Circadian distribution of autostimulations in rVNS therapy in patients with refractory focal epilepsy.

BACKGROUND: Responsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion. OBJECTIVE: The aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE). MATERIALS AND METHODS: We performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy "OFF" time compared with both the previous autostimulation and the following autostimulation. RESULTS: Autostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration. CONCLUSIONS: Early morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic-pituitary-adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy.

Modulation of Cav2.3 channels by unconjugated bilirubin (UCB) - Candidate mechanism for UCB-induced neuromodulation and neurotoxicity.

Elevated levels of unbound unconjugated bilirubin (UCB) can lead to bilirubin encephalopathy and kernicterus. In spite of a large number of studies demonstrating UCB-induced changes in central neurotransmission, it is still unclear whether these effects involve alterations in the function of specific ion channels. To assess how different UCB concentrations and UCB:albumin (U/A) molar ratios affect neuronal R-type voltage-gated Ca2+ channels, we evaluated their effects on whole-cell currents through recombinant Cav2.3 + ß3 channel complexes and ex-vivo electroretinograms (ERGs) from wildtype and Cav2.3-deficient mice. Our findings show that modestly elevated levels of unbound UCB (U/A = 0.5) produce subtle but significant changes in the voltage-dependence of activation and prepulse inactivation, resulting in a stimulation of currents activated by weak depolarization and inhibition at potentials on the plateau of the activation curve. Saturation of the albumin binding capacity (U/A = 1) produced additional suppression that became significant when albumin was omitted completely and might involve a complete loss of channel function. Acutely administered UCB (U/A = 0.5) has recently been shown to affect transsynaptic signaling in the isolated vertebrate retina. The present report reveals that sustained exposure of the murine retina to UCB significantly suppresses also late responses of the inner retina (b-wave) from wildtype compared to Cav2.3-deficient mice. In addition, recovery during washout was significantly more complete and faster in retinae lacking Cav2.3 channels. Together, these findings show that UCB affects cloned and native Cav2.3 channels at clinically relevant U/A molar ratios and indicate that supersaturation of albumin is not required for modulation but associated with a loss of channel functional that could contribute to chronic neuronal dysfunction.

Frequency of Automatic Stimulations in Responsive Vagal Nerve Stimulation in Patients With Refractory Epilepsy.

BACKGROUND: In vagal nerve stimulation (VNS) therapy, the release of VNS model 106 (AspireSR) allowed for responsive VNS (rVNS). rVNS utilizes a cardiac-based seizure detection algorithm to detect seizure-induced tachycardia to trigger additional stimulation. There are some studies suggesting clinical benefits of rVNS over traditional VNS, but the performance and significance of autostimulation mode in clinical practice are poorly understood. OBJECTIVES: To assess the effect of initiation of rVNS therapy and altered stimulation settings on the number of daily stimulations and energy consumption in VNS therapy and to compare autostimulation performance in different epilepsy types. MATERIALS AND METHODS: Retrospective follow-up of 30 patients with drug-resistant epilepsy treated with rVNS including 17 new implantations and 13 battery replaces at a single center in Finland. Our data consist of 208 different stimulation periods, that is, episodes with defined stimulation settings and both autostimulation and total stimulation performance-related data along with clinical follow-up. RESULTS: The variation in autostimulation frequency was highly dependent on the duration of the OFF-time and autostimulation threshold (p < 0.05). There was a large additional effect of autostimulation mode on therapy time and energy consumption with longer OFF-times, but a minor effect with shorter OFF-times. Significantly more autostimulations were triggered in the temporal lobe and multifocal epilepsies than in extratemporal lobe epilepsies. CONCLUSIONS: The initiation of autostimulation mode in VNS therapy increased the total number of stimulations. Shortening the OFF-time leads to a decreased number and share of automatic activations. Epilepsy type may affect autostimulation activity.

[Vagus Nerve Stimulation for Affective Disorders]. / Vagusnervstimulation bei affektiven Störungen.

Vagus nerve stimulation (VNS) is a minimally invasive neurostimulation method and was approved for drug-resistant epilepsy in children and adults in Europe in 1994. The observation that depression -the most common comorbidity in epilepsy - improved with VNS prompted trials of VNS in treatment-resistant depression (TRD) leading to European approval of VNS for TRD in 2001. Use of VNS for TRD patients in Germany is currently limited to a few highly specialized tertiary centers and the method is largely unknown in psychiatric clinical practice. We therefore systematically review the most recent publications on VNS in TRD as well as recommendations in guidelines and discuss the use of VNS in clinical practice. In the past 5 years, 5 level-2 studies and 4 level-3 studies were published on the effect of VNS in TRD patients. Clinical studies have failed to demonstrate short-term efficacy of VNS in TRD patients. Long-term efficacy of VNS in TRD patients is documented by multiple studies: the recently published largest ever investigation on the subject confirms favorable outcomes in TRD patients receiving adjunctive VNS in addition to treatment-as-usual compared to patients receiving treatment-as-usual-only over a 5-year period. Long-term efficacy of VNS is documented by level-2 evidence; however, it is not known which TRD patients have a higher probability of responding to VNS, which may complicate patient selection in clinical practice. Additionally, the unclear and variable definition of TRD may hinder or postpone adequate use of neurostimulation treatments.

Is 5-ALA fluorescence of cerebral metastases a prognostic factor for local recurrence and overall survival?

BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence-guided resection technique was first introduced for malignant glioma. However, the impact of the 5-ALA fluorescence behaviour of cerebral metastases is still unclear. Aim of this study was to determine the impact of PpIX-fluorescence on the local progression-free and overall survival. MATERIALS AND METHODS: A secondary analysis was performed and included an updated follow-up of 136 patients comprised in two previous studies. Additionally, 82 new patients were included. All patients underwent surgical resection of cerebral metastasis and intraoperative estimation of 5-ALA-induced fluorescence. The 5-ALA fluorescence behaviour of cerebral metastases was correlated with the rate of local recurrences, the local progression-free and overall survival. RESULTS: 218 patients suffering from cerebral metastatic spread fulfilled the inclusion criteria and were analysed: complete surgical resection could be achieved in 123/218 patients (56.4%). Dichotomised degree of surgical resection (complete vs. incomplete or questionable complete resection) was not related to dichotomized 5-ALA fluorescence of cerebral metastases (p = 0.66). 51 patients (23.4%) developed a local in-brain progression within or at the border of the resection cavity. Of these, 8 patients showed a PpIX-fluorescent metastasis. There was a trend towards a correlation between a higher local in-brain progression in PpIX-non-fluorescent metastases (p = 0.03). Median time to local in-brain progression was 4 ± 11 months. PpIX-fluorescent and PpIX-non-fluorescent metastases showed a significantly different progression-free survival (p = 0.01). PpIX-positive and -negative metastases showed a significantly different overall survival (20 and 14 months respectively; p = 0.006). CONCLUSION: The 5-ALA fluorescence behaviour was related to the local progression-free and the overall survival in the present retrospective series and might be considered a prognostic marker. Further studies are required to appreciate the oncological impact of the 5-ALA induced fluorescence behaviour of cerebral metastases.

Intracerebroventricular administration of histidine reduces kainic acid-induced convulsive seizures in mice.

Kainic acid (KA)-induced seizures and other experimental models of epilepsy have been proven to be instrumental in identifying novel targets that could be responsible for human icto- and epileptogenesis. We have previously shown that the ablation of pharmacoresistant voltage-gated Ca2+ channels with Cav2.3 as central ion-conducting pore (R-type Ca2+ channel) reduces the sensitivity towards KA-induced epilepsy in mice. In vivo, Cav2.3 channels are thought to be under tight allosteric control by endogenous loosely bound trace metal cations (Zn2+ and Cu2+) that suppress channel gating via a high-affinity trace metal-binding site. Metal dyshomeostasis in the brain, which is a common feature of (KA-induced) seizures, could therefore alter the normal function of Cav2.3 channels and may shift hippocampal and neocortical signaling towards hyperexcitation. To investigate the role of loosely bound metal ions for KA-induced hyperexcitation in vivo, we examined the effects of manipulating brain trace metal homeostasis in mice. To this end, we developed a murine system for intracerebroventricular administration of trace metal ions and/or histidine (His), which can bind Zn2+ and Cu2+ and is involved in their transendothelial transport at the blood-brain barrier. Unexpectedly, our preliminary findings indicate that application of His alone but not in the presence of Zn2+ has substantial beneficial effects on the outcome of KA-induced epilepsy in mice. As such, our results emphasize previous findings on the complex, two-sided role of loosely bound metal ions with regard to neuronal excitation and degeneration under pathophysiological conditions.

Is it all a matter of size? Impact of maximization of surgical resection in cerebral tumors.

The oncological impact of cytoreductive surgery for malignant glioma has been analyzed in a few prospective, randomized studies; however, the impact of different cytoreductive surgical techniques of cerebral tumors remains controversial. Despite retrospective analyses revealing an oncological impact of complete surgical resection in cerebral metastases and low-grade glioma, the oncological impact of further extension of resection to a supramarginal resection remains disputable lacking high-grade evidence: supramarginal resections have yet to be analyzed in malignant glioma. Although extension of resection towards a supramarginal resection was thought to improve outcome and prevent malignant transformation in low-grade glioma, the rate of (temporary) deficits was higher than 50% in recent retrospective studies, and the oncological impact and long-term results have to be analyzed in further (prospective and controlled) studies. Cerebral metastases show a growth pattern different from glioma with less and more locally limited brain invasion. Therefore, local control may be achieved by extension of resection after complete lesionectomy of cerebral metastases. Therefore, supramarginal resection may be a promising approach but must be evaluated in further studies.

Reciprocal modulation of Cav 2.3 voltage-gated calcium channels by copper(II) ions and kainic acid.

Kainic acid (KA) is a potent agonist at non-N-methyl-D-aspartate (non-NMDA) ionotropic glutamate receptors and commonly used to induce seizures and excitotoxicity in animal models of human temporal lobe epilepsy. Among other factors, Cav 2.3 voltage-gated calcium channels have been implicated in the pathogenesis of KA-induced seizures. At physiologically relevant concentrations, endogenous trace metal ions (Cu2+ , Zn2+ ) occupy an allosteric binding site on the domain I gating module of these channels and interfere with voltage-dependent gating. Using whole-cell patch-clamp recordings in human embryonic kidney (HEK-293) cells stably transfected with human Cav 2.3d and ß3 -subunits, we identified a novel, glutamate receptor-independent mechanism by which KA can potently sensitize these channels. Our findings demonstrate that KA releases these channels from the tonic inhibition exerted by low nanomolar concentrations of Cu2+ and produces a hyperpolarizing shift in channel voltage-dependence by about 10 mV, thereby reconciling the effects of Cu2+ chelation with tricine. When tricine was used as a surrogate to study the receptor-independent action of KA in electroretinographic recordings from the isolated bovine retina, it selectively suppressed a late b-wave component, which we have previously shown to be enhanced by genetic or pharmacological ablation of Cav 2.3 channels. Although the pathophysiological relevance remains to be firmly established, we speculate that reversal of Cu2+ -induced allosteric suppression, presumably via formation of stable kainate-Cu2+ complexes, could contribute to the receptor-mediated excitatory effects of KA. In addition, we discuss experimental implications for the use of KA in vitro, with particular emphasis on the seemingly high incidence of trace metal contamination in common physiological solutions.

An introduction to the pathophysiology of aneurysmal subarachnoid hemorrhage.

Pathophysiological processes following subarachnoid hemorrhage (SAH) present survivors of the initial bleeding with a high risk of morbidity and mortality during the course of the disease. As angiographic vasospasm is strongly associated with delayed cerebral ischemia (DCI) and clinical outcome, clinical trials in the last few decades focused on prevention of these angiographic spasms. Despite all efforts, no new pharmacological agents have shown to improve patient outcome. As such, it has become clear that our understanding of the pathophysiology of SAH is incomplete and we need to reevaluate our concepts on the complex pathophysiological process following SAH. Angiographic vasospasm is probably important. However, a unifying theory for the pathophysiological changes following SAH has yet not been described. Some of these changes may be causally connected or present themselves as an epiphenomenon of an associated process. A causal connection between DCI and early brain injury (EBI) would mean that future therapies should address EBI more specifically. If the mechanisms following SAH display no causal pathophysiological connection but are rather evoked by the subarachnoid blood and its degradation production, multiple treatment strategies addressing the different pathophysiological mechanisms are required. The discrepancy between experimental and clinical SAH could be one reason for unsuccessful translational results.

Predictors for a further local in-brain progression after re-craniotomy of locally recurrent cerebral metastases.

Treatment of recurrent cerebral metastases is an emerging challenge due to the high local failure rate after surgery or radiosurgery and the improved prognosis of patients with malignancies. A total of 36 patients with 37 metastases who underwent surgery for a local in-brain progression of a cerebral metastasis after previous metastasectomy were retrospectively analyzed. Degree of surgical resection on an early postoperative MRI within 72 h after surgery was correlated with the local in-brain progression rate and overall survival. Complete surgical resection of locally recurrent cerebral metastases as confirmed by early postoperative MRI could only be achieved in 37.8%. Detection of residual tumor tissue on an early MRI following recurrent metastasis surgery correlated with further local in-brain progression when defining a significance level of p = 0.05 but not after Sidák or Bonferroni significance level correction for multiple testing: However, definite local tumor control could finally be achieved in 91.9% after adjuvant therapy. Overall survival after recurrent metastasectomy was significantly higher as predicted by diagnosis-specific graded prognostic assessment (12.9 ± 2.3 vs. 8.4 ± 0.7 months; p < 0.0001). However, our series involved a limited number of heterogeneous patients. A larger, prospective, and controlled study is required. Considering the adequate local tumor control achieved in the vast majority of patients, surgery of recurrent metastases may represent one option in a multi-modal treatment approach of patients suffering from locally recurrent cerebral metastases.

Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo.

BACKGROUND/AIMS: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Cav2.3-deficient mice and controls on KA-induced seizures. METHODS: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). RESULTS: Ablation of Cav2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Cav2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice. CONCLUSION: These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice.

Cardiac functions of voltage-gated Ca(2+) channels: role of the pharmacoresistant type (E-/R-Type) in cardiac modulation and putative implication in sudden unexpected death in epilepsy (SUDEP).

Voltage-gated Ca(2+) channels (VGCCs) are ubiquitous in excitable cells. These channels play key roles in many physiological events like cardiac regulation/pacemaker activity due to intracellular Ca(2+) transients. In the myocardium, the Cav1 subfamily (L-type: Cav1.2 and Cav1.3) is the main contributor to excitation-contraction coupling and/or pacemaking, whereas the Cav3 subfamily (T-type: Cav3.1 and Cav3.2) is important in rhythmically firing of the cardiac nodal cells. No established cardiac function has been attributed to the Cav2 family (E-/R-type: Cav2.3) despite accumulating evidence of cardiac dysregulation observed upon deletion of the Cav2.3 gene, the only member of this family so far detected in cardiomyocytes. In this review, we summarize the pathophysiological changes observed after ablation of the E-/R-type VGCC and propose a cardiac mechanism of action for this channel. Also, considering the role played by this channel in epilepsy and its reported sensitivity to antiepileptic drugs, a putative involvement of this channel in the cardiac mechanism of sudden unexpected death in epilepsy is also discussed.

Early postoperative magnet resonance tomography after resection of cerebral metastases.

BACKGROUND: In contrast to malignant gliomas, the impact of an early postoperative MRI after surgery of cerebral metastasis is still unclear. The present study analyses early MRI-based postoperative resection controls and incidence of in-brain progression in 116 patients suffering from 130 cerebral metastases. METHODS: The extent of surgical resection was verified by an early postoperative contrast-enhanced 1.5-T MRI within 72 h after surgery of cerebral metastases and correlated with in-brain progression, leptomeningeal carcinomatosis, and progression-free survival. RESULTS: MRI confirmed complete resection was seen in 80 out of 130 metastases (61.5 %). In 24 metastases (18.5 %), no final decision on degree of resection could be made. Residual tumor was seen in 26 cases (20 %). Local in-brain progression was observed in 40 of 130 (30.8 %) cases. The incidence of in-brain progression significantly correlated with dural contact of the metastasis (p < 0.05) and residual tumor on early postoperative MRI (p < 0.0001). The odds ratio for local recurrence with residual tumor is 8.2-fold compared to no residual tumor. CONCLUSIONS: Residual tumor after metastasis extirpation was shown in nearly 20 % of patients by an early postoperative MRI and significantly correlated with local in-brain progression. Furthermore, dural contact of cerebral metastases was identified as a risk factor for local recurrence. Further studies are mandatory to clearly identify the incidence of incomplete resections of cerebral metastases and their oncologic impact. An early postoperative MRI after resection of cerebral metastases is recommended as residual tumor promotes local recurrence.

Incidence of local in-brain progression after supramarginal resection of cerebral metastases.

BACKGROUND: Microsurgical circumferential stripping of intracerebral metastases is often insufficient in achieving local tumor control. Supramarginal resection may improve local tumor control. METHODS: A retrospective analysis was performed for patients who underwent supramarginal resection of a cerebral metastasis by awake surgery with intraoperative cortical and subcortical stimulation, MEPs, and SSEPs. Supramarginal resection was achieved by circumferential stripping of the metastasis and additional removal of approximately 3 mm of the surrounding tissue. Pre- and postsurgical neurological status was assessed by the NIH Stroke Scale. Permanent deficits were defined by persistence after 3-month observation time. RESULTS: Supramarginal resection of cerebral metastases in eloquent brain areas was performed in 34 patients with a mean age of 60 years (range, 33-83 years). Five out of 34 patients (14.7%) had a new transient postoperative neurological deficit, which improved within a few days due to supplementary motor area (SMA) syndrome. Five out of 34 patients (14.7%) developed a local in-brain progression and nine patients (26.4%) a distant in-brain progression. CONCLUSIONS: Supramarginal resection of cerebral metastases in eloquent locations is feasible and safe. Safety might be increased by intraoperative neuromonitoring. The better outcome in the present series may be entirely based on other predictors than extend of surgical resection and not necessarily on the surgical technique applied. However, supramarginal resection was safe and apparently did not lead to worse results than regular surgical techniques. Prospective, controlled, and randomized studies are mandatory to determine the possible benefit of supramarginal resection on local tumor control and overall outcome.

Aminolevulinic acid-mediated photodynamic therapy of human meningioma: an in vitro study on primary cell lines.

OBJECTIVE: Five-aminolevulinic acid (5-ALA)-induced porphyrins in malignant gliomas are potent photosensitizers. Promising results of ALA-PDT (photodynamic therapy) in recurrent glioblastomas have been published. Recently, 5-ALA-induced fluorescence was studied in meningioma surgery. Here, we present an experimental study of ALA-PDT in an in vitro model of primary meningioma cell lines. METHODS: We processed native tumor material obtained intra-operatively within 24 h for cell culture. Epithelial membrane antigen (EMA) immunohistochemistry was performed after the first passage to confirm that cells were meningioma cells. For 5-ALA-PDT treatment, about 5000 cells per well were seeded in 20 wells of a blank 96-well plate. Each block of 4 wells was inoculated with 150 µL of 0, 25, 50 and 100 µg/mL 5-ALA solutions; one block was used as negative control without 5-ALA and without PDT. Following incubation for 3 h PDT was performed using a laser (635 nm, 18.75 J/cm²). The therapeutic response was analyzed by the water soluble tetrazolium salt (WST-1) cell viability assay 90 min after PDT. RESULTS: 5-ALA-PDT was performed in 14 primary meningioma cell lines. EMA expression was verified in 10 primary cell cultures. The remaining 4 were EMA negative and PDT was without any effect in these cultures. All 10 EMA-positive cell lines showed a significant and dose-dependent decrease in viability rate (p < 0.001). Cell survival at 5-ALA concentrations of 12.5, 25, 50 and 100 µg/mL was 96.5% ± 7.6%, 67.9% ± 29.9%, 24.0% ± 16.7% and 13.8% ± 7.5%, respectively. For the negative controls (no 5-ALA/PDT and ALA/no PDT), the viability rates were 101.72% ± 3.5% and 100.17% ± 3.6%, respectively. The LD50 for 5-ALA was estimated between 25 and 50 µg/mL. CONCLUSION: This study reveals dose-dependent cytotoxic effects of 5-ALA-PDT on primary cell lines of meningiomas. Either 5-ALA or PDT alone did not affect cell survival. Further efforts are necessary to study the potential therapeutic effects of 5-ALA-PDT in vivo.

30 years of vagus nerve stimulation trials in epilepsy: Do we need neuromodulation-specific trial designs?

Neuromodulation therapies represent an important treatment arm for patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery. Vagus nerve stimulation (VNS) - the neurostimulation modality in focus in this review - was the first available neuromodulatory therapy for DRE and was followed by anterior thalamic deep brain stimulation (ANT-DBS) and responsive neurostimulation (RNS). Although no comparative trials of these treatments have been performed, published data and clinical experience suggest comparable effectiveness. In VNS, DBS and RNS seizure reduction is delayed and increases over time raising the question of anti-epileptogenic mechanisms of neuromodulation. Considering the long-term effectiveness assumed for neuromodulatory treatments and the chronic nature of drug-resistant epilepsy, study designs allowing for long-term comparative observations would be of great value, but are hindered by the inherent nature of a long-term [surgical] control group and the bias associated with open-label trials. New trial designs using objective endpoints are needed, and may be aided by novel biomarkers of risk and disease severity for specific epilepsy populations.

Vagus nerve stimulation in refractory and super-refractory status epilepticus - A systematic review.

RATIONALE: Refractory status epilepticus (RSE) is the persistence of status epilepticus despite second-line treatment. Super-refractory SE (SRSE) is characterized by ongoing status despite 48 h of anaesthetic treatment. Due to the high case fatality in RSE of 16-39%, off label treatments without strong evidence of efficacy in RSE are often administered. In single case-reports and small case series totalling 28 patients, acute implantation of VNS in RSE was associated with 76% and 26% success rate in generalized and focal RSE respectively. We performed an updated systematic review of the literature on efficacy of VNS in RSE/SRSE by including all reported patients. METHODS: We systematically searched EMBASE, CENTRAL, Opengre.eu, and ClinicalTrials.gov, and PubMed databases to identify studies reporting the use of VNS for RSE and/or SRSE. We also searched conference abstracts from AES and ILAE meetings. RESULTS: 45 patients were identified in total of which 38 were acute implantations of VNS in RSE/SRSE. Five cases had VNS implantation for epilepsia partialis continua, one for refractory electrical status epilepticus in sleep and one for acute encephalitis with refractory repetitive focal seizures. Acute VNS implantation was associated with cessation of RSE/SRSE in 74% (28/38) of acute cases. Cessation did not occur in 18% (7/38) of cases and four deaths were reported (11%); all of them due to the underlying disease and unlikely related to VNS implantation. Median duration of the RSE/SRSE episode pre and post VNS implantation was 18 days (range: 3-1680 days) and 8 days (range: 3-84 days) respectively. Positive outcomes occurred in 82% (31/38) of cases. CONCLUSION: VNS can interrupt RSE and SRSE in 74% of patients; data originate from reported studies classified as level IV and the risk for reporting bias is high. Further prospective studies are warranted to investigate acute VNS in RSE and SRSE.

Is the Intensity of 5-Aminolevulinic Acid-Derived Fluorescence Related to the Light Source?

OBJECTIVE: With the introduction of the 5-aminolevulinic acid (5-ALA) technique, surgical neuro-oncology has made a major advance. 5-ALA fluorescence-guided resection of malignant glioma results in more complete surgical resections and subsequently prolonged survival. However, it remains uncertain how light intensities of the blue light source and 5-ALA-derived fluorescence intensities of the illuminated tissue are connected. The aim of the present study was to compare light intensities of different blue light sources and protoporphyrin (PpIX) fluorescence intensities of PpIX solutions with defined concentrations after illumination with different light sources. MATERIAL AND METHODS: The light spectrum of 7 different blue light sources and the fluorescence intensity of 2 PpIX solutions (0.15 µg/mL and 5 µg/mL) were quantified after illumination. We compared the Zeiss OPMI Pentero microscope, the Zeiss OPMI Pentero 900 microscope, the Leica M530 OH6 microscope, an endoscope equipped with the 5-ALA technique, a mini-spectrometer equipped with a multi-channel light-emitting diode (LED) source emitting monochromatic light, a modified commercially available LED head lamp, and a commercially available unmodified UV-LED lamp. PpIX fluorescence was quantified in a standardized setup using a mini-spectrometer. RESULTS: Maximum light intensities of the evaluated light sources were reached at different wavelengths. All tested devices were able to detect PpIX-induced fluorescence. However, the intensity of PpIX fluorescence of the differently concentrated PpIX solutions (0.15 µg/mL and 5 µg/mL) was significantly dependent on the light source used. CONCLUSIONS: Intensity of the 5-ALA-derived fluorescence is related to the light source used.

Risk factors for in-brain local progression in elderly patients after resection of cerebral metastases.

Intracranial metastases are the most frequent brain tumor with recurrence rates after treatment of around 40-60%. Age is still considered a determinant of treatment and prognosis in this pathology. Recent studies analyzing the impact of metastasectomy in elderly patients focused on reporting perioperative mortality and morbidity rates but not on the evaluation of oncological outcome parameters. Aim of this study is to determine risk factors for in-brain local recurrence after brain surgery in this sub-population. From October 2009 until September 2016 all patients aged 65 years and above with histopathologically confirmed metastasis after surgical resection were retrospectively studied. Clinical, radiological and perioperative information was collected and statistically analysed. Follow-up consisted of clinical and radiological assessment every 3-months following surgery. 78 patients were included, of these 50% were female (39 patients). Median age was 71 years (66-83). Early postoperative-MRI verified a complete surgical resection in 41 patients (52.6%) and showed a tumor-remnant in 15 patients (19.2%). In 22 patients the MRI result was inconclusive (28.2%). None of the patients experienced severe complications due to surgery. The median postoperative NIHSS was adequate 1 ± 1.4 (0-6), nonetheless, insignificantly improved in comparison to the preoperative NIHSS (p = 0.16). A total of 20 patients (25.6%) presented local recurrence. The only statistically significant factor for development of local in-brain recurrence after resection of cerebral metastases in patients above 65 years of age was a tumor-remnant in the early postoperative MRI (p = 0.00005). Median overall survival was 13 months. Local in-brain recurrence after surgical resection of a cerebral metastasis in patients above 65 years of age was 25.6%. In our analysis, tumor-remnant in early postoperative MRI is the only risk factor for local in-brain recurrence. Oncological parameters in the present cohort do not seem to differ from recent phase III studies with non-geriatric patients. Nevertheless, controlled studies on the impact of metastasectomy in elderly patients delivering high quality reliable data are required.