CSF leukocytosis (p=0.004) and CSF eosinophil numbers (p=0.02). CSF uPA and MMP-9 levels are potentially useful for the understanding of immunologic pathogenesis, for therapeutic targets, for the diagnosis of EOMA and for monitoring treatment efficacy.

Inhibition of inducible nitric oxide controls pathogen load and brain damage by enhancing phagocytosis of Escherichia coli K1 in neonatal meningitis.

Escherichia coli K1 is a leading cause of neonatal meningitis in humans. In this study, we sought to determine the pathophysiologic relevance of inducible nitric oxide (iNOS) in experimental E. coli K1 meningitis. By using a newborn mouse model of meningitis, we demonstrate that E. coli infection triggered the expression of iNOS in the brains of mice. Additionally, iNOS-/- mice were resistant to E. coli K1 infection, displaying normal brain histology, no bacteremia, no disruption of the blood-brain barrier, and reduced inflammatory response. Treatment with an iNOS specific inhibitor, aminoguanidine (AG), of wild-type animals before infection prevented the development of bacteremia and the occurrence of meningitis. The infected animals treated with AG after the development of bacteremia also completely cleared the pathogen from circulation and prevented brain damage. Histopathological and micro-CT analysis of brains revealed significant damage in E. coli K1-infected mice, which was completely abrogated by AG administration. Peritoneal macrophages and polymorphonuclear leukocytes isolated from iNOS-/- mice or pretreated with AG demonstrated enhanced uptake and killing of the bacteria compared with macrophages and polymorphonuclear leukocytes from wild-type mice in which E. coli K1 survive and multiply. Thus, NO produced by iNOS may be beneficial for E. coli to survive inside the macrophages, and prevention of iNOS could be a therapeutic strategy to treat neonatal E. coli meningitis.

Detection of Meningeosis neoplastica by real-time quantitation of telomerase activity.

BACKGROUND: Analysis of cerebrospinal fluid (CSF) to discriminate between benign and malignant conditions is of fundamental importance for the physician and the patient because of the differential therapeutic options and resulting morbidity and mortality. Most human tumours demonstrate increased telomerase activity (TA). Recent technical advances in the detection of TA allow for sensitive and specific detection within 4 h. Thus, the detection of TA is suitable for routine clinical testing. METHODS: This study examines TA in cellular proteins in CSF from 111 patients compared to cytomorphological and laboratory examination. RESULTS: A positive result for TA in cellular proteins of CSF was correlated significantly with Meningeosis neoplastica, but not with non-malignant conditions. Telomerase was not detected in CSF supernatant, despite positive results in cellular proteins from identical patients. Furthermore, a 48-h time delay during the pre-analytic processing is not critical for detection of TA detection in native CSF when stored at room temperature. CONCLUSIONS: We conclude that TA is a promising marker for the detection of Meningeosis neoplastica and warrants further study.

[Matrix metalloproteinases in the central nervous system: clinical significance and therapeutic prospects]. / Metaloproteinazy macierzy w osrodkowym ukladzie nerwowym: znaczenie kliniczne oraz perspektywy terapeutyczne.

Matrix metalloproteinases (MMPs) were originally described as proteases capable of degrading extracellular matrix components. Increasing evidence indicates a much more complex role of MMPs. Diverse functions of MMPs include cellular differentiation, migration, survival or death, angiogenesis and signalling. Metalloproteinases are crucially involved in a number of inflammatory conditions in the central nervous system facilitating blood-brain barrier breakdown, leukocyte recruitment and shedding of cytokines and growth factors. These enzymes contribute to pathogenesis of meningitis, multiple sclerosis and neurodegenerative disorders. While most studied in the context of disease, beneficial role of metalloproteinases during nervous system development and following injury is now being appreciated. The present study aimed at reviewing clinical relevance of these enzymes and potential therapeutic prospects for the coming future.

Biochemical and pathological evaluation of albendazole/thalidomide co-therapy against eosinophilic meningitis or meningoencephalitis induced by Angiostrongylus cantonensis.

OBJECTIVES: To evaluate the curative effect of albendazole/thalidomide co-therapy on eosinophilic meningitis in BALB/c mice caused by Angiostrongylus cantonensis. METHODS: Male mice were infected with 50 A. cantonensis larvae and treated with albendazole (5, 10 or 20 mg/kg per day) alone, thalidomide (25, 50 or 100 mg/kg per day) alone, or a combination of albendazole (10 mg/kg per day) and thalidomide (50 mg/kg per day) for 7 consecutive days on days 5, 10 and 15 post-inoculation (PI), respectively. RESULTS: Indicators used to measure this effect included: (i) worm recovery; (ii) histopathological score of meningitis; (iii) eosinophil counts; (iv) level of pro-inflammatory cytokines, such as tumour necrosis factor-alpha, interleukin-1beta and interleukin-5; (v) activity of enzymes, such as tissue-type plasminogen activator, urokinase-type plasminogen activator and matrix metalloproteinase-9; and (vi) CSF/serum albumin ratio. The results showed that albendazole/thalidomide co-therapy significantly decreased (P < 0.05) these factors when treatment was initiated on days 5 or 10 PI compared with treatment initiated on day 15 PI. CONCLUSIONS: The timing of medication use is important and is closely related to the anthelmintic efficacy of a drug. For a given dosage, earlier medication use is more effective. This novel approach to treating parasitic meningitis may suggest other new methods of treatment.

Induction of matrix metalloproteinase-9 in murine eosinophilic meningitis caused by Angiostrongylus cantonensis.

Matrix metalloproteinases (MMP) have been implicated in the pathogenesis of various inflammatory diseases of the central nervous system. In the present study, a gelatinase was found to be induced in parasitic meningitis caused, in mice, by Angiostrongylus cantonensis. The enzyme had a molecular weight of about 94 kDa, showed maximal activity between pH 6 and pH 8, and was clearly inhibited by EDTA and 1,10-phenanthroline but not by leupeptin or phenylmethanesulphonyl fluoride. When samples of cerebrospinal fluid from the mice with meningitis were blotted with specific antiserum against gelatinase B (MMP-9), a 94-kDa immunopositive band was observed, indicating that the induced gelatinase was MMP-9. In the A. cantonensis-infected mice, immuno-histochemistry demonstrated MMP-9 within the endothelial cells lining the vascular spaces of the brain and in the leucocytes that were found, in aggregates, in the subarachnoid space. Leucocytes may play an important role in the pathogenesis of inflammatory disorders of the central nervous system.

Use of neuron-specific enolase for assessing the severity and outcome in patients with neurological disorders.

Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. NSE levels in cerebrospinal fluid (CSF) are assumed to be useful to estimate neuronal injury and clinical outcome of patients with serious clinical manifestations such as those observed in stroke, head injury, anoxic encephalopathy, encephalitis, brain metastasis, and status epilepticus. We compared levels of NSE in serum (sNSE) and in CSF (cNSE) among four groups: patients with meningitis (N=11), patients with encephalic injuries associated with impairment of consciousness (ENC, N=7), patients with neurocysticercosis (N=25), and normal subjects (N=8). Albumin was determined in serum and CSF samples, and the albumin quotient was used to estimate blood-brain barrier permeability. The Glasgow Coma Scale score was calculated at the time of lumbar puncture and the Glasgow Outcome Scale (GOS) score was calculated at the time of patient discharge or death. The ENC group had significantly higher cNSE (P=0.01) and albumin quotient (P=0.005), but not sNSE (P=0.14), levels than the other groups (Kruskal-Wallis test). Patients with lower GOS scores had higher cNSE levels (P=0.035) than patients with favorable outcomes. Our findings indicate that sNSE is not sensitive enough to detect neuronal damage, but cNSE seems to be reliable for assessing patients with considerable neurological insult and cases with adverse outcome. However, one should be cautious about estimating the severity of neurological status as well as outcome based exclusively on cNSE in a single patient.

Ultrastructural localization of matrix metalloproteinase-9 in eosinophils from the cerebrospinal fluid of mice with eosinophilic meningitis caused by Angiostrongylus cantonensis.

Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of eosinophilic meningitis caused by Angiostrongylus cantonensis. In the present study, such meningitis in mice was found to be associated with elevated expression of MMP-9 mRNA, elevated MMP-9 concentrations and enhanced MMP-9 activity in the cerebrospinal fluid (CSF). Immunocytochemistry showed that an anti-MMP-9 antibody reacted with macrophages, neutrophils and eosinophils from the CSF. As eosinophils are generally considered to be effector cells in host defence against A. cantonensis infection, high-resolution immuno-electron microscopy was then used to confirm the localization of MMP-9 in the eosinophils from the CSF. The method used, which was based on immunogold, indicated that the eosinophilic MMP-9 was mostly localized in the 'small' granules in the cytoplasm and along the cell membrane, and not in the crystalloid-containing secretory granules observed. It therefore appears that MMP-9 is synthesised and/or stored in the small granules of the eosinophils, and is released into the subarachnoid space of the host's brain by secretion or cell rupture.

Detection and characterization of 45 kDa platelet activating factor acetylhydrolase in cerebrospinal fluid of children with meningitis.

Platelet activating factor acetylhydrolase (PAF-AH) activity has been identified in cerebrospinal fluid (CSF) samples taken from children with meningitis. We reported that PAF-AH activity is significantly increased, by about 3 fold, in patients with meningitis compared to control subjects. Because of limited knowledge about this enzyme in CSF, we examined the biochemical properties of CSF PAF-AH. PAF-AH of CSF was calcium independent, showed a broad pH spectrum and was relatively heat stable. In addition, this enzyme activity was strongly inhibited by phenylmethanesulfonyl fluoride (PMSF), partially inhibited by p-bromophenacylbromide (p-BPB), uninhibited by iodoacetamide, and moderately stimulated by dithiothreitol (DTT). PAF-AH of CSF did not degrade phospholipid with a long chain fatty acyl group at sn-2 position. This enzyme hydrolyzed PAF and oxidatively modified phosphatidylcholine. Furthermore, we identified a monomeric polypeptide with a molecular weight of approximately 45 kDa by Western blot using human plasma PAF-AH antibody. These results suggested that plasma type PAF-AH activity exist in CSF taken from children with meningitis.

[Estimation of LDH activity determination in CSF during bacterial meningitis]. / Ocena oznaczania aktywnosci dehydrogenazy mleczanowej (LDH) w plynie mózgowo-rdzeniowym w ropnym zapaleniu opon mózgowych.

According to performed researchers statistically important highest increase activity of LDH was indicated in the group of patients with the most severe course of illness which remains after the treatment. No correlation was shown between increased LDH activity in CSF and pleocytosis, protein and glucose concentrations.

Neuronal acetylcholinesterase levels in cerebrospinal fluid and serum determined by a specific and sensitive immunoassay.

Acetylcholinesterase levels were determined in cerebrospinal fluid and serum of 272 patients with various neurological disorders. The patients were ordered in 13 diagnostic groups. The assay employed was an antigen capture assay based on an immobilized monoclonal antibody selective for neuronal acetylcholinesterase (Rasmussen et al., Clin. Chim. Acta 166 (1987) 17-25 (1)). In 100% of the cases the acetylcholinesterase levels in cerebrospinal fluid were 500-10,000 fold higher than expected for a regular serum-derived protein (0.1-0.5%) at the intact blood-brain barrier. In both compartments the test values showed wide variations, which were much greater in serum than in cerebrospinal fluid. No specific relationship was discernible between the values obtained and any of the diagnostic groups, although decreased levels of acetylcholinesterase were found in bacterial and viral meningitis, and elevated levels were found in groups with more chronic diseases. A possible transfer of acetylcholinesterase from cerebrospinal fluid to blood is discussed.

Proteinase-antiproteinase imbalance in meningitis: determination of alpha 1 proteinase inhibitor (alpha 1PI), elastase-alpha 1PI complex, and elastase inhibition capacity in cerebrospinal fluid.

Mortality and long-term neurologic sequelae are still frequent complications of meningitis despite effective antibiotic treatment. This suggests that pathogen-independent inflammatory mechanisms may play an important role in the course of this illness. Neutrophil granulocytes form the primary immune defense in meningitis. Once activated, these cells release elastase into the cerebrospinal fluid (CSF). Elastase may induce tissue damage if local antiproteinase capacity is low as under normal conditions. To define the relevance of this mechanism we studied 22 patients with meningitis. Concentrations of elastase in complex with the main antiproteinase alpha 1-proteinase inhibitor (elastase-alpha 1 PI), alpha 1-proteinase inhibitor (alpha 1PI), and elastase inhibition capacity (EIC) were measured in CSF of 9 patients with bacterial meningitis (BM), aged 1 month-14 years; 13 patients with non-bacterial meningitis (NBM), aged 1 month-15 years; and 20 patients in whom meningitis was excluded after spinal tap (control group), aged 6 months-15 years. The concentration of elastase-alpha 1PI in the BM group (median 552 micrograms/l) was significantly higher than in either the NBM group (median 30 micrograms/l, p less than 0.01) or the control group (median 30 micrograms/l, p less than 0.01). Similarly, the alpha 1PI-concentration in the BM group was significantly higher (median 113 mg/l) than either the NBM group (median 13.7 mg/l, p less than 0.025) or the control group (median 6.3 mg/l, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline phosphatase level in CSF in various brain tumors and pulmonary carcinomatous meningitis.

Twenty-six patients with various brain tumors or carcinomatous meningitis were examined for alkaline phosphatase (ALP) in the cerebrospinal fluid. ALP enzyme levels were compared with the respective levels in control groups of 75 patients with epilepsy, stroke, bacterial and viral meningitis and intervertebral disc prolapse. Extremely high ALP levels in CSF (9516 mu/l, 1425 mu/l, and 871 mu/l) were found in patients with pulmonary carcinomatous meningitis. Among all other patients with brain tumors, ALP levels in CSF were in the normal range. Examination of ALP in serum yielded normal results in all patients. In patients with pulmonary carcinomatous meningitis, the enzyme level in CSF was examined during various stages of radiotherapy and chemotherapy. Decreased ALP enzyme level was found during treatment followed by recurring rising levels a month after the treatment coinciding with clinical relapse. No correlation was found between the level of ALP enzyme and the biochemical and cellular content of the CSF during the various stages of treatment.

[Evaluation of the value of determining lysozyme levels in cerebrospinal fluid in myeloencephalitis]. / Ocena przydatnosci oznaczania stezenia lizozymu w plynie mózgowo-rdzeniowym w przebiegu zapalen opon mózgowo-rdzeniowych.

The study aimed at assessing the value lysozyme assay in CFS as indicator of the damage to blood-cerebrospinal fluid barrier and intensification of inflammatory process in the course of meningitis. The study involved 20 patients with suppurative and 66 with viral meningitis. Control group included 26 patients without nervous system disease. To estimate the degree of blood-cerebrospinal fluid barrier damage albumin and lysozyme indicators were calculated. It was proved, that CSF lysozyme levels are bigger in the suppurative meningitis than in viral meningitis. According to the author, CSF lysozyme levels the value of lysozyme indicator may inform on intensification of the inflammatory process and the degree of blood-cerebrospinal fluid barrier damage in suppurative meningitis, whereas in the viral meningitis they inform on degree of blood-cerebrospinal fluid barrier damage, only.