Anti-inflammatory treatment influences neuronal apoptotic cell death in the dentate gyrus in experimental pneumococcal meningitis.

Apoptotic neuronal death and the increase of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF) were studied in a rabbit model of experimental pneumococcal meningitis after treatment with antimicrobial (ceftriaxone) and antiinflammatory agents (dexamethasone, monoclonal antibodies against the beta-subunit of beta 2-integrins [anti-CD18 mAb]). Twenty-four hours after infection, apoptotic cell death was found solely in the granular cell layer of the dentate gyrus. Neurons with DNA fragmentation were quantified with the in situ tailing (IST) reaction. Dexamethasone and anti-CD18 mAb inhibited the NSE increase in CSF significantly (p = 0.003, p = 0.011). After administration of dexamethasone the density of apoptotic neurons was significantly higher than in control animals receiving only ceftriaxone (p = 0.044). The median of the density of apoptotic neurons was lower in the dentate gyrus in animals receiving anti-CD18 mAb and ceftriaxone vs those receiving only ceftriaxone, although the difference did not reach statistic significance (p = 0.058). In conclusion, apoptotic cell death occurs in the dentate gyrus during the early phase of bacterial meningitis. The extent was influenced by antiinflammatory therapy. The systemic administration of glucocorticoids increased the quantity of apoptotic neurons in the dentate gyrus but reduced overall neuronal damage as indicated by low levels of NSE concentration in CSF.

Demonstration of locally synthesized immunoglobulin M antibodies to Treponema pallidum in the central nervous system of patients with untreated neurosyphilis.

Immunoglobulin M (IgM) antibodies to Treponema pallidum (TP) in serum and cerebrospinal fluid (CSF) can be evaluated quantitatively using a recently introduced enzyme-linked immunosorbent assay (ELISA). In 19 patients with untreated neurosyphilis, local synthesis of TP-specific IgM antibodies within the central nervous system (CNS) was demonstrated by estimation of the CSF/serum ratio of the TP-IgM-ELISA titer/mg total IgM. The TP-specific IgM antibody levels/mg total IgM in the CSF were between 3- and 75-fold higher than those in the corresponding serum of the same patients. Patients with untreated syphilis but without CNS involvement showed equal amounts of TP-specific IgM antibody levels/mg total IgM in CSF and serum, and served as controls.

Pharmacokinetic optimisation of the treatment of bacterial central nervous system infections.

Central nervous system (CNS) infections caused by bacteria with reduced sensitivity to antibacterials are an increasing worldwide challenge. In successfully treating these infections the following conditions should be considered: (i) Antibacterials do not distribute homogeneously in the central nervous compartments [cerebrospinal fluid (CSF), extracellular space of the nervous tissue, intracellular space of the neurons, glial cells and leucocytes]. Even within the CSF, after intravenous administration, a ventriculo-lumbar concentration gradient is often observed. (ii) Valid parameters of drug entry into the CSF are the CSF: serum concentration ratio in steady state and the CSF: serum ratio of the area under the concentration-time curves (AUCCSF/AUCS). Frequently, the elimination half-life (t1/2 beta) in CSF is longer than t1/2 beta in serum. (iii) For most antibacterials, lipophilicity, molecular weight and serum protein binding determine the drug entry into the CSF and brain tissue. With an intact blood-CSF and blood-brain barrier, the entry of hydrophilic antibacterials (beta-lactam antibacterials, glycopeptides) into the CNS compartments is poor and increases during meningeal inflammation. More lipophilic compounds [metronidazole, quinolones, rifampicin (rifampin) and chloramphenicol] are less dependent on the function of the blood-CSF and blood-brain barrier. (iv) Determination of the minimal inhibitory concentrations (MIC) of the causative organism is necessary for optimisation of treatment. (v) For rapid sterilisation of CSF, drug concentrations of at least 10 times MIC are required. The minimum CSF concentration: MIC ratio ensuring successful therapy is unknown. Strategies to achieve optimum antibacterial concentrations in the presence of minor disturbances of the blood-CSF and blood-brain barrier include, the increased use of low toxicity antibacterials (e.g., beta-lactam antibiotics), the use of moderately lipophilic compounds, and the combination of intravenous and intraventricular administration. Antibacterials which do not interfere with bacterial cell wall synthesis delay and/or decrease the liberation of proinflammatory bacterial products, delay or inhibit tumour necrosis factor release, and may reduce brain oedema in experimental meningitis. Conclusive evidence of the reduction of neuronal damage by this approach, however, is lacking.

Results of four technical investigations in fifty clinically brain dead patients.

Fifty consecutive patients (aged 19-77 years, median 56 years) with primary cerebral diseases and the clinical signs of absent cortical and brainstem function were subjected to electroencephalography (EEG), brainstem acoustic evoked potentials (BAEP), extracranial Doppler ultrasonography (ECD) and arterial digital subtraction angiography (DSA). In the majority of cases the results of the technical tests agreed with the clinical signs and were suggestive of brain death. However, in one patient EEG revealed clear bioelectrical activity. In 6 cases, doubts existed about whether the EEG was isoelectric; in 3 of the 6 cases biological activity might have been present. In 31 of 42 patients ECD showed a typical pattern of intracranial circulatory arrest, in 9 of 42 ECD revealed a pattern suggestive of the cessation of cerebral blood flow. In four patients BAEP recordings compatible with brain death were recorded 2-3 days before intracranial circulatory arrest. In 2 patients with isoelectric EEG and absent BAEP arterial DSA demonstrated residual perfusion. The findings are discussed in view of the conceptional differences concerning brain death. It is concluded that the strict application of the concept of death of the whole brain requires angiographic demonstration of absent intracerebral blood flow.

Polyradiculoneuritis following botulinum toxin therapy.

The development of Guillain-Barré syndrome is reported in a patient, who had previously received botulinum toxin type A injections into both orbicularis oculi muscles to treat idiopathic blepharospasm. The possibility of a causal relationship is discussed with consideration of the literature on adverse effects of vaccinations and of Clostridium botulinum and its toxin.

Brainstem compression by basilar artery anomalies as visualized by MRI.

The use of MRI in the diagnosis of vascular anomalies of the basilar artery is demonstrated in two cases. The first patient had a partially thrombosed giant aneurysm of the basilar artery; the second had an atypical course of the basilar artery. MRI is indicated whenever other imaging procedures do not provide a definite diagnosis or the use of contrast medium for conventional X-ray examination or computed tomography is contraindicated.

Reactivity of locally produced CSF antibodies in patients with neurosyphilis against antigens of Treponema pallidum.

The reactivity and specificity of locally produced cerebrospinal fluid (CSF) antibodies against antigens of Treponema pallidum were assessed by Western blotting in patients with clinical signs of parenchymal or meningovascular neurosyphilis. All nine patients showed local production of treponeme-specific antibodies in the central nervous system (CNS). In most of the patients serum and CSF antibodies were bound to the same antigens: the common treponemal 48/45 kDa protein and the putative specific T. pallidum protein in the range of 12-14 kDa. In some patients the intensity of staining obtained by CSF antibodies was higher than that derived from serum, indicating locally produced antibodies. In contrast to other more acute inflammatory CNS diseases, no expanded or different antigen binding of the CSF antibodies compared with serum antibodies was found in neurosyphilic patients. The results presented are discussed with regard to the role of the blood-brain barrier in antibody concentrations of CSF and serum.

Relationship between neurological features and intrathecal synthesis of IgG antibodies to Treponema pallidum in untreated and treated human neurosyphilis.

In syphilitic patients with or without CNS involvement the correlation of Treponema-specific IgG titre per milligram total IgG in CSF and serum (ITPA index) is a dependable source of information on the synthesis of treponemal IgG antibodies in the CNS. This index also provides a more reliable definition of asymptomatic neurosyphilis. Further, a discrimination between Treponema-specific and Treponema-non-specific IgG synthesis in the CNS is possible. Of 261 patients with clinical symptoms of neurosyphilis, 82% had a local production of treponemal IgG antibodies as shown by an elevated ITPA index. In patients with neurosyphilis and intrathecal synthesis of Treponema-specific IgG antibodies, 94% had oligoclonal IgG in the CSF. Comparison of different CSF protein alteration groups in untreated and treated neurosyphilitic patients showed that early diagnosis (and early treatment) led to improvement of the impairment of the blood-CSF barrier and reduction of the immune reaction in the CNS. However, synthesis of treponemal IgG antibodies in the CNS could persist as a 'scar syndrome' even after adequately cured infection.

Beta-trace protein concentration in cerebrospinal fluid is decreased in patients with bacterial meningitis.

Although meninges represent a major site of biosynthesis, beta-trace protein (beta-trace) has not been studied in the cerebrospinal fluid (CSF) of meningitis patients. We measured beta-trace in lumbar CSF of normal controls (n = 27) and in patients with various neurological diseases (n = 92) by an immunonephelometric assay. The mean concentration of beta-trace in CSF of control patients was 16.6+/-3.6 mg/l. In bacterial meningitis (n = 41), CSF beta-trace was significantly decreased (8.7+/-3.9 mg/l; P< 0.001), whereas in spinal canal stenosis it was elevated (29.2+/-10.3 mg/l; P= 0.002). In viral meningoencephalitis (n = 12), beta-trace CSF concentrations were normal. Beta-trace concentrations remained below the normal range even after curing of bacterial meningitis, and normalisation of CSF leucocytes and blood-CSF barrier function. Beta-trace may be a useful tool for studying the pathophysiology of bacterial meningitis.

Cerebrospinal fluid paraproteins in neurological disorders.

Paraproteins display a characteristic pattern of limited heterogeneity on isoelectric focusing. In a group of 50 patients with various neurological disorders and paraproteinaemia this pattern could be demonstrated in serum and cerebrospinal fluid simultaneously, regardless of the form of nervous system involvement or of the function of the blood-cerebrospinal fluid barrier. Although there were no qualitative differences in the pattern between paraproteins from benign and malignant cases, a distinct quantitative difference was found: Paraproteins from myeloma patients had significantly more subfractions extending over a wider pH range than paraproteins from patients with benign monoclonal gammopathy. Due to the high sensitivity of isoelectric focusing, more paraproteins could be detected in cases where other electrophoretic methods including immunoelectrophoresis were negative. A surprisingly high percentage of patients was found with benign monoclonal gammopathy and vascular lesions of the central nervous system.

Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges.

Physicochemical properties of drugs were related to their ability to enter the cerebrospinal fluid (CSF) in humans by reevaluation of previously reported studies. Either the quotients of the drug concentrations in CSF and serum at steady state (CCSFSS/CSSS) or, since in most cases CSF passage was studied after a short-term infusion, the ratios of the areas under the concentration-time curves in CSF and serum (AUCCSF/AUCS) were taken as measures of CSF passage. AUCS and CSSS were corrected for binding to serum proteins (AUCSf, CSssf). Of the drugs studied the quotient of the octanol/water partition coefficient at pH 7.4 (PC) as a measure of lipophilicity and the square root of the molecular weight (MW1/2) correlated with AUCCSF/AUCS (Spearman's rank correlation coefficient rS = 0.78, P < 0.01) and with AUCCSF/AUCSf (rS = 0.90, P < 0.01). PC.MW-1/2 was related to AUCCSF/AUCSf (or CCSFSS/CSssf, respectively) by the equation: AUCCSF/AUCSf = 0.96 + 0.091.1n(PC.MW-1/2). For 0.0001 < or = PC.MW-1/2 < or = 1.0 this function may be of value for the prediction of CSF penetration in humans when the physicochemical properties of a drug are known and when active transport or metabolism are negligible.

Inverse correlation between disappearance of intrathecally injected 111In-DTPA from CSF with CSF protein content and CSF-to-serum albumin ratio.

By means of cerebrospinal fluid (CSF) scintigraphy with 111In-DTPA injected following lumbar puncture in 18 patients after meningitis (12), with traumatic head injury (4), cholesteatoma (1) or a communicating hydrocephalus (1) the hypothesis of whether slow movement of CSF may contribute to the elevation of CSF protein and albumin content in neurological diseases other than spinal block was tested. The ratios of the count rates over the head (geometric mean of anterior and posterior view) at 23-25 h to 4-6 h after 111In-DTPA application (C24 h/C5 h) and the ratio 47-49 h to 23-25 h after injection (C48 h/24 h) were taken as measures of the velocity of 111In-DTPA disappearance from CSF. Both the CSF protein content and the CSF-to-serum albumin ratio correlated with C24 h/C5 h and C48 h/C24 h. Assuming log-linear elimination between 24 and 48 h the elimination half-life of 111In-DTPA was estimated to be 12.4-131.1 h (median = 31.7 h). It was concluded that slow CSF kinetics probably are involved in the elevation of CSF protein content in several neurological diseases.

Immunocytochemical analysis of immunoglobulin-containing cells in CSF and blood in inflammatory disorders of the central nervous system.

Cells containing immunoglobulins G, A, and M were evaluated in paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples. These were obtained from 12 patients with bacterial meningitis, 14 patients with viral meningitis, 6 cases of lymphocytic meningoradiculitis (LMR), 10 cases of multiple sclerosis (MS), 6 cases of herpes zoster ganglionitis and 27 patients with non-infectious disorders of the CNS. PB cells from 20 healthy donors served as controls. Using alkaline phosphatase (AP)-conjugated antibodies to human immunoglobulin (Ig) G, A, and M in a carrageenan solution it was possible to demonstrate repeatedly intracytoplasmic Igs over more than 1 year without any detectable loss of specificity and staining intensity. Immunoglobulin-containing cells (ICC) could be detected in the CSF of 96% of patients with inflammatory diseases of the central nervous system (CNS) or with MS but not in the control cases.

[Neurologic diseases in herpesvirus infections]. / Neurologische Erkrankungen bei Herpesviren-Infektionen.

Herpes viruses can give rise to numerous virological infections. Life-threatening situations arise with encephalitis caused by HSV or VZV. Zoster vasculitis is probably more frequent than its diagnosis would suggest, and usually results in paralysis. A particularly troublesome condition is post-herpetic neuralgia that requires a wearisome and often complex treatment. Cerebral nerve involvement and polyradiculitis may be associated with almost all the human pathogenic herpes viruses. In patients with herpetic CNS involvement, early treatment is necessary.

[Pathophysiology, therapy and prognosis of hypoxic-ischemic brain damage]. / Pathophysiologie, Therapie und Prognose des hypoxisch-ischämischen Hirnschadens.

Generally accepted treatment regimens of hypoxic-ischemic brain damage have not been established so far. Therefore, therapeutic measures are oriented to the pathophysiological mechanisms known at present, including ischemic calcium cascade, excitotoxicity, NO overformation, and disturbances of re-circulation (e.g., no reflow phenomenon). Bioelectric changes in the brain parenchyma evolving during hypoxia-ischemia become successively apparent as hyperpolarization, failure of synaptic transmission, massive depolarization of cells resembling the spreading depression of Leâo, neuronal K+ loss and uptake of large amounts of Na+, Cl-, Ca++, accompanied by H2O, causing cell swelling. Up to now, the rapid progress of these pathological events has hardly permitted an efficacious treatment. If any therapy, the combination of NMDA receptor antagonists, glucocorticosteroids, GABAergic drugs and heparin could be helpful in preventing the delayed postischemic injury that often occurs after initial apparent recovery. The therapeutic role of lazaroids, NO donators, and endothelin antagonists still has to be defined. An early assessment of the brain damage subsequent to hypoxia-ischemia is possible by means of somatosensory evoked potentials (SSEP) and serum concentration of neuronspecific enolase (NSE), respectively. NSE values exceeding 120 ng/ml during the first 5 days after hypoxia-ischemia point to an unfavorable outcome. In contrast, NSE concentrations below 35 ng/ml mostly indicate a good recovery.

Adenylate kinase enzyme activity in cases of brain infarction.

The adenylate kinase (AK) enzyme activity in plasma and CSF of acute brain infarctions was examined. The normal values of enzyme activity in plasma reached from 1.7-5.6 U/l, and in CSF from 0.23-0.71 U/l. According to this present classification a significant CSF increase in AK activity was found with semi-severe and severe brain infarctions. With the CCT an increased enzyme activity was shown with infarction in or close to the cortex. In no case was an alteration of AK activity in the serum sample. CSF samples showing blood contamination or pleocytosis led to false pathological results with examination of AK activity.