Walter Hader

Neuropsychological outcomes after epilepsy surgery: systematic review and pooled estimates

Purpose:u2002 Epilepsy surgery is a safe surgical procedure, but it may be associated with cognitive changes. Estimates of the risk of decline in specific neuropsychological domains after epilepsy surgery would assist surgical decision making in clinical practice. The goal of this study was to conduct a systematic review to derive pooled estimates of the rate of losses and gains in neuropsychological functions after epilepsy surgery, using empirically based methods for quantifying cognitive change.

Complications of epilepsy surgery: a systematic review of focal surgical resections and invasive EEG monitoring.

Underutilization of epilepsy surgery remains a major problem and is in part due to physicians misconceptions about the risks associated with epilepsy surgery. The purpose of this study was to systematically review the literature on complications of focal epilepsy surgery.

Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell‐microglia interaction

Minocycline, a tetracycline with anti‐inflammatory properties, has been reported to down‐regulate the activity of microglia, whose activation occurs in inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis and Alzheimer’s disease. In these disorders, a T cell component is also evident, and we have demonstrated previously that the interaction of activated T cells with microglia led to the substantial increase in tumor necrosis factor α (TNF‐α) levels. Here, we report that minocycline decreases TNF‐α levels produced in human T cell‐microglia interaction. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which resulted in the decreased ability of T cells to contact microglia. In correspondence, minocycline decreased the expression on T cells of the CD40 ligand (CD40L), a key molecule regulating the contact‐mediated interaction of T cells with microglia. These results demonstrate that the mechanism of action of minocycline involves not only microglia but also T cells and their subsequent activation of microglia. The capacity of minocycline to down‐regulate CD40L on T cells may provide a new means to target the CD40‐CD40L pathway, which regulates several inflammatory processes.

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient–derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.

The value of routine cultures of the cerebrospinal fluid in patients with external ventricular drains.

OBJECTIVEnThe purpose of this study was to determine whether routine cerebrospinal fluid (CSF) bacteriological cultures in patients with external ventricular drains (EVDs) can identify infections early and prevent complications related to bacterial ventriculitis.nnnMETHODSnWe retrospectively reviewed the microbiological reports and clinical data for all patients in whom an EVD was placed at a tertiary care pediatric neurosurgical center between 1984 and 1997. EVDs were inserted in the operating room or intensive care unit, and, in most patients whose EVD remained in place for more than 2 days, daily cultures of CSF were performed.nnnRESULTSnOne hundred fifty-seven patients in whom 160 EVDs had been placed were included in the study. Forty-eight positive cultures were identified, of which the majority were determined to be contaminants. Seven infections were identified on the basis of microbiological criteria (i.e., a gram-positive stain and positive culture) and a subsequent positive culture. In all patients in whom infections developed, routine daily cultures of CSF were performed, and, in each instance, these cultures failed to identify the infections before clinical changes occurred. All seven patients with infection had fever (>38.5 degrees C) and peripheral leukocytosis (>11 x 10(3)/mm3) on the day the infection was identified, and one had a change in CSF appearance.nnnCONCLUSIONnThe results of this study suggest that routine culture of CSF in children with EVDs is not necessary, and that if CSF cultures are performed for new fever (>38.5 degrees C) or peripheral leukocytosis, neurological deterioration, or a change in CSF appearance, infections will be identified in a timely fashion. In situations in which these clinical indicators might be masked, routine cultures may be valuable.

Epidemiology of multiple sclerosis in London and Middlesex County, Ontario, Canada

A case-controlled epidemiologic study of multiple sclerosis (MS) was carried out in London, Ontario, and its surrounding Middlesex County for the period 1974–1983. The prevalence rates for clinically definite/probable MS on January 1, 1984 were 94/100,000 for the city and 91/100,000 for the county. The estimated annual incidence rate for the decade 1974–83 was 3.4/100,000. The female-to-male sex ratio was 2.5:1. A familial history of MS was recorded in 14.4% of close relatives and a total of 17% when distant relatives are included. The MS group is predominantly of British (70%) and European (23%) origin. The urban-rural residence pattern analysis indicates no significant regional influence on the risk of developing MS.

A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis

Glioma cells in situ are surrounded by microglia, suggesting the potential of glioma-microglia interactions to produce various outcomes. As chemokines are important mediators of cell-cell communication, we sought first to identify commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage chemoattractant protein-1) messenger RNA to be expressed by the majority of glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which has low basal level of CCL2, to investigate the hypothesis that glioma-secreted CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 12-fold elevation of CCL2 have similar growth rate and invasive capacity as vector controls when cultured in isolation. However, in coculture with microglia in a three-dimensional collagen gel matrix, the invasiveness of CCL2-overexpressing clones was increased. Gene array analyses were then undertaken and they revealed that interleukin (IL)-6 was consistently increased in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated glioma invasiveness. Finally, we found that human glioma specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ cells. This study has uncovered a mechanism by which glioma cells exploit microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable malignant gliomas.

Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children.

Surgical removal of cystic craniopharyngiomas in children is associated with significant operative morbidity and recurrence rates. The purpose of this study was to review our experience with a less invasive therapy, namely, intratumoral bleomycin, in the treatment of predominantly cystic craniopharyngiomas. All children with craniopharyngiomas treated at a tertiary care pediatric neurosurgical center since 1994, when bleomycin was first used, were reviewed retrospectively. Seven patients received intratumoral bleomycin therapy. Patients received 2–5 mg bleomycin per dose, 3 times per week, for 3–5 weeks as an initial course. Mean follow-up of these patients was 3 years. In 4 patients, treatment resulted in a significant decrease (>50%) in tumor size, which has remained stable. Two patients’ tumors progressed and underwent resection, and 1 patient had surgical removal because of persistent headaches, although no growth of residual tumor had been noted. One patient developed peritumoral edema as a result of bleomycin therapy. Intratumoral bleomycin is a useful alternative therapy for cystic craniopharyngiomas, and may control tumor growth and delay potentially harmful resection and/or radiotherapy in young children.

Metalloproteinases are enriched in microglia compared with leukocytes and they regulate cytokine levels in activated microglia

Microglia are resident immune cells within the central nervous system (CNS). They become activated following neurological insults and increase their expression of cytokines. Also elevated in CNS injuries are proteases, including matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). The spectrum of metalloproteinase members expressed by microglia and by the systemic leukocytes that infiltrate the injured CNS is unknown, as are their functions. We determined the levels of transcripts encoding all 24 MMPs, nine ADAMs, and their four physiological antagonists, tissue inhibitor of metalloproteinases (TIMPs), in human microglia, B and T cells, monocytes, and neutrophils. We found a distinct pattern for each immune subset and an enrichment of metalloproteinases in microglia compared with leukocytes. When microglia were activated, there was an upregulation of transcripts for nine metalloproteinases, and reduction of TIMP3. Activation of microglia also resulted in increased levels of tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐10 protein in the conditioned media of cells. The amount of secreted TNF‐α, but not IL‐1β or IL‐10, was suppressed by BB94, a broad spectrum metalloproteinase inhibitor, and by TIMP3 but not TIMP1 or TIMP2. This inhibitory profile suggests the involvement of an ADAM member in TNF‐α secretion. We conclude that microglia bear a metalloproteinase signature distinct from systemic cells, and that following activation, microglia upregulate TNF‐α protein levels through a combination of elevated cytokine transcripts, increased metalloproteinase level and activity, and through the decrease of TIMP3. The results have implications for the regulation of neuroinflammation and its outcomes following CNS injuries.

Endoscopic versus microsurgical resection of third ventricle colloid cysts.

OBJECTIVEnEndoscopic resection of colloid cysts has been performed as an alternative to microsurgical resection and stereotactic aspiration since 1982. To date, there are limited published studies comparing these procedures. In this study, we present the largest series of endoscopic resections published to date and compare outcomes to a cohort of microsurgical resections performed at the same institution.nnnMETHODSnA retrospective chart review was conducted for all patients in the Calgary Health Region undergoing resection of a colloid cyst between 1991 and 2004. Comparison was made between patients treated with endoscopic resection versus microsurgical resection.nnnRESULTSnTwenty-five endoscopic and nine microsurgical procedures were performed. Complete resection was achieved in 24 of 25 procedures in the Endoscopic group, compared with all 9 procedures in the Microsurgical group. Patients in the Endoscopic group had a reduced operative time (mean 104 minutes versus 217 minutes) and reduced length of stay (3.8 days versus 8.4 days) compared to the Microsurgical group. One patient in the Endoscopic group had a complication (hemiparesis/pulmonary embolus). By contrast, 3 patients in the Microsurgical group had complications (seizure, ventriculitis/bone flap infection, and transient memory deficit). There was one recurrence in each group which both occurred at 5 years follow-up. The mean length of follow-up is 38 months in the Endoscopic group and 33 months in the Microsurgical group.nnnCONCLUSIONnEndoscopic resection of colloid cysts can be performed with significantly lower risk of complication than microsurgical resection and with equivalent surgical success. Operative time and length of hospital stay are both significantly reduced with endoscopic resection.