GABAB receptor outward currents are transiently disclosed by the convulsant 4-aminopyridine in vitro.

The K+ channel blocker 4-aminopyridine (4AP) has been extensively used to investigate the mechanisms underlying neuronal network synchronization in both in vitro and in vivo animal models of focal epilepsy. 4AP-induced effects are paralleled by an increase in both excitatory and inhibitory neurotransmitter release, but the mechanisms of action of 4AP on neuronal networks remain unclear. By employing simultaneous whole-cell patch clamp and field potential recordings from hippocampal CA3/4 pyramidal layer of acute brain slices obtained from mice (n = 30), we found that the appearance of epileptiform discharges induced by 4AP (100 µM) is consistently preceded by the transient recurrence of presumptive GABAB outward currents, which are not mirrored by any field activity. These GABAB outward currents still occurred during application of ionotropic glutamatergic antagonists (n = 12 cells) but were blocked by the GABAB receptor antagonist CGP55845 (n = 7). Our findings show that the transient occurrence of distinct GABAB outward currents precedes the appearance of 4AP-induced neuronal network synchronization leading to epileptiform activity in the rodent hippocampus in vitro.

A single center experience of adjusting valve pressure ventriculoperitoneal shunts for the treatment of hydrocephalus in infants under 6 months old.

INTRODUCTION: Ventriculoperitoneal shunt (VPS) with adjustable differential pressure valves are commonly used to treat infants with hydrocephalus avoiding shunt related under- or overdrainage. The aim of this study was to analyse the influence of VPS adjustable differential pressure valve on the head circumference (HC) and ventricular size (VS) stabilization in infants with post intraventricular haemorrhage, acquired and congenital hydrocephali. METHODS: Forty-three hydrocephalic infants under 6 months old were prospectively included between 2014 and 2018. All patients were treated using a VPS with adjustable differential pressure valve. HC and transfontanelle ultrasonographic VS measurements were regularly performed and pressure valve modifications were done aiming HC and VS percentiles between the 25th and 75th. The patients were divided into two groups: infants with hydrocephalus due to an intraventricular haemorrhage (IVH-H), and infants with hydrocephalus due to other aetiologies (OAE-H). RESULTS: The mean of pressure valve modification was 3.7 per patient in the IVH-H group, versus 2.95 in the OAE-H group. The median of last pressure valve value was higher at 8.5 cm H2O in the IVH-H group comparing to 5 cm H2O in the OAE-H group (p = 0.013). CONCLUSION: Optimal VPS pressure valve values could be extremely difficult to settle in order to gain normalisation of the HC and VS in infants. However, after long term follow up (mean of 18 months) and several pressure valve modifications, this normalisation is possible and shows that infants with IVH-H need a higher pressure valve value comparing to infants with OAE-H.

Comparison of frame-less robotic versus frame-based stereotactic biopsy of intracranial lesions.

OBJECTIVE: Robotic guidance might be an alternative to classic stereotaxy for biopsies of intracranial lesions. Both methods were compared regarding time efficacy, histopathological results and complications. METHODS: A retrospective analysis enrolling all patients undergoing robotic- or stereotactic biopsies between 01/2015 and 12/2018 was conducted. Trajectory planning was performed on magnetic resonance imaging (MRI). With the Robotic Surgery Assistant (ROSA), patient registration was accomplished using a facial laser scan in the operating room (OR), immediately followed by biopsy. In stereotaxy, patients were transported to the CT for Leksell Frame registration, followed by biopsy in the OR. RESULTS: The average overall procedure time amounted in robotics to 169 min and in stereotaxy to 179 min (p = 0.005). The difference was greatest for temporal targets, amounting in robotics to 161 min and in stereotaxy to 188 min (p = 0,0007). However, the average time spent purely in the OR amounted in robotics to 140 min and in stereotaxy to 113 min (p < 0.001). In 150 robotic biopsies, diagnostic yield amounted to 98%, in 266 stereotactic biopsies to 91%. Symptomatic postoperative hemorrhages were observed in 3 patients (2%) in robotic biopsy and 7 patients (2,7%) in stereotactic biopsy. CONCLUSION: Robotics showed a shorter overall procedure time as there is no need for a transport to the CT whereas the pure OR time was shorter in stereotaxy due to skipping the laser registration process. Diagnostic yield was higher in robotics, most likely due to case selection, complication rates were equal.

First clinical experience with the new noninvasive transfontanelle ICP monitoring device in management of children with premature IVH.

We previously introduced a novel noninvasive technique of intracranial pressure (ICP) monitoring in children with open fontanelles. Within this study, we describe the first clinical implementation and results of this new technique in management of children with hydrocephalus caused by intraventricular hemorrhage (IVH). In neonates with posthemorrhagic hydrocephalus (PHH), an Ommaya reservoir was implanted for initial treatment of hydrocephalus. The ICP obtained noninvasively with our new device was measured before and after CSF removal and correlated to cranial ultra-sonographies. Six children with a mean age of 27.3 weeks and mean weight of 1082.3 g suffering from PHH were included in this study. We performed an overall of 30 aspirations due to ventricular enlargement. Before CSF removal, the mean ICP was 15.3 mmHg and after removal of CSF the mean ICP measured noninvasively decreased to 3.4 mmHg, p = 0.0001. The anterior horn width (AHW), which reflects early expansion of the ventricles, was before and after CSF removal 15.1 mm and 5.5 mm, respectively, p < 0.0006. There was a strong correlation between noninvasively measured ICP values and sonographically obtained AHW, r = 0.81. Ultimately, all children underwent ventriculoperitoneal shunt procedures. This is the first study providing proof for a noninvasively ICP-based approach for management of posthemorrhagic hydrocephalus in newborn children.

Invasive EEG-electrodes in presurgical evaluation of epilepsies: Systematic analysis of implantation-, video-EEG-monitoring- and explantation-related complications, and review of literature.

INTRODUCTION: Stereoelectroencephalography (sEEG) is a diagnostic procedure for patients with refractory focal epilepsies that is performed to localize and define the epileptogenic zone. In contrast to grid electrodes, sEEG electrodes are implanted using minimal invasive operation techniques without large craniotomies. Previous studies provided good evidence that sEEG implantation is a safe and effective procedure; however, complications in asymptomatic patients after explantation may be underreported. The aim of this analysis was to systematically analyze clinical and imaging data following implantation and explantation. RESULTS: We analyzed 18 consecutive patients (mean age: 30.5 years, range: 12-46; 61% female) undergoing invasive presurgical video-EEG monitoring via sEEG electrodes (n = 167 implanted electrodes) over a period of 2.5 years with robot-assisted implantation. There were no neurological deficits reported after implantation or explantation in any of the enrolled patients. Postimplantation imaging showed a minimal subclinical subarachnoid hemorrhage in one patient and further workup revealed a previously unknown factor VII deficiency. No injuries or status epilepticus occurred during video-EEG monitoring. In one patient, a seizure-related asymptomatic cross break of two fixation screws was found and led to revision surgery. Unspecific symptoms like headaches or low-grade fever were present in 10 of 18 (56%) patients during the first days of video-EEG monitoring and were transient. Postexplantation imaging showed asymptomatic and small bleedings close to four electrodes (2.8%). CONCLUSION: Overall, sEEG is a safe and well-tolerated procedure. Systematic imaging after implantation and explantation helps to identify clinically silent complications of sEEG. In the literature, complication rates of up to 4.4% in sEEG and in 49.9% of subdural EEG are reported; however, systematic imaging after explantation was not performed throughout the studies, which may have led to underreporting of associated complications.

Electrode placement accuracy in robot-assisted epilepsy surgery: A comparison of different referencing techniques including frame-based CT versus facial laser scan based on CT or MRI.

BACKGROUND: Precise robotic or stereotactic implantation of stereoelectroencephalography (sEEG) electrodes relies on the exact referencing of the planning images in order to match the patient's anatomy to the stereotactic device or robot. We compared the accuracy of sEEG electrode implantation with stereotactic frame versus laser scanning of the face based on computed tomography (CT) or magnetic resonance imaging (MRI) datasets for referencing. METHODS: The accuracy was determined by calculating the Euclidian distance between the planned trajectory and the postoperative position of the sEEG electrode, defining the entry point error (EPE) and the target point error (TPE). The sEEG electrodes (n = 171) were implanted with the robotic surgery assistant (ROSA) in 19 patients. Preoperative trajectory planning was performed on three-dimensional (3D) MRI datasets. Referencing was accomplished either by performing (A) 1.25-mm slice CT with the patient's head fixed in a Leksell stereotactic frame (CT-frame, n = 49), fused with a 3D-T1-weighted, contrast enhanced- and T2-weighted 1.5 Tesla (T) MRI; (B) 1.25 mm CT (CT-laser, n = 60), fused with 3D-3.0-T MRI; (C) 3.0-T MRI T1-based laser scan (3.0-T MRI-laser, n = 56) or (D) in one single patient, because of a pacemaker, 3D-1.5-T MRI T1-based laser scan (1.5-T MRI-laser, n = 6). RESULTS: In (A) CT-frame referencing, the mean EPE amounted to 0.86 mm and the mean TPE amounted to 2.28 mm (n = 49). In (B) CT-laser referencing, the EPE amounted to 1.85 mm and the TPE to 2.41 mm (n = 60). In (C) 3.0-T MRI-laser referencing, the mean EPE amounted to 3.02 mm and the mean TPE to 3.51 mm (n = 56). In (D) 1.5-T MRI, surprisingly the mean EPE amounted only to 0.97 mm and the TPE to 1.71 mm (n = 6). In 3 cases using CT-laser and 1 case using 3.0 T MRI-laser for referencing, small asymptomatic intracerebral hemorrhages were detected. No further complications were observed. CONCLUSION: Robot-guided sEEG electrode implantation using CT-frame referencing and CT-laser-based referencing is most accurate and can serve for high precision placement of electrodes. In contrast, 3.0-T MRI-laser-based referencing is less accurate, but saves radiation. Most trajectories can be reached if alternative routes over less vascularized brain areas are used. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Robot-guided stereoelectroencephalography without a computed tomography scan for referencing: Analysis of accuracy.

OBJECTIVE: Recent studies with robot-guided stereotaxy use computed tomography (CT) scans for referencing. We will provide evidence that using preoperative MRI datasets referenced with a laser scan of the patient's face is sufficient for sEEG implantation. METHODS: In total, 40 sEEG electrodes were implanted in five patients by the robotic surgical assistant (ROSA). The postoperative CT scan for identifying electrode positions was fused with the preoperative MRI-based planning data. The accuracy was determined by the target point error (TPE) and the entry point error (EPE), applying the Euclidean distance. RESULTS: The mean TPE amounted to 2.96 mm, the mean EPE to 2.53 mm. The accuracy was improved in 1.5 T MRI: the mean TPE amounted to 1.72 mm, the EPE to 0.97 mm. No complications, haemorrhages, infections, etc., were observed. CONCLUSIONS: Robot-guided sEEG based on 3 T MRI reduces radiation exposure for the patient and can still be performed safely.

Surgical Treatment of Spinal Synovial Cysts in Elderly Patients: Symptoms, Treatment Course, and Outcome in Patients >75 Years of Age.

BACKGROUND: With the aging of our society comes a rising number of elderly patients with progressive degeneration of the spine associated with synovial cysts. Surgical treatment may be particularly challenging in elderly patients because of comorbidities. METHODS: Patients treated in our department between 1999 and 2014 for spinal synovial cysts were screened. The 28 patients ≥75 years old were classified as elderly and were compared with 96 patients 50-74 years old. No patient underwent fusion as part of cyst resection. RESULTS: Despite a significantly higher frequency of muscle reflex changes in elderly patients at presentation, symptoms, cyst levels, rate of complications, and surgical method were not different between groups. Cyst adherence to the dura and subtotal resection were observed significantly more often in the elderly group (18% vs. 3%; P < 0.05). Outcome according to the Oswestry Disability Index was classified as no disability or minimal disability in 85% of the elderly group and in 82% of the control group. Recurrent cyst and delayed fusion rates were lower in the elderly group (4% and 4%) compared with the control group (7% and 8%). CONCLUSIONS: The clinical course of elderly patients with surgical treatment of spinal synovial cysts did not differ compared with younger patients. Good or excellent results could be achieved and persisted for a long time in most cases. Fusion should be performed only in cases of severe instability. Nonaggressive cyst removal in cases of dural attachment enables low cerebrospinal fluid fistula rates without increasing cyst recurrence rates.

Acute subdural hematoma in patients on oral anticoagulant therapy: management and outcome.

OBJECTIVE Isolated acute subdural hematoma (aSDH) is increasing in older populations and so is the use of oral anticoagulant therapy (OAT). The dramatic increase of OAT-with direct oral anticoagulants (DOACs) as well as with conventional anticoagulants-is leading to changes in the care of patients who present with aSDH while receiving OAT. The purpose of this study was to determine the management and outcome of patients being treated with OAT at the time of aSDH presentation. METHODS In this single-center, retrospective study, the authors analyzed 116 consecutive cases involving patients with aSDH treated from January 2007 to June 2016. The following parameters were assessed: patient characteristics, admission status, anticoagulation status, perioperative management, comorbidities, clinical course, and outcome as determined at discharge and through 6 months of follow-up. Oral anticoagulants were classified as thrombocyte inhibitors, vitamin K antagonists, and DOACs. Patients were stratified based on which type of medication they were taking, and subgroup analyses were performed. Predictors of unfavorable outcome at discharge and follow-up were identified. RESULTS Of 116 patients, 74 (64%) had been following an OAT regimen at presentation with aSDH. The patients who were taking oral anticoagulants (OAT group) were significantly older (OR 12.5), more often comatose 24 hours postoperatively (OR 2.4), and more often had ≥ 4 comorbidities (OR 3.2) than patients who were not taking oral anticoagulants (no-OAT group). Accordingly, the rate of unfavorable outcome was significantly higher in patients in the OAT group, both at discharge (OR 2.3) and at follow-up (OR 2.2). Of the patients in the OAT group, 37.8% were taking a thrombocyte inhibitor, 54.1% a vitamin K antagonist, and 8.1% DOACs. In all cases, OAT was stopped on discovery of aSDH. For reversal of anticoagulation, patients who were taking a thrombocyte inhibitor received desmopressin 0.4 µg/kg, 1-2 g tranexamic acid, and preoperative transfusion with 2 units of platelets. Patients following other oral anticoagulant regimens received 50 IU/kg of prothrombin complex concentrates and 10 mg of vitamin K. There was no significant difference in the rebleeding rate between the OAT and no-OAT groups. The in-hospital mortality rate was significantly higher for patients who were taking a thrombocyte inhibitor (OR 3.3), whereas patients who were taking a vitamin K antagonist had a significantly higher 6-month mortality rate (OR 2.7). Patients taking DOACs showed a tendency toward unfavorable outcome, with higher mortality rates than patients on conventional OAT or patients in the vitamin K antagonist subgroup. Independent predictors for unfavorable outcome at discharge were comatose status 24 hours after surgery (OR 93.2), rebleeding (OR 9.8), respiratory disease (OR 4.1), and infection (OR 11.1) (Nagelkerke R2 = 0.684). Independent predictors for unfavorable outcome at follow-up were comatose status 24 hours after surgery (OR 12.7), rebleeding (OR 3.1), age ≥ 70 years (OR 3.1), and 6 or more comorbidities (OR 3.1, Nagelkerke R2 = 0.466). OAT itself was not an independent predictor for worse outcome. CONCLUSIONS An OAT regimen at the time of presentation with aSDH is associated with increased mortality rates and unfavorable outcome at discharge and follow-up. Thrombocyte inhibitor treatment was associated with increased short-term mortality, whereas vitamin K antagonist treatment was associated with increased long-term mortality. In particular, patients on DOACs were seriously affected, showing more unfavorable outcomes at discharge as well as at follow-up. The suggested medical treatment for aSDH in both OAT and no-OAT patients seems to be effective and reasonable, with comparable rebleeding and favorable outcome rates in the 2 groups. In addition, prior OAT is not a predictor for aSDH outcome.

Synovial cysts of the spine: long-term follow-up after surgical treatment of 141 cases in a single-center series and comprehensive literature review of 2900 degenerative spinal cysts.

OBJECTIVE Synovial cysts of the spine are rare lesions, predominantly arising in the lumbar region. Despite their generally benign behavior, they can cause severe symptoms due to compression of neural structures in the spinal canal. Treatment strategies are still a matter of discussion. The authors performed a single-center survey and literature search focusing on long-term results after minimally invasive surgery. METHODS A total of 141 consecutive patients treated for synovial cysts of the lumbar spine between 1997 and 2014 in the authors' department were analyzed. Medical reports with regard to signs and symptoms, operative findings, complications, and short-term outcome were reviewed. Assessment of long-term outcome was performed with a standardized telephone questionnaire based on the Oswestry Disability Index (ODI). Furthermore, patients were questioned about persisting pain, symptoms, and further operative procedures, if any. Subjective satisfaction was classified as excellent, good, fair, or poor based on the Macnab classification. RESULTS The approach most often used for synovial cyst treatment was partial hemilaminectomy in 70%; hemilaminectomy was necessary in 27%. At short-term follow-up, the presence of severe and moderate leg pain had decreased from 93% to 5%. The presence of low-back pain decreased from 90% to 5%. Rates of motor and sensory deficits were reduced from 40% to 14% and from 45% to 6%, respectively. The follow-up rate was 58%, and the mean follow-up period was 9.3 years. Both leg pain and low-back pain were still absent in 78%. Outcome based on the Macnab classification was excellent in 80%, good in 14%, fair in 1%, and poor in 5%. According to the ODI, 78% of patients had no or only minimal disability, 16% had moderate disability, and 6% had severe disability at the time of follow-up. In this cohort, 7% needed surgery due to cyst recurrence, and 9% required a delayed stabilization procedure after the initial operation. CONCLUSIONS Surgical treatment with resection of the cyst provides favorable results in outcome. Excellent or good outcome persisting for a long-term follow-up period can be achieved in the vast majority of cases. Complication rates are low despite an increased risk of dural injury. With facet-sparing techniques, the stability of the segment can be preserved, and resection of spinal synovial cysts does not necessarily require segmental fusion.

A systematic review of epileptic seizures in adults with subdural haematomas.

BACKGROUND: Posttraumatic epileptic seizures (PTS) are a serious complication in patients with subdural haematoma (SDH). However, to date, several studies have shown discordances about SDH-associated seizures in terms of incidence, risk factors and prophylactic antiepileptic treatment. OBJECTIVE: The aim of this study was to analyse the incidence, risk factors of PTS and the role of prophylactic antiepileptic treatment in patients with SDH. DATA SOURCES: A systematic literature review examining PTS in patients with SDH was performed using PubMed gateway, Cochrane Central Register of Controlled Trials, and Excerpta Medica dataBASE between September 1961 and February 2016. Search terms included subdural haematoma, seizure, epilepsy, prophylactic antiepileptic drugs, anticonvulsive medication, and risk factors. DATA SELECTION: Human-based clinical studies focusing on epileptic seizures in patients with SDH. DATA EXTRACTION AND SYNTHESIS: PRISMA statements were used for assessing data quality. Two independent reviewers extracted data from included studies and disagreement was solved by consensus. Twenty-four studies were identified for inclusion into the study. RESULTS: Overall incidence of early PTS (ePTS) and late PTS (lPTS)/2 years was 28% and 43% in acute SDH (aSDH) whereas the incidence of e- and lPTS was lower in chronic SDH (cSDH; 5.3% vs. 10%). Overall risk factors for PTS in patients with aSDH were: 24h postoperative Glasgow Coma Score (GCS) score below 9 (OR 10.5), craniotomy (OR 3.9), preoperative GCS below 8 (OR 3.1). In patients with cSDH the risk factors were alcohol abuse (OR 14.3), change of mental status (OR 7.2), previous stroke (OR 5.3) and density of haematoma in computer tomography (OR 3.8). Age, sex, haematoma size/side and midline shifts were not significant risk factors for PTS in both types of SDH. In prevention of PTS phenytoin and levetiracetam showed similar efficacy (OR 1.3), whereas levetiracetam was associated with significantly lower adverse effects (OR 0.1). LIMITATIONS: Most of the studies were of retrospective nature with a small sample size. Due to the inclusion criteria, some studies had to be excluded and that might lead to selection bias. CONCLUSIONS: PTS are a serious complication in patients with SDH, particularly in aSDH. The "prophylactic use" of antiepileptic drugs might be beneficial in patients with cumulative risk factors.

Involvement of microRNAs in epileptogenesis.

Patients who have sustained brain injury or had developmental brain lesions present a non-negligible risk for developing delayed epilepsy. Finding therapeutic strategies to prevent development of epilepsy in at-risk patients represents a crucial medical challenge. Noncoding microRNA molecules (miRNAs) are promising candidates in this area. Indeed, deregulation of diverse brain-specific miRNAs has been observed in animal models of epilepsy as well as in patients with epilepsy, mostly in temporal lobe epilepsy (TLE). Herein we review deregulated miRNAs reported in epilepsy with potential roles in key molecular and cellular processes underlying epileptogenesis, namely neuroinflammation, cell proliferation and differentiation, migration, apoptosis, and synaptic remodeling. We provide an up-to-date listing of miRNAs altered in epileptogenesis and assess recent functional studies that have interrogated their role in epilepsy. Last, we discuss potential applications of these findings for the future development of disease-modifying therapeutic strategies for antiepileptogenesis.

Sequential generation of two distinct synapse-driven network patterns in developing neocortex.

Developing cortical networks generate a variety of coherent activity patterns that participate in circuit refinement. Early network oscillations (ENOs) are the dominant network pattern in the rodent neocortex for a short period after birth. These large-scale calcium waves were shown to be largely driven by glutamatergic synapses albeit GABA is a major excitatory neurotransmitter in the cortex at such early stages, mediating synapse-driven giant depolarizing potentials (GDPs) in the hippocampus. Using functional multineuron calcium imaging together with single-cell and field potential recordings to clarify distinct network dynamics in rat cortical slices, we now report that the developing somatosensory cortex generates first ENOs then GDPs, both patterns coexisting for a restricted time period. These patterns markedly differ by their developmental profile, dynamics, and mechanisms: ENOs are generated before cortical GDPs (cGDPs) by the activation of glutamatergic synapses mostly through NMDARs; cENOs are low-frequency oscillations (approximately 0.01 Hz) displaying slow kinetics and gradually involving the entire network. At the end of the first postnatal week, GABA-driven cortical GDPs can be reliably monitored; cGDPs are recurrent oscillations (approximately 0.1 Hz) that repetitively synchronize localized neuronal assemblies. Contrary to cGDPs, cENOs were unexpectedly facilitated by short anoxic conditions suggesting a contribution of glutamate accumulation to their generation. In keeping with this, alterations of extracellular glutamate levels significantly affected cENOs, which are blocked by an enzymatic glutamate scavenger. Moreover, we show that a tonic glutamate current contributes to the neuronal membrane excitability when cENOs dominate network patterns. Therefore, cENOs and cGDPs are two separate aspects of neocortical network maturation that may be differentially engaged in physiological and pathological processes.

Generation of slow network oscillations in the developing rat hippocampus after blockade of glutamate uptake.

Cell-surface glutamate transporters are essential for the proper function of early cortical networks because their dysfunction induces seizures in the newborn rat in vivo. We have now analyzed the consequences of their inhibition by DL-TBOA on the activity of the developing CA1 rat hippocampal network in vitro. DL-TBOA generated a pattern of recurrent depolarization with an onset and decay of several seconds' duration in interneurons and pyramidal cells. These slow network oscillations (SNOs) were mostly mediated by gamma-aminobutyric acid (GABA) in pyramidal cells and by GABA and N-methyl-D-aspartate (NMDA) receptors in interneurons. However, in both cell types SNOs were blocked by NMDA receptor antagonists, suggesting that their generation requires a glutamatergic drive. Moreover, in interneurons, SNOs were still generated after the blockade of NMDA-mediated synaptic currents with MK-801, suggesting that SNOs are expressed by the activation of extrasynaptic NMDA receptors. Long-lasting bath application of glutamate or NMDA failed to induce SNOs, indicating that they are generated by periodic but not sustained activation of NMDA receptors. In addition, SNOs were observed in interneurons recorded in slices with or without the strata pyramidale and oriens, suggesting that the glutamatergic drive may originate from the radiatum and pyramidale strata. We propose that in the absence of an efficient transport of glutamate, the transmitter diffuses in the extracellular space to activate extrasynaptic NMDA receptors preferentially present on interneurons that in turn activate other interneurons and pyramidal cells. This periodic neuronal coactivation may contribute to the generation of seizures when glutamate transport dysfunction is present.