The interictal suppression hypothesis is the dominant differentiator of seizure onset zones in focal epilepsy.

Successful surgical treatment of drug-resistant epilepsy traditionally relies on the identification of seizure onset zones (SOZs). Connectome-based analyses of electrographic data from stereo electroencephalography (SEEG) may empower improved detection of SOZs. Specifically, connectome-based analyses based on the Interictal Suppression Hypothesis (ISH) posit that when the patient is not having a seizure, SOZs are inhibited by non-SOZs through high inward connectivity and low outward connectivity. However, it is not clear whether there are other motifs that can better identify potential SOZs. Thus, we sought to use unsupervised machine learning to identify network motifs that elucidate SOZs and investigate if there is another motif that outperforms the ISH. Resting-state SEEG data from 81 patients with drug-resistant epilepsy undergoing a pre-surgical evaluation at Vanderbilt University Medical Center were collected. Directed connectivity matrices were computed using the alpha band (8-12Hz). Principal component analysis (PCA) was performed on each patient's connectivity matrix. Each patient's components were analyzed qualitatively to identify common patterns across patients. A quantitative definition was then used to identify the component that most closely matched the observed pattern in each patient. A motif characteristic of the Interictal Suppression Hypothesis (high-inward and low-outward connectivity) was present in all individuals and found to be the most robust motif for identification of SOZs in 64/81 (79%) patients. This principal component demonstrated significant differences in SOZs compared to non-SOZs. While other motifs for identifying SOZs were present in other patients, they differed for each patient, suggesting that seizure networks are patient specific, but the ISH is present in nearly all networks. We discovered that a potentially suppressive motif based on the Interictal Suppression Hypothesis was present in all patients, and it was the most robust motif for SOZs in 79% of patients. Each patient had additional motifs that further characterized SOZs, but these motifs were not common across all patients. This work has the potential to augment clinical identification of SOZs to improve epilepsy treatment.

Indirect structural changes and reduced controllability after temporal lobe epilepsy resection.

OBJECTIVE: To understand the potential behavioral and cognitive effects of mesial temporal resection for temporal lobe epilepsy (TLE) a method is required to characterize network-wide functional alterations caused by a discrete structural disconnection. The objective of this study was to investigate network-wide alterations in brain dynamics of patients with TLE before and after surgical resection of the seizure focus using average regional controllability (ARC), a measure of the ability of a node to influence network dynamics. METHODS: Diffusion-weighted imaging (DWI) data were acquired in 27 patients with drug-resistant unilateral mesial TLE who underwent selective amygdalohippocampectomy. Imaging data were acquired before and after surgery and a presurgical and postsurgical structural connectome was generated from whole-brain tractography. Edge-wise strength, node strength, and node ARC were compared before and after surgery. Direct and indirect edge-wise strength changes were identified using patient-specific simulated resections. Direct edges were defined as primary edges disconnected by the resection zone itself. Indirect edges were secondary measured edge strength changes. Changes in node strength and ARC were then related to both direct and indirect edge changes. RESULTS: We found nodes with significant postsurgical changes in both node strength and ARC surrounding the resection zone (paired t tests, p < .05, Bonferroni corrected). ARC identified additional postsurgical changes in nodes outside of the resection zone within the ipsilateral occipital lobe, which were associated with indirect edge-wise strength changes of the postsurgical network (Fisher's exact test, p < .001). These indirect edge-wise changes were facilitated through the "hub" nodes including the thalamus, putamen, insula, and precuneus. SIGNIFICANCE: Discrete network disconnection from TLE resection results in widespread structural and functional changes not predicted by disconnection alone. These can be well characterized by dynamic controllability measures such as ARC and may be useful for investigating changes in brain function that may contribute to seizure recurrence and behavioral or cognitive changes after surgery.

Structural disconnection relates to functional changes after temporal lobe epilepsy surgery.

Epilepsy surgery consists of surgical resection of the epileptic focus and is recommended for patients with drug-resistant focal epilepsy. However, focal brain lesions can lead to effects in distant brain regions. Similarly, the focal resection in temporal lobe epilepsy surgery has been shown to lead to functional changes distant from the resection. Here we hypothesize that there are changes in brain function caused by temporal lobe epilepsy surgery in regions distant from the resection that are due to their structural disconnection from the resected epileptic focus. Therefore, the goal of this study was to localize changes in brain function caused by temporal lobe epilepsy surgery and relate them to the disconnection from the resected epileptic focus. This study takes advantage of the unique opportunity that epilepsy surgery provides to investigate the effects of focal disconnections on brain function in humans, which has implications in epilepsy and broader neuroscience. Changes in brain function from pre- to post-epilepsy surgery were quantified in a group of temporal lobe epilepsy patients (n = 36) using a measure of resting state functional MRI activity fluctuations. We identified regions with significant functional MRI changes that had high structural connectivity to the resected region in healthy controls (n = 96) and patients based on diffusion MRI. The structural disconnection from the resected epileptic focus was then estimated using presurgical diffusion MRI and related to the functional MRI changes from pre- to post-surgery in these regions. Functional MRI activity fluctuations increased from pre- to post-surgery in temporal lobe epilepsy in the two regions most highly structurally connected to the resected epileptic focus in healthy controls and patients-the thalamus and the fusiform gyrus ipsilateral to the side of surgery (PFWE < 0.05). Broader surgeries led to larger functional MRI changes in the thalamus than more selective surgeries (P < 0.05), but no other clinical variables were related to functional MRI changes in either the thalamus or fusiform. The magnitude of the functional MRI changes in both the thalamus and fusiform increased with a higher estimated structural disconnection from the resected epileptic focus when controlling for the type of surgery (P < 0.05). These results suggest that the structural disconnection from the resected epileptic focus may contribute to the functional changes seen after epilepsy surgery. Broadly, this study provides a novel link between focal disconnections in the structural brain network and downstream effects on function in distant brain regions.

The Interictal Suppression Hypothesis in focal epilepsy: network-level supporting evidence.

Why are people with focal epilepsy not continuously having seizures? Previous neuronal signalling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure-onset zones have increased inward connectivity that could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure-onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug-resistant focal epilepsy undergoing presurgical evaluation. We used intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation and non-involved zones. We then used diffusion imaging to acquire estimates of white-matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure-onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inwards connectivity and decreased outwards connectivity using both resting-state (one-way ANOVA, P-value = 3.13 × 10-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, P-value = 2.5 × 10-3). When controlling for the distance between regions, the difference between inwards and outwards connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect P-value of 2.6 × 10-12). Structure-function coupling analyses revealed that seizure-onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect P-value of 9.76 × 10-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0 ± 2.2% to classify early propagation and seizure-onset zones. These results suggest that seizure-onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure-onset zones. These findings have implications for the identification of seizure-onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug-resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative and neuromodulation approaches to improve surgical success rates in those suffering from drug-resistant focal epilepsy.

Periventricular nodular heterotopia is coupled with the neocortex during resting and task states.

Periventricular nodular heterotopia (PVNH) is a well-defined developmental disorder characterized by failed neuronal migration, which forms ectopic neuronal nodules along the ventricular walls. Previous studies mainly focus on clinical symptoms caused by the PVNH tissue, such as seizures. However, little is known about whether and how neurons in the PVNH tissue functionally communicate with neurons in the neocortex. To probe this, we applied magnetoencephalography (MEG) and stereo-electroencephalography (sEEG) recordings to patients with PVNH during resting and task states. By estimating frequency-resolved phase coupling strength of the source-reconstructed neural activities, we found that the PVNH tissue was spontaneously coupled with the neocortex in the α-ß frequency range, which was consistent with the synchronization pattern within the neocortical network. Furthermore, the coupling strength between PVNH and sensory areas effectively modulated the local neural activity in sensory areas. In both MEG and sEEG visual experiments, the PVNH tissue exhibited visual-evoked responses, with a similar pattern and latency as the ipsilateral visual cortex. These findings demonstrate that PVNH is functionally integrated into cognition-related cortical circuits, suggesting a co-development perspective of ectopic neurons after their migration failure.

Disparities in Access to Deep Brain Stimulation for Parkinson's Disease and Proposed Interventions: A Literature Review.

BACKGROUND: Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD), but disparities exist in access to DBS along gender, racial, and socioeconomic lines. SUMMARY: Women are underrepresented in clinical trials and less likely to undergo DBS compared to their male counterparts. Racial and ethnic minorities are also less likely to undergo DBS procedures, even when controlling for disease severity and other demographic factors. These disparities can have significant impacts on patients' access to care, quality of life, and ability to manage their debilitating movement disorders. KEY MESSAGES: Addressing these disparities requires increasing patient awareness and education, minimizing barriers to equitable access, and implementing diversity and inclusion initiatives within the healthcare system. In this systematic review, we first review literature discussing gender, racial, and socioeconomic disparities in DBS access and then propose several patient, provider, community, and national-level interventions to improve DBS access for all populations.

Global Economic Evaluation of the Reported Costs of Deep Brain Stimulation.

INTRODUCTION: Despite the known benefits of deep brain stimulation (DBS), the cost of the procedure can limit access and can vary widely. Our aim was to conduct a systematic review of the reported costs associated with DBS, as well as the variability in reporting cost-associated factors to ultimately increase patient access to this therapy. METHODS: A systematic review of the literature for cost of DBS treatment was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase databases were queried. Olsen & Associates (OANDA) was used to convert all reported rates to USD. Cost was corrected for inflation using the US Bureau of Labor Statistics Inflation Calculator, correcting to April 2022. RESULTS: Twenty-six articles on the cost of DBS surgery from 2001 to 2021 were included. The median number of patients across studies was 193, the mean reported age was 60.5 ± 5.6 years, and median female prevalence was 38.9%. The inflation- and currency-adjusted mean cost of the DBS device was USD 21,496.07 ± USD 8,944.16, the cost of surgery alone was USD 14,685.22 ± USD 8,479.66, the total cost of surgery was USD 40,942.85 ± USD 17,987.43, and the total cost of treatment until 1 year of follow-up was USD 47,632.27 ± USD 23,067.08. There were no differences in costs observed across surgical indication or country. CONCLUSION: Our report describes the large variation in DBS costs and the manner of reporting costs. The current lack of standardization impedes productive discourse as comparisons are hindered by both geographic and chronological variations. Emphasis should be put on standardized reporting and analysis of reimbursement costs to better assess the variability of DBS-associated costs in order to make this procedure more cost-effective and address areas for improvement to increase patient access to DBS.

Vigilance associates with the low-dimensional structure of fMRI data.

The human brain exhibits rich dynamics that reflect ongoing functional states. Patterns in fMRI data, detected in a data-driven manner, have uncovered recurring configurations that relate to individual and group differences in behavioral, cognitive, and clinical traits. However, resolving the neural and physiological processes that underlie such measurements is challenging, particularly without external measurements of brain state. A growing body of work points to underlying changes in vigilance as one driver of time-windowed fMRI connectivity states, calculated on the order of tens of seconds. Here we examine the degree to which the low-dimensional spatial structure of instantaneous fMRI activity is associated with vigilance levels, by testing whether vigilance-state detection can be carried out in an unsupervised manner based on individual BOLD time frames. To investigate this question, we first reduce the spatial dimensionality of fMRI data, and apply Gaussian Mixture Modeling to cluster the resulting low-dimensional data without any a priori vigilance information. Our analysis includes long-duration task and resting-state scans that are conducive to shifts in vigilance. We observe a close alignment between low-dimensional fMRI states (data-driven clusters) and measurements of vigilance derived from concurrent electroencephalography (EEG) and behavior. Whole-brain coactivation analysis revealed cortical anti-correlation patterns that resided primarily during higher behavioral- and EEG-defined levels of vigilance, while cortical activity was more often spatially uniform in states corresponding to lower vigilance. Overall, these findings indicate that vigilance states may be detected in the low-dimensional structure of fMRI data, even within individual time frames.

Intraoperative physiology augments atlas-based data in awake deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is commonly performed with patients awake to perform intraoperative microelectrode recordings and/or macrostimulation testing to guide final electrode placement. Supplemental information from atlas-based databases derived from prior patient data and visualised as efficacy heat maps transformed and overlaid onto preoperative MRIs can be used to guide preoperative target planning and intraoperative final positioning. Our quantitative analysis of intraoperative testing and corresponding changes made to final electrode positioning aims to highlight the value of intraoperative neurophysiological testing paired with image-based data to optimise final electrode positioning in a large patient cohort. METHODS: Data from 451 patients with movement disorders treated with 822 individual DBS leads at a single institution from 2011 to 2021 were included. Atlas-based data was used to guide surgical targeting. Intraoperative testing data and coordinate data were retrospectively obtained from a large patient database. Medical records were reviewed to obtain active contact usage and neurologist-defined outcomes at 1 year. RESULTS: Microelectrode recording firing profiles differ per track, per target and inform the locations where macrostimulation testing is performed. Macrostimulation performance correlates with the final electrode track chosen. Centroids of atlas-based efficacy heat maps per target were close in proximity to and may predict active contact usage at 1 year. Overall, patient outcomes at 1 year were improved for patients with better macrostimulation response. CONCLUSIONS: Atlas-based imaging data is beneficial for target planning and intraoperative guidance, and in conjunction with intraoperative neurophysiological testing during awake DBS can be used to individualize and optimise final electrode positioning, resulting in favourable outcomes.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Neuro-stimulation in focal epilepsy: A systematic review and meta-analysis.

OBJECTIVES: Different neurostimulation modalities are available to treat drug-resistant focal epilepsy when surgery is not an option including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). Head-to-head comparisons of efficacy do not exist between them nor are likely to be available in the future. We performed a meta-analysis on VNS, RNS, and DBS outcomes to compare seizure reduction efficacy for focal epilepsy. METHODS: We systematically reviewed the literature for reported seizure outcomes following implantation with VNS, RNS, and DBS in focal-onset seizures and performed a meta-analysis. Prospective or retrospective clinical studies were included. RESULTS: Sufficient data were available at years one (n = 642, two (n = 480), and three (n = 385) for comparing the three modalities with each other. Seizure reduction for the devices at years one, two, and three respectively were: RNS: 66.3%, 56.0%, 68.4%; DBS- 58.4%, 57.5%, 63.8%; VNS 32.9%, 44.4%, 53.5%. Seizure reduction at year one was greater for RNS (p < 0.01) and DBS (p < 0.01) compared to VNS. CONCLUSIONS: Our findings indicate the seizure reduction efficacy of RNS is similar to DBS, and both had greater seizure reductions compared to VNS in the first-year post-implantation, with the differences diminishing with longer-term follow-up. SIGNIFICANCE: The results help guide neuromodulation treatment in eligible patients with drug-resistant focal epilepsy.

Characterization of resting functional MRI activity alterations across epileptic foci and networks.

Brain network alterations have been studied extensively in patients with mesial temporal lobe epilepsy (mTLE) and other focal epilepsies using resting-state functional magnetic resonance imaging (fMRI). However, little has been done to characterize the basic fMRI signal alterations caused by focal epilepsy. Here, we characterize how mTLE affects the fMRI signal in epileptic foci and networks. Resting-state fMRI and diffusion MRI were collected from 47 unilateral mTLE patients and 96 healthy controls. FMRI activity, quantified by amplitude of low-frequency fluctuations, was increased in the epileptic focus and connected regions in mTLE. Evidence for spread of this epileptic fMRI activity was found through linear relationships of regional activity across subjects, the association of these relationships with functional connectivity, and increased activity along white matter tracts. These fMRI activity increases were found to be dependent on the epileptic focus, where the activity was related to disease severity, suggesting the focus to be the origin of these pathological alterations. Furthermore, we found fMRI activity decreases in the default mode network of right mTLE patients with different properties than the activity increases found in the epileptic focus. This work provides insights into basic fMRI signal alterations and their potential spread across networks in focal epilepsy.

Network dysfunction in pre and postsurgical epilepsy: connectomics as a tool and not a destination.

PURPOSE OF REVIEW: Patients with focal drug-resistant epilepsy (DRE) sometimes continue to have seizures after surgery. Recently, there is increasing interest in using advanced network analyses (connectomics) to better understand this problem. Connectomics has changed the way researchers and clinicians view DRE, but it must be applied carefully in a hypothesis-driven manner to avoid spurious results. This review will focus on studies published in the last 18 months that have thoughtfully used connectomics to advance our fundamental understanding of network dysfunction in DRE - hopefully for the eventual direct benefit to patient care. RECENT FINDINGS: Impactful recent findings have centered on using patient-specific differences in network dysfunction to predict surgical outcome. These works span functional and structural connectivity and include the modalities of functional and diffusion magnetic resonance imaging (MRI) and electrophysiology. Using functional MRI, many groups have described an increased functional segregation outside of the surgical resection zone in patients who fail surgery. Using electrophysiology, groups have reported network characteristics of resected tissue that suggest whether a patient will respond favorably to surgery. SUMMARY: If we can develop accurate models to outline functional and structural network characteristics that predict failure of standard surgical approaches, then we can not only improve current clinical decision-making; we can also begin developing alternative treatments including network approaches to improve surgical success rates.

Temporal lobe epilepsy lateralisation and surgical outcome prediction using diffusion imaging.

OBJECTIVE: We sought to augment the presurgical workup of medically refractory temporal lobe epilepsy by creating a supervised machine learning technique that uses diffusion-weighted imaging to classify patient-specific seizure onset laterality and surgical outcome. METHODS: 151 subjects were included in this analysis: 62 patients (aged 18-68 years, 36 women) and 89 healthy controls (aged 18-71 years, 47 women). We created a supervised machine learning technique that uses diffusion-weighted metrics to classify subject groups. Specifically, we sought to classify patients versus healthy controls, unilateral versus bilateral temporal lobe epilepsy, left versus right temporal lobe epilepsy and seizure-free versus not seizure-free surgical outcome. We then reduced the dimensionality of derived features with community detection for ease of interpretation. RESULTS: We classified the subject groups in withheld testing data sets with a cross-fold average testing areas under the receiver operating characteristic curve of 0.745 for patients versus healthy controls, 1.000 for unilateral versus bilateral seizure onset, 0.662 for left versus right seizure onset, 0.800 for left-sided seizure-free vsersu not seizure-free surgical outcome and 0.775 for right-sided seizure-free versus not seizure-free surgical outcome. CONCLUSIONS: This technique classifies important clinical decisions in the presurgical workup of temporal lobe epilepsy by generating discerning white-matter features. We believe that this work augments existing network connectivity findings in the field by further elucidating important white-matter pathology in temporal lobe epilepsy. We hope that this work contributes to recent efforts aimed at using diffusion imaging as an augmentation to the presurgical workup of this devastating neurological disorder.

Neurostimulation in people with drug-resistant epilepsy: Systematic review and meta-analysis from the ILAE Surgical Therapies Commission.

OBJECTIVE: Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis. METHODS: We followed the Preferred Reporting Items of Systematic reviews and Meta-Analyses reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCTs) and their corresponding open-label extension studies, as well as prospective case series, with ≥20 participants (excluding studies limited to children). Our primary outcome was the mean (or median, when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included the proportion of treatment responders and proportion with seizure freedom. RESULTS: We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% confidence interval [CI]: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at 2, 5, and 9 years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at 2, 5, and 7 years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS, whereas a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, and cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS. SIGNIFICANCE: Neurostimulation modalities are an effective treatment option for drug-resistant epilepsy, with improving outcomes over time and few major complications. Seizure-reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS.

Timing of referral to evaluate for epilepsy surgery: Expert Consensus Recommendations from the Surgical Therapies Commission of the International League Against Epilepsy.

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.

OBJECTIVE: Clinical trials of a brain-responsive neurostimulator, RNS® System (RNS), excluded patients with a vagus nerve stimulator, VNS® System (VNS). The goal of this study was to evaluate seizure outcomes and safety of concurrent RNS and VNS stimulation in adults with drug-resistant focal-onset seizures. METHODS: A retrospective multicenter chart review was performed on all patients with an active VNS and RNS who were treated for a minimum of 6 months with both systems concurrently. Frequency of disabling seizures at baseline before RNS, at 1 year after RNS placement, and at last follow-up were used to calculate the change in seizure frequency after treatment. Data on adverse events and complications related to each device were collected. RESULTS: Sixty-four patients from 10 epilepsy centers met inclusion criteria. All but one patient received RNS after VNS. The median follow-up time after RNS implantation was 28 months. Analysis of the entire population of patients with active VNS and RNS systems revealed a median reduction in seizure frequency at 1 year post-RNS placement of 43% with a responder rate of 49%, and at last follow-up a 64% median reduction with a 67% responder rate. No negative interactions were reported from the concurrent use of VNS and RNS. Stimulation-related side-effects were reported more frequently in association with VNS (30%) than with RNS (2%). SIGNIFICANCE: Our findings suggest that concurrent treatment with VNS and RNS is safe and that the addition of RNS to VNS can further reduce seizure frequency.

People with mesial temporal lobe epilepsy have altered thalamo-occipital brain networks.

While temporal lobe epilepsy (TLE) is a focal epilepsy, previous work demonstrates that TLE causes widespread brain-network disruptions. Impaired visuospatial attention and learning in TLE may be related to thalamic arousal nuclei connectivity. Our prior preliminary work in a smaller patient cohort suggests that patients with TLE demonstrate abnormal functional connectivity between central lateral (CL) thalamic nucleus and medial occipital lobe. Others have shown pulvinar connectivity disturbances in TLE, but it is incompletely understood how TLE affects pulvinar subnuclei. Also, the effects of epilepsy surgery on thalamic functional connectivity remains poorly understood. In this study, we examine the effects of TLE on functional connectivity of two key thalamic arousal-nuclei: lateral pulvinar (PuL) and CL. We evaluate resting-state functional connectivity of the PuL and CL in 40 patients with TLE and 40 controls using fMRI. In 25 patients, postoperative images (>1 year) were also compared with preoperative images. Compared to controls, patients with TLE exhibit loss of normal positive connectivity between PuL and lateral occipital lobe (p < 0.05), and a loss of normal negative connectivity between CL and medial occipital lobe (p < 0.01, paired t-tests). FMRI amplitude of low-frequency fluctuation (ALFF) in TLE trended higher in ipsilateral PuL (p = 0.06), but was lower in the lateral occipital (p < 0.01) and medial occipital lobe in patients versus controls (p < 0.05, paired t-tests). More abnormal ALFF in the ipsilateral lateral occipital lobe is associated with worse preoperative performance on Rey Complex Figure Test Immediate (p < 0.05, r = 0.381) and Delayed scores (p < 0.05, r = 0.413, Pearson's Correlations). After surgery, connectivity between PuL and lateral occipital lobe remains abnormal in patients (p < 0.01), but connectivity between CL and medial occipital lobe improves and is no longer different from control values (p > 0.05, ANOVA, post hoc Fischer's LSD). In conclusion, thalamic arousal nuclei exhibit abnormal connectivity with occipital lobe in TLE, and some connections may improve after surgery. Studying thalamic arousal centers may help explain distal network disturbances in TLE.

Resting-state hippocampal networks related to language processing reveal unique patterns in temporal lobe epilepsy.

OBJECTIVE: Patients with temporal lobe epilepsy (TLE) commonly experience a broad range of language impairments. These deficits are thought to arise from repeated seizure activity that damages language regions. However, connectivity between the seizure onset region in the hippocampus and regions related to language processing has rarely been studied, and could also have a strong impact on language function. The purpose of this study was to use resting-state functional connectivity (FC) measures to assess hippocampal network patterns and their relation to language abilities in patients with right TLE (RLTE), left TLE (LTLE), and healthy controls. METHODS: Presurgical resting-state 3T functional MRI data were acquired from 40 patients with mesial TLE (27 RTLE, 13 LTLE) and 54 controls. The regions of interest were the anterior and posterior bilateral hippocampi and eleven regions grouped by frontal or temporo-parietal locations, including large areas of language-related cortex. FC values were computed with the right/left anterior and posterior hippocampi as the seeds and frontal and temporo-parietal regions as targets. Resting-state lateralization indices were also calculated (LI-Rest), and all FC measures were correlated to neuropsychological language scores and measures related to manifestation of epilepsy including age of onset, duration of disease, monthly seizure frequency, and hippocampal volume. RESULTS: We found significant group differences between the anterior hippocampi and temporo-parietal regions closest to the seizure focus, in which RTLE and LTLE showed stronger connectivity to their contralateral hippocampus, while controls showed similar connectivity to both hippocampi. In addition, LI-Rest demonstrated significantly more right lateralization in LTLE compared to RTLE for temporo-parietal regions only. In LTLE, we found significant associations between stronger hippocampal network resting-state FC and later age of onset and decreased left anterior hippocampal volume. SIGNIFICANCE: The results of our study indicate that the presence of TLE impacts hippocampal-temporo-parietal networks relevant to language processing.

Structural Correlates of the Sensorimotor Cerebellum in Parkinson's Disease and Essential Tremor.

BACKGROUND: Parkinson's disease (PD) and essential tremor (ET) are commonly encountered movement disorders. Pathophysiologic processes that localize to the cerebellum are described in both. There are limited studies investigating cerebellar structural changes in these conditions, largely because of inherent challenges in the efficiency of segmentation. METHODS: We applied a novel multiatlas cerebellar segmentation method to T1-weighted images in 282 PD and 111 essential tremor patients to define 26 cerebellar lobule volumes. The severity of postural and resting tremor in both populations and gait and postural instability in PD patients were defined using subscores of the UPDRS and Washington Heights-Inwood Genetic Study motor scales. These clinical measurements were related to lobule volume size. Multiple comparisons were controlled using a false discovery rate method. RESULTS: Group differences were identified between ET and PD patients, with reductions in deep cerebellar nucleus volume in ET versus reduced lobule VI volume in PD. In ET patients, lobule VIII was negatively correlated with the severity of postural tremor. In PD patients, lobule IV was positively correlated with resting tremor and total tremor severity. We observed differences in cerebellar structure that localized to sensorimotor lobules of the cerebellum. Lobule volumes appeared to differentially relate to clinical symptoms, suggesting important clinicopathologic distinctions between these conditions. These results emphasize the role of the cerebellum in tremor symptoms and should foster future clinical and pathologic investigations of the sensorimotor lobules of the cerebellum. © 2020 International Parkinson and Movement Disorder Society.