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Long-term seizure outcomes of pediatric epilepsy surgery are understudied. A systematic review and independent patient data meta-analysis was performed to study seizure outcomes ≥ 10 years following pediatric resective epilepsy surgery.Electronic literature searches of PubMed, Web of Science, and CINAHL were conducted for relevant articles from inception to April 2020. The following search terms were used in various combinations: "pediatric", "child", "adolescent", "epilepsy", "resective", "surgery", "long-term", "longitudinal", "10 year". Two reviewers (W.B.H., T.B.C.) performed title, abstract, and full-text screening. All relevant perioperative factors reported that may be associated with long-term seizure outcomes were recorded at a study or individual participant level. The primary outcome was long-term (≥ 10 year) seizure freedom measured by the Engel Classification scale, and available data on functional outcomes were also reviewed.Twenty-five articles met criteria for inclusion in the study, which were analyzed for proportions of 10-year seizure freedom ranging from 57.6% at the study level to 64.8% at the individual patient level. At the study level, the proportion of patients remaining seizure free at least 10 years postoperatively (61.2%; 95% CI 52.5-69.3) was significantly less than at 1 year (74.2%; 95% CI 69.3-78.6; p = 0.008) but not at 2 years (67.9%; 95% CI 58.6-76.0) or 5 years (63.7%; 95% CI 55.4-71.2). No differences in long-term seizure freedom were detected by etiology or surgery type. At the individual patient level, univariate logistic regression analyses of all variables putatively associated with seizure freedom demonstrated that lobectomy (OR 0.280, 95% CI 0.117-0.651, p = 0.003) was associated with decreased long-term seizure freedom (41.9%) compared to lesionectomy (75.7%) and hemispherectomy (69.4%), which achieved similar results.Resective surgery is a durable and potentially curative treatment option for select pediatric patients with refractory epilepsy. On a group level, two-thirds of children have long-term seizure freedom ≥ 10 years after resective epilepsy surgery. Given the greatest rate of change occurs in the first 2 years, this may serve as the best short-term follow-up period to predict long-term outcome. Although lobectomy appears to be a strong predictor for lower likelihood of long-term seizure freedom, long-term prognostication on an individual patient level is still not possible. Uniform data reporting and prospective, multicenter studies collecting high quality, stratified (e.g., by etiology, surgery type) data over an extended postoperative interval are recommended to further examine the durability of resective surgery as a treatment for pediatric epilepsy.

We describe here 11 consecutive patients with recurrence of high-grade glioma treated with regorafenib at our university medical center. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions in 5/11. Response to treatment was observed in 4/11 (PR in 1/11, and SD in 3/11). Median overall survival for the cohort was 16.1 months, median progression-free survival 9.0 months, and median time to treatment failure 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23–119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile.

The Subdural Hematoma in the Elderly (SHE) score was developed as a model to predict 30-day mortality from acute, chronic, and mixed subdural hematoma in the elderly population after minor or no trauma. Emerging evidence suggests frailty to be predictive of mortality and morbidity in the elderly. In this study, we aim to externally validate the SHE for chronic subdural hematoma (CSDH) alone, and we hypothesize that the incorporation of frailty into the SHE may increase its predictive power. A retrospective cohort of elderly patients with CSDH after minor or no trauma being treated at our institution was evaluated with the SHE. Thirty-day mortality and outcome were documented. Patients were assessed with the Clinical Frailty Scale (CFS), which was incorporated into a modified SHE (mSHE). Both the SHE and the mSHE were then assessed in their predictive powers through receiver operating characteristic statistics. We included 168 patients. Most (n = 124, 74%) had a favorable outcome at 30 days. Mortality was low at n = 7, 4%. The SHE failed to predict mortality (AUC = .564, p = .565). Contrarily, the mSHE performed well in both mortality (AUC = .749, p = .026) and outcome (AUC = .862, p

Background and Purpose: The role of decompressive hemicraniectomy (DC) in malignant cerebral infarction (MCI) has clearly been established, but little is known about the course of intracranial pressure (ICP) in patients undergoing this surgical measure. In this study, we investigated the role of invasive ICP monitoring in patients after DC for MCI, postulating that postoperative ICP predicts mortality. Methods: In this retrospective observational study of MCI patients undergoing DC, ICP were recorded continuously in hourly intervals for the first 72 hours after DC. For every hour, mean ICP was calculated, pooling ICP of every patient. A receiver operating characteristic analysis was performed for hourly mean ICP. A subgroup analysis by age (≥60 years and Results: A total of 111 patients were analyzed, with 29% mortality rate in patients Conclusions: Our study suggests the need to reevaluate postoperative ICP after DC in MCI and calls for a redefinition of ICP thresholds in these patients to indicate further therapy.

Objective Current evidence-based guidelines for the management of aneurysmal subarachnoid hemorrhage (aSAH) focus primarily on timing, modality and technique of aneurysm occlusion, and on prevention and treatment of delayed cerebral ischemia. Significant aspects of management in the intensive care unit (ICU) during the later course of aSAH such as ventilation and sedation (VST) remain unaddressed. aSAH patients present unique challenges not accounted for in general ICU recommendations and guidelines, which is why we attempted to further characterize ICU practices in aSAH patients in Germany. Methods We conducted a nationwide survey on ICU practices in aSAH in Germany. Secondarily, we assessed the existence of and compliance with current guidelines regarding ICU practices. The questionnaire was designed in interdisciplinary fashion and distributed online through the kwiksurvey® platform (Bristol, UK). Results A total of 50 responses were received, accounting for a response rate of 49%. Twenty-one were university hospitals (UH), 23 high-volume centers (HVC), 6 low-volume centers (LVC). Half of the participating centers do not take into consideration WFNS at presentation to indicate ventilation. While 42% of centers rely on the P/F ratio to indicate ventilation, 62% of them have a cutoff value of

Introduction A subpopulation of patients with hydrocephalus and idiopathic intracranial hypertension (IIH) treated for elevated intracranial pressure (ICP) with a cerebrospinal fluid (CSF) shunt may continue to suffer from symptoms or develop new symptoms despite valve adjustments. The use of telemetric ICP measurements may help confirm a clinical suspicion of CSF under- or overdrainage in these patients. However, point in time, duration and activity during the measurements, which may influence the results, have never been standardized. We devised a simple and repeatable maneuver for outpatient telemetric ICP recording. The aim of this study is to evaluate its test-retest reliability. Methods Data of patients who underwent ventriculoperitoneal or ventriculoatrial shunt placement and subsequent telemetric ICP sensor implantation were retrospectively reviewed. Telemetric ICP recordings in these patients were conducted in a standardized manner: The standing-supine-sitting-paradigm requires postural changes in 10-minute intervals over 30 minutes. First, the patient is requested to walk (upright body position), secondly to lay down (supine body position), and lastly to sit down with a headrest elevation of 60°. All ICP measurements were analyzed using a dedicated freeware tool developed by the first author ( www.icp-analyzer.org ). ICP data were given as mean values (SD) in mmHg. Test-retest validity was assessed using Pearson´s correlation analysis. Results We evaluated 66 ICP data sets obtained repeatedly with a time difference of at least 24 hours under condition of unchanged valve settings in seven patients (1 male, 6 female). Implantation diagnoses were IIH (n=2), congenital hydrocephalus (n=2), normal pressure hydrocephalus (NPH) (n=1) and malresorptive hydrocephalus (n=2). Overall test re-test reliability was excellent (Pearsons correlation coefficient 0.99, p Conclusions We confirmed the high test-retest reliability of the standing-supine-sitting-paradigm for telemetric ICP measurements in the outpatient setting. The high test-retest reliability should be considered as pre-requisite for clinical decision making. We advocate the implementation and further testing of this method to validate its utility in guiding treatment decisions.

Background Scalp defects represent a therapeutic challenge. The aim of this study is to present our experience with local and regional flaps in the treatment of trauma-induced scalp defects. Furthermore, a comparison with other surgical techniques was performed. Methods A retrospective evaluation of patient records was performed. Only patients who underwent surgery using local flaps between January 2010 and September 2020 due to traumatic scalp defects were included in the study. Results In all, 10 cases were identified (3 females, 7 males, average age at surgery of 46.5 years [range: 18–82 years]). Six patients underwent surgery due to tissue defects and four due to scar keloids. Three patients experienced minor postoperative complications, one of which required additional surgery. The mean defect size was 35.75 cm2 (range: 4–79 cm2) among the four patients where the defect size could be determined retrospectively. The mean inpatient follow-up was 12.4 days (range: 2–34 days). Conclusions Local flaps can be widely used. In carefully selected cases, they have the fewest disadvantages of all surgical techniques. In our experience, large angiosomes of the main scalp arteries allow the treatment of defects larger than 30 cm2 with local flaps. Our experience also suggests that the dimensions of flap length to flap width can exceed a ratio of 2:1 in the scalp.

Background Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood–brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies.

Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In order to understand the molecular basis of these observations, we overexpressed ROR2 in human breast cancer cell lines, inducing a BRCAness-like phenotype and rendering them resistant to PARP inhibition. High levels of ROR2 were associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. Using gene expression analysis we demonstrated an upregulation of several non-canonical WNT ligands in ROR2-overexpressing breast cancer cells, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 is indeed a novel ligand for ROR2 that interacts with its cysteine-rich domain and triggers the invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells. Taken together, our studies revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis.

Objective: Diagnosis of symptomatic valve malfunction in hydrocephalic patients treated with VP-Shunt (VPS) is still a challenge. Clinical symptoms such as headache or nausea are unspecific, hence cerebrospinal fluid over- or underdrainage can only be suspected but not proven. Knowledge concerning valve[for full text, please go to the a.m. URL], 71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie

Background World Health Organization (WHO) grade II low-grade gliomas (LGGs) in adults are rare, and patients' mean overall survival (OS) is relatively long. Epidemiological data on factors influencing tumor genesis and progression are scarce, and prospective data on surgical management are still lacking. Because of the molecular heterogeneity of LGG, a comprehensive molecular characterization is required for any clinical and epidemiological research. Further, a detailed radiologic assessment is needed as the only established objective criterion for progressive disease. Both radiologic and molecular assessments have to be standardized to produce comparable data. The aim of the registry is to improve the evidence for surgical management of LGG patients by establishing a multicenter registry with a strong surgical and clinical focus including mandatory biobanking. Methods The LoG-Glio project is a prospective national observational multicenter registry that began on November 1, 2015. Inclusion criteria encompass all patients > 18 years of age with a radiologic suspicion of LGG. Patients with severe neurologic or psychiatric disorders that may interfere with their informed consent or if there is no possibility for further follow-up are excluded. Diagnosis of glioblastoma WHO grade IV isocitrate dehydrogenase (IDH) wild type leads to a secondary exclusion of patients. In addition to demographic data, results of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, add-on for patients with brain tumors, and National Health Institute Stroke Scale before and after surgery and during regular follow-ups are collected. At each time point a detailed recording of surgical and adjuvant treatment is performed. Radiologic assessment involves three-dimensional (3D) acquisition of T1, fluid-attenuated inversion recovery, and T2 sequences. For the final evaluation, a central detailed neuropathologic and molecular assessment of tumor samples and a radiologic evaluation of imaging sets are part of the study protocol. Results We report the first 100 consecutively registered patients for LoG-Glio. Three patients dropped out due to loss of follow-up. Of the remaining recruited patients, 8 were classified as wait and scan; 89 had surgery. Using the inclusion criteria described previously, 70 patients had an IDH-mutated glioma, 10 had miscellaneous rare LGGs, and 8 patients had an IDH wild-type WHO grade II or III glioma. Conclusion The LoG-Glio registry has been successfully implemented. Applied selection criteria result in an appropriately balanced patient cohort. Short-term outcome data on epidemiology as well as the influence of current surgical techniques and adjuvant treatment on patient outcomes are expected. In the long run, the aim of the registry is to validate the new molecular-based WHO classification and the influence of the extent of resection on progression-free survival and OS. The registry provides an open platform for future research projects benefiting patients with LGG.

It was suggested that D, L-Methadone might improve the clinical course of glioma patients. Owing to massive press coverage, patients demand the prescription of D, L-Methadone, but regarding its adjunctive use in glioma therapy there is no standard medication plan. Furthermore, it is not known which side effects the administration of D, L-Methadone might harbor, especially if the patients are opioid-naive and if D, L-Methadone therapy was managed by the patients themselves or their general practitioners. Opioid-naive patients with high-grade glioma (new diagnosis or recurrent) receiving D, L-Methadone were included in this retrospective observational analysis. Side effects were assigned if the condition deteriorated in conjunction with the initiation of D, L-Methadone and resolved/ ameliorated after cessation of the intake/reduction of the dosage. Side effects were categorized according to the common toxicity criteria (CTC). Twenty-four patients were included. All patients were opioid-naive and received D, L-Methadone from their general practitioners. Sixteen patients experienced side effects. The median dosage when side effects began to occur was 15.8 mg/ 24 h. Fatigue and mood changes were reported most frequently (14 of 24 patients). Five patients had severe side effects related to relatively high doses. In all cases, symptoms resolved after cessation or dose reduction. Our results show that D/L M intake lead to frequent occurrence of side effects in opioid-naive patients especially when not handled with caution and close supervision. Patients, their relatives, their GPs and neuro-oncologists need to be informed about the broad spectrum of side effects in order to thoroughly counsel glioma patients.

Objective Patients suffering from aneurysmatic Subarachnoid Hemorrhage (SAH) may present with a variety of symptoms. The aim of this study is to evaluate the spectrum of misdiagnoses and to analyze the significance of delay of correct diagnosis on the clinical outcome. Methods The data was collected prospectively from 2003 to 2013. Patients diagnosed with disease different from aneurysmal SAH by the initially treating physician, and admitted to our department with a delay of at least 24 h after the beginning of the symptoms, were included in this study. We analyzed the various diagnoses that were ascertained instead of SAH and which medical specialty had provided them. Results Overall 704 patients were treated with acute SAH. The inclusion criteria were matched in 76 patients (13.7%). Eleven specialties were involved in the initial patients' treatment. The time interval between initial symptoms and neurosurgical admission varied enormously. Statistically, higher Hunt & Hess score did not lead to an earlier diagnosis (p = 0.56) nor did localisation of the aneurysm (p = 0.75). Lower Fisher score was led to delayed diagnosis (p = 0.02). Delay of diagnosis was not significantly associated with the outcome (p = 0.08) whereas Hunt & Hess grade on admission was a strong predictor for bad outcome (p = 0.00001) as was cerebral vasospasm on the first angiogram (p Conclusion A straightforward diagnosis of SAH despite diffuse and unspecific symptoms is crucial for the successful treatment of these patients, especially with high grade SAH.

Objective: Sophisticated shunt valves provide the possibility of pressure adjustment and antisiphon control but have a higher probability of valve dysfunction especially in a posthemorrhagic setting. The aim of the present study is to analyze the clinical outcome of patients with shunt dependent posthemorrhagic[for full text, please go to the a.m. URL], 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

OBJECTIVEPyogenic spondylodiscitis affects a fragile patient population. Surgical treatment in cases of instability entails instrumentation, and loosening of this instrumentation is a frequent occurrence in pyogenic spondylodiscitis. The authors therefore attempted to investigate whether low bone mineral density (BMD)—which is compatible with the diagnosis of osteoporosis—is underdiagnosed in patients with pyogenic spondylodiscitis. How osteoporosis was treated and how it affected implant stability were further analyzed.METHODSCharts of patients who underwent operations for pyogenic spondylodiscitis were retrospectively reviewed for clinical data, prior medical history of osteoporosis, and preoperative CT scans of the thoracolumbar spine. In accordance with a previously validated high-fidelity opportunistic CT assessment, average Hounsfield units (HUs) in vertebral bodies of L1 and L4 were measured. Based on the validation study, the authors opted for a conservative cutoff value for low BMD, being compatible with osteoporosis ≤ 110 HUs. Baseline and outcome variables, including implant failure and osteoporosis interventions, were entered into a multivariate logistic model for statistical analysis.RESULTSOf 200 consecutive patients who underwent fusion surgery for pyogenic spondylodiscitis, 64% (n = 127) were male and 66% (n = 132) were older than 65 years. Seven percent (n = 14) had previously been diagnosed with osteoporosis. The attenuation analysis revealed HU values compatible with osteoporosis in 48% (95/200). The need for subsequent revision surgery due to implant failure showed a trend toward an association with estimated low BMD (OR 2.11, 95% CI 0.95–4.68, p = 0.067). Estimated low BMD was associated with subsequent implant loosening (p < 0.001). Only 5% of the patients with estimated low BMD received a diagnosis and pharmacological treatment of osteoporosis within 1 year after spinal instrumentation.CONCLUSIONSRelying on past medical history of osteoporosis is insufficient in the management of patients with pyogenic spondylodiscitis. This is the first study to identify a substantially missed opportunity to detect osteoporosis and to start pharmacological treatment after surgery for prevention of implant failure. The authors advocate for routine opportunistic CT evaluation for a better estimation of bone quality to initiate diagnosis and treatment for osteoporosis in these patients.

Patients from contemporary populations with traumatic brain injury (TBI) resulting from epidural hematoma (EDH) may differ regarding age, comorbidities, and coagulation status. We therefore analyzed predictors for the clinical outcome of patients with EDH treated surgically regarding modern approaches to resuscitation and trauma care.A retrospective observational analysis was carried out. All patients included underwent surgery. The indication for surgery followed international guidelines. Retrospective data evaluation considered data reflecting the effectiveness of trauma care, baseline characteristics, and radiologic findings. In this analysis, we divided patients into 2 groups (isolated EDH vs. EDH plus other intracranial traumatic injuries). The neurologic outcome was assessed at discharge using the Glasgow Outcome Scale.Two hundred and sixty-eight patients with epidural hematoma, of whom 131 underwent surgery, were treated between January 1997 and December 2012 in our level-1 trauma center. The overall mortality was 6.8% (mortality for patients with Glasgow Outcome Scale score9, 15%). As expected, factors with a highly significant (P 0.01) impact on outcome were concomitant with other intracranial injuries, brain midline shift, and higher Injury Severity Score. Alcohol intoxication was a significant (P 0.05) predictor of an unfavorable outcome. Anticoagulants and Glasgow Coma Scale score at admission had no significant impact on the outcome.The outcome for EDH is more favorable than decades ago, most probably reflecting a well-established chain of trauma care. Therefore, EDH is a treatable disease with a high probability of a favorable outcome.

Background Isolated traumatic subarachnoid hemorrhage (itSAH) is found in approximately 25% of all patients with mild traumatic brain injury (TBI). The aim of this study was to analyze the clinical course and identify risk factors for potential clinical and radiologic deterioration in consideration of impaired coagulation in patients with itSAH. Methods A retrospective analysis of 735 patients with TBI resulting in a pathologic computer-assisted tomography (CAT) was performed. Only those patients with itSAH and Glasgow Coma Scale (GCS) of greater than 8 points and follow-up CAT scan were included. Patients with hemorrhage in any other brain compartment (subdural, epidural, and intracerebral) were excluded. Impaired coagulation was operationally defined. Results Of the 735 patients, 89 met the inclusion criteria. The majority of these patients experienced mild TBI. The rate of radiologic expansion or conversion of the SAH was 28.1%. The rate of clinical deterioration was 6.7%. Neither the initial pattern of itSAH on different intracranial localizations nor the number of sulci involved in the itSAH was associated with clinical worsening. The rate of patients with impaired coagulation was 38%; 17.9% of all patients showed elevated international normalized ratio (INR). Radiologic and clinical deterioration was significantly associated with elevated INR. INR was shown to be independent of age in a logistic regression analysis. Conclusion TBI patients with itSAH and impaired coagulation especially those who showed elevated INR are at risk of clinical and radiologic deterioration. Despite coagulation status, routine repetition of cranial CAT scan is advised in patients with itSAH to detect potential radiologic worsening, which if occurring should result in close clinical monitoring. Level of evidence Therapeutic study, level IV; prognostic study, level III.

Platelet function might play an essential role in the pathogenesis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH). Thus, impaired platelet function and disturbed primary haemostasis induced by intake of acetylsalicylic acid (ASA) might influence the rate of DCI. Primary haemostasis and platelet function can be measured with in vitro diagnosis (platelet function analyser test, PFA 100). The aim of this study is to evaluate the rate of DCI, haemorrhagic complications and the neurological outcome. Two groups were compared (patients with regular platelet function versus patients with impaired platelet function). This is a retrospective observational study. An initial cohort of 787 patients with SAH has been treated from January 2005 to September 2012. Seventy-nine patients (10%) with aneurysmal SAH, a history of ASA medication and PFA testing within the first 24 h after aneurysm rupture have been included. The overall rate of DCI in the present study was 43%. In vitro platelet function testing showed pathological primary haemostasis in 69.6%. The DCI rate was higher in patients with regular tested primary haemostasis (p = 0.02, OR = 3.16, 95%CI = [1.19; 8.83]). However, outcome assessment by mGOS did not show a significant difference between the groups. Patients with impaired primary haemostasis did not display a higher rate of haemorrhagic complications. Impairment of primary haemostasis resulting from an impairment of platelet function at an early stage after SAH might lead to a lower rate of DCI. In vitro testing of platelet function might be useful to predict the occurrence of DCI in the course.

Background Multiple cerebral cavernous malformations (mCCMs) are known as potentially epileptogenic lesions. Treatment might be multimodal. Management of patients with mCCMs and epilepsy is challenging. Objective To evaluate (1) algorhythmic therapeutic sequences in patients with epilepsy associated to mCCMs, (2) whether there are predictive parameters to anticipate the development of drug-resistant epilepsy, and (3) seizure after epilepsy surgery compared to conservatively-treated drug-resistant patients. Methods All inpatients and outpatients with epilepsy associated to mCCMs from 1990 to 2010 and follow-up >12 months available were retrospectively analyzed. Results Twenty-three patients matched inclusion criteria. Epilepsy became drug-resistant in 18/23 (78%) patients. No predictors were found for development of drug-resistant epilepsy. Median follow-up for both groups was 7.8 years. Nine patients did not qualify for surgical therapy and were treated conservatively. One patient of this cohort (11%) was seizure-free (International League Against Epilepsy [ILAE] class 1). Surgical treatment was performed in 9 patients; 7/9 (78%) of these patients were seizure-free (ILAE class 1) after epilepsy surgery for at least 12 months compared with 1/9 patients in the non-operated group. In 7/9 cases (78%) the largest CCM was resected. In 8/9 (89%) not all CCMs were resected. Conclusion After initial diagnosis of epilepsy associated to mCCMs, a primary conservative approach is reasonable. Surgical treatment can be successful in a large fraction of cases with drug-resistant epilepsy where an epileptogenic lesion is identified. Cases where surgery is not undertaken are likely to remain intractable.

The distinction of isolated malformations and combined lesions constitutes a major novelty in the 2011 consensus classification of the International League against Epilepsy (ILAE) for focal cortical dysplasias (FCD). Cortical lamination abnormalities together with vascular lesions are subsumed as FCD IIIc. Little is known regarding frequency and etiology of this entity. Here, we systematically evaluated biopsy specimens from 72 drug-refractory epilepsy patients with cerebral cavernous malformations (CCM) regarding presence of associated FCD. Due to a non-perpendicular orientation of the cortical structures or absence of sufficient cortical tissue adjacent to the vascular lesion 25 samples were not classifiable. In the remaining 47 cases FCD IIIc was rare (4.3%), but significantly increased in patients with multiple CCM (28.6%; p

Background In aneurysmal subarachnoid haemorrhage cerebral vasospasm leads to clinical worsening and poor outcome. Interventional treatment with nimodipine might be a therapeutic option. Objective To evaluate the clinical course of patients with different interventional treatment types. Methods A retrospective, observational analysis was performed. Inclusion criteria were aneurysmal subarachnoid haemorrhage, clinical and/or radiologic evidence of vasospasm and interventional intra-arterial treatment. Patients were divided into 3 groups: continuous nimodipine infusion, repetitive nimodipine infusions, and singular nimodipine infusion. Pre- and postinterventional parameters were analyzed to evaluate the efficacy of the procedure in terms of responder status. Outcome was determined using the modified Rankin scale. Results A total of 163 interventions (97 patients) were examined. Patients with continuous treatment showed a greater World Federation of Neurological Surgeons grade. Response to intra-arterial nimodipine in the continuous group was comparatively worse. Transcranial Doppler monitoring as well as brain tissue oxygenation measuring showed good correlation with imaging results. The rate of intraprocedural complications in the continuous treatment group was significantly greater. We observed a worse clinical outcome in the patients who underwent continuous treatment. None of the patients in the continuous group achieved favorable outcome after 3 months. Conclusions Facing the poor clinical outcome and the greater complication rate, continuous intra-arterial infusion of nimodipine in patients with angiographically refractory cerebral vasospasm has to be indicated strictly. Transcranial Doppler and brain tissue oxygenation monitoring seem to be reliable tools for evaluation of the clinical postinterventional course.

Background Ketamine has neuroprotective characteristics as well as beneficial cardiocirculatory properties and may thus reduce vasopressor consumption. In contrast, sedation with ketamine (like any other sedative drug) has side effects. This study assesses the influence of ketamine on intracranial pressure (ICP), on the consumption of vasopressors in induced hypertension therapy, and on the occurrence of delayed cerebral ischemia (DCI)-associated cerebral infarctions, with particular focus on the complications of sedation in patients with aneurysmal subarachnoid hemorrhage (SAH). Methods This is a retrospective, observational study. Sixty-five patients with SAH who underwent a period of sedation were included. The clinical course variables (Richmond Agitation and Sedation scale score, ICP values, consumption of vasopressors, complications of sedation, outcome, and other clinical parameters) were analyzed. Cranial computed tomography results were analyzed. Results Forty-one patients underwent sedation including ketamine (63.1%). Ketamine decreased the ICP in 92.7% of the cases. Vasopressors was reduced in 53.6%. DCI-associated cerebral infarctions occurred significantly less often in the patient cohort being treated with sedation including ketamine (7.3% vs. 25% in the nonketamine group; P = 0.04). The rate of major complications was not higher in the ketamine group. Outcome was not different regarding the groups if they were sedated with or without ketamine. Conclusions Ketamine decreases the ICP and is not associated with a higher rate of complications. The rate of DCI-associated cerebral infarctions was lower in the ketamine group. Ketamine administration led to a reduction of vasopressors used for induced hypertension.

Cerebrospinal fluid (CSF) shunt-associated infection is one of the most frequent complications of CSF shunt surgery. We evaluated our institutional guideline for the treatment of shunt-associated infections.We retrospectively analysed all 92 episodes of shunt-associated infections in 78 patients treated in our institution from 2002 to 2008. All patients underwent urgent surgery, i.e. removal of the complete shunt hardware or externalisation of the distal tubing in cases with an infection restricted to the distal shunt (10 %), placement of an external ventricular drainage as necessary and antibiotic therapy. Standard empirical first-line antibiotic treatment consisted of a combination of flucloxacillin and cefuroxime.We observed 38 % early (1 month after shunt surgery) and 20 % late infections (1 year after shunt placement). Coagulase-negative staphylococci (CoNS) were isolated in 38 %. In 38 % no pathogens could be isolated. Of cases with a first shunt infection, 58 % were initially treated with flucloxacillin/cefuroxime. Only 53 % of all infections were treated successfully with the first course of antibiotics. Only 51 % of bacterial isolates were sensitive to empirical first-line antibiotics. Twenty percent of infections caused by sensitive bacterial isolates nevertheless required second-line antibiotic therapy.Urgent surgery for shunt removal and antibiotic therapy will usually cure a shunt-associated infection. The choice of antibiotics should reflect the spectrum of pathogens seen at one's institution, paying particular attention to the role of CoNS isolates, and in vitro sensitivity testing results.

Objective To investigate whether independent predictors of complications after cranioplasty are identifiable. Methods Parameters that could predict the occurrence of complications were analyzed retrospectively. The end point of the study was the explantation of the bone flap. Results A total of 219 patients with a mean age of 42.8 years (standard deviation: 17.89) were included. History of trauma and especially open traumatic brain injury (TBI) were associated with a higher complication rate (p = 0.01 and p = 0.02, respectively). Multivariate testing showed that fragmented bone flap resulted in a more frequent occurrence of bone flap necrosis (p = 0.014). The risk of complications following cranioplasty was higher if a ventriculoperitoneal (VP) shunt was placed at the same time (p = 0.01). Longer duration of the cranioplasty procedure was significantly associated with a higher postoperative complication rate (p = 0.001). Subsequent rehabilitation is more frequent if patients develop a complication. Conclusions To avoid complications after cranial vault reconstruction, indications for simultaneous VP shunt implantation should be carefully evaluated. The implantation of traumatically fragmented bone flaps should be avoided. Patients after open TBI should either primarily be treated with an allogenic graft or they should be carefully followed up because they are prone to develop aseptic necrosis.

Background Epilepsy is the second most common symptom in cerebral arteriovenous malformation (AVM) patients. The consecutive reduction of life quality is a clinically underrated problem because treatment usually focuses on the prevention of intracerebral hemorrhage. Objective To evaluate postoperative seizure outcome with the aim of more accurate counseling for postoperative seizure outcome. Methods From 1985 to 2012, 293 patients with an AVM were surgically treated by J.S. One hundred twenty-six patients with preoperative seizures or epilepsy could be identified; 103 of 126 had a follow-up of at least 12 months and were included in the analysis. The different epilepsy subtypes were categorized (sporadic seizures, chronic epilepsy, drug-resistant epilepsy [DRE]). Preoperative workup and surgical technique were evaluated. Seizure outcome was analyzed by using International League Against Epilepsy classification. Results Sporadic seizures were identified in 41% of patients (chronic epilepsy and DRE were identified in 36% and 23%, respectively). Detailed preoperative epileptological workup was done in 13%. Seizure freedom was achieved in 77% (79% at 5 years, 84% at 10 years). Outcome was significantly poorer in DRE cases. More extensive resection was performed in 11 cases with longstanding symptoms (>24 months) and resulted in better seizure outcome as well as the short duration of preoperative seizure history. Conclusion Patients presenting with AVM-associated epilepsy have a favorable seizure outcome after surgical treatment. Long-standing epilepsy and the progress into DRE markedly deteriorate the chances to obtain seizure freedom and should be considered an early factor in establishing the indication for AVM removal.

Tuberous sclerosis complex (TSC) is a common hereditary disorder caused by mutations in either the TSC1 or TSC2 genes, and characterized by severe epilepsy, cerebral hamartomas and mental retardation. We have used rats that are heterozygous for an autosomal-dominant germline mutation in the TSC2 gene (TSC2+/- rats) to examine the consequences of TSC2 mutations for hippocampal synaptic plasticity. While basal synaptic transmission in the Schaffer collateral-CA1 synapse was not altered, paired-pulse plasticity was significantly enhanced in TSC2+/- rats (interpulse intervals 20-200 ms). Moreover, TSC2+/- rats exhibited a marked reduction of different forms of synaptic plasticity. Long-term potentiation (LTP) elicited following high-frequency tetanization of Schaffer collaterals was significantly decreased from 1.45 +/- 0.05-fold potentiation to 1.15 +/- 0.04 (measured after 60 min). This difference in LTP levels between TSC2+/- and wild-type rats also persisted in the presence of the gamma-aminobutyric acid (GABA)(A) receptor antagonist bicuculline. In addition to changed LTP, the level of long-term depression (LTD) elicited by different forms of low-frequency stimulation was significantly less in TSC2+/- rats. These results suggest that TSC2 mutations may cause hippocampal synapses to lose much of their potential for activity-dependent synaptic modification. An understanding of the underlying molecular pathways may suggest new therapeutic approaches aimed at inhibiting the development of the profound mental retardation in TSC.

Specific agonists of metabotropic glutamate receptors (mGluRs) provide powerful tools to discriminate afferent fibers originating from different presynaptic neurons. The group II mGluR agonists L-CCG-I ((2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine) and DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine) are commonly used to distinguish between mossy fiber and associational-commissural (A/C) fiber input to the hippocampal CA3 region because only on the former group II mGluRs are expressed. Since previous reports indicated that L-CCG-I can activate group III mGluRs as well, we investigated whether L-CCG-I depresses A/C field potentials. L-CCG-I (10-300 microM) exhibited a significant dose-dependent and reversible reduction of A/C field potentials by 8 +/- 4% (10 microM), by 32 +/- 4% (100 microM, p0.001) and by 38 +/- 7% (300 microM, p0.05) that was accompanied by a concomitant increase in paired-pulse facilitation. Moreover, the selective group III antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP; 100 microM) significantly reduced the field potential inhibition by L-CCG-I (100 microM) to 9 +/- 4% (p0.05). In contrast, DCG-IV did not affect A/C field potentials. In conclusion, the purported group II mGluR agonist L-CCG-I depresses A/C synaptic transmission by activation of group III mGluRs. For this reason, DCG-IV should be the drug of choice when aiming to discriminate between mossy fiber and A/C input to CA3 pyramidal cells.

The aim of this study was to identify the effects of coagulopathy on the outcome of patients with traumatic subdural hematoma (SDH). Based on a retrospective study, the records of all patients admitted between 2001 and 2007 to a large emergency hospital with acute SDH resulting from traumatic brain injury (TBI) were analyzed. An initial Glasgow coma score (GCS), clinical state, and Glasgow outcome score (GOS) were recorded for all patients. All computer assisted tomography and MRI scans obtained from patients were saved on an electronic storage device and were reviewed by a neurosurgeon and a neuroradiologist. The coagulation parameters were analyzed for all patients. Coagulopathy was defined as international normalized ratio more than 1.2 or partial thromboplastin time more than 37 s. One hundred and five women and 214 men aged between 1 and 100 years (mean 59 years) were included in the study. Patients with coagulopathy had a significantly worse outcome. Almost twice as many patients died in the coagulopathy group (mean GOS 3.10 ± 1.46) than in the group without coagulopathy (mean GOS 2.16 ± 1.45), (P 0.001). In-hospital mortality is twice as frequent in patients with coagulopathy with traumatic SDH compared with noncoagulopathic patients, even if the initial severity of the TBI does not differ.

Sufficient data on surgical treatment and seizure outcome of pediatric patients with different types of epilepsy, especially drug-resistant epilepsy and associated cerebral cavernous malformations, are scarce. The aim of this study was to carefully evaluate seizure outcome using the International League Against Epilepsy (ILAE) classification with regard to the presurgical symptom duration.Fifty-one pediatric patients younger than 19 years with cerebral cavernous malformations of all CNS localizations have been surgically treated at the authors' institution. Twenty-two patients with seizures or epilepsy who harbored cortically located supratentorial cerebral cavernous malformations underwent surgical treatment and were retrospectively analyzed.More extensive resections were used in 82% of all patients with epilepsy symptoms for longer than 2 years. Eighty-two percent of patients with symptom duration shorter than 2 years underwent circumscribed lesionectomy including the surrounding hemosiderotic rim. The overall rate of mild permanent, unanticipated postoperative deficits was 4.5%; the rate of anticipated neurological deficits was 9%. The mean follow-up was longer than 117 months in all groups. Seizure outcome was excellent in the group with symptom duration shorter than 2 years (100% ILAE Class 1). Seizure outcome was significantly worse in the group with longer symptom duration (p = 0.02). Seven patients were seizure free after surgery. Seizure outcome was stable over the years.Since seizure outcome is worse with longer seizure duration, early surgery and, if needed, interdisciplinary intervention, is recommended. Even in cases of multiple cerebral cavernous malformations and epilepsy, surgery should be considered.

Summary Purpose Precise outcome data about the surgical therapy of cerebral cavernous malformation (CCM)–associated epilepsy is scarce regarding different epilepsy types, surgical approach, and outcome. Long-term outcome in patients with CCM-associated epilepsy is analyzed in a large single-center series. Methods Seizure outcome data >24 months was available in 118 patients. The influence of different parameters of preoperative workup and surgical technique was analyzed with regard to seizure outcome. Key Findings The study cohort comprised 76 patients with drug-resistant epilepsy (DRE), 20 patients with chronic epilepsy that did not meet the definition of DRE, as well as 22 patients with sporadic seizures. Temporal localization of CCMs predisposed to develop DRE. Detailed epileptologic workup was performed in 85 patients; invasive monitoring was done in 23 (37%) of 76 DRE cases. In 84% of DRE cases more extensive resections were performed. Mean follow-up varied between 107 and 137 months for the three groups. Seizure freedom in DRE was 88%, in chronic epilepsy 80%, and in sporadic seizures was 91%. Longer symptom duration was associated with worse seizure outcome. Outcome of patients who underwent invasive monitoring was not worse. The outcome in CCM-associated DRE can be good if more extensive resections are used and if noninvasive and/or invasive presurgical epileptologic workup is used whenever indicated. DRE was considerably more frequent in the temporal lobe, suggesting that temporal localization predisposes development of DRE. Seizure freedom rates were stable over a long period. Significance Surgical therapy of CCM-associated seizures and epilepsy can be successful if different surgical techniques according to presurgical evaluation are realized. To prevent clinical worsening into DRE, surgical intervention in CCM-associated epilepsy may be considered early.

Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood-brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion-associated epileptogenesis.We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation.Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups.Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients.

The synapses formed by the mossy fiber (MF) axons of hippocampal dentate gyrus granule neurons onto CA3 pyramidal neurons exhibit an intriguing form of experience-dependent synaptic plasticity that is induced and expressed presynaptically. In contrast to most other CNS synapses, long-term potentiation (LTP) at the MF–CA3 synapse is readily induced even during blockade of postsynaptic glutamate receptors. Furthermore, blocking voltage-gated Ca2+channels prevents MF-LTP, supporting an involvement of presynaptic Ca2+signaling via voltage-gated Ca2+channels in MF-LTP induction. We examined the contribution of activity in both dentate granule cell somata and MF terminals to MF-LTP. We found that the induction of stable MF-LTP requires tetanization-induced action potentials not only at MF boutons, but also at dentate granule cell somata. Similarly, blocking Ca2+influx via voltage-gated Ca2+channels only at the granule cell soma was sufficient to disrupt MF-LTP. Finally, blocking protein synthesis or blocking fast axonal transport mechanisms via disruption of axonal tubulin filaments resulted in decremental MF-LTP.Collectively, these data suggest that—in addition to Ca2+influx at the MF terminals—induction of MF synaptic plasticity requires action potential-dependent Ca2+signaling at granule cell somata, protein synthesis, and fast axonal transport along MFs. A parsimonious interpretation of these results is that somatic activity triggers protein synthesis at the soma; newly synthesized proteins are then transported to MF terminals, where they contribute to the stabilization of MF-LTP. Finally, the present data imply that synaptic plasticity at the MF–CA3 synapse can be affected by local modulation of somatic and presynaptic Ca2+channel activity.

The advent of ventriculoperitoneal shunts (VPS) represented a substantial progress in the neurosurgical management of hydrocephalus in children. VPS infection is the most frequently observed complication. VPS infection is related to substantial morbidity and mortality, and exerts a negative impact on the quality of life of patients. Considerable personnel and financial resources have been devoted to its diagnosis and treatment. This article reviews the current literature and includes suggestions for the prevention, diagnosis and management of VPS infections.

Ischemic brain damage triggers overt disseminated intravascular coagulation in a young woman with cerebral venous sinus thrombosis

Ca2+ influx into presynaptic terminals via voltage-dependent Ca2+ channels triggers fast neurotransmitter release as well as different forms of synaptic plasticity. Using electrophysiological and genetic techniques we demonstrate that presynaptic Ca2+ entry through Cav2.3 subunits contributes to the induction of mossy fiber LTP and posttetanic potentiation by brief trains of presynaptic action potentials while they do not play a role in fast synaptic transmission, paired-pulse facilitation, or frequency facilitation. This functional specialization is most likely achieved by a localization remote from the release machinery and by a Cav2.3 channel-dependent facilitation of presynaptic Ca2+ influx. Thus, the presence of Cav2.3 channels boosts the accumulation of presynaptic Ca2+ triggering presynaptic LTP and posttetanic potentiation without affecting the low release probability that is a prerequisite for the enormous plasticity displayed by mossy fiber synapses.