Guidelines for Specialized Epilepsy Centers: Executive Summary of the Report of the National Association of Epilepsy Centers Guideline Panel.

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Specific afterdischarge properties can enhance the clinical utility of electrical stimulation mapping during intracranial monitoring.

OBJECTIVE: Extraoperative electrical cortical stimulation (ECS) facilitates defining the seizure onset zone (SOZ) and eloquent cortex. The clinical relevance of stimulation-induced afterdischarges (ADs) is not well defined. METHODS: Fifty-five patients who underwent intracranial electroencephalogram evaluations with ECS were retrospectively identified. ADs were identified in these recordings and categorized by pattern, location, and association with stimulation-induced seizures. RESULTS: ADs were generated in 1774/9285 (19%) trials. Rhythmic spikes and irregular ADs within the stimulated bipolar contact pair were predictive of location within the SOZ compared to non-epileptogenic/non-irritative cortex (rhythmic spikes OR 2.24, p = 0.0098; irregular OR 1.39; p = 0.013). ADs immediately preceding stimulated seizures occurred at lower stimulation intensity thresholds compared to other stimulations (mean 2.94 ± 0.28 mA vs. 4.16 ± 0.05 mA respectively; p = 0.0068). CONCLUSIONS: Changes in AD properties can provide clinically relevant data in extraoperative stimulation mapping. SIGNIFICANCE: Although not exclusive to the SOZ, the generation of rhythmic spikes may suggest that a stimulation location is within the SOZ, while decreased stimulation intensity thresholds eliciting ADs may alert clinicians to a heightened probability of seizure generation with subsequent stimulation.

The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

Spatiotemporally-specific cortical-subthalamic coupling differentiates aspects of speech performance.

Speech provides a rich context for exploring human cortical-basal ganglia circuit function, but direct intracranial recordings are rare. We recorded electrocorticographic signals in the cortex synchronously with single units in the subthalamic nucleus (STN), a basal ganglia node that receives direct input from widespread cortical regions, while participants performed a syllable repetition task during deep brain stimulation (DBS) surgery. We discovered that STN neurons exhibited spike-phase coupling (SPC) events with distinct combinations of frequency, location, and timing that indexed specific aspects of speech. The strength of SPC to posterior perisylvian cortex predicted phoneme production accuracy, while that of SPC to perirolandic cortex predicted time taken for articulation Thus, STN-cortical interactions are coordinated via transient bursts of behavior-specific synchronization that involves multiple neuronal populations and timescales. These results both suggest mechanisms that support auditory-sensorimotor integration during speech and explain why firing-rate based models are insufficient for explaining basal ganglia circuit behavior.

Epilepsy Surgery for Cognitive Improvement in Epileptic Encephalopathy.

Epileptic encephalopathies are defined by the presence of frequent epileptiform activity that causes neurodevelopmental slowing or regression. Here, we review evidence that epilepsy surgery improves neurodevelopment in children with epileptic encephalopathies. We describe an example patient with epileptic encephalopathy without drug refractory seizures, who underwent successful diagnostic and therapeutic surgeries. In patients with epileptic encephalopathy, cognitive improvement alone is a sufficient indication to recommend surgical intervention in experienced centers.

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Implantation accuracy and operative variables in robot-assisted stereoelectroencephalography.

OBJECTIVE: The stereoelectroencephalography (SEEG) procedure provides a unique 3D overview of the seizure-onset zone. Although the success of SEEG relies on the accuracy of depth electrode implantation, few studies have investigated how different implantation techniques and operative variables affect accuracy. This study examined the effect of two different electrode implantation techniques (external vs internal stylet) on implantation accuracy while controlling for other operative variables. METHODS: The implantation accuracy of 508 depth electrodes from 39 SEEG cases was measured after coregistration of postimplantation CT or MR images with planned trajectories. Two different implantation techniques were compared: preset length with internal stylet use and measured length with external stylet use. Correlations between implantation accuracy and technique type, entry angle, intended implantation depth, and other operative variables were determined statistically using multiple regression analysis. RESULTS: Multiple regression analysis showed that the internal stylet technique exhibited a larger target radial error (p = 0.046) and angular deviation (p = 0.039) with a smaller depth error (p < 0.001) than the external stylet technique. Entry angle and implantation depth were positively correlated with target radial error (p = 0.007 and < 0.001, respectively) only for the internal stylet technique. CONCLUSIONS: Better target radial accuracy was achieved when an external stylet was used to open the intraparenchymal pathway for the depth electrode. In addition, more oblique trajectories were equally accurate to orthogonal ones with the usage of an external stylet, while more oblique trajectories were associated with larger target radial errors with the usage of an internal stylet (without an external stylet).

Future directions in psychiatric neurosurgery: Proceedings of the 2022 American Society for Stereotactic and Functional Neurosurgery meeting on surgical neuromodulation for psychiatric disorders.

OBJECTIVE: Despite advances in the treatment of psychiatric diseases, currently available therapies do not provide sufficient and durable relief for as many as 30-40% of patients. Neuromodulation, including deep brain stimulation (DBS), has emerged as a potential therapy for persistent disabling disease, however it has not yet gained widespread adoption. In 2016, the American Society for Stereotactic and Functional Neurosurgery (ASSFN) convened a meeting with leaders in the field to discuss a roadmap for the path forward. A follow-up meeting in 2022 aimed to review the current state of the field and to identify critical barriers and milestones for progress. DESIGN: The ASSFN convened a meeting on June 3, 2022 in Atlanta, Georgia and included leaders from the fields of neurology, neurosurgery, and psychiatry along with colleagues from industry, government, ethics, and law. The goal was to review the current state of the field, assess for advances or setbacks in the interim six years, and suggest a future path forward. The participants focused on five areas of interest: interdisciplinary engagement, regulatory pathways and trial design, disease biomarkers, ethics of psychiatric surgery, and resource allocation/prioritization. The proceedings are summarized here. CONCLUSION: The field of surgical psychiatry has made significant progress since our last expert meeting. Although weakness and threats to the development of novel surgical therapies exist, the identified strengths and opportunities promise to move the field through methodically rigorous and biologically-based approaches. The experts agree that ethics, law, patient engagement, and multidisciplinary teams will be critical to any potential growth in this area.

Accurate Deep Brain Stimulation Lead Placement Concurrent With Research Electrocorticography.

BACKGROUND: Using electrocorticography for research (R-ECoG) during deep brain stimulation (DBS) surgery has advanced our understanding of human cortical-basal ganglia neurophysiology and mechanisms of therapeutic circuit modulation. The safety of R-ECoG has been established, but potential effects of temporary ECoG strip placement on targeting accuracy have not been reported. OBJECTIVE: To determine whether temporary subdural electrode strip placement during DBS implantation surgery affects lead implantation accuracy. METHODS: Twenty-four consecutive patients enrolled in a prospective database who underwent awake DBS surgery were identified. Ten of 24 subjects participated in R-ECoG. Lead locations were determined after fusing postoperative computed tomography scans into the surgical planning software. The effect of brain shift was quantified using Lead-DBS and analyzed in a mixed-effects model controlling for time interval to postoperative computed tomography. Targeting accuracy was reported as radial and Euclidean distance errors and compared with Mann-Whitney tests. RESULTS: Neither radial error nor Euclidean distance error differed significantly between R-ECoG participants and nonparticipants. Pneumocephalus volume did not differ between the 2 groups, but brain shift was slightly greater with R-ECoG. Pneumocephalus volume correlated with brain shift, but neither of these measures significantly correlated with Euclidean distance error. There were no complications in either group. CONCLUSION: In addition to an excellent general safety profile as has been reported previously, these results suggest that performing R-ECoG during DBS implantation surgery does not affect the accuracy of lead placement.

Closed-Loop Brain Stimulation and Paradigm Shifts in Epilepsy Surgery.

Advances in device technology have created greater flexibility in treating seizures as emergent properties of networks that exist on a local to global continuum. All patients with drug-resistant epilepsy are potential surgical candidates, given that intracranial neuromodulation through deep brain stimulation and responsive neurostimulation can reduce seizures and improve quality of life, even in multifocal and generalized epilepsies. To achieve this goal, indications and strategies for diagnostic epilepsy surgery are evolving. This article describes the state-of-the-art in epilepsy surgery and related changes in how we define indications for diagnostic and therapeutic surgical intervention.

Hyperdirect connectivity of opercular speech network to the subthalamic nucleus.

How the basal ganglia participate in the uniquely human behavior of speech is poorly understood, despite their known role in modulating critical aspects of cognitive and motor behavior. The subthalamic nucleus (STN) is well positioned to facilitate basal ganglia functions critical for speech. Using electrocorticography in patients undergoing awake deep brain stimulation (DBS) surgery, evidence is reported for a left opercular hyperdirect pathway in humans via stimulating the STN and examining antidromic-evoked activity in the left temporal, parietal, and frontal opercular cortex. These high-resolution cortical and subcortical mapping data provide evidence for hyperdirect connectivity between the inferior frontal gyrus and the STN. In addition, evoked potential data are consistent with the presence of monosynaptic projections from areas of the opercular speech cortex that are primarily sensory, including the auditory cortex, to the STN. These connections may be unique to humans, evolving alongside the ability for speech.

Responsive neurostimulation of the thalamus improves seizure control in idiopathic generalised epilepsy: initial case series.

OBJECTIVES: Up to 40% of patients with idiopathic generalised epilepsy (IGE) are drug resistant and potentially could benefit from intracranial neuromodulation of the seizure circuit. We present outcomes following 2 years of thalamic-responsive neurostimulation for IGE. METHODS: Four patients with pharmacoresistant epilepsy underwent RNS System implantation in the bilateral centromedian (CM) nucleus region. Electrophysiological data were extracted from the clinical patient data management system and analysed using a specialised platform (BRAINStim). Postoperative visualisation of electrode locations was performed using Lead-DBS. Seizure outcomes were reported using the Engel scale. RESULTS: Patients experienced a 75%-99% reduction in seizure frequency with decreased seizure duration and severity (Engel class IB, IC, IIA and IIIA), as well as significant improvements in quality of life. Outcomes were durable through at least 2 years of therapy. Detection accuracy for all patients overall decreased over successive programming epochs from a mean of 96.5% to 88.3%. Most electrodes used to deliver stimulation were located in the CM (7/10) followed by the posterior dorsal ventral lateral (2/2), posterior ventral posterior lateral (3/4) and posterior ventral ventral lateral (2/3). In all patients, stimulation varied from 0.2 to 2.0 mA and amplitude only increased over successive epochs. The raw percentage of intracranial electroencephalography recordings with stimulations delivered to electrographic seizures was 24.8%, 1.2%, 7.6% and 8.8%. CONCLUSION: Closed-loop stimulation of the CM region may provide significant improvement in seizure control and quality of life for patients with drug-resistant IGE. Optimal detection and stimulation locations and parameters remain an active area of investigation for accelerating and fine-tuning clinical responses.

Differentiation of speech-induced artifacts from physiological high gamma activity in intracranial recordings.

There is great interest in identifying the neurophysiological underpinnings of speech production. Deep brain stimulation (DBS) surgery is unique in that it allows intracranial recordings from both cortical and subcortical regions in patients who are awake and speaking. The quality of these recordings, however, may be affected to various degrees by mechanical forces resulting from speech itself. Here we describe the presence of speech-induced artifacts in local-field potential (LFP) recordings obtained from mapping electrodes, DBS leads, and cortical electrodes. In addition to expected physiological increases in high gamma (60-200 Hz) activity during speech production, time-frequency analysis in many channels revealed a narrowband gamma component that exhibited a pattern similar to that observed in the speech audio spectrogram. This component was present to different degrees in multiple types of neural recordings. We show that this component tracks the fundamental frequency of the participant's voice, correlates with the power spectrum of speech and has coherence with the produced speech audio. A vibration sensor attached to the stereotactic frame recorded speech-induced vibrations with the same pattern observed in the LFPs. No corresponding component was identified in any neural channel during the listening epoch of a syllable repetition task. These observations demonstrate how speech-induced vibrations can create artifacts in the primary frequency band of interest. Identifying and accounting for these artifacts is crucial for establishing the validity and reproducibility of speech-related data obtained from intracranial recordings during DBS surgery.

Intracranial monitoring contributes to seizure freedom for temporal lobectomy patients with nonconcordant preoperative data.

OBJECTIVE: The question of whether a patient with presumed temporal lobe seizures should proceed directly to temporal lobectomy surgery versus undergo intracranial monitoring arises commonly. We evaluate the effect of intracranial monitoring on seizure outcome in a retrospective cohort of consecutive subjects who specifically underwent an anterior temporal lobectomy (ATL) for refractory temporal lobe epilepsy (TLE). METHODS: We performed a retrospective analysis of 85 patients with focal refractory TLE who underwent ATL following: (a) intracranial monitoring via craniotomy and subdural/depth electrodes (SDE/DE), (b) intracranial monitoring via stereotactic electroencephalography (sEEG), or (c) no intracranial monitoring (direct ATL-dATL). For each subject, the presurgical primary hypothesis for epileptogenic zone localization was characterized as unilateral TLE, unilateral TLE plus (TLE+), or TLE with bilateral/poor lateralization. RESULTS: At one-year and most recent follow-up, Engel Class I and combined I/II outcomes did not differ significantly between the groups. Outcomes were better in the dATL group compared to the intracranial monitoring groups for lesional cases but were similar in nonlesional cases. Those requiring intracranial monitoring for a hypothesis of TLE+had similar outcomes with either intracranial monitoring approach. sEEG was the only approach used in patients with bilateral or poorly lateralized TLE, resulting in 77.8% of patients seizure-free at last follow-up. Importantly, for 85% of patients undergoing SEEG, recommendation for ATL resulted from modifying the primary hypothesis based on iEEG data. SIGNIFICANCE: Our study highlights the value of intracranial monitoring in equalizing seizure outcomes in difficult-to-treat TLE patients undergoing ATL.

Hippocampal spindles and barques are normal intracranial electroencephalographic entities.

OBJECTIVE: To assess whether hippocampal spindles and barques are markers of epileptogenicity. METHODS: Focal epilepsy patients that underwent stereo-electroencephalography implantation with at least one electrode in their hippocampus were selected (n = 75). The occurrence of spindles and barques in the hippocampus was evaluated in each patient. We created pairs of pathologic and pathology-free groups according to two sets of criteria: 1. Non-invasive diagnostic criteria (patients grouped according to focal epilepsy classification). 2. Intracranial neurophysiological criteria (patient's hippocampi grouped according to their seizure onset involvement). RESULTS: Hippocampal spindles and barques appear equally often in both pathologic and pathology-free groups, both for non-invasive (Pspindles = 0.73; Pbarques = 0.46) and intracranial criteria (Pspindles = 0.08; Pbarques = 0.26). In Engel Class I patients, spindles occurred with similar incidence both within the non-invasive (P = 0.67) and the intracranial criteria group (P = 0.20). Barques were significantly more frequent in extra-temporal lobe epilepsy defined by either non-invasive (P = 0.01) or intracranial (P = 0.01) criteria. CONCLUSIONS: Both spindles and barques are normal entities of the hippocampal intracranial electroencephalogram. The presence of barques may also signify lack of epileptogenic properties in the hippocampus. SIGNIFICANCE: Understanding that hippocampal spindles and barques do not reflect epileptogenicity is critical for correct interpretation of epilepsy surgery evaluations and appropriate surgical treatment selection.

Extrapial Hippocampal Resection in Anterior Temporal Lobectomy: Technical Description and Clinical Outcomes in a 62-Patient Case Series.

BACKGROUND: Anterior temporal lobectomy (ATL) is the most effective treatment for drug-resistant mesial temporal lobe epilepsy. Extrapial en bloc hippocampal resection facilitates complete removal of the hippocampus. With increasing use of minimally invasive treatments, considering open resection techniques that optimize the integrity of tissue specimens is important both for obtaining the correct histopathological diagnosis and for further study. OBJECTIVE: To describe the operative strategy and clinical outcomes associated with an extrapial approach to hippocampal resection during ATL. METHODS: A database of epilepsy surgeries performed by a single surgeon between October 2011 and February 2019 was reviewed to identify all patients who underwent ATL using an extrapial approach to hippocampal resection. To reduce confounding variables for outcome analysis, subjects with prior resections, tumors, and cavernous malformations were excluded. Seizure outcomes were classified using the Engel scale. RESULTS: The surgical technique is described and illustrated with intraoperative images. A total of 62 patients met inclusion criteria (31 females) for outcome analysis. Patients with most recent follow-up <3 yr (n = 33) and >3 yr (n = 29) exhibited 79% and 52% class I outcomes, respectively. An infarct was observed on postoperative magnetic resonance imaging in 3 patients (1 asymptomatic and 2 temporarily symptomatic). An en bloc specimen in which the subiculum and all hippocampal subfields were preserved was obtained in each case. Examples of innovative research opportunities resulting from this approach are presented. CONCLUSION: Extrapial resection of the hippocampus can be performed safely with seizure freedom and complication rates at least as good as those reported with the use of subpial techniques.

Convection-Enhanced Delivery and Principles of Extracellular Transport in the Brain.

Stereotactic neurosurgery involves a targeted intervention based on congruence of image guidance to a reference fiducial system. This discipline has widespread applications in radiosurgery, tumor therapy, drug delivery, functional lesioning, and neuromodulation. In this article, we focused on convection-enhanced delivery to deliver therapeutic agents to the brain addressing areas of research and clinical development. We performed a robust literature review of all relevant articles highlighting current efforts and challenges of making this delivery technique more widely understood. We further described key biophysical properties of molecular transport in the extracellular space that may impact the efficacy and control of drug delivery using stereotactic methods. Understanding these principles is critical for further refinement of predictive models that can inform advances in stereotactic techniques for convection-enhanced delivery of therapeutic agents to the brain.