Palliative care for in-patient malignant glioma patients in Germany.

OBJECTIVE: Malignant gliomas impose a significant symptomatic burden on patients and their families. Current guidelines recommend palliative care for patients with advanced tumors within eight weeks of diagnosis, emphasizing early integration for malignant glioma cases. However, the utilization rate of palliative care for these patients in Germany remains unquantified. This study investigates the proportion of malignant glioma patients who either died in a hospital or were transferred to hospice care from 2019 to 2022, and the prevalence of in-patient specialized palliative care interventions. METHODS: In this cross-sectional, retrospective study, we analyzed data from the Institute for the Hospital Remuneration System (InEK GmbH, Siegburg, Germany), covering 2019 to 2022. We included patients with a primary or secondary diagnosis of C71 (malignant glioma) in our analysis. To refine our dataset, we identified cases with dual-coded primary and secondary diagnoses and excluded these to avoid duplication in our final tally. The data extraction process involved detailed scrutiny of hospital records to ascertain the frequency of hospital deaths, hospice transfers, and the provision of complex or specialized palliative care for patients with C71-coded diagnoses. Descriptive statistics and inferential analyses were employed to evaluate the trends and significance of the findings. RESULTS: From 2019 to 2022, of the 101,192 hospital cases involving malignant glioma patients, 6,129 (6% of all cases) resulted in in-hospital mortality, while 2,798 (2.8%) led to hospice transfers. Among these, 10,592 cases (10.5% of total) involved the administration of complex or specialized palliative medical care. This provision rate remained unchanged throughout the COVID-19 pandemic. Notably, significantly lower frequencies of complex or specialized palliative care implementation were observed in patients below 65 years (p < 0.0001) and in male patients (padjusted = 0.016). In cases of in-hospital mortality due to malignant gliomas, 2,479 out of 6,129 cases (40.4%) received specialized palliative care. CONCLUSION: Despite the poor prognosis and complex symptomatology associated with malignant gliomas, only a small proportion of affected patients received advanced palliative care. Specifically, only about 10% of hospitalized patients with malignant gliomas, and approximately 40% of those who succumb to the disease in hospital settings, were afforded complex or specialized palliative care. This discrepancy underscores an urgent need to expand palliative care access for this patient demographic. Additionally, it highlights the importance of further research to identify and address the barriers preventing wider implementation of palliative care in this context.

Latest Views on the Mechanisms of Action of Surgically Implanted Cervical Vagal Nerve Stimulation in Epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant epilepsy. Although there is a substantial amount of literature aiming at unraveling the mechanisms of action of VNS in epilepsy, it is still unclear how the cascade of events triggered by VNS leads to its antiepileptic effect. OBJECTIVE: In this review, we integrated available peer-reviewed data on the effects of VNS in clinical and experimental research to identify those that are putatively responsible for its therapeutic effect. The topic of transcutaneous VNS will not be covered owing to the current lack of data supporting the differences and commonalities of its mechanisms of action in relation to invasive VNS. SUMMARY OF THE MAIN FINDINGS: There is compelling evidence that the effect is obtained through the stimulation of large-diameter afferent myelinated fibers that project to the solitary tract nucleus, then to the parabrachial nucleus, which in turn alters the activity of the limbic system, thalamus, and cortex. VNS-induced catecholamine release from the locus coeruleus in the brainstem plays a pivotal role. Functional imaging studies tend to point toward a common vagal network that comes into play, made up of the amygdalo-hippocampal regions, left thalamus, and insular cortex. CONCLUSIONS: Even though some crucial pieces are missing, neurochemical, molecular, cellular, and electrophysiological changes occur within the vagal afferent network at three main levels (the brainstem, the limbic system [amygdala and hippocampus], and the cortex). At this final level, VNS notably alters functional connectivity, which is known to be abnormally high within the epileptic zone and was shown to be significantly decreased by VNS in responders. The effect of crucial VNS parameters such as frequency or current amplitude on functional connectivity metrics is of utmost importance and requires further investigation.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.

Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression.

BACKGROUND: A substantial number of patients with major depressive disorder (MDD) do not sufficiently remit after the first lines of antidepressant treatments, making them vulnerable to poor clinical outcomes. Patients who have not had adequate resolution of their depressive symptoms after four antidepressant treatments and/or have been experiencing their current episode of MDD for two years or more (with insufficient responses to adequate antidepressant treatments) should be evaluated for antidepressant vagus nerve stimulation (VNS Therapy). Adjunctive VNS Therapy is a promising long-term treatment option for patients with difficult-to-treat depression (DTD), offering significantly improved remission rates in comparison with usual treatments. However, VNS Therapy requires specialized treatment centers to support patients. MATERIALS AND METHODS: In this narrative review, we aim to outline the necessary steps for setting up an antidepressant VNS Therapy service in an efficient manner. RESULTS: Establishing a VNS Therapy service requires several high-level considerations: initiation of a collaborative multidisciplinary team of health care professionals; developing a surgical pathway for implantation; consideration of reimbursement and health care coverage; setting up a specialist clinic to identify optimal candidates for VNS Therapy; educating patients and their families about VNS Therapy; and training health care providers on patient-specific VNS Therapy treatment and long-term treatment management. CONCLUSIONS: Antidepressant VNS Therapy is a promising treatment option for the long-term treatment of patients with DTD. We have successfully initiated four VNS Therapy service centers for DTD in the United States, Austria, and Germany. Based on our experiences and lessons learned, herein, we have provided advice to psychiatric centers planning to set up a VNS Therapy service for their patients with DTD.

Vagus nerve stimulation in patients with Lennox-Gastaut syndrome: A meta-analysis.

OBJECTIVES: Lennox-Gastaut syndrome (LGS) is among the most severe epileptic and developmental encephalopathies. A meta-analysis was performed to evaluate the effectiveness of adjunctive vagus nerve stimulation (VNS Therapy) in patients with LGS. MATERIALS & METHODS: PubMed database was queried (January 1997 to September 2018) to identify publications reporting on the efficacy of VNS Therapy in patients with LGS, with or without safety findings. Primary endpoint of the meta-analysis was the proportion of responders (≥50% reduction in seizure frequency). Random-effects analysis was used to calculate weighted mean estimates and confidence intervals. Heterogeneity was evaluated by statistical tests including I2 . RESULTS: Of 2752 citations reviewed, 17 articles (480 patients) were eligible including 10 retrospective studies and seven prospective studies. A random-effects model produced a pooled proportion of 54% (95% confidence intervals [CI]: 45%, 64%) of patients with LGS who responded to adjunctive VNS Therapy (p for heterogeneity <0.001, I2 =72.9%). Per an exploratory analysis, the calculated incidence of serious adverse events associated with VNS Therapy was 9% (95% CI: 5%, 14%); the rate was higher than in long-term efficacy studies of heterogeneous cohorts with drug-resistant epilepsy and likely attributed to variable definitions of serious adverse events across studies. CONCLUSIONS: The meta-analysis of 480 patients with LGS suggests that 54% of patients responded to adjunctive VNS Therapy and that the treatment option was safe and well-tolerated. The response in patients with LGS was comparable to heterogeneous drug-resistant epilepsy populations. A clinical and surgical overview has been included to facilitate the use of VNS in LGS.

VNS implantation in a NF1 patient: massive nerve hypertrophy discovered intra-operatively preventing successful electrode placement. Case report.

For the vast majority of surgeons, no specific investigation is necessary before vagal nerve stimulation (VNS) implantation. We report our intraoperative unexpected finding of a massively enlarged vagus nerve in a patient with neurofibromatosis type 1 (NF1). The nerve hypertrophy prevented wrapping the coils of the helical electrode. The patient had no signs of vagus nerve dysfunction preoperatively (no hoarseness or dysphonia). This exceptional mishap is undoubtedly related to NF1-associated peripheral nerve sheath tumors. Even though it is not advisable to routinely perform any imaging prior to VNS, in such specific context, preoperative imaging work-up, especially cervical ultrasound, might be judicious to rule out any asymptomatic enlarged left vagus nerve.

5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy.

BACKGROUND: The 5-aminolevulinic acid (5-ALA) fluorescence-guided resection of recurrent malignant glioma is a standard surgical procedure at many neuro-oncological centers and is considered to be equally reliable as the primary resection of these tumors. 5-ALA induced fluorescence (5-AIF)-guided resection has been demonstrated to be highly predictive for tumor tissue. As pseudoprogression and radiation-induced necrosis are critical differential diagnoses of glioma recurrence, the purpose of the present analysis was to analyze 5-AIF behavior in resected tissue specimens histopathologically showing regressive and reactive changes but lacking active, that is, cellular recurrent tumor tissue after adjuvant treatment of malignant glioma. METHODS: A retrospective analysis was performed in patients suffering from malignant glioma who underwent surgical resection for suspected contrast-enhancing tumor recurrence (according to RANO criteria) at our institution between 2007 and 2013, but in whom histopathological analysis only revealed reactive changes. The presence of AIF in the resected tissue samples was intraoperatively assessed and classified by the surgeon, using the categories (1) no, (2) vague and (3) solid AIF. RESULTS: A total of 13 out of 313 patients who underwent AIF-guided surgical resection of tissue suspicious for recurrent glioma histologically demonstrated only reactive changes without active recurrent tumor tissue after adjuvant therapy. Pretreatment was chemotherapy with temozolomide in 1 patient and combined radio-/chemotherapy in 12 patients. Six patients had suffered previous tumor recurrence with a subsequently intensified adjuvant therapy. Seven of the 13 patients displayed solid, 5 patients vague and 1 patient no 5-AIF of the resected tissue specimens. However, all 5-AIF-positive lesions exhibited heterogeneous fluorescence patterns with vaguely or solidly fluorescent as well as nonfluorescent regions. CONCLUSIONS: Resection of reactive tissue without active recurrent tumor after multimodal treatment for glioblastoma is frequently associated with solid or vague 5-AIF. Therefore, neurosurgeons should remain cautious when attempting to employ intraoperative 5-AIF to discriminate radiation- and chemotherapy-induced tissue changes from true disease progression. Nevertheless, 5-AIF-guided resection remains a valid tool in the neurosurgical treatment of recurrent gliomas.

Right-sided vagus nerve stimulation for drug-resistant epilepsy: A systematic review of the literature and perspectives.

BACKGROUND: Right-sided vagus nerve stimulation (RS-VNS) is indicated when the procedure was deemed not technically feasible or too risky on the indicated left side. OBJECTIVE: The present study aims to systematically review the literature on RS-VNS, assessing its effectiveness and safety. METHODS: A systematic review following PRISMA guidelines was conducted: Pubmed/MEDLINE, The Cochrane Library, Scopus, Embase and Web of science databases were searched from inception to August 13th,2023. Gray literature was searched in two libraries. Eligible studies included all studies reporting, at least, one single case of RS-VNS in patients for the treatment of drug-resistant epilepsy. RESULTS: Out of 2333 initial results, 415 studies were screened by abstract. Only four were included in the final analysis comprising seven patients with RS-VNS for a drug-resistant epilepsy. One patient experienced nocturnal asymptomatic bradycardia whereas the other six patients did not display any cardiac symptom. RS-VNS was discontinued in one case due to exercise-induced airway disease exacerbation. Decrease of epileptic seizure frequency after RS-VNS ranged from 25 % to 100 % in six cases. In the remaining case, VNS effectiveness was unclear. In one case, RS-VNS was more efficient than left-sided VNS (69 % vs 50 %, respectively) whereas in another case, RS-VNS was less efficient (50 % vs 95 %, respectively). CONCLUSION: Literature on the present topic is limited. In six out of seven patients, RS-VNS for drug-resistant epilepsy displayed reasonable effectiveness with a low complication rate. Further research, including prospective studies, is necessary to assess safety and effectiveness of RS-VNS for drug-resistant epilepsy patients.

Cav 2.3 (R-type) calcium channels are critical for mediating anticonvulsive and neuroprotective properties of lamotrigine in vivo.

PURPOSE: 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 Cav 2.3 (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 two other AEDs in Cav 2.3-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 30 mg/kg LTG, 50 mg/kg topiramate (TPM), or 30 mg/kg lacosamide (LSM). KEY FINDINGS: Ablation of Cav 2.3 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 Cav 2.3-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 AEDs reduced seizure activity in control mice; however, only the non-calcium channel modulating AED, LSM, had an anticonvulsive effect in Cav 2.3-deficient mice. Furthermore, LTG altered electrocorticographic parameters differently in the two genotypes: decreasing relative power of ictal spikes in control mice but increasing relative power of high frequency fast ripple discharges during seizures in Cav 2.3-deficient mice. SIGNIFICANCE: These findings provided the first in vivo evidence for an essential role for Cav 2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav 2.3-deficient mice by increasing high frequency components of seizures, resulting in increased neurotoxicity in the CA1. 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.

Impact of the moon on cerebral aneurysm rupture.

BACKGROUND: Several external and internal risk factors for cerebral aneurysm rupture have been identified to date. Recently, it has been reported that moon phases correlate with the incidence of aneurysmal subarachnoid hemorrhage (SAH), however, another author found no such association. Therefore, the present study investigates the influence of the lunar cycle on the incidence of aneurysmal rupture, the initial clinical presentation, and the amount of subarachnoid blood. METHODS: Lunar phase and the particular day of the lunar cycle were correlated to the date of aneurysm rupture, aneurysm location, initial clinical presentation, and amount of subarachnoid blood assessed from CT scans of all patients treated for basal SAH in our department from 2003 to 2010. RESULTS: We found no correlation between incidence of aneurysmal SAH, location of the aneurysm, initial clinical presentation, or amount of subarachnoid blood and the lunar cycle. CONCLUSIONS: The moon influences neither the incidence of aneurysmal SAH nor the grade of initial neurological deterioration or amount of subarachnoid blood.

Evidence for direct impairment of neuronal function by subarachnoid metabolites following SAH.

Dysfunction of neuronal signal processing and transmission occurs after subarachnoid hemorrhage (SAH) and contributes to the high morbidity and mortality of this pathology. The underlying mechanisms include early brain injury due to elevation of the intracranial pressure, disruption of the blood-brain barrier, brain edema, reduction of cerebral blood flow, and neuronal cell death. Direct influence of subarachnoid blood metabolites on neuronal signaling should be considered. After SAH, some metabolites were shown to directly induce disruption of neuronal integrity and neuronal signaling, whereas the effects of other metabolites on neurotoxicity and neuronal signaling have not yet been investigated. Therefore, this mini-review will discuss recent evidence for a direct influence of subarachnoid blood and its metabolites on neuronal function.

Does response to vagus nerve stimulation for drug-resistant epilepsy differ in patients with and without Lennox-Gastaut syndrome?

INTRODUCTION: Literature on outcomes of patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types. METHODS: The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response. RESULTS: A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, "other" seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic-clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p = .015. CONCLUSIONS: Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs.

Frequency of social burden and underage children in neuro-oncological patients.

OBJECTIVE: Brain tumours can cause significant burden for patients and their families, including physical, psychological, and social challenges. This burden can be particularly difficult for patients with malignant brain tumours and those with underage children. However, the frequency of social burden among neuro-oncological patients and the proportion of patients with underaged children is currently unknown. The aim of this retrospective study is to determine the frequency of social and family dysfunction among neuro-oncological patients, the percentage of such patients who have underage children, and to assess their associated burden. METHODS: During a 22-month period, all brain tumour patients were asked to complete a short questionnaire that included epidemiological data, the EORTC-qlq-C30 and -BN20 questionnaire, and the distress thermometer. Data were collected and analysed using Prism 9 for macOS (version 9, GraphPad Prism). RESULTS: Our analysis included 881 brain tumour patients, of which 540 were female. Median age was 61 years (ranging from 16 to 88 years). Of all patients, 228 suffered from malignant intracranial tumours. More than half of all patients and more than 65% of patients with malignant tumours reported that their illness or medical treatment interfered with their social activities and family life. Almost 30% of patients reported moderate or severe complaints. About 27% of all patients (and 31% of patients with malignancies) expressed moderate or major concerns that their family life could be disrupted. Among the patients with malignancies, 83.5% of patients had a total of 318 children at the time of tumour diagnosis, with a mean age of 33 ± 0.9. Of these patients with malignancies, 38 (17.9%) had a total of 56 underage children at the time of tumour diagnosis, and currently have 53 underage children. Patients with minor children had more financial worries but less interference of their disease with social activities, less psycho-oncological distress, and a more positive outlook into the future (each, p < 0.0001). They evaluated their general health status and quality of life in the week prior to their current appointment significantly better (each p < 0.0001). CONCLUSION: Our study found that 17.9% of patients with malignant brain tumours have underage children. However, having underage children may actually be a positive resource for these patients, as they show lower distress values and better quality of life.

Efficacy and safety following two or more years of vagus nerve stimulation (VNS Therapy) in pediatric patients with drug-resistant epilepsy enrolled in a Russian VNS Registry.

INTRODUCTION: Following approval in 2009 of vagus nerve stimulation (VNS Therapy) for drug-resistant epilepsy (DRE) in the Russian Federation, this is the first multicenter study across Russia to evaluate the safety and efficacy of adjunctive VNS Therapy. METHODS: The retrospective, observational registry included 58 pediatric patients with DRE (5-17 years old at implantation) who had ≥2 years of VNS. To ensure a robust evaluation process, changes in seizure frequency were evaluated for all seizure types as well as "most disabling" seizures (defined as seizures accompanied by falls, physical trauma, and/or incontinence in the absence of preventative measures). RESULTS: With 2 years of VNS Therapy, 37 of 49 patients (76%) experiencing the most disabling epileptic seizures had a >50% decrease in frequency of such seizures, and 16 (33%) reported no longer experiencing the "most disabling" seizure type. In addition, based on the McHugh Outcome scale, VNS Therapy had a positive outcome on both frequency and severity of all epileptic seizure types, with a >50% decrease in frequency of all epileptic seizure types noted in 37 of 58 patients (64%), and 31% of patients had a Class I outcome, including 11 patients (19%) who achieved seizure freedom. VNS Therapy also had a positive effect on the frequency of status epilepticus: 13 patients (22%) had status epilepticus prior to implantation with a mean rate of 9.4 ± 17.7 events per year (range, 0-52), and after VNS Therapy, only one patient continued to experience status epilepticus (at 1 event per 4-6 months). VNS Therapy had an acceptable safety profile and no adverse events leading to VNS discontinuation were reported. CONCLUSIONS: The results demonstrate that VNS Therapy is being safely and effectively applied to pediatric patients in the Russian healthcare system.

Proof of principle: supramarginal resection of cerebral metastases in eloquent brain areas.

BACKGROUND: Cerebral metastases are not sharply delimitatable; therefore, microsurgical circumferential stripping of intracerebral metastases is often insufficient for preventing local tumor recurrence. Supramarginal resection significantly improves local tumor control but was suggested not to be suitable for metastases in eloquent brain areas. Therefore, we retrospectively analyzed a series of patients with cerebral metastases situated in eloquent areas for newly occurring neurologic deficits after supramarginal resection performed as awake surgery. METHODS: A retrospective analysis was performed for all patients who underwent supramarginal resection for a cerebral metastasis performed as awake surgery between June 2011 and April 2012. All metastases were localized in eloquent brain areas. Pre- and postsurgical neurologic status was documented as well as data regarding the primary cancer and histopathologic data. Postoperative MRI within 72 h was scheduled routinely to verify complete resection. RESULTS: A total of 19 patients underwent awake surgery for a cerebral metastasis in eloquent brain areas. Surgery was well tolerated in all patients. Neurologic symptoms improved in five patients after surgery. In three patients, neurologic deficits existing before surgery worsened. The postoperative median National Institute of Health Stroke Scale (NIHSS) score did not differ from the preoperative value. CONCLUSIONS: Awake surgery is a feasible tool for metastases in eloquent areas, minimizing postoperative neurologic deficits and morbidity. Therefore, eloquently situated metastases may also be eligible for supramarginal resection. Further studies are needed in order to analyze the benefit of this method in achieving better tumor control.

Variation in access to specialist services for neurosurgical procedures in adults with epilepsy in England, a cohort study.

PURPOSE: To understand if primary consultation at tertiary epilepsy centres (TEC) in England impacts access to neurosurgical procedures (resective surgery, vagus nerve stimulator [VNS], deep brain stimulator [DBS]). METHODS: Adults with epilepsy, and with a first neurology outpatient visit (index) between 01/01/2013 and 31/12/2015, were followed using English Hospital Episode Statistics from index date to 31/12/2019. Analyses were stratified by geographic location, learning disability record, and whether the index or follow-up visits were at a TEC. RESULTS: 84,093 people were included, with mean 5.5 years of follow-up. 12.4% of the cohort had learning disability (range 10.1%-17.4% across regions). TEC consultations varied by National Health Service regions and Clinical Commissioning Groups. 37.5% of people (11.2%-75.0% across regions) had their index visit at a TEC; and, of those not initially seen at a TEC, 10.6% (6.5%-17.7%) subsequently attended a tertiary centre. During follow-up, 11.1% people (9.5%-13.2%) visited a neurosurgery department, and 2.3% of those (0.9%-5.0%) then underwent a neurosurgical procedure, mainly VNS implantation. Median time from index date to first visit at a neurosurgery centre was 7 months (range 6-8 months across regions) and 40 months to procedure (36.5-49 months, 37.0 months in people with index visit at a TEC and 49.0 months otherwise). People with learning disability were less likely to have resective surgery (<0.5% versus 1.0% in those without) and more likely to undergo VNS implantation (5.8% versus 0.8%). CONCLUSION: Although clinically recommended for suitable individuals, neurosurgical procedures in epilepsy remain uncommon even after consultation at a TEC. Geographical variation in access to TECs was present.

APLP1 and Rab5A interact with the II-III loop of the voltage-gated Ca-channel Ca(v)2.3 and modulate its internalization differently.

BACKGROUND: Voltage gated calcium channels (VGCCs) regulate cellular activity in response to membrane depolarization by altering calcium homeostasis. Because calcium is the most versatile second messenger, regulation of the amount of VGCCs at the plasma membrane is highly critical for several essential cellular processes. Among the different types of VGCCs, the Ca(v)2.3 calcium channel and its regulation mechanisms are least understood due to Ca(v)2.3's resistance to most pharmacological agents. METHODS: In order to study regulation and surface expression of Ca(v)2.3, a yeast two hybrid (Y2H) screen with the II-III loop of human Ca(v)2.3 as bait, was performed. APLP1, a member of the APP gene family and Rab5A, an endocytotic catalyst were identified as putative interaction partners. The interaction were confirmed by immunoprecipitation. To study the functional importance of the interaction, patch-clamp recordings in Ca(v)2.3 stably transfected HEK-293 cells (2C6) and surface biotin endocytosis assays were performed. RESULTS: We are able to show that the II-III loop of the Ca(v)2.3 calcium channel binds APLP1 and that this binding promotes internalization of the channel. In addition, Rab5A also binds to the same loop of the channel and exerts an inhibitory effect on APLP1 mediated channel internalization. CONCLUSIONS: This study identifies a regulation mechanism of Ca(v)2.3's surface expression, which implicates APLP1 as a regulator of calcium homeostasis. Thus APLP1 may play a crucial role in neuropathological mechanisms, which involve modulation of surface expression of voltage-gated Ca(2+) channels.

Quantifying the burden of disease in patients with Lennox Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy but there is limited literature characterizing the disease burden despite this being crucial for disease management strategies, and for designing and interpreting clinical trials. We searched the Vagus Nerve Stimulation (VNS) Therapy Patient Outcome Registry including over 7000 patients with drug­resistant epilepsy (DRE). Propensity Score Matching (PSM) matched LGS-DRE patients and non-LGS-DRE patients and frequencies of individual seizure types were assessed. The PSM population included 705 and 1410 DRE patients with and without LGS. 40% of the LGS-DRE group had polypharmacy with 3 antiseizure medications (ASM) while 42% in non-LGS-DRE had polypharmacy with 2 ASMs. Median total monthly seizure frequency was over double in the LGS group: 90 (IQR, 28-312) versus 40 (IQR, 10-150); p < 0.001. This analysis suggests that seizure frequency in LGS patients who later receive VNS is more than double than in non-LGS DRE patients with mostly bilateral tonic-clonic seizures contributing to this difference. Furthermore, ASM burden with poorer seizure control may be greater in LGS patients, however data collection ceased in 2003 and therefore does not take recent ASMs approved for LGS into account. This analysis offers quantitative insight into the burden of disease in patients with LGS.

Vagus nerve stimulation therapy in people with drug-resistant epilepsy (CORE-VNS): rationale and design of a real-world post-market comprehensive outcomes registry.

INTRODUCTION: The Vagus Nerve Stimulation Therapy System (VNS Therapy) is an adjunctive neuromodulatory therapy that can be efficacious in reducing the frequency and severity of seizures in people with drug-resistant epilepsy (DRE). CORE-VNS aims to examine the long-term safety and clinical outcomes of VNS in people with DRE. METHODS AND ANALYSIS: The CORE-VNS study is an international, multicentre, prospective, observational, all-comers, post-market registry. People with DRE receiving VNS Therapy for the first time as well as people being reimplanted with VNS Therapy are eligible. Participants have a baseline visit (prior to device implant). They will be followed for a minimum of 36 months and a maximum of 60 months after implant. Analysis endpoints include seizure frequency (average number of events per month), seizure severity (individual-rated categorical outcome including very mild, mild, moderate, severe or very severe) as well as non-seizure outcomes such as adverse events, use of antiseizure medications, use of other non-pharmacological therapies, quality of life, validated measures of quality of sleep (Pittsburgh Sleep Quality Index or Children's Sleep Habit Questionnaire) and healthcare resource utilisation. While the CORE-VNS registry was not expressly designed to test hypotheses, subgroup analyses and exploratory analysis that require hypothesis testing will be conducted across propensity score matched treatment groups, where possible based on sampling. ETHICS AND DISSEMINATION: The CORE-VNS registry has already enrolled 823 participants from 61 centres across 15 countries. Once complete, CORE-VNS will represent one of the largest real-world clinical data sets to allow a more comprehensive understanding of the management of DRE with adjunctive VNS. Manuscripts derived from this database will shed important new light on the characteristics of people receiving VNS Therapy; the practical use of VNS across different countries, and factors influencing long-term response. TRAIL REGISTRATION NUMBER: NCT03529045.

The Long and Winding Road of Vagus Nerve Stimulation: Challenges in Developing an Intervention for Difficult-to-Treat Mood Disorders.

PURPOSE: The Vagus Nerve Stimulation (VNS) Therapy System has been studied for more than 20 years in patients with severe, treatment-resistant, chronic mood disorder, i.e., difficult-to-treat depression (DTD). This review distills some of the implications of this research for future therapeutic trials in this population. METHODS: A narrative review is provided on VNS in DTD. Protocols for a new, large, sham-controlled trial and a global, longitudinal observational study are described. RESULTS: Following encouraging results in open studies, a randomized, masked, sham-controlled trial of VNS for DTD failed to demonstrate an effect on the primary outcome. The negative results may have been partly due to inadequate treatment duration (10 weeks). In long-term observational studies, adjunctive VNS, combined with treatment-as-usual (VNS+TAU), was administered to more than 1100 DTD patients and compared with TAU alone in more than 400 patients. VNS+TAU had superior antidepressant effects, but maximal symptom reduction was often observed after 12 months or longer of stimulation. VNS+TAU had also marked superiority in durability of benefit. Sustained levels of symptom reduction below the traditional cutoff for response (i.e. < 50%) were associated with improved quality of life. LIMITATIONS: Most comparisons of VNS+TAU and TAU were derived from observational, open label studies. CONCLUSION: The history of VNS in DTD has implications for interventional studies in this population, and perhaps other chronic medical disorders. The slow onset of benefit with VNS necessitates considerably longer controlled observation periods to establish efficacy. Durability of benefit should be routinely incorporated in efficacy assessment. New outcome metrics are needed to both categorically identify clinically meaningful benefit and to integrate information on symptom burden over time.