Etiological analysis of 167 cases of drug-resistant epilepsy in children.

BACKGROUND: To analyze the etiological distribution characteristics of drug-resistant epilepsy (DRE) in children, with the aim of providing valuable perspectives to enhance clinical practice. METHODS: In this retrospective study, clinical data were collected on 167 children with DRE who were hospitalized between January 2020 and December 2022, including gender, age of onset, seizure types, video electroencephalogram(VEEG) recordings, neuroimaging, and genetic testing results. Based on the etiology of epilepsy, the enrolled children were categorized into different groups. The rank-sum test was conducted to compare the age of onset for different etiologies. RESULTS: Of the 167 cases, 89 (53.3%) had a clear etiology. Among them, structural factors account for 23.4%, genetic factors for 19.2%, multiple factors for 7.2%, and immunological factors for 3.6%. The age of onset was significantly earlier in children with genetic causes than those with structural (P < 0.001) or immunological (P = 0.001) causes. CONCLUSIONS: More than half of children with DRE have a distinct underlying cause, predominantly attributed to structural factors, followed by genetic factors. Genetic etiology primarily manifests at an early age, especially among children aged less than one year. This underscores the need for proactive enhancements in genetic testing to unveil the underlying causes and subsequently guide treatment protocols.

Drug-resistant juvenile myoclonic epilepsy: A literature review.

The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy disorder, but this definition may well change again in the future. Although good drug response could almost be a diagnostic criterion for JME, drug resistance (DR) is observed in up to a third of patients. It is important to distinguish this from pseudoresistance, which is often linked to psychosocial problems or psychiatric comorbidities. After summarizing these aspects and the various definitions applied to JME, the present review lists the risk factors for DR-JME that have been identified in numerous studies and meta-analyses. The factors most often cited are absence seizures, young age at onset, and catamenial seizures. By contrast, photosensitivity seems to favor good treatment response, at least in female patients. Current hypotheses on DR mechanisms in JME are based on studies of either simple (e.g., cortical excitability) or more complex (e.g., anatomical and functional connectivity) neurophysiological markers, bearing in mind that JME is regarded as a neural network disease. This research has revealed correlations between the intensity of some markers and DR, and above all shed light on the role of these markers in associated neurocognitive and neuropsychiatric disorders in both patients and their siblings. Studies of neurotransmission have mainly pointed to impaired GABAergic inhibition. Genetic studies have generally been inconclusive. Increasing restrictions have been placed on the use of valproate, the standard antiseizure medication for this syndrome, owing to its teratogenic and developmental risks. Levetiracetam and lamotrigine are prescribed as alternatives, as is vagal nerve stimulation, and there are several other promising antiseizure drugs and neuromodulation methods. The development of better alternative treatments is continuing to take place alongside advances in our knowledge of JME, as we still have much to learn and understand.

Drug-resistant generalized epilepsies: Revisiting the frontiers of idiopathic generalized epilepsies.

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities.

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

Hippocampal sclerosis is associated with celiac disease type immunity in patients with drug-resistant temporal lobe epilepsy.

BACKGROUND: A prior small-scale single center study suggested an association between celiac disease (CD)-type immunity and refractory temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). The present study addresses this putative association in a large, well-characterized group of drug-resistant epilepsy (DRE) patients. These patients were grouped based on the spectrum of CD and gluten sensitivity-associated antibodies. METHODS: In this cross-sectional study, 253 consecutive adult epilepsy patients (135 females, 118 males; age 16-76 years) were categorized into three groups: (i) CD-positive group with either prior diagnosis of CD or CD-specific TG2/EmA antibodies, (ii) AGA-positive group with antigliadin antibodies (AGA) but without CD, and (iii) CD/AGA-negative group without any gluten sensitivity-associated antibodies or CD. Clinical and immunological findings were then compared among the groups. RESULTS: TLE with HS was more common in the CD-positive group compared to CD/AGA-negative group (31.8% versus 11.9%, P = 0.019). Autoimmune disorders were more common in the AGA-positive group than in the CD/AGA-negative group (P = 0.025). Considering HS lateralization; left lateralization was more common in CD-positive group compared to CD/AGA-negative group (71.4% versus 25%, P = 0.030). TG6 seropositivity did not differ among the groups (P > 0.05). CONCLUSIONS: This study provides further evidence linking TLE with HS and CD-type autoimmunity suggesting that CD-type immune response to gluten can be one potential mechanism as a disease modifier leading to DRE and HS. Understanding these immunological factors is imperative for developing immunomodulatory or dietary treatments for DRE potentially preventing HS progression.

Neurological function and drug-refractory epilepsy in Sturge-Weber syndrome children: a retrospective analysis.

Epilepsy in Sturge-Weber syndrome (SWS) is common, but drug-refractory epilepsy (DRE) in SWS has rarely been studied in children. We investigated the characteristics of epilepsy and risk factors for DRE in children with SWS. A retrospective study was conducted to analyze the clinical characteristics of children with SWS with epilepsy in our hospital from January 2013 to October 2022. Univariate and multivariate logistic analyses were performed to investigate the factors influencing DRE in children with SWS. A total of 35 SWS children with epilepsy were included (51% male; mean age of presentation 3.6 ± 0.5 years), 71% of children with SWS had their first seizure within the first year of life, and the most common type of seizure was focal seizure (77%). Eleven (31%) patients developed DRE. The median age of onset for the first seizure was 1.0 years and all these cases were of SWS type I. Multivariate logistic analysis revealed that stroke-like episodes and seizure clusters were risk factors for DRE in SWS children. A poor neurological function group was observed in twenty-five children with SWS. Status epilepticus was a risk factor that affected the neurological function of SWS children with epilepsy.  Conclusion: The study explored the epileptic features of children with SWS. The results revealed that stroke-like episodes and seizure clusters are risk factors for DRE in children with SWS. The occurrence of status epilepticus impacts the neurological function of SWS children with epilepsy. Thus, long-term follow-up is necessary to monitor outcomes. What is Known: • Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder, over 75% of children with SWS experience seizures, and 30-57% develop drug-refractory epilepsy (DRE), which leads to a poor outcome. • Drug-refractory epilepsy in SWS has been rarely studied in children, and the risk factors associated with DRE are unclear. What is New: • Clinical features of SWS children with drug-refractory epilepsy. • In SWS, stroke-like episodes and seizure clusters are risk factors of DRE, the occurrence of status epilepticus impacts the neurological function.

Clinical and pathologic features of Sturge-Weber syndrome in patients with refractory epilepsy.

OBJECTIVES: We aimed to investigate the clinicopathologic features of and genetic changes in Sturge-Weber syndrome (SWS) in patients with refractory epilepsy. METHODS: Clinical data were retrospectively analyzed. H&E and immunohistochemistry were performed to assess pathologic changes. Targeted amplicon sequencing was applied to investigate the somatic GNAQ (c.548G>A) mutation. The potential predictors of seizure outcomes were estimated by univariate and multivariate statistical analyses. RESULTS: Forty-eight patients with SWS and refractory epilepsy were enrolled. According to the imaging data and pathologic examination, ipsilateral hippocampal sclerosis (HS), calcification of leptomeningeal arteries, and focal cortical dysplasia were found in 14 (29.2%), 31 (64.6%), and 37 (77.1%) patients, respectively. A high frequency of GNAQ alteration was detected in both cerebral cortex (57.7%) and ipsilateral hippocampus (50.0%) from patients with SWS. During follow-up, 43 of 48 patients (85.4%) had achieved seizure control (Engel class I). Statistically, HS signs on imaging were found to be independent predictors of unfavorable seizure outcomes (P = .015). CONCLUSIONS: Calcification of leptomeningeal arteries, focal cortical dysplasia, and GNAQ alteration are common features in SWS pathology. Patients with refractory epilepsy caused by SWS can achieve satisfactory seizure control after surgery, but seizure control was compromised in patients with comorbid HS.

Surgical treatment for drug-resistant epilepsy due to early brain injury in children.

BACKGROUND: The study aimed to summarize the indications and clinical features of pediatric drug-resistant epilepsy associated with early brain injury, surgical outcomes, and prognostic factors. METHODS: We retrospectively analyzed children diagnosed with drug-resistant epilepsy due to early brain injury, who had undergone surgery at the Pediatric Epilepsy Center of Peking University First Hospital from May 2014 to May 2021. Clinical data of vasculogenic and non-vasculogenic injuries from early brain damage were compared and analyzed. The surgical outcomes were assessed using the Engel grading system. RESULTS: The median ages at acquiring injury, seizure onset, and surgery among 65 children were 19.0 (0-120) days, 8.6 (0-136.5) months, and 62.9 (13.5-234) months, respectively. Of the 14 children with non-vasculogenic injuries, 12 had posterior ulegyria. Unilateral or bilateral synchronous interictal epileptiform discharges were located mainly in the posterior quadrant in 10 children (71 %), and unilateral posterior quadrant or non-lateralized ictal region in eight children (57 %). The surgical approach was mainly temporo-parieto-occipital or parieto-occipital disconnection in nine children. Of 49 children with vasculogenic injuries, magnetic resonance imaging revealed hemispheric abnormalities in 38. Unilaterally hemispheric or bilateral interictal epileptiform discharges were observed in 36 children (73 %), whereas 42 (86 %) had unilateral hemispheric or non-lateralized ictal onset. The surgical procedure involved hemispherotomy in 38 children (78 %) and lobectomy or disconnection, multilobectomy or disconnection and hemispherotomy in 5, 20, and 40 children, respectively. Fifty-five patients (84.6 %) achieved remission from seizure during follow-up at 5.4 years. Age at surgery (odds ratio = 1.022, 95 % confidence interval = 1.003-1.042, P = 0.023) and etiology (odds ratio = 17.25, 95 % confidence interval = 2.778-107.108, P = 0.002) affected the seizure outcomes. CONCLUSION: Children with drug-resistant epilepsy due to early brain injury can successfully be treated with surgery after rigorous preoperative screening. Good surgical outcomes are associated with an early age at surgery and an etiology of vasculogenic injury.

Navigated transcranial magnetic stimulation to measure motor evoked potentials in a child with hemispheric polymicrogyria and focal epilepsy.

Malformations of cortical development such as polymicrogyria can cause medically refractory epilepsy. Epilepsy surgery (hemispherotomy) can be a good treatment option. In recent years, navigated transcranial magnetic stimulation (nTMS), a noninvasive brain mapping technique, has been used to localize the eloquent cortex for presurgical evaluation of patients with epilepsy. In the present case study, neurophysiological markers of the primary motor cortex (M1), including resting motor threshold (rMT), motor evoked potentials (MEPs), and silent period (SP), were assessed in both hands of a right-handed 10-year-old girl with a history of epilepsy and right hemispheric polymicrogyria. Bilateral MEPs with short latencies were elicited from the contralesional side. The average MEP amplitude and the latency for the patient's paretic and non-paretic hands differed significantly. We conclude that nTMS is a safe and tolerable procedure that can be used for presurgical evaluation in children with intractable epilepsy.

[Evaluation of the relevance of the pharmaceutical educational interview on the knowledge and satisfaction of patients who received a vagus nerve neurostimulator implantation]. / Évaluation de la pertinence de l'entretien pharmaceutique éducatif sur les connaissances et la satisfaction de patients ayant bénéficié d'une implantation d'un neurostimulateur du nerf vague.

INTRODUCTION: Vagal neurostimulation (VNS) medical devices (MDs) are used to treat drug-resistant epilepsy. Using a magnet, the patient can activate on the stimulations in order to stop a seizure or interrupt the adverse effects (AEs) of the device. The objective is to evaluate the improvement of the patients' knowledge about the VNS following a pharmaceutical educational interview (PEI) as well as their satisfaction. MATERIALS AND METHODS: The pharmaceutical educational interview regarding drugs and DMs was performed by the clinical pharmacist at the patient's bed after VNS implantation. A questionnaire about VNS devices (operation, adverse effects, recommendations) and assessing knowledge was submitted to patients before and after the PEI. Satisfaction was assessed by the Likert scale. RESULTS: From March 2020 to August 2021, 18 implanted patients were included in the study. In 78% of cases (14/18), the total number of good responses after PEI increased. The mean good response was significantly increased from 16.11/25 (64%) before PEI to 22.33/25 (89%) after PEI (P-value<0.01). The maximum satisfaction score (4/4) was given in 71% of the items. DISCUSSION-CONCLUSION: The results support the relevance of PEI. Patients feel a need for information and consider the interview useful. An improvement in knowledge was observed, which allows us to hope for an optimization of the effectiveness of the device, in particular, a reduction in seizures and AE. This study shows the feasibility and the interest of the development of clinical pharmacy applied to medical devices in complementarity with the expertise on drugs.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark.

OBJECTIVE: To evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. METHODS: A review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. RESULTS: The median age of epilepsy onset was two years (interquartile range (IQR): 0.0-5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6-1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0-55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: -10.0-+4.0]). Callosotomy resulted in a seizure reduction of 86-99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0-30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). CONCLUSION: Hemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

Spectrum, Evolution, and Clinical Relationship of Magnetic Resonance Imaging in 31 Children with Febrile Infection-Related Epilepsy Syndrome.

OBJECTIVE: Describing spectrum, evolution, and clinical relationship of brain magnetic resonance imaging (MRI) findings in a large case series of children with febrile infection-related epilepsy syndrome (FIRES). METHODS: This retrospective study included 31 children with FIRES. Clinical data and MRI findings of the brain were evaluated. Poor clinical outcome was defined as severe disability, persistent vegetative state or stupor, very low intelligence quotient (<80), or death (modified Rankin scale 4-6 and Glasgow Outcome Score 1-3). RESULTS: Seventeen (54.8%) children with FIRES showed no abnormalities in the initial MRI, whereas 28 (90.3%) children showed MRI abnormalities at follow-up. The most frequent abnormalities were brain atrophy (74.2%) and T2/fluid-attenuated inversion recovery changes (64.5%), mostly hippocampal (45.2%). Generalized brain atrophy was the most frequent type of atrophy (58%). The earliest atrophy was recorded 9 days after the onset of disease. It progressed even beyond the acute phase in most children (51.6%). The exploratory data analysis revealed nominal significance between all MRI abnormalities considered together and poor outcome (p = 0.049) and between generalized brain atrophy and anesthesia (p = 0.024). After adjustment for multiple testing, the p-values were not significant. The outcome in four (12.9%) children was not poor despite generalized brain atrophy. CONCLUSION: In contrast to the uniform clinical course, MRI demonstrated a broad spectrum of findings. Initially, these were mostly normal and therefore indicative of FIRES but then changed rapidly and were mostly progressive despite the stable chronic course. The cause may be ongoing disease, treatment intensity, or both. Future studies should focus on what process underlies the onset and the progression of brain atrophy. However, brain atrophy was not always related to poor outcomes in children despite FIRES.

Intraventricular hemorrhage volume and younger age at surgery may be risk factors for postoperative hydrocephalus after hemispherotomy in children.

OBJECTIVE: Hemispherotomy is an effective treatment for intractable hemispheric epilepsy; however, hydrocephalus remains a common complication of the procedure. The causes of hydrocephalus following hemispherotomy have not been fully elucidated; therefore, the purpose of this study was to identify the risk factors associated with the condition. METHODS: The authors investigated the records of all patients aged < 18 years who underwent hemispherotomy at their institution between 2003 and 2020 and were monitored for hydrocephalus for at least 1 year after the procedure. To identify the risk factors for hydrocephalus, the following information about each patient was collected: sex, corrected age at surgery, body weight at surgery, previous intracranial surgery, etiology of epilepsy, results of PET for hypermetabolism, side of surgery, type of operation (vertical or horizontal approach), operation time, blood loss during surgery, use of intraventricular drainage, occurrence of intraventricular hemorrhage (IVH) on the 1st postoperative day, duration of postoperative fever of > 38°C, and maximum C-reactive protein level after the operation. Multivariate logistic regression analyses were performed. RESULTS: This study included 51 children who underwent hemispherotomies for drug-resistant epilepsy at our hospital. Seven patients (13.7%) experienced hydrocephalus and were treated with ventricular or subdural peritoneal shunts or fenestration. Multivariate logistic analysis using the Bayesian information criterion revealed that 3 factors were associated with the occurrence of hydrocephalus: age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C. CONCLUSIONS: This study showed that younger age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C might be risk factors for hydrocephalus after hemispherotomy. The risk of hydrocephalus should be considered in cases of early surgical indication in children. Intraoperative hemostasis and postoperative use of anti-inflammatory measures may reduce the risk of hydrocephalus.

Accuracy and Utility of Frameless Stereotactic Placement of Stereoelectroencephalography Electrodes.

BACKGROUND: Successful surgery for epilepsy hinges on identification of the epileptogenic focus. Stereoelectroencephalography (sEEG) is the most effective way to identify most seizure foci. There are multiple methods of inserting depth electrodes, including frame-based, frameless, and robot-assisted techniques. Studies have shown the accuracy of frame-based and robotic-assisted techniques to be statistically similar, while only one study has detailed the frameless sEEG insertion technique. METHODS: Patients underwent placement of sEEG depth electrodes using frameless stereotaxy from September 2019 to September 2021 at Geisinger Medical Center by a single surgeon. Seizure history, electrode placement accuracy relative to the planned trajectories, surgical times, success rate of identifying the epileptogenic focus, and subsequent seizure control rates after surgical treatment were documented. RESULTS: Data were available for 21 patients and 181 electrodes inserted using the VarioGuide frameless stereotactic system. Each insertion took an average of 14.5 minutes per lead. Average entry variance was 2.7 mm with an average target variance of 4.6 mm. The epileptogenic focus was identified in 19 of 21 patients, and further surgical treatment was performed in 18 of 21 patients (85.7%). CONCLUSIONS: VarioGuide frameless stereotaxy for sEEG placement is comparable to frame-based and robotic-assisted techniques with statistically similar rates of epileptic focus identification. Lead placement accuracy is slightly lower and time per lead is slightly higher relative to robot-assisted surgeries. When a robot system is unavailable, surgeons can consider using a frameless stereotactic technique for sEEG insertion, allowing patients to benefit from a similarly high rate of epileptic zone identification.

Aesthetic transaxillary subpectoral placement of vagus nerve stimulator in children and young adults: A technical note.

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy for drug-resistant epilepsy (DRE), refractory status epilepticus, and treatment-resistant depression. The lead is tunneled into the subcutaneous space and connected to the generator, which is usually implanted in a subcutaneous pocket below the clavicle. Surgical complications in the chest region include skin breakdown or infection. An alternative approach is to perform a subclavear subpectoral implantation. In our surgical series, we report a new aesthetic implantation method for VNS generators in children and young patients: the transaxillary subpectoral placement. MATERIALS AND METHODS: From May 2021 to May 2023, 10 vagus nerve stimulation generators were placed subpectorally with a transaxillary approach by the authors. We considered operative time, surgical complications such as blood loss, infections, device migration, pain, and adverse events at follow-up. RESULTS: In this surgical series, we reviewed all cases of subpectoral implantation of VNS generators in children and young adults at our institution in the last 2 years. All patients were treated with subpectoral Sentiva 1000 (Livanova PLC) insertion with axillary access by a neurosurgeon and a pediatric surgeon. The operative time was slightly longer compared to the traditional subcutaneous implant. All generators reported impedances within the optimal range. Blood loss was not significant and no other perioperative complications were reported. Patients and families were highly satisfied with the outcomes in terms of comfort and aesthetic results after surgery and at the last follow-up. No cases of infection occurred, and no malfunctions or displacements of the generator were registered at clinical follow-up. CONCLUSION: The transaxillary subpectoral placement of theVNS generator is an aesthetic and anatomic approach, which provides several benefits to children and young adults.

Externalization of an infected vagus nerve stimulator generator without a break in anti-seizure therapy: a technical note.

INTRODUCTION: Vagus nerve stimulation (VNS) is a widely used treatment for drug-resistant epilepsy. An infection of the VNS generator pocket occurs in 3-8% of cases. Current standard of care requires the removal of the device, antibiotic therapy, and then replacement of the device. The consequential break in VNS therapy leaves patients highly susceptible to seizures. METHODS: Retrospective case report. RESULTS: The externalized generator continued to provide electroceutical coverage of the patient's seizures while the pocket was sterilized with IV antibiotics as well as betadine and local antibiotics. The externalized generator was kept safe against the patient's chest with ioban and an entriely new system was implanted on post-externalization day 5. The patient is now 7 months post-operative and without any evidence of infection. CONCLUSIONS: We report successful management of an infected VNS generator with externalization and short interval replacement of the entire system without any break in anti-seizure therapy.

Initial case series of a novel sensing deep brain stimulation device in drug-resistant epilepsy and consistent identification of alpha/beta oscillatory activity: A feasibility study.

OBJECTIVE: Here, we report a retrospective, single-center experience with a novel deep brain stimulation (DBS) device capable of chronic local field potential (LFP) recording in drug-resistant epilepsy (DRE) and explore potential electrophysiological biomarkers that may aid DBS programming and outcome tracking. METHODS: Five patients with DRE underwent thalamic DBS, targeting either the bilateral anterior (n = 3) or centromedian (n = 2) nuclei. Postoperative electrode lead localizations were visualized in Lead-DBS software. Local field potentials recorded over 12-18 months were tracked, and changes in power were associated with patient events, medication changes, and stimulation. We utilized a combination of lead localization, in-clinic broadband LFP recordings, real-time LFP response to stimulation, and chronic recordings to guide DBS programming. RESULTS: Four patients (80%) experienced a >50% reduction in seizure frequency, whereas one patient had no significant reduction. Peaks in the alpha and/or beta frequency range were observed in the thalamic LFPs of each patient. Stimulation suppressed these LFP peaks in a dose-dependent manner. Chronic timeline data identified changes in LFP amplitude associated with stimulation, seizure occurrences, and medication changes. We also noticed a circadian pattern of LFP amplitudes in all patients. Button-presses during seizure events via a mobile application served as a digital seizure diary and were associated with elevations in LFP power. SIGNIFICANCE: We describe an initial cohort of patients with DRE utilizing a novel sensing DBS device to characterize potential LFP biomarkers of epilepsy that may be associated with seizure control after DBS in DRE. We also present a new workflow utilizing the Percept device that may optimize DBS programming using real-time and chronic LFP recording.

ASCEND: A randomized controlled trial of titration strategies for vagus nerve stimulation in drug-resistant epilepsy.

Vagus Nerve Stimulation (VNS) therapy is widely understood to provide clinically meaningful improvements in seizure control to patients with drug-resistant epilepsy, and has been a staple in the clinical armamentaria available to epileptologists for over 25 years. Despite the long history of evidence-based reviews by neurology professional societies, there is still evidence of a practice gap in VNS titration and dosing that aims to maximize clinical benefit. Recent retrospective analyses have strongly argued for a more consistent application of a population-wide target dose of VNS, and further argued the importance of quickly achieving this target dose to hasten the onset of clinical benefits; however, these analyses failed to provide evidence for practical implementation. Herein, we describe a randomized controlled trial assessing the impact of titrating VNS according to three different protocols to achieve the target dose of 1.5 mA at 500µsec, for a 20-Hz signal frequency. The study was registered as NCT02385526 on March 11, 2015. Sixty-two patients were randomized into treatment groups that followed different titration protocols. One protocol (Group A) was designed to align with currently accepted professional guidance for VNS titration and the manufacturer's labeling for VNS in epilepsy (Heck et al., 2002), while the other two protocols were derived from VNS applications in other therapeutic areas. Group A participants were most likely to achieve the target dose parameters in 12 weeks or less (81.8%), with a median time-until-achievement of the target dose of 8.1 weeks, while less than 60% of patients in other groups were able to achieve the same endpoint. Participants in all groups experienced low levels of transient tolerability concerns and adverse events, suggesting titration to the target dose in 12 weeks or less following the Group A protocol is generally acceptable to most patients. These findings indicate that patients receiving VNS for epilepsy can achieve the manufacturer-recommended dose range in 12 weeks or less. A wider implementation of the approach will likely improve the clinical impact of VNS on seizure control and prevent undertreatment.

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.