Neurosurgical treatment of pediatric brain tumors - results from a single center multidisciplinary setup.

OBJECTIVE: The challenge of pediatric brain tumor surgery is given due to a relative low prevalence but high heterogeneity in age, localization, and pathology. Improvements of long-term overall survival rates were achieved during the past decades stressing the importance of a multidisciplinary decision process guided by a national treatment protocol. We reviewed the entire spectrum of pediatric brain tumor surgeries from the perspective of an interdisciplinary pediatric neuro-oncology center in Germany. METHODS: Every patient who underwent brain tumor surgery from January 2010 to June 2017 in our Pediatric Neurosurgery department was retrospectively included and evaluated regarding the course of treatment. Perioperative data such as tumor localization, timing of surgery, extent of resection, neuropathological diagnosis, transfusion rates, oncologic and radiation therapy, and neurological follow-up including morbidity and mortality were evaluated. RESULTS: Two hundred ninety-three pediatric brain tumor patients were applicable (age: 8.28 ± 5.62 years, 1.22:1.0 m:f). A total of 531 tumor surgical interventions was performed within these patients (457 tumor resections, 74 tumor biopsies; mean interventions per patient 1.8 ± 1.2). Due to a critical neurologic status, 32 operations (6%) were performed on the day of admission. In 65.2% of all cases, tumor were approached supratentorially. Most frequent diagnoses of the cases were glial tumors (47.8%) and embryonal tumors (17.6%). Preoperative planned extent of resection was achieved in 92.7%. Pre- and postoperative neurologic deficits resolved completely in 30.7%, whereas symptom regressed in 28.6% of surgical interventions. New postoperative neurologic deficit was observed in 10.7%, which resolved or improved in 80% of these cases during 30 days. The mortality rate was 1%. CONCLUSION: We outlined the center perspective of a specialized pediatric neuro-oncological center describing the heterogeneous distribution of cases regarding age-related prevalence, tumor localization, and biology, which requires a high multidisciplinary expertise. The study contributes to define challenges in treating pediatric brain tumors and to develop quality indicators for pediatric neuro-oncological surgery. We assume that an adequate volume load of patients within a interdisciplinary infrastructure is warranted to aim for effective treatment and decent quality of life for the majority of long-term surviving pediatric tumor patients.

Retrospective single-center historical comparative study between proGAV and proGAV2.0 for surgical revision and implant duration.

OBJECTIVE: Cerebrospinal fluid (CSF) diversion shunt systems remain to be the most common treatment for pediatric hydrocephalus. Different valve systems are used to regulate CSF diversion. Preventing complications such as occlusions, ruptures, malpositioning, and over- or underdrainage are the focus for further developments. The proGAV and proGAV2.0 valve system are compared in this retrospective study for revision-free survival and isolated valve revision paradigms. METHODS: In the first part of the study, the shunt and valve revision-free survival rates were investigated in a retrospective historical comparison design for a period of 2 years in which each valve was used as standard valve (proGAV: July 2012-June 2014; proGAV2.0: January 2015-December 2016) with subsequent 30-month follow-up period, respectively. In the second part of the study, the implant duration was calculated by detecting isolated valve (valve-only) revisions together with another valve explantation during the entire period of the first study and its follow-up period. RESULTS: Two hundred sixty-two patients (145 male and 117 female, mean age 6.2 ± 6.1 years) were included in the cohort of revision-free survival. During the 30-month follow-up period, 41 shunt revisions, including 27 valve revisions (shunt survival rate: 72.1%, valve survival rate: 81.6%) were performed in the proGAV cohort and 37 shunt revisions, including 21 valve revisions (shunt survival rate: 74.8% and valve survival rate: 85.0%) were performed in the proGAV2.0 cohort without showing statistically significant differences. In the second part of the study, 38 cases (mean age 4.0 ± 3.9 years) met the inclusion criteria of receiving a valve-only-revision. In those patients, a total of 44 proGAV and 42 proGAV2.0 were implanted and explanted during the entire study time. In those, a significantly longer implant duration was observed for proGAV (mean valve duration 961.9 ± 650.8 days) compared to proGAV2.0 (mean length of implantation period 601.4 ± 487.8 days; p = 0.004). CONCLUSION: The shunt and valve revision-free survival rates were found to be similar among the groups during 30 month follow-up. In patients who received "valve only" revisions and a subsequent explanation, the implant duration was significantly longer in the proGAV. Although the amount of patients with valve-only-revisions are small compared to the entire cohort certain patients seem to be at higher risk for repeated valve revisions.

Integrated understanding of hydrocephalus - a practical approach for a complex disease.

Most of childhood hydrocephalus are originating during infancy. It is considered to be a complex disease since it is developed on the basis of heterogeneous pathophysiological mechanisms and different pathological conditions as well as during different age groups. Hence, it is of relevant importance to have a practical concept in mind, how to categorize hydrocephalus to surgically better approach this disease. The current review should offer further basis of discussion on a disease still most frequently seen in Pediatric Neurosurgery. Current literature on pathophysiology and classification of pediatric hydrocephalus has been reviewed to integrate the different published concepts of hydrocephalus for pediatric neurosurgeons. The current understanding of infant and childhood hydrocephalus pathophysiology is summarized. A simplified concept based on seven factors of CSF dynamics is elaborated and discussed in the context of recent discussions. The seven factors such as pulsatility, CSF production, major CSF pathways, minor CSF pathways, CSF absorption, venous outflow, and respiration may have different relevance and may also overlap for the individual hydrocephalic condition. The surgical options available for pediatric neurosurgeons to approach hydrocephalus must be adapted to the individual condition. The heterogeneity of hydrocephalus causes mostly developing during infancy warrant a simplified overview and understanding for an everyday approach. The proposed guide may be a basis for further discussion and may serve for a more or less simple categorization to better approach hydrocephalus as a pathophysiological complex disease.

Biparietal meander expansion technique for sagittal suture synostosis in patients older than 1 year of age-technical note.

OBJECTIVE: Sagittal suture synostosis (SSS) is the most common form of craniosynostosis. For older patients, the strategy for surgical correction needs to consider diminished growth dynamics of the skull and an active reconstruction cranioplasty aims to sustain stability for the active child. We describe our technique of biparietal meander expansion (BME) technique for SSS for patients older than 1 year and retrospectively reviewed the perioperative course as well as the subjective experience of patients and caregivers during follow-up. METHODS: The BME technique incorporates bilateral serpentine craniotomies and fixation of the consecutively expanded bone tongues with crossing sutures for patients with SSS older than 12 months of age at surgery. We reviewed patients undergoing this surgical technique for correction of SSS and collected data about the clinical course and performed a patients reported outcome measure (PROM) for patients or caregivers to evaluate subjective experience and outcome after surgical treatment. RESULTS: BME was performed in 31 patients (8 females; median age: 43 months; range 13-388). The mean length of operation was 172.7±43 minutes (range 115-294). Patients experienced no immediate complications or neurological morbidity after surgery. Considering a total of 21 completed PROM questionnaires, the head shape after surgery was evaluated as either "better" (57%) or "much better" (43%) compared to preoperatively. Eighty-one percent of patients or caregivers answered that the patient experiences no limitation in daily activities. Although 42.8% perceived the hospital as strenuous, 90.5% would choose to undergo this treatment again. CONCLUSION: BME is a feasible technique for older SSS patients resulting in immediate stability of the remodelled calvarium with a more normal head shape. The survey among caregivers or patients revealed a favourable subjectively experienced outcome after this type of surgical treatment of SSS in the more complex context of an older patient cohort.

TROPHY registry - status report.

INTRODUCTION: The TROPHY registry has been established to conduct an international multicenter prospective data collection on the surgical management of neonatal intraventricular hemorrhage (IVH)-related hydrocephalus to possibly contribute to future guidelines. The registry allows comparing the techniques established to treat hydrocephalus, such as external ventricular drainage (EVD), ventricular access device (VAD), ventricular subgaleal shunt (VSGS), and neuroendoscopic lavage (NEL). This first status report of the registry presents the results of the standard of care survey of participating centers assessed upon online registration. METHODS: On the standard of treatment forms, each center indicated the institutional protocol of interventions performed for neonatal post-hemorrhagic hydrocephalus (nPHH) for a time period of 2 years (Y1 and Y2) before starting the active participation in the registry. In addition, the amount of patients enrolled so far and allocated to a treatment approach are reported. RESULTS: According to the standard of treatment forms completed by 56 registered centers, fewer EVDs (Y1 55% Y2 46%) were used while more centers have implemented NEL (Y1 39%; Y2 52%) to treat nPHH. VAD (Y1 66%; Y2 66%) and VSGS (Y1 42%; Y2 41%) were used at a consistent rate during the 2 years. The majority of the centers used at least two different techniques to treat nPHH (43%), while 27% used only one technique, 21% used three, and 7% used even four different techniques. Patient data of 110 infants treated surgically between 9/2018 and 2/2021 (13% EVD, 15% VAD, 30% VSGS, and 43% NEL) were contributed by 29 centers. CONCLUSIONS: Our results emphasize the varying strategies used for the treatment of nPHH. The international TROPHY registry has entered into a phase of growing patient recruitment. Further evaluation will be performed and published according to the registry protocol.

In vitro performance of combinations of anti-siphon devices with differential pressure valves in relation to the spatial position.

BACKGROUND: Programmable differential pressure (DP) valves combined with an anti-siphon device (ASD) represent the current standard of care in preemtping overdrainage associated with ventriculoperitoneal shunting for hydrocephalus. OBJECTIVE: We aimed to provide comparative data of four combinations of two ASDs of different working principles in combination with two DP valves in an in vitro model in order to achieve a better understanding of the flow characteristics and potential clinical application. METHODS: We analyzed the flow performance of four possible combinations of two DP valves (CHPV [HM]; proGAV 2.0[PG]) in combination with either a gravity-regulated (Shuntassistant [SA]) or a flow-regulated (SiphonGuard [SG]) ASD in an in vitro setup. A DP between 4 and 60 cmH2O was generated, and the specific flow characteristics were measured. In addition, the two combinations with gravity-regulated ASDs were measured in defined spatial positions. RESULTS: Flow characteristics of the SA combinations corresponded to the DP in linear fashion and to the spatial position. Flow characteristics of the SG combinations were dependent upon the DP in a non-linear fashion and independent of the spatial position. Highest mean flow rate of the PG-SG- (HM-SG-) combination was 1.41 ± 0.24 ml/min (1.16 ± 0.06 ml/min). The mean flow rates sharply decreased with increasing inflow pressure and subsequently increased slowly up to 0.82 ± 0.26 ml/min (0.77 ± 0.08 ml/min). CONCLUSION: All tested device combinations were able to control hydrostatic effect and prevent consecutive excessive flow, to varying degrees. However, significant differences in flow characteristics can be seen, which might be relevant for their clinical application.

In vitro performance of six combinations of adjustable differential pressure valves and fixed anti-siphon devices with and without vertical motion.

OBJECTIVE: Adjustable differential pressure (DP) valves in combination with fixed anti-siphon devices are currently a popular combination in counteracting the effects of cerebrospinal fluid overdrainage following implantation of a ventriculoperitoneal shunt system. The study examined the flow performance of three DP valves in successive combination with an anti-siphon device in an in vitro shunt laboratory with and without vertical motion. METHODS: We analyzed three DP valves (Codman Hakim Medos programmable valve [HM], Codman CertasPlus [CP], and Miethke proGAV [PG], in combination with either Codman SiphonGuard [SG] or Miethke ShuntAssistant [SA]), resulting in the evaluation of six different valve combinations. Defined DP conditions between 4 and 40 cm H2O within a simulated shunt system were generated and the specific flow characteristics were measured. In addition, combinations with SA, which is a gravity-dependent valve, were measured in defined spatial positions (90°, 60°). All device combinations were tested during vertical motion with movement frequencies of 2, 3, and 4 Hz. RESULTS: All valve combinations effectively counteracted the siphon effect in relation to the chosen DP. Angulation-related flow changes were similar in the three combinations of DP valve and SA in the 60° and 90° position. In CP-SA and PG-SA, repeated vertical movement at 2, 3, and 4 Hz led to significant increase in flow, whereas in HM-SA, constant increase was seen at 4 Hz only (flow change at 4Hz, DP 40 cm H2O: PG (opening pressure 4 cm H2O) 90°: 0.95 ml/min, 60°: 0.71 ml/min; HM (opening pressure 4 cm H2O) 90°: 0.66 ml/min, 60°: 0.41 ml/min; CP (PL 2) 90°: 0.94 ml/min, 60°: 0.79 ml/min; p < 0.01); however, HM-SA showed relevant motion-induced flow already at low DPs (0.85 ml/min, DP 4 cm H2O). In combinations of DP valve with SG, increase of flow was far less pronounced and even led to significant reduction of flow in certain constellations. Maximum overall flow increase was 0.46 ± 0.04 ml/min with a HM (opening pressure 12 cm H2O) at 2 Hz and a DP of 10 cm H2O, whereas maximum flow decrease was 1.12 ± 0.08 with a PG (opening pressure 4 cm H2O) at 3 Hz and a DP of 10 cmH2O. CONCLUSION: In an experimental setup, all valve combinations effectively counteracted the siphon effect in the vertical position according to their added resistance. Motion-induced increased flow was consistently demonstrated in combinations of DP valve and SA. The combination of HM and SA especially showed relevant motion-induced flow already at low DPs. In combinations of DP and SG, the pattern of the motion induced flow was more inconsistent and motion even led to significant flow reduction, predominantly at DPs of 10 and 20 cmH2O.

Endoscopic third ventriculostomy in children with third ventricular pressure gradient and open ventricular outlets on MRI.

OBJECTIVE: Patients with non-communicating hydrocephalus due to aqueductal stenosis are often successfully treated with endoscopic third ventriculocisternostomy (ETV). In hydrocephalus, due to other locations of obstruction of the major CSF pathways, endoscopic treatment may also be a good option. We investigated our cohort of patients treated by ETV with patent ventricular outflow but pressure gradient signs at the third ventricle in a single-center retrospective study. METHODS: We retrospectively reviewed records and imaging studies of 137 patients who underwent an ETV in our department in the time period of June 2010 to March 2018. We included patients who showed the following findings in MRI: 1st: open Sylvian aqueduct, 2nd: open outlets of the 4th ventricle, 3rd: open spinal canal, 4th: intra-/extraventricular pressure gradient seen at the 3rd ventricle and excluded patients with history of CSF infection or hemorrhage. Perioperative clinical state and possible complications or reoperations were recorded. Shunt dependency and changes in ventricular dilatation were measured as frontal and occipital horn ratio (FOHR) before surgery and during follow-up. RESULTS: A total of 21 patients met the defined criteria. During the mean follow-up time of 40.7 ± 30 months (range; 5-102 months), two children had to undergo a re-ETV, and six children (all < 1 year of age) received a VP shunt. ETV shunt-free survival was 100% for children > 1 year of age. The ventricular width measured as FOHR was significantly reduced after ETV 0.5 ± 0.08 (range 0.42-0.69; p < 0.05). FOHR was significantly reduced at last follow-up shunt independent patients (0.47 ± 0.05; range 0.41-0.55; p < 0.001) CONCLUSION: We conclude that ETV seems to be a successful treatment option for patients with MRI signs of intra-/extraventricular pressure gradient at the 3rd ventricle and patent aqueduct and fourth ventricular outlets in children older than 1 year of age. This condition is observed only rarely and warrants further research on a multicenter basis in order to get more solid data of its pathophysiology.

Neuroendoscopic lavage for the treatment of CSF infection with hydrocephalus in children.

OBJECTIVE: The treatment of infectious CSF condition with ventriculitis and hydrocephalus in children is an interdisciplinary challenge. Conventional surgical treatment includes external ventricular drain (EVD) and systemic antibiotic therapy. However, infectious contamination of large ventricles combined with CSF protein overload often requires long treatment regimens. We retrospectively investigated neuroendoscopic lavage as a new option for clearance of CSF in children with hydrocephalus and active CSF infection. PATIENTS AND METHODS: A database review identified 50 consecutive patients treated for CSF infection with hydrocephalus at our institution. Twenty-seven patients (control group, CG) were treated conventionally between 2004 and 2010, while 23 patients (neuroendoscopic group, NEG) underwent neuroendoscopic lavage for removal of intraventricular debris between 2010 and 2015. Clinical data, microbiology, laboratory measures, shunt dependency, and shunt revision rate were evaluated retrospectively. RESULTS: The patient groups did not differ regarding basic clinical characteristics. Patients in NEG received neuroendoscopic lavage at mean of 1.6 ± 1times (1-4). No immediate postoperative complications were observed in NEG patients. Shunt rate in NEG patients was 91% as compared 100% in CG patients (p = 0.109). Within 24 months after shunt implantation, incidence of shunt revision was higher in CG (23/27) compared to NEG (5/23; p < 0.001). Reinfection was observed more often in CG (n = 17) compared to one patient in NEG (p < 0.001). CONCLUSIONS: We experienced that neuroendoscopic lavage is a safe and effective treatment for hydrocephalus in children with infectious conditions. Neuroendoscopic lavage resulted in a decreased number of overall shunt revisions in shunt-depended patients as well as a lower number of recurrent infections.

The use of a smartphone-assisted ventricle catheter guide for Ommaya reservoir placement-experience of a retrospective bi-center study.

BACKGROUND: For intraventricular chemotherapy (IVC) as part of many oncological treatment protocols, Ommaya reservoir is enabling repeated access to the cerebro-spinal fluid (CSF). The correct placement of the catheter in the ventricle is essential for correct application of drugs, which is enabled by sophisticated techniques such as neuronavigation. OBJECTIVE: In a bi-center retrospective study, we reviewed our experience using a smartphone-assisted ventricle catheter guide as simple solution for correct Ommaya reservoir placement. METHODS: Sixty Ommaya reservoirs have been placed in 60 patients between 2011 and 2017 with the smartphone-assisted ventricular catheter guidance technique. Patient characteristics, preoperative frontal and occipital horn ratio (FOHR), postoperative catheter position, and complications were assessed. RESULTS: The majority of our patients (71.6%) have got narrow or slit-like ventricles (FOHR ≤ 0.4). All Ommaya reservoirs were placed successfully. Fifty-eight ventricular catheters (97%) were inserted at the first and 2 (3%) at the second attempt using the same technique. No immediate perioperative complications were observed. All catheters (100%) could be used for IVC. Postoperative imaging was available in 52 patients. Thirty-two (61.5%) of ventricular catheters were rated as grade I, 20 (38.5%) as grade II, and none (0%) as grade III. Four patients (6.7%) showed postoperative complications during a median follow-up of 8.5 months (hydrocephalus, n = 1; infection, n = 1; parenchymal cyst around catheter, n = 1; shunt revision, n = 1). CONCLUSIONS: The smartphone-assisted guide offers decent accuracy of ventricle catheter placement with ease and simplicity for a small surgical intervention. We propose this technique as routine tool for Ommaya reservoir placement independent of lateral ventricular size to decrease the rate of ventricle catheter malposition as reasonable alternative to a neuronavigation system.

Altered cerebrospinal fluid dynamics in neurofibromatosis type l: severe arachnoid thickening in patients with neurofibromatosis type 1 may cause abnormal CSF dynamic.

INTRODUCTION: The object of this study is to understand abnormal dynamic of cerebrospinal fluid (CSF) in patients with neurofibromatosis type 1 (NF1), which may cause temporal lobe herniation and bulging of temporal fossa. METHODS: Four patients, three females and one male, with NF1 were studied retrospectively. They presented with a similar craniofacial deformity, which consisted of pulsatile exophthalmos, an enlarged bony orbit, dysplasia of the sphenoid wing with the presence of a herniation of the temporal lobe into the orbit, and a bulging temporal fossa. RESULTS AND DISCUSSION: Surgical exploration demonstrated abnormally thickened arachnoid membrane in one case. Protruding temporal lobe, which was one of the main symptoms in NF1 patients, could be stopped by control of intracranial pressure (ICP) via programmable ventriculoperitoneal shunt (VPS) or extra ventricle drainage implantation. The dense fibrosis of the arachnoid membrane and consequent altered hemispheric CSF dynamics may cause symptoms including pulsatile exophthalmos and consequent worsening of vision, prolapse of the temporal lobe, and enlargement of the temporal fossa. This finding may not present with general features of hydrocephalus, so that delays in diagnosis often result. CONCLUSION: For the NF1 patients with cranio-orbito-temporal deformities, prior to any surgical reconstruction, control of increased ICP (IICP) should be primarily considered.

Smartphone-assisted guide for the placement of ventricular catheters.

OBJECTIVE: Freehand placement of ventricular catheters (VC) is reported to be inaccurate in 10-40 %. Endoscopy, ultrasound, or neuronavigation are used in selected cases with significant technical and time-consuming efforts. We suggest a smartphone-assisted guiding tool for the placement of VC. METHODS: Measurements of relevant parameters in 3D-MRI datasets in a patient cohort with narrow ventricles for a frontal precoronal VC placement were performed. In this context, a guiding tool was developed to apply the respective measures for VC placement. The guiding tool was tested in a phantom followed by CT imaging to quantify placement precision. A smartphone application was designed to assist the relevant measurements. The guide was applied in 35 patients for VC placement. RESULTS: MRI measurements revealed the rectangular approach in the sagittal plane and the individual angle towards the tangent in the coronal section as relevant parameter for a frontal approach. The latter angle ranged from medial (91.96° ± 2.75°) to lateral margins (99.56° ± 4.14°) of the ventricle, which was similar in laterally shifted (±5 mm) entry points. The subsequently developed guiding tool revealed precision measurements in an agarose model with 1.1° ± 0.7° angle deviation. Using the smartphone-assisted guide in patients with narrow ventricles (frontal occipital horn ratio, 0.38 ± 0.05), a primary puncture of the ventricles was possible in all cases. No VC failure was observed during follow-up (9.1 ± 5.3 months). CONCLUSIONS: VC placement in narrow ventricles requires accurate placement with simple means in an every-case routine. The suggested smartphone-assisted guide meets these criteria. Further data are planned to be collected in a prospective randomized study.

Measurements of burr-hole localization for endoscopic procedures in the third ventricle in children.

OBJECTIVE: In a retrospective study, we measured the localization for the burr hole for neuroendoscopic procedures in the third ventricle, which are determined by anatomical landmarks like the foramen of Monro (FM) and the respective targets. PATIENTS AND METHODS: In 48 children, thin-sliced T2-weighted magnetic resonance images were analyzed within an imaging software tool to determine the trajectory between the FM to the floor of the third ventricle (F3V) or the entrance of the sylvian aqueduct (SA). The crossing point at the skull convexity defined the entry points. Coordinates are given relative to nasion and midline. A mean virtual entry point to reach both targets was compared to the burr-hole localization used in the respective surgeries. The tissue shift at the FM was quantified for the trajectories. RESULTS: The entry point to reach the F3V or the SA measured 119.7+/-26.4 mm (to nasion)-20.5+/-11.5 mm (to midline) and 57.4+/-26.5-18.8+/-8.3 mm, respectively. The virtual mean entry point to reach both targets was located at 86.5+/-25.3-20.9+/-9.8 mm. There was a statistical difference in the entry point localization relative to nasion of the virtual mean trajectory compared with the burr-hole localization used in these patients. The tissue shift at the level of the FM using the mean virtual trajectory was significantly lower than by using the actual burr hole to the SA. CONCLUSIONS: Planning an optimal burr-hole localization is important in neuroendoscopic procedures in children, especially where the target is located around the sylvian aqueduct.

Local chemotherapy in the rat brainstem with multiple catheters: a feasibility study.

OBJECTS: Technical aspects of local chemotherapy in inoperable brainstem gliomas by convection-enhanced delivery (CED) are still under experimental considerations. In this study, we characterize the feasibility of multiple cannula placements in the rat brainstem. MATERIALS AND METHODS: In 38 male Fisher rats, up to three guided screws were positioned in burr holes paramedian at 2.5 mm anterior and posterior to as well as at the lambdoid suture. Using Alzettrade mark pumps (1 microl/h flow rate over 7 days) either vehicle (5% dextrose) or 0.1 mg carboplatin was delivered via one, two, or three cannulas, respectively. During cannula insertion, electrocardiogram and respiratory rate was monitored. All rats were subsequently evaluated neurologically for 8 days. For drug distribution in coronal sections, the brain tissue concentration of platinum was measured. HE staining was used to evaluate the local site of drug delivery. Heart and respiratory rate remained within normal range during surgical procedure. Neurological scoring showed only mild neurological impairment in the groups receiving two or three cannulas, which resolved after vehicle delivery. However, after carboplatin delivery, this deficit remained unchanged. Drug distribution was more homogeneous in the three cannula group. Histological slices visualized edematous changes at the sight of cannula placement. CONCLUSION: The unilateral application of up to three cannulas in the brainstem of rats for local drug delivery studies is feasible. The remaining neurological deficit in carboplatin-treated animals underlines the need of low toxicity drugs for CED in the brainstem.

Neurological grading, survival, MR imaging, and histological evaluation in the rat brainstem glioma model.

OBJECTIVE: Convection-enhanced delivery using carboplatin in brainstem glioma models was reported to prolong survival. Functional impairment is of additional importance to evaluate the value of local chemotherapy. We established a neurological scoring system for the rat brainstem glioma model. MATERIAL AND METHODS: In 46 male Fisher rats stereotactically 10(5) F-98 cells were implanted at 1.4-mm lateral to midline and at the lambdoid suture using guided screws. Following 4 days local delivery was performed using Alzet pumps (1 microl/h over 7 days) with either vehicle (5% dextrose) or carboplatin via one or two cannulas, respectively. All rats were subsequently tested neurologically using a specified neurological score. In 38 animals survival time was recorded. Representative MR imaging were acquired in eight rats, respectively, at day 12 after implantation. HE staining was used to evaluate tumor extension. RESULTS: Neurological scoring showed significantly higher impairment in the high dose carboplatin group during the treatment period. Survival was significantly prolonged compared to control animals in the high dose carboplatin-one cannula group as well as in both low dose carboplatin groups (18.6 +/- 3 versus 26.3 +/- 9, 22.8 +/- 2, 23.6 +/- 2 days; p < 0.05). Overall neurological grading correlated with survival time. MR imaging showed a focal contrast enhancing mass in the pontine brainstem, which was less exaggerated after local chemotherapy. Histological slices visualized decreased cellular density in treatment animals versus controls. CONCLUSION: Local chemotherapy in the brainstem glioma model showed significant efficacy for histological changes and survival. Our neurological grading enables quantification of drug and tumor-related morbidity as an important factor for functional performance during therapy.

Cerebral metabolism and intracranial hypertension in high grade aneurysmal subarachnoid haemorrhage patients.

We evaluated the effect of intracranial hypertension on cerebral metabolism in patients with high grade aneurysmal subarachnoid hemorrhage (SAH) using bedside cerebral microdialysis (MD). Thirty-six patients with SAH were studied and classified into two groups (intracranial pressure, ICP > 20 mmHg, n = 25) and (ICP < 20 mmHg, n = 11). ICP was monitored hourly using an intraventricular drainage (n = 36). The MD catheter was placed after aneurysm clipping into the vascular territory of interest and was perfused with Ringer's solution (0.3 microl/min). The MD samples were collected hourly for measurements of glucose, lactate, and glutamate (CMA 600, Sweden). Lactate/pyruvate ratio was also calculated. To calculate group specific differences, the 24 hours median values of the first 7 days after SAH were compared. Differences were considered statistically significant at P < 0.05. Patient groups were comparable for age, severity of SAH, Fisher's grade and duration of MD sampling. In patients with ICP > 20 mmHg from day 1 to 7 after SAH, extracellular concentrations of glucose were significantly lower, while the lactate/ pyruvate ratio was higher compared to SAH patients with normal ICP values. The differences between groups in glutamate levels was only significant on day 1 after SAH due to high inter-individual differences. We concluded that intracranial hypertension in associated with an anaerobic cerebral metabolism indicated cerebral ischemia in high grade SAH patients.

The antioxidant effect of N-acethylcysteine on experimental contusion in rats.

N-acethylcysteine (NAC) is known to have direct and indirect antioxidant abilities. We investigated the potential protective effect of NAC on ICP, brain edema and contusion volume after Controlled Cortical Impact (CCI) injury. A moderate CCI injury was induced on the left hemisphere in 48 Sprague Dawley rats. The animals were treated with intraperitoneal injection of NAC (163 mg/kg/KG) or physiological saline. Measurements of intracranial pressure (ICP) were performed and brains were removed at 24 hours. Gravimetric analysis of post-traumatic edema and morphometric measurements (TTC staining) of contusion volume were carried out in 24 animals, respectively. ICP measurements increased significantly over time with no significant differences between both groups. The relative difference in water content in NAC treated animals (1.45 +/- 0.1%) did not differ significantly versus placebo (1.47 +/- 0.2%). The contusion volume was diminished by 19% in the NAC group (53.52 +/- 5.3 mm3) versus placebo (66.28 +/- 4.7 mm3) without showing statistical significance. The antioxidant properties of NAC did not affect intracranial pressure or posttraumatic brain edema formation, although the moderate reduction of contusion volume might reveal beneficial effects on focal contusion.

Lubeluzole following traumatic brain injury in the rat.

Lubeluzole, a novel nitric oxide synthase (NOS) pathway modulator, was shown to be neuroprotective in cerebral ischemia as studied in animal models and clinical trials. The present study investigated the effect of lubeluzole on contusion volume and brain edema following traumatic brain injury. Sprague-Dawley rats (n = 36) were subjected to cortical impact injury. Lubeluzole (0.8 mg/kg i.v.; n = 18) or a corresponding volume of vehicle (n = 18) was injected 15 and 75 minutes following trauma. Animals were sacrificed 24 hours following trauma. Contusion volume was measured planimetrically from coronal slices stained with hematoxylin and eosin. In this group, T2-weighted magnetic resonance imaging (MRI) was also performed 90 minutes and 6 and 24 hours after trauma. Hemispheric swelling and water content were determined gravimetrically 24 hours after trauma. In this group, intracranial pressure (ICP), mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were monitored for 30 minutes before sacrifice. Lubeluzole did not reduce contusion volume, hemispheric swelling, or water content. ICP, MABP, and the resulting CPP did not differ between treated and untreated rats 24 hours after injury. T2-weighted MRI revealed a higher volume of edema at 90 minutes after trauma in treated rats. However, at 6 and 24 hours after trauma, no significant difference was discernible. Under these experimental conditions, lubeluzole fails to exert beneficial effects following experimental traumatic brain injury (TBI).

Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat.

Recent studies have demonstrated a neuroprotective effect of the noncompetitive N-methyl-D-aspartate receptor antagonist aptiganel HCl (Cerestat) in focal cerebral ischemia. In the present study, we investigated the protective ability of aptiganel HCl after controlled cortical impact injury (impact depth = 2 mm; impactor velocity = 7 mm/sec) of the left temporoparietal cortex in rats. Intravenous aptiganel HCl (2 mg/kg) or a respective volume of vehicle was injected 15 min after trauma. Animals were sacrificed 24 h after trauma. Contusion volume was measured planimetrically from hematoxylin-eosin-stained coronal slices. Hemispheric swelling and water content were determined gravimetrically. Thirty minutes before sacrifice, a Codman intracranial pressure (ICP) probe was placed in the right hemisphere, and ICP as well as mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored. Aptiganel HCl reduced contusion volume by 13.6% in treated rats (p < 0.05). Hemispheric swelling was also significantly diminished by 31.5% in accordance to a decrease in hemispheric water content (controls, 82.78 +/- 0.12%, vs. aptiganel HCl, 82.30 +/- 0.18%, p < 0.05). Posttraumatic ICP was not significantly lower in the aptiganel HCl treated animals (25.5 +/- 2.4 mm Hg vs. 32.0 +/- 2.7 mm Hg, p = 0.096). MABP was found to be higher in the treatment group 24 h after injury (107.8 +/- 3.6 mm Hg vs. 89.9 +/- 2.4 mm Hg, p < 0.001), resulting in a higher CPP (82.6 +/- 4.2 mm Hg vs. 57.2 +/- 4.6 mm Hg, p < 0.05). Taken together, aptiganel HCl exerts various beneficial effects following experimental traumatic brain injury. It decreases contusion volume and hemispheric swelling as well as water content. Thus, this drug appears promising for further clinical trials in brain trauma.

Visualization of rat pial microcirculation using the novel orthogonal polarized spectral (OPS) imaging after brain injury.

Recently, the novel optical system, orthogonal polarized spectral (OPS) imaging was developed to visualize microcirculation. Investigation of changes in microcirculation is essential for physiological, pathophysiological, and pharmacological studies. In the present study applicability of OPS imaging was assessed to study pial microcirculation in normal and traumatized rat brain. High quality images of rat pial microcirculation in normal and traumatized rats were generated with the OPS imaging, allowing to easily differentiate arterioles and venules with the dura remaining intact. In non-traumatized rats, mean vessel diameter of arterioles and venules of five different cortical regions was 19.1+/-2.7 and 22.2+/-1.4 microm, respectively. In the early phase following focal cortical contusion vessel diameter was significantly decreased in arterioles by 28% while diameter in venules was significantly increased by 27%. For technical reasons velocity in arterioles was not measurable. In venules, mean flow velocity of 0.68+/-0.08 mm/s was significantly decreased by 50% at 30 min after trauma. OPS imaging is an easy to use optical system allowing to generate high quality images and to reliably investigate pial microcirculation without having to remove the dura. This technique opens the possibility to perform longitudinal studies investigating changes in pial microcirculation.