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.

Deep net detection and onset prediction of electrographic seizure patterns in responsive neurostimulation.

OBJECTIVE: Managing the progress of drug-resistant epilepsy patients implanted with the Responsive Neurostimulation (RNS) System requires the manual evaluation of hundreds of hours of intracranial recordings. The generation of these large amounts of data and the scarcity of experts' time for evaluation necessitate the development of automatic tools to detect intracranial electroencephalographic (iEEG) seizure patterns (iESPs) with expert-level accuracy. We developed an intelligent system for identifying the presence and onset time of iESPs in iEEG recordings from the RNS device. METHODS: An iEEG dataset from 24 patients (36 293 recordings) recorded by the RNS System was used for training and evaluating a neural network model (iESPnet). The model was trained to identify the probability of seizure onset at each sample point of the iEEG. The reliability of the net was assessed and compared to baseline methods, including detections made by the device. iESPnet performance was measured using balanced accuracy and the F1 score for iESP detection. The prediction time was assessed via both the error and the mean absolute error. The model was evaluated following a hold-one-out strategy, and then validated in a separate cohort of 26 patients from a different medical center. RESULTS: iESPnet detected the presence of an iESP with a mean accuracy value of 90% and an onset time prediction error of approximately 3.4 s. There was no relationship between electrode location and prediction outcome. Model outputs were well calibrated and unbiased by the RNS detections. Validation on a separate cohort further supported iESPnet applicability in real clinical scenarios. Importantly, RNS device detections were found to be less accurate and delayed in nonresponders; therefore, tools to improve the accuracy of seizure detection are critical for increasing therapeutic efficacy. SIGNIFICANCE: iESPnet is a reliable and accurate tool with the potential to alleviate the time-consuming manual inspection of iESPs and facilitate the evaluation of therapeutic response in RNS-implanted patients.

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.

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.

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.

Expert-Level Intracranial Electroencephalogram Ictal Pattern Detection by a Deep Learning Neural Network.

Background: Decision-making in epilepsy surgery is strongly connected to the interpretation of the intracranial EEG (iEEG). Although deep learning approaches have demonstrated efficiency in processing extracranial EEG, few studies have addressed iEEG seizure detection, in part due to the small number of seizures per patient typically available from intracranial investigations. This study aims to evaluate the efficiency of deep learning methodology in detecting iEEG seizures using a large dataset of ictal patterns collected from epilepsy patients implanted with a responsive neurostimulation system (RNS). Methods: Five thousand two hundred and twenty-six ictal events were collected from 22 patients implanted with RNS. A convolutional neural network (CNN) architecture was created to provide personalized seizure annotations for each patient. Accuracy of seizure identification was tested in two scenarios: patients with seizures occurring following a period of chronic recording (scenario 1) and patients with seizures occurring immediately following implantation (scenario 2). The accuracy of the CNN in identifying RNS-recorded iEEG ictal patterns was evaluated against human neurophysiology expertise. Statistical performance was assessed via the area-under-precision-recall curve (AUPRC). Results: In scenario 1, the CNN achieved a maximum mean binary classification AUPRC of 0.84 ± 0.19 (95%CI, 0.72-0.93) and mean regression accuracy of 6.3 ± 1.0 s (95%CI, 4.3-8.5 s) at 30 seed samples. In scenario 2, maximum mean AUPRC was 0.80 ± 0.19 (95%CI, 0.68-0.91) and mean regression accuracy was 6.3 ± 0.9 s (95%CI, 4.8-8.3 s) at 20 seed samples. We obtained near-maximum accuracies at seed size of 10 in both scenarios. CNN classification failures can be explained by ictal electro-decrements, brief seizures, single-channel ictal patterns, highly concentrated interictal activity, changes in the sleep-wake cycle, and progressive modulation of electrographic ictal features. Conclusions: We developed a deep learning neural network that performs personalized detection of RNS-derived ictal patterns with expert-level accuracy. These results suggest the potential for automated techniques to significantly improve the management of closed-loop brain stimulation, including during the initial period of recording when the device is otherwise naïve to a given patient's seizures.

Quantifying a frequency modulation response biomarker in responsive neurostimulation.

Objective.Responsive neurostimulation (RNS) is an effective treatment for controlling seizures in patients with drug-resistant focal epilepsy who are not suitable candidates for resection surgery. A lack of tools for detecting and characterizing potential response biomarkers, however, contributes to a limited understanding of mechanisms by which RNS improves seizure control. We developed a method to quantify ictal frequency modulation, previously identified as a biomarker of clinical responsiveness to RNS.Approach.Frequency modulation is characterized by shifts in power across spectral bands during ictal events, over several months of neurostimulation. This effect was quantified by partitioning each seizure pattern into segments with distinct spectral content and measuring the extent of change from the baseline distribution of spectral content using the squared earth mover's distance.Main results.We analyzed intracranial electroencephalography data from 13 patients who received RNS therapy, six of whom exhibited frequency modulation on expert evaluation. Patients in the frequency modulation group had, on average, significantly larger and more sustained changes in their squared earth mover's distances (mean = 13.97 × 10-3± 1.197 × 10-3). In contrast, those patients without expert-identified frequency modulation exhibited statistically insignificant or negligible distances (mean = 4.994 × 10-3± 0.732 × 10-3).Significance.This method is the first step towards a quantitative, feedback-driven system for systematically optimizing RNS stimulation parameters, with an ultimate goal of truly personalized closed-loop therapy for epilepsy.

Electrocorticography During Deep Brain Stimulation Surgery: Safety Experience From 4 Centers Within the National Institute of Neurological Disorders and Stroke Research Opportunities in Human Consortium.

BACKGROUND: Intraoperative research during deep brain stimulation (DBS) surgery has enabled major advances in understanding movement disorders pathophysiology and potential mechanisms for therapeutic benefit. In particular, over the last decade, recording electrocorticography (ECoG) from the cortical surface, simultaneously with subcortical recordings, has become an important research tool for assessing basal ganglia-thalamocortical circuit physiology. OBJECTIVE: To provide confirmation of the safety of performing ECoG during DBS surgery, using data from centers involved in 2 BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative-funded basic human neuroscience projects. METHODS: Data were collected separately at 4 centers. The primary endpoint was complication rate, defined as any intraoperative event, infection, or postoperative magnetic resonance imaging abnormality requiring clinical follow-up. Complication rates for explanatory variables were compared using point biserial correlations and Fisher exact tests. RESULTS: A total of 367 DBS surgeries involving ECoG were reviewed. No cortical hemorrhages were observed. Seven complications occurred: 4 intraparenchymal hemorrhages and 3 infections (complication rate of 1.91%; CI = 0.77%-3.89%). The placement of 2 separate ECoG research electrodes through a single burr hole (84 cases) did not result in a significantly different rate of complications, compared to placement of a single electrode (3.6% vs 1.5%; P = .4). Research data were obtained successfully in 350 surgeries (95.4%). CONCLUSION: Combined with the single report previously available, which described no ECoG-related complications in a single-center cohort of 200 cases, these findings suggest that research ECOG during DBS surgery did not significantly alter complication rates.

Neuromodulation of Epilepsy Networks.

Neuromodulation, including first-generation open-loop devices and second-generation closed-loop devices, is a valuable but poorly understood therapeutic option for patients with drug-refractory epilepsy. The precise therapy a patient receives is contingent on the relationship between the patient's own unique neurophysiology and the custom programming of detection and stimulation parameters. Recent evidence demonstrates that therapeutic efficacy can be achieved through neuromodulation of seizure networks, rather than simple disruption of seizure evolution. Nevertheless, the improvement in outcomes achieved combined with its minimally invasive, nondestructive nature make closed-loop stimulation a promising therapy for additional indications, such as generalized and pediatric epilepsy.

Responsive Neurostimulation of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy: A Case Report.

BACKGROUND AND IMPORTANCE: At least 25% of patients with idiopathic generalized epilepsy do not obtain adequate seizure control with medication. This report describes the first use of responsive neurostimulation (RNS), bilaterally targeting the centromedian/ventrolateral (CM/VL) region in a patient with drug-refractory Jeavons syndrome (eyelid myoclonia with absences). CLINICAL PRESENTATION: A patient, diagnosed with eyelid myoclonia with absences (EMA) and refractory to medication, was offered RNS treatment in the CM/VL region of the thalamus. Stimulation was triggered by thalamic neural activity having morphological, spectral, and synchronous features that corresponded to 3- to 5-Hz spike-wave discharges recorded on prior scalp electroencephalography. CONCLUSION: RNS decreased daily absence seizures from a mean of 60 to ≤10 and maintained the patient's level of consciousness during the occurring episodes. This therapy should be evaluated further for its potential to treat patients with pharmaco-refractory generalized epilepsy.

A Rational Approach to Understanding and Evaluating Responsive Neurostimulation.

Closed-loop brain stimulation is increasingly used in level 4 epilepsy centers without an understanding of how the device behaves on a daily basis. This lack of insight is a barrier to improving closed-loop therapy and ultimately understanding why some patients never achieve seizure reduction. We aimed to quantify the accuracy of closed-loop seizure detection and stimulation on the RNS device through extrapolating information derived from manually reviewed ECoG recordings and comprehensive device logging information. RNS System event logging data were obtained, reviewed, and analyzed using a custom-built software package. A weighted-means methodology was developed to adjust for bias and incompleteness in event logs and evaluated using Bland-Altman plots and Wilcoxon signed-rank tests to compare adjusted and non-weighted (standard method) results. Twelve patients implanted for a mean of 21.5 (interquartile range 13.5-31) months were reviewed. The mean seizure frequency reduction post-RNS implantation was 40.1% (interquartile range 0-96.2%). Three primary levels of event logging granularity were identified (ECoG recordings: 3.0% complete (interquartile range 0.3-1.8%); Event Lists: 72.9% complete (interquartile range 44.7-99.8%); Activity Logs: 100% complete; completeness measured with respect to Activity Logs). Bland-Altman interpretation confirmed non-equivalence with unpredictable differences in both magnitude and direction. Wilcoxon signed rank tests demonstrated significant (p < 10-6) differences in accuracy, sensitivity, and specificity at >5% absolute mean difference for extrapolated versus standard results. Device behavior logged by the RNS System should be used in conjunction with careful review of stored ECoG data to extrapolate metrics for detector performance and stimulation.

Safety and efficacy of repeat radiosurgery for acromegaly: an International Multi-Institutional Study.

PURPOSE: Surgical resection is the first line treatment for growth hormone (GH) secreting tumors. Stereotactic radiosurgery (SRS) is recommended for patients who do not achieve endocrine remission after resection. The purpose of this study was to evaluate safety and efficacy of repeat radiosurgery for acromegaly. METHODS: Three hundred and ninety-eight patients with acromegaly treated with the Gamma Knife radiosurgery (Elekta AB, Stockholm) were identified from the International Gamma Knife Research Foundation database. Among these, 21 patients underwent repeated SRS with sufficient endocrine follow-up and 18 patients had sufficient imaging follow-up. Tumor control was defined as lack of adenoma progression on imaging. Endocrine remission was defined as a normal IGF-1 concentration while off medical therapy. RESULTS: Median time from initial SRS to repeat SRS was 5.0 years. The median imaging and endocrine follow-up duration after repeat SRS was 3.4 and 3.8 years, respectively. The median initial marginal dose was 17 Gy, and the median repeat marginal dose was 23 Gy. Of the 18 patients with adequate imaging follow up, 15 (83.3%) patients had tumor control and of 21 patients with endocrine follow-up, 9 (42.9%) patients had endocrine remission at last follow-up visit. Four patients (19.0%) developed new deficits after repeat radiosurgery. Of these, 3 patients had neurologic deficits and 1 patient had endocrine deficit. CONCLUSIONS: Repeat radiosurgery for persistent acromegaly offers a reasonable benefit to risk profile for this challenging patient cohort. Further studies are needed to identify patients best suited for this type of approach.

Long term results of primary radiosurgery for vestibular schwannomas.

BACKGROUND: Stereotactic radiosurgery (SRS) has become a primary option for management for both newly diagnosed vestibular schwannomas (VS), as well as VS that enlarge after initial observation. METHODS: A retrospective review of our prospectively maintained data base found 871 patients who underwent Gamma knife® SRS as their initial (primary) management between 1987 and 2008. Follow-up ranged from 1-25 years (median = 5.2 years) Median tumor volume was 0.9 cc (0.02-36) and median margin dose was 13 Gy (12-25). RESULTS: Progression free survival (PFS) after SRS was 97% at 3 years, 95% at 5 years, and 94% at 10 years. Freedom from delayed surgical resection was found in 98.7% of patients. Smaller tumor volume was significantly associated with improved PFS. There were 326 patients with serviceable hearing (Gardner-Robertson 1 or 2) at the time of SRS with audiological follow-up of ≥ 1 year. Serviceable hearing preservation rates after SRS were 89.8% at 1 year, 76.9% at 3 years, 68.4% at 5 years, 62.5% at 7 years, and 51.4% at 10 years. Factors associated with improved serviceable hearing preservation included younger age, Gardner-Robertson grade 1 at SRS, and absence of subjective complaints of dysequilibrium or vertigo (vestibulopathy). Fifty-one patients (5.8%) developed trigeminal neuropathy. Fourteen (1.6%) developed a transient House-Brackmann grade 2 or 3 facial neuropathy. CONCLUSIONS: In this report with extended follow-up, primary SRS achieved tumor growth control in 94% of patients. Optimization of long- term cranial nerve outcomes remains an important achievement of this management strategy for VS.

The benefit and risk of stereotactic radiosurgery for prolactinomas: an international multicenter cohort study.

OBJECTIVE: The most common functioning pituitary adenoma is prolactinoma. Patients with medically refractory or residual/recurrent tumors that are not amenable to resection can be treated with stereotactic radiosurgery (SRS). The aim of this multicenter study was to evaluate the role of SRS for treating prolactinomas. METHODS: This retrospective study included prolactinomas treated with SRS between 1997 and 2016 at ten institutions. Patients' clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications. RESULTS: The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087). CONCLUSIONS: In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event.

Gamma Knife radiosurgery for the treatment of Nelson's syndrome: a multicenter, international study.

OBJECTIVE: Nelson's syndrome is a rare and challenging neuroendocrine disorder, and it is associated with elevated adrenocorticotrophic hormone (ACTH) level, skin hyperpigmentation, and pituitary adenoma growth. Management options including resection and medical therapy are traditional approaches. Ionizing radiation in the form of Gamma Knife radiosurgery (GKRS) is also being utilized to treat Nelson's syndrome. In the current study the authors sought to better define the therapeutic role of stereotactic radiosurgery (SRS) in Nelson's syndrome. METHODS: Study patients with Nelson's syndrome were treated with single-fraction GKRS (median margin dose of 25 Gy) at 6 different centers as part of an International Radiosurgery Research Foundation (IRRF) investigation. Data including neurological function, endocrine response, and radiological tumor response were collected and sent to the study-coordinating center for review. Fifty-one patients with median endocrine and radiological follow-ups of 91 and 80.5 months from GKRS, respectively, were analyzed for endocrine remission, tumor control, and neurological outcome. Statistical methods were used to identify prognostic factors for these endpoints. RESULTS: At last follow-up, radiological tumor control was achieved in 92.15% of patients. Endocrine remission off medical management and reduction in pre-SRS ACTH level were achieved in 29.4% and 62.7% of patients, respectively. Improved remission rates were associated with a shorter time interval between resection and GKRS (p = 0.039). Hypopituitarism was seen in 21.6% and new visual deficits were demonstrated in 15.7% of patients. CONCLUSIONS: GKRS affords a high rate of pituitary adenoma control and improvement in ACTH level for the majority of Nelson's syndrome patients. Hypopituitarism is the most common adverse effect from GKRS in Nelson's syndrome patients and warrants longitudinal follow-up for detection and endocrine replacement.

Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy.

Importance: A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown. Objective: To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes. Design, Setting, and Participants: Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer's management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern. Main Outcomes and Measures: Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement. Results: Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects-those occurring remote from triggered stimulation-were associated with improved clinical outcomes (OR, infinity; 95% CI, -infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation. Conclusions and Relevance: These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

Stereotactic Radiosurgery for Acromegaly: An International Multicenter Retrospective Cohort Study.

BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment option for persistent or recurrent acromegaly secondary to a growth hormone secreting pituitary adenoma, but its efficacy is inadequately defined. OBJECTIVE: To assess, in a multicenter, retrospective cohort study, the outcomes of SRS for acromegaly and determine predictors. METHODS: We pooled and analyzed data from 10 participating institutions of the International Gamma Knife Research Foundation for patients with acromegaly who underwent SRS with endocrine follow-up of ≥6 mo. RESULTS: The study cohort comprised 371 patients with a mean endocrine follow-up of 79 mo. IGF-1 lowering medications were held in 56% of patients who were on pre-SRS medical therapy. The mean SRS treatment volume and margin dose were 3.0 cm3 and 24.2 Gy, respectively. The actuarial rates of initial and durable endocrine remission at 10 yr were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 mo. Biochemical relapse after initial remission occurred in 9%, with a mean time to recurrence of 17 mo. Cessation of IGF-1 lowering medication prior to SRS was the only independent predictor of durable remission (P = .01). Adverse radiation effects included the development of ≥1 new endocrinopathy in 26% and ≥1 cranial neuropathy in 4%. CONCLUSION: SRS is a definitive treatment option for patients with persistent or recurrent acromegaly after surgical resection. There appears to be a statistical association between the cessation of IGF-1 lowering medications prior to SRS and durable remission.

Closed-Loop Brain Stimulation for Drug-Resistant Epilepsy: Towards an Evidence-Based Approach to Personalized Medicine.

Closed-loop brain stimulation is one of the few treatments available for patients who are ineligible for traditional surgical resection of the epileptogenic zone, due to having generalized epilepsy, multifocal epilepsy, or focal epilepsy localized to an eloquent brain region. Due to its clinical efficacy and potential to delivery personalized therapy based on an individual's own intracerebral electrophysiology, this treatment is becoming an important part of clinical practice, despite a limited understanding of how to program detection and stimulation parameters for optimal, patient-specific benefit. To bring this challenge into focus, we review the evolution of neural stimulation for epilepsy, provide a technical overview of the RNS System (the only FDA-approved closed-loop device), and discuss the major challenges of working with a closed-loop device. We then propose an evidence-based solution for individualizing therapy that is driven by a bottom-up informatics approach.

Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study.

BACKGROUND: A major concern of patients who have stereotactic radiosurgery is the long-term risk of having a secondary intracranial malignancy or, in the case of patients with benign tumours treated with the technique, the risk of malignant transformation. The incidence of stereotactic radiosurgery-associated intracranial malignancy remains unknown; therefore, our aim was to estimate it in a population-based study to assess the long-term safety of this technique. METHODS: We did a population-based, multicentre, cohort study at five international radiosurgery centres (Na Homolce Hospital, Prague, Czech Republic [n=2655 patients]; Ruber International Hospital, Madrid, Spain [n=1080], University of Pittsburgh Medical Center, Pittsburgh, PA, USA [n=1027]; University of Virginia, Charlottesville, VA, USA [n=80]; and NYU Langone Health System, New York, NY, USA [n=63]). Eligible patients were of any age, and had Gamma Knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumours, which included vestibular or other benign schwannomas, WHO grade 1 meningiomas, pituitary adenomas, and haemangioblastoma. Patients were excluded if they had previously had radiotherapy or did not have a minimum follow-up time of 5 years. The primary objective of the study was to estimate the incidence of stereotactic radiosurgery-associated intracranial malignancy, including malignant transformation of a benign lesion or development of radiation-associated secondary intracranial cancer, defined as within the 2 Gy isodose line. Estimates of age-adjusted incidence of primary CNS malignancies in the USA and European countries were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer (IARC) Global Cancer statistics. FINDINGS: Of 14 168 patients who had Gamma Knife stereotactic radiosurgery between Aug 14, 1987, and Dec 31, 2011, in the five contributing centres, 4905 patients were eligible for the analysis (had a minimum follow-up of 5 years and no history of previous radiation therapy). Diagnostic entities included vestibular schwannomas (1011 [20·6%] of 4905 patients), meningiomas (1490 [30·4%]), arteriovenous malformations (1089 [22·2%]), trigeminal neuralgia (565 [11·5%]), pituitary adenomas (641 [13·1%]), haemangioblastoma (29 [0·6%]), and other schwannomas (80 [1·6%]). With a median follow-up of 8·1 years (IQR 6·0-10·6), two (0·0006%) of 3251 patients with benign tumours were diagnosed with suspected malignant transformation and one (0·0002%) of 4905 patients was considered a case of radiosurgery-associated intracranial malignancy, resulting in an incidence of 6·87 per 100 000 patient-years (95% CI 1·15-22·71) for malignant transformation and 2·26 per 100 000 patient-years (0·11-11·17) for radiosurgery-associated intracranial malignancy. Two (0·0004%) of 4905 patients developed intracranial malignancies, which were judged unrelated to the radiation field. Overall incidence of radiosurgery-associated malignancy was 6·80 per 100 000 patients-years (95% CI 1·73-18·50), or a cumulative incidence of 0·00045% over 10 years (95% CI 0·00-0·0034). The overall incidence of 6·8 per 100 000, which includes institutions from Europe and the USA, after stereotactic radiosurgery was found to be similar to the risk of developing a malignant CNS tumour in the general population of the USA and some European countries as estimated by the CBTRUS and IARC data, respectively. INTERPRETATION: These data show that the estimated risk of an intracranial secondary malignancy or malignant transformation of a benign tumour in patients treated with stereotactic radiosurgery remains low at long-term follow-up, and is similar to the risk of the general population to have a primary CNS tumour. Although prospective cohort studies with longer follow-up are warranted to support the results of this study, the available evidence suggests the long-term safety of stereotactic radiosurgery and could support physicians counselling patients on Gamma Knife stereotactic radiosurgery. FUNDING: None.

Upfront Gamma Knife radiosurgery for Cushing's disease and acromegaly: a multicenter, international study.

OBJECTIVE: Gamma Knife radiosurgery (GKS) is typically used after failed resection in patients with Cushing's disease (CD) and acromegaly. Little is known about the upfront role of GKS for patients with CD and acromegaly. In this study, the authors examine the outcome of upfront GKS for patients with these functioning adenomas. METHODS: An international group of 7 Gamma Knife centers sent pooled data from 46 patients (21 with CD and 25 with acromegaly) undergoing upfront GKS to the coordinating center of the study for analysis. Diagnosis was established on the basis of clinical, endocrine, and radiological studies. All patients were treated on a common radiosurgical platform and longitudinally followed for tumor control, endocrine remission, and hypopituitarism. Patients received a tumor median margin dose of 25 Gy (range 12-40.0 Gy) at a median isodose of 50%. RESULTS: The median endocrine follow-up was 69.5 months (range 9-246 months). Endocrine remission was achieved in 51% of the entire cohort, with 28% remission in acromegaly and 81% remission for those with CD at the 5-year interval. Patients with CD achieved remission earlier as compared to those with acromegaly (p = 0.0005). In patients post-GKS, the pituitary adenoma remained stable (39%) or reduced (61%) in size. Hypopituitarism occurred in 9 patients (19.6%), and 1 (2.2%) developed third cranial nerve (CN III) palsy. Eight patients needed further intervention, including repeat GKS in 6 and transsphenoidal surgery in 2. CONCLUSIONS: Upfront GKS resulted in good tumor control as well as a low rate of adverse radiation effects in the whole group. Patients with CD achieved a faster and far better remission rate after upfront GKS in comparison to patients with acromegaly. GKS can be considered as an upfront treatment in carefully selected patients with CD who are unwilling or unable to undergo resection, but it has a more limited role in acromegaly.