Efficacy and safety of a collagen matrix for cranial and spinal dural reconstruction using different fixation techniques.

OBJECT: The use of dural grafts is frequently unavoidable when tension-free dural closure cannot be achieved following neurosurgical procedures or trauma. Biodegradable collagen matrices serve as a scaffold for the regrowth of natural tissue and require no suturing. The aim of this study was to investigate the efficacy and safety of dural repair with a collagen matrix using different fixation techniques. METHODS: A total of 221 patients (98 male and 123 female; mean age 55.6 +/- 17.8 years) undergoing cranial (86.4%) or spinal (13.6%) procedures with the use of a collagen matrix dural graft were included in this retrospective study. The indications for use, fixation techniques, and associated complications were recorded. RESULTS: There were no complications of the dural graft in spinal use. Five (2.6%) of 191 patients undergoing cranial procedures developed infections, 3 of which (1.6%) were deep infections requiring surgical revision. There was no statistically significant relationship between the operative field status before surgery and the occurrence of a postoperative wound infection (p = 0.684). In the 191 patients undergoing a cranial procedure, cerebrospinal fluid (CSF) collection occurred in 5 patients (2.6%) and a CSF fistula in 5 (2.6%), 3 of whom (1.6%) required surgical revision. No patient who underwent an operation with preexisting CSF leakage had postoperative CSF leakage. Postoperative infection significantly increased the risk for postoperative CSF leakage. The collagen matrix was used without additional fixation in 124 patients (56.1%), with single fixation in 55 (24.9%), and with multiple fixations in 42 (19%). There were no systemic allergic reactions or local skin changes. Follow-up imaging in 112 patients (50.7%) revealed no evidence of any adverse reaction to the collagen graft. CONCLUSIONS: The collagen matrix is an effective and safe cranial and spinal dural substitute that can be used even in cases of an existing local infection. Postoperative deep infection increases the risk for CSF leakage.

Sensor-based neuronavigation: evaluation of a large continuous patient population.

OBJECTIVE: Navigation systems enable neurosurgeons to guide operations with imaging data. Sensor-based neuronavigation uses an electromagnetic field and sensors to measure the positions of the patient's brain anatomy and the surgical instruments. The aim of this investigation was to determine the accuracy level of sensor-based tracking in a large patient collection. METHODS: This study covers 250 patients operated upon during a continuous 5.5-year period. The patients had a wide range of indications and surgical procedures. The operations were performed with a direct current (DC) pulsed sensor-based electromagnetic navigation system. Four kinds of errors were measured: the fiducial registration error (FRE), the target registration error (TRE), brain shift, and the position error (PE). These errors were calculated for five subgroups of indications: target determination and trajectory guidance, functional navigation, skull base and neurocranium, determination of resection volume, and transnasal and transsphenoidal access. RESULTS: The overall mean FRE was 1.66mm (+/-0.61mm). The overall mean TREs were 1.33mm (+/-0.51mm) centroid and 1.59mm (+/-0.57mm) lesional. The overall mean brain shift for applicable cases was 1.61mm (+/-1.14mm). The overall mean PE was 0.92mm (+/-0.54mm). CONCLUSIONS: By and large, modern sensor-based neuronavigation operates within an acceptable and commonplace degree of error. However, the neurosurgeon must remain critical in cases of small lesions, and must exert caution not to introduce further interference from metal objects or electromagnetic devices.

Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients.

BACKGROUND AND OBJECTIVE: Taurolidine is known to have antimicrobial activity. Furthermore, at lower concentrations, it has been found to exert a selective antineoplastic effect in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of taurolidine in vivo following repeated intravenous infusion in a schedule used for the treatment of glioblastoma. As a prerequisite, the pharmacokinetics of taurolidine in human blood plasma and whole blood in vitro was investigated. PATIENTS AND METHODS: The pharmacokinetics of taurolidine and its derivatives taurultame and taurinamide were investigated in human blood plasma and in whole blood in vitro using blood from a healthy male volunteer. During repeated intravenous infusion therapy with taurolidine, plasma samples were taken every hour for a period of 13 hours per day in seven patients (three male, four female; mean age 48.4 +/- 12.8 years, range 27-66 years) with a glioblastoma. Following dansyl derivatisation, the concentrations of taurultame and taurinamide were determined using a new method based on high-performance liquid chromatography (HPLC) online coupled to electrospray ionisation tandem mass spectrometry (ESI-MS/MS) in the multiple reaction monitoring mode. Under the experimental conditions used, taurolidine could not be determined directly and was back-calculated from the taurultame and taurinamide values. RESULTS: The new HPLC-ESI-MS/MS method demonstrated high accuracy and reproducibility. In vitro plasma concentrations of taurultame and taurinamide remained constant over the incubation period. In whole blood in vitro, a time-dependent formation of taurinamide was observed. At the start of the incubation, the taurultame-taurinamide ratio (TTR) was 0.95 at an initial taurolidine concentration of 50 microg/mL, and 1.69 at 100 microg/mL. The concentration of taurultame decreased at the same rate as the taurinamide concentration increased, showing logarithmic kinetics. The calculated taurolidine concentration remained largely constant over the 6-hour incubation period. During repeated infusions in patients, calculated plasma concentrations of taurolidine showed a strong increase after the start of each infusion and continued to increase until the end of infusion, followed by a rapid decline. The TTR was found to fluctuate between 0.1 and 0.3, depending on the relation to the previous or next infusion period. The volume of distribution was markedly higher for taurolidine, taurultame and taurinamide than the plasma volume. CONCLUSIONS: Taurolidine displayed a stable pattern of derivatives in plasma in vitro, whereas in whole blood, a time- and concentration-dependent conversion was apparent. In patients, the calculated average taurolidine plasma concentration, achieved with the repeated infusion regimen, was in the antineoplastic-effective concentration range. The tissue concentrations of taurolidine and taurultame are expected to be higher than the plasma concentrations, taking into account the calculated volumes of distribution. Repeated infusion of taurolidine is the therapeutically adequate mode of administration for the indication of glioblastoma.

Rapidly progressive paraplegia due to an extradural lumbar meningocele mimicking a cyst. Case report.

Unlike arachnoid meningoceles, arachnoid cysts frequently cause local pressure effects probably because there is no free communication between the cyst and the subarachnoid space. Following the first detailed description of cystic lesions of spinal nerve roots by Tarlov in 1938, a simplified classification of spinal meningeal cysts was developed in 1988, containing three major categories. The authors report on a lumbar intraspinal extradural meningocele that caused incomplete paraplegia in an otherwise healthy 31-year-old man in whom magnetic resonance imaging revealed stigmata of Scheuermann disease. Intraoperatively, the lesion was classified as a transitional-type lesion, in accordance with Type IA of the Nabors classification, because a communication with the subarachnoid space was observed. After complete removal of the meningocele, the patient's recovery was prompt and complete.

Use of gelatin-thrombin matrix hemostatic sealant in cranial neurosurgery.

The present study evaluated the hemostatic efficacy and handling of gelatin-thrombin matrix hemostatic sealant during intracranial procedures. A retrospective analysis of 478 consecutive patients undergoing intracranial procedures identified seven patients with acute intense or persistent intraoperative bleeding which could not be arrested in time by standard hemostatic methods. The efficacy of gelatin-thrombin matrix was assessed by determining bleeding severity before and after application, time to hemostasis, amount of gelatin-thrombin matrix necessary, need for additional hemostatic measures, and need for reoperation to control hemorrhage. Immediate hemostasis was achieved in five of seven patients. Two of these five patients had abnormal clotting parameters. Cessation of bleeding was achieved by additionally applying either fibrinogen or gelatin sponge to the bleeding site in the other two patients. No complications attributable to gelatin-thrombin matrix use were recorded. The gelatin-thrombin matrix was ready to use within 1 minute in every case. Gelatin-thrombin matrix appears to be an effective, easy-to-use, and readily available hemostatic agent for cranial neurosurgery. Combination with fibrinogen is recommended in special situations.

Pure Endovascular Management of an Arteriovenous Malformation and an Aneurysm Both Supplied by Anterio-Inferior Cerebellar Artery: A Case Report and a Review of Literature.

BACKGROUND AND IMPORTANCE: The tendency of posterior fossa arteriovenous malformations (pfAVM) to develop associated aneurysms (AA) is a well-known phenomenon with an increased total risk of rupture. Most pfAVM and AA develop in the territory of the posterior inferior cerebellar artery while the involvement of the anterior inferior cerebellar artery (AICA) is extremely rare. We describe an unusual case of an arteriovenous malformation (AVM) supplied by the AICA with a "proximal" AA. This unique combination of vascular lesions has been reported in only four cases so far, limiting the available experience that can safely guide the therapeutic intervention. CLINICAL PRESENTATION: This study describes a 59-year-old female presented with a subarachnoid hemorrhage, Hunt and Hess grade 4. Angiography demonstrated an AVM fed mainly by the right AICA and draining superficially into the transverse sinus (Spetzler-Martin grade II). In addition, there was a ruptured proximal AICA aneurysm. An endovascular approach was chosen to coil the aneurysm and obliterate the AVM using ONYX in a multi-staged process. The patient recovered well without residual deficit at 6-month follow-up. CONCLUSION: To the best of our knowledge, this is the first report describing a proximal AICA aneurysm and AVM treated by endovascular means. The outcome was very good, considering the technically demanding location. All previously reported cases with exactly similar lesions were managed surgically, with inconclusive outcomes. The data presented in this study are meant to help in decision-making process for similar cases till more data are available.

The influence of ethanol on blood flow velocity in major cerebral vessels. A prospective and controlled study.

Cerebral vasospasm secondary to subarachnoid hemorrhage leads to increased cerebrovascular resistance and may cause ischemia in the affected vascular territories. The currently available therapeutic options for treating vasospasm are limited. The effect of ethanol at a concentration of 0.75 g/kg body weight on blood flow velocity in the major cerebral arteries was studied. In 31 healthy persons, the major extra- and intracranial cerebral vessels were examined by Doppler ultrasonography before and following oral ingestion of 0.75 g/kg body weight of ethanol. An additional 20 healthy subjects served as a control group. Ethanol in the applied concentration significantly increased the systolic, diastolic, and mean blood flow velocities and significantly decreased the pulsatility indices in the middle cerebral artery (MCA). It may reduce vascular resistance and may increase cerebral blood flow in the area supplied by the MCA in healthy persons.

Taurolidine-Fibrin-Sealant-Matrix using spray application for local treatment of brain tumors.

Malignant gliomas tend to recur in the vast majority of cases. Recurrent gliomas may arise from vital tumor cells present in this zone around the resection margin. It appears promising to combine tumor resection with local chemotherapy using an antineoplastic, but non-toxic agent. Taurolidine exerts a selective antineoplastic effect by induction of programmed cell death and has anti-angiogenic activity. Fibrin sealant is completely degradable and firmly adheres to brain tissue, suggesting that it would provide a suitable matrix for taurolidine delivery--a Taurolidine-Fibrin-Sealant-Matrix (TFM)--in the local treatment of brain tumors. The potential of local delivery of taurolidine out of a fibrin sealant matrix was investigated. Taurolidine could be suspended homogeneously in both the thrombin and the procoagulant protein components of the fibrin sealant. The fibrin sealant matrix was a suitable carrier for the suspension of taurolidine at a concentration that ensured the release of therapeutically effective amounts of the drug over a period of 2 weeks in vitro. The antineoplastic action of taurolidine was not affected by embedding in the fibrin sealant matrix. The described drug delivery system may be suitable for local taurolidine treatment of brain tumors following complete or partial resection or of tumors that are non-resectable because of their location.

Enhancement of Fas-ligand-mediated programmed cell death by taurolidine.

BACKGROUND: Taurolidine was recently found to have a direct and selective antineoplastic effect on brain tumor cells. The ability of taurolidine to exert antineoplastic action by enhancement of Fas-mediated apoptosis in different malignant glioma cell lines was investigated. MATERIALS AND METHODS: Human derived U373 cells were cultured and incubated with taurolidine and the median inhibitory concentration (IC50) was calculated. Flow cytometric analysis was performed to assess changes in DNA content. The cells were qualitatively and quantitatively examined using light microscopy and electron microscopy. LN-18 and LN-229 cells were incubated in the absence or presence of either Fas-ligand, taurolidine or respective combinations thereof. The cell viability was determined by adding a double concentrated WST-1 reagent. The activity of the mitochondrial succinate reductase was measured in an ELISA reader. RESULTS: The exposure of U373 cells to taurolidine led to a concentration-dependent (IC50 35.8 +/- 2.2 micrograms/ml) loss of cell viability. Flow cytometric analysis demonstrated a concentration-dependent appearance of DNA debris in the sub-Go/G1 region. In the presence of 6.25 vol.% Fas-ligand, LN-18 cells displayed more than 90% loss of cell viability, whereas the viability of LN-229 cells was reduced only at higher concentrations of Fas-ligand. Taurolidine by itself did not appreciably affect the viability of LN-18 cells in the investigated concentration range, but was able to enhance the effect of Fasligand on LN-18 cells. The exposure of LN-229 cells to taurolidine alone caused an appreciable loss of cell viability by about 70% at the highest concentration tested. Cell destruction by Fas-ligand (10 vol.%) was enhanced in the presence of taurolidine. CONCLUSION: The antineoplastic activity of taurolidine seems to be partially based on the enhancement of Fas-ligand-induced apoptosis. In addition, taurolidine was demonstrated to have an antieoplastic effect independent of Fas-ligand. Perhaps taurolidine exerts antineoplastic activity based on different mechanisms.

The effect of taurolidine on brain tumor cells.

BACKGROUND: Although an inhibiting effect of the antibacterial substance taurolidine on several tumor cell lines was suggested in 1990, no specific research has been performed concerning its effect on brain tumor cells. MATERIALS AND METHODS: Monolayers of rat-derived C6 glioma, mouse-derived HT22 neuronal tumor, and human-derived U373 astrocytoma/glioblastoma cell lines were cultured and incubated with 1 microg/ml to 4 mg/ml of taurolidine. Neuronal and glial brain cells were obtained from rat fetuses at day 15 of gestation and incubated with taurolidine to investigate its effect on normal brain cells. RESULTS: Following incubation with taurolidine, the tumor cells started to shrink and to become denser. Ultrastructurally, shrinkage of cytoplasm and condensation and marginalization of chromatin could be observed. Exposure to taurolidine at concentrations of 2.8 microg/ml to 2 mg/ml led to cell death of the evaluated tumor cell types. Results of flow cytometry suggested a fragmentation of DNA. Phosphatidylserine expression increased from 6% to 25% following exposure to taurolidine at a concentration of 25 microg/ml. Normal brain cells did not show any significant changes following incubation with taurolidine. CONCLUSION: The characteristics identified by light and electron microscopy and the data obtained by flow cytometry indicate an apoptotic mechanism of cell death via currently unknown pathways. Taurolidine was found to have a direct and selective antineoplastic effect on glial and neuronal brain tumor cells in vitro.

Treatment of glioblastoma with intravenous taurolidine. First clinical experience.

BACKGROUND: Despite progress in diagnosis and therapy, the prognosis of patients with glioblastoma remains poor. Recently it has been found that the antibacterial agent taurolidine has a direct and selective antineoplastic effect on brain tumor cells by the induction of programmed cell death. This paper reports on intravenous taurolidine treatment in two patients with a progressive glioblastoma despite conventional therapy. PATIENTS AND METHODS: Two male patients with histopathologically diagnosed glioblastoma were included. The tumors were progressive despite conventional therapy. Intravenous taurolidine treatment was initiated. RESULTS: The neurological condition and quality of life improved in both patients such that they could be discharged for further outpatient treatment. Follow-up demonstrated partial remission of the tumor in both patients. However, both patients died about 4 months following the start of taurolidine treatment, from pneumonia and acute thrombembolism, respectively. CONCLUSION: Both patients achieved a transient, marked improvement in quality of life and partial tumor remission. There was a clear response to the taurolidine treatment.

Ruptured intracranial dermoid cysts.

BACKGROUND: Intracranial dermoid cysts are rare congenital neoplasms that are believed to arise from ectopic cell rests incorporated in the closing neural tube. The rupture of an intracranial dermoid cyst is a relatively rare event that typically occurs spontaneously. In the past it was believed that rupture is always fatal, a hypothesis that is not supported by more recently reported cases. The symptoms associated with rupture vary from no symptoms to sudden death. METHODS: The present paper analyzes published cases of ruptured intracranial dermoid cysts in terms of their age profile and their clinical presentation and describes an additional case. RESULTS: Analysis of published cases revealed headache (14 out of 44 patients; 31.8%) and seizures (13 out of 44 patients; 29.5%), to be the most common signs of rupture followed by, often temporary, sensory or motor hemisyndrome (7 out of 44 patients; 15.9%), and chemical meningitis (3 out of 44 patients; 6.9%). CONCLUSION: Headache occurred primarily in younger patients (mean age 23.5 +/- 9.3 years), whereas seizures primarily occurred in older patients (mean age 42.8 +/- 11.3 years). The patients with sensory or motor hemisyndrome associated with rupture of an intracranial dermoid cyst showed a more homogeneous age distribution (mean age 38.4 +/- 23.5 years).

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death.

The antibacterial amino-acid derivative taurolidine (TAU) has been recently shown to exhibit anti-neoplastic activity based on a mechanism, which is still unknown in detail. Cytotoxicity and clonogenic assays were performed and the impact of apoptosis modulators, a radical scavenger, autophagy inhibitors, silencing of apoptosis inducing actor (AIF) and cytochrome-c (Cyt-C) by siRNA, and knockdown of autophagy related genes were evaluated in vitro. The intracellular ATP-content, release of AIF and Cyt-C, and DNA-laddering were investigated. This study could demonstrate cell killing, inhibition of proliferation, and inhibition or prevention of colony formation in human glioma cell lines and ex vivo glioblastoma cells after incubation with TAU. This effect is based on the induction of a mixed type of programmed cell death with the main preference of autophagy, and involvement of senescence, necroptosis and necrosis. This mechanism of action may open a new approach for therapeutic intervention.

Changes of medium-latency SEP-components following peripheral nerve lesion.

BACKGROUND: Animal studies have demonstrated complex cortical reorganization following peripheral nerve lesion. Central projection fields of intact nerves supplying skin areas which border denervated skin, extended into the deafferentiated cortical representation area. As a consequence of nerve lesions and subsequent reorganization an increase of the somatosensory evoked potentials (SEPs) was observed in cats when intact neighbouring nerves were stimulated. An increase of SEP-components of patients with nerve lesions may indicate a similar process of posttraumatic plastic cortical reorganization. METHODS: To test if a similar process of post-traumatic plastic cortical reorganization does occur in humans, the SEP of intact neighbouring hand nerves were recorded in 29 patients with hand nerve lesions. To hypothetically explain the observed changes of SEP-components, SEP recording following paired stimulation of the median nerve was performed in 12 healthy subjects. RESULTS: Surprisingly 16 of the 29 patients (55.2%) showed a reduction or elimination of N35, P45 and N60. Patients with lesions of two nerves showed more SEP-changes than patients with a single nerve lesion (85.7%; 6/7 nerves; vs. 34.2%; 13/38 nerves; Fisher's exact test, p < 0.05). With paired stimulation a suppression of the amplitude of N20, P25 and P45 (p < 0.05; sign test), and a marked increment of N35 (p < 0.05; sign test) and N60 (not significant; sign test) of the second response could be observed. CONCLUSION: The results of the present investigation do not provide evidence of collateral innervation of peripherally denervated cortical neurons by neurons of adjacent cortical representation areas. They rather suggest that secondary components of the excitatory response to nerve stimulation are lost in cortical areas, which surround the denervated region.