Neuropsychological sequelae of bacterial and viral meningitis.

Survivors of meningitis often complain about neurological and neuropsychological consequences. In this study, the extent of these sequelae was quantified and correlated to MRI findings. Neurological, neuropsychological and neuroradiological examinations were performed with adult patients younger than 70 years, 1-12 years after recovery from bacterial meningitis (BM; n = 59), or from viral meningitis (VM; n = 59). Patients with other potential causes for neuropsychological deficits (e.g. alcoholism) were carefully excluded. Patients were compared to 30 healthy subjects adjusted for age, gender and length of school education. With the exception of attention functions, both patient groups showed more frequently pathological results than the control group for all domains examined. Applying an overall cognitive sum score, patients after BM did not differ significantly in their performance from patients after VM. Separate analyses of various cognitive domains, however, revealed a higher rate of persistent disturbances in short-term and working memory after BM than after VM. Moreover, patients after BM exhibited greater impairment of executive functions. Associative learning of verbal material was also reduced. These deficits could not be ascribed to impaired alertness functions or decreased motivation in BM patients. Applying a logistic regression model, the neuropsychological outcome was related to the neurological outcome. Patients with a Glasgow Outcome Scale (GOS) of <5 had more frequently impaired test results for non-verbal learning and memory. GOS was also correlated with performance in executive functions. Brain volume was lower and ventricular volume was higher in the bacterial than in the VM group, and cerebral volume and the amount of white matter lesions of patients after BM were negatively correlated with short-term and working memory. In conclusion, patients after both BM and VM with favourable outcome showed affected learning and memory functions. More patients after BM than after VM displayed pathological short-term and working memory. BM resulted in poorer performance in executive functions, language, short-term memory and verbal learning/memory tests. As a result of neurological and neuropsychological sequelae, BM with a GOS > or = 4 led to decreased activities of daily living but only a minority of patients were disabled in a way that social functions were affected. The extent of neuropsychological sequelae of BM might have been overestimated in earlier studies which often had not been controlled for comorbidity factors such as alcoholism.

Temozolomide enhances herpes simplex virus thymidine kinase/ganciclovir therapy of malignant glioma.

Gene therapy for malignant glioma with the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is already in the stage of clinical trials, but still needs major improvement to achieve greater clinical efficacy. The aim of this study was to determine whether combining HSV-tk/GCV gene therapy with temozolomide (TMZ), an alkylating drug clinically proven to be efficient in recurrent high-grade gliomas, would result in enhanced antitumor effect in malignant glioma in culture and in vivo. Human U87MG glioblastoma (GBM) cells with or without expression of HSV-tk were treated with different concentrations of GCV, TMZ, or both drugs. Cell viability was accessed by an automated microplate assay (MTT). The isobologram method and the combination index (CI) method of Chou-Talalay were used to measure the interactions between the two drugs when applied simultaneously. U87-tk and control U87 cells (5x10(6) each) were implanted in the flanks of nude mice, and animals were treated with GCV or TMZ or with both drugs. All tumors were measured and weighed at specified time points. IC(50) for GCV was 511 microM in control U87 cells and 14.3 microM in U87-tk cells, resulting in 35.7-fold increase of toxicity in the HSV-tk-expressing cells. TMZ had an IC(50) of 20.2 mM in control cells and 2.35 mM in U87-tk cells, resulting in 8.6-fold increase in sensitivity of the HSV-tk-expressing cells. TMZ and HSV-tk/GCV actions were synergistic (CI<1) in both control and U87-tk cells with higher synergism in U87-tk cells at high effect levels. Tumors expressing HSV-tk and treated with TMZ and GCV were significantly smaller than those treated by TMZ, but not by GCV. There was also a significant difference between the weight of HSV-tk expressing versus control tumors treated with TMZ, with GCV, or with both drugs. These data demonstrate synergism between HSV-tk/GCV and TMZ and higher sensitivity against TMZ in HSV-tk-expressing GBM cells. The potential importance for clinical studies combining both local tumor gene therapy and systemic chemotherapy should be explored further.

Epidural electrical stimulation of the motor cortex in patients with facial neuralgia.

Chronic facial neuralgias often do not respond sufficiently to standard treatment methods. Alternative modalities are needed for long-term reduction of pain in such cases. The present preliminary report describes two patients with trigeminal and glossopharyngeal neuralgia, respectively, treated with standard methods without obtaining satisfactory pain relief. Electrical stimulation of the motor cortex contralateral to the pain area was employed in both cases and proved able to produce a long-term facial pain reduction. Alleviation of pain occurred after activation of the flat quadripolar electrode placed epidurally on the precentral cortical area and lasted as long as the stimulator was working. By changing the polarity of the electrodes, it was possible to induce tingling sensations and muscle activation not only contralaterally to the stimulated motor cortex, but also in the ipsilateral part of the face. No stimulator-independent pain reduction resulted from long-term use of the stimulation device. During a follow-up period of 18 months, a sufficient and relatively stable analgesic effect of electrostimulation was observed. One major complication of motor cortex stimulation during the follow-up period was a single generalized epileptic seizure in one of the patients.

Neurosarcoidosis: findings in MRI.

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. Neurologic manifestations occur usually as a part of the spectrum of the systemic disease. The aim of this retrospective study was to evaluate the role of magnetic resonance imaging (MRI) in the diagnosis of patients with neurosarcoidosis (NS). Seven patients with sarcoidosis could be included into the study. All patients had neurological symptoms and were evaluated with MRI revealing a wide spectrum of findings: periventricular and white matter lesions, multiple or solitary supra- and infratentorial brain lesions, leptomeningeal enhancement, involvement of brain nerves and intramedullar lesions. These findings are not specific for sarcoidosis and must be considered with the clinical course of the patient in arriving at the correct diagnosis.

Three-dimensional reconstruction and volumetry of intracranial haemorrhage and its mass effect.

Intracerebral haemorrhage still causes considerable disability and mortality. The studies on conservative and operative management are inconclusive, probably due to inexact volumetry of the haemorrhage. We investigated whether three-dimensional (3-D), voxel-based volumetry of the haemorrhage and its mass effect is feasible with routine computed tomography (CT) scans. The volumes of the haemorrhage, ventricles, midline shift, the intracranial volume and ventricular compression in CT scans of 12 patients with basal ganglia haemorrhage were determined with the 3-D slicer software. Indices of haemorrhage and intracranial or ventricular volume were calculated and correlated with the clinical data. The intended measures could be determined with an acceptable intra-individual variability. The 3-D volumetric data tended to correlate better with the clinical course than the conventionally assessed distance of midline shift and volume of haemorrhage. 3-D volumetry of intracranial haemorrhage and its mass effect is feasible with routine CT examination. Prospective studies should assess its value for clinical studies on intracranial space-occupying diseases.

Bcl-2 expression in higher-grade human glioma: a clinical and experimental study.

Bcl-2 protein plays an important role in inhibiting apoptosis and protecting normal and neoplastic cells from toxicity. Bcl-2 overexpression in malignant tumors, on the other hand, may cause resistance against adjuvant treatment. Since there are subpopulations of patients with glioma that differ considerably in their treatment benefit, it is important to identify prognostic factors for outcome and to tailor adjuvant protocols in accordance with specific biological features of the respective tumor. The present study aimed at investigating the role of bcl-2 expression in higher-grade glioma (WHO grade III and IV). Bcl-2 expression was correlated with clinical and paraclinical parameters, and evaluated in univariate and multivariate statistical models. In addition, bcl-2-overexpressing human glioma cells in culture were used for modeling the in vivo findings and for investigating the importance of bcl-2 for tumor resistance against cytotoxic treatment. A group of 86 patients with higher-grade glioma were investigated. Anaplastic astrocytoma (AA; WHO G III, n = 29) showed bcl-2 expression in 48% of the cases, and immunohistochemical positivity was associated with a significantly shorter survival time (p = 0.0068). In glioblastoma patients (GBM; WHO G IV, n = 57), 51% of tumors were bcl-2 positive, but bcl-2 expression did not correlate significantly with survival (p = 0.39). In a Cox proportional hazards regression model, bcl-2 positivity was confirmed as a negative prognostic parameter in AA, but not in GBM. Bcl-2 overexpressing and control human glioma cell clones (T98MG line) were treated in culture with the cytotoxic drugs carmustine (BCNU), paclitaxel, vincristine, and doxorubicin. In addition, bcl-2-overexpressing and control cells were infected with a retrovirus carrying the herpes-simplex-virus thymidine kinase gene (HSV-tk), and then treated with ganciclovir (GCV). Bcl-2 overexpression significantly increased tumor cell resistance against all of the above cytotoxic drugs, and also against HSV-TK/GCV mediated gene therapy.

CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children.

Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.

Gamma-glutamyl transferase expression in higher-grade astrocytic glioma.

Increased expression of gamma-glutamyltransferase (GGT) has been detected in a range of human malignancies and is thought to be involved in neoplastic proliferation and treatment resistance. Since GGT expression and its role in malignant glioma biology remain largely unknown, we investigated this phenomenon by immunostaining 26 higher-grade human astrocytic gliomas (WHO grades III and IV) with a monoclonal anti-GGT-antibody (138H11). Further, human pancreatic GGT cDNA was used for liposome-mediated transfection of 9L gliosarcoma cells. GGT-expressing and control 9L cells were cultured in media containing different amounts of essential amino acids and/or cytotoxic agents. Cell viability was evaluated by microplate MTT assay. Immunohistochemical staining of tumor specimens demonstrated that GGT expression is a frequent feature of higher-grade human astrocytic gliomas, but not of normal brain tissue. Human tumors were strongly GGT-positive in 6 of 7 cases of grade III astrocytoma, and in 12 of 19 grade IV astrocytoma (glioblastoma multiforme, GBM) cases. In the cell culture model, 9L-GGT cells had a growth advantage over control cells in cysteine-deficient medium. but not in standard or glutamine-free medium. No significant difference in numbers of viable cells of either clone was found in media containing the alkylating drug BCNU (5-200 microg/ml). In conclusion, GGT is expressed in a high percentage of human WHO grade III astrocytomas and GBM, but not in normal brain tissue. This molecule seems to give neoplastic cells a moderate growth advantage under in vivo conditions.