Advancing thalamic neuromodulation in epilepsy: Bridging adult data to pediatric care.

Thalamic neuromodulation has emerged as a treatment option for drug-resistant epilepsy (DRE) with widespread and/or undefined epileptogenic networks. While deep brain stimulation (DBS) and responsive neurostimulation (RNS) depth electrodes offer means for electrical stimulation of the thalamus in adult patients with DRE, the application of thalamic neuromodulation in pediatric epilepsy remains limited. To address this gap, the Neuromodulation Expert Collaborative was established within the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Special Interest Group. In this expert review, existing evidence and recommendations for thalamic neuromodulation modalities using DBS and RNS are summarized, with a focus on the anterior (ANT), centromedian(CMN), and pulvinar nuclei of the thalamus. To-date, only DBS of the ANT is FDA approved for treatment of DRE in adult patients based on the results of the pivotal SANTE (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy) study. Evidence for other thalamic neurmodulation indications and targets is less abundant. Despite the lack of evidence, positive responses to thalamic stimulation in adults with DRE have led to its off-label use in pediatric patients. Although caution is warranted due to differences between pediatric and adult epilepsy, the efficacy and safety of pediatric neuromodulation appear comparable to that in adults. Indeed, CMN stimulation is increasingly accepted for generalized and diffuse onset epilepsies, with recent completion of one randomized trial. There is also growing interest in using pulvinar stimulation for temporal plus and posterior quadrant epilepsies with one ongoing clinical trial in Europe. The future of thalamic neuromodulation holds promise for revolutionizing the treatment landscape of childhood epilepsy. Ongoing research, technological advancements, and collaborative efforts are poised to refine and improve thalamic neuromodulation strategies, ultimately enhancing the quality of life for children with DRE.

Pediatric neuromodulation for drug-resistant epilepsy: Survey of current practices, techniques, and outcomes across US epilepsy centers.

Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug-resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty-two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6-10 new RNS devices per year; all DBS programs implant <5 annually. The youngest RNS patient was 3 years old. Most centers (11/12) utilize MP2RAGE and/or FGATIR sequences for planning. Centromedian thalamic nuclei were the unanimous target for Lennox-Gastaut syndrome. Surgeon exposure to neuromodulation occurred mostly in clinical practice (14/17). Clinically significant hemorrhage (n = 2) or infection (n = 3) were rare. Meaningful seizure reduction (>50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue. PLAIN LANGUAGE SUMMARY: We surveyed 32 pediatric epilepsy centers in USA to highlight current practices of intracranial neuromodulation. Of the 17 that replied, we found that most centers are implanting thalamic targets in pediatric drug-resistant epilepsy using the RNS device. DBS device is starting to be used in pediatric epilepsy, especially after 2020. Different strategies for target identification are enumerated. This study serves as a starting point for future collaborative research.

Neuropsychological outcomes after epilepsy surgery: A comparison of stereo electroencephalography and subdural electrodes.

BACKGROUND AND PURPOSE: We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language. METHODS: Drug-resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM. RESULTS: Ninety-nine patients aged 6-29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter-Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores. CONCLUSIONS: Intracranial evaluations with SEEG and SDE are comparable in terms of long-term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

Comparing electrical stimulation functional mapping with subdural electrodes and stereoelectroencephalography.

OBJECTIVE: Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM-induced seizures (EISs) between the two electrode types. METHODS: Incidence and current thresholds for functional responses (sensory, motor, speech/language), ADs, and EISs were compared between SDE and SEEG using mixed models incorporating relevant covariates. RESULTS: We identified 67 SEEG ESM and 106 SDE ESM patients (7207 and 4980 stimulated contacts, respectively). We found similar incidence of language and motor responses between electrode types; however, more SEEG patients reported sensory responses. ADs and EISs occurred less commonly with SEEG than SDE. Current thresholds for language, face motor, and upper extremity (UE) motor responses and EIS significantly decreased with age. However, they were not affected by electrode type, premedication, or dominant hemispheric stimulation. AD thresholds were higher with SEEG than with SDE. For SEEG ESM, language thresholds remained below AD thresholds up to 26 years of age, whereas this relationship was inverse for SDE. Also, face and UE motor thresholds fell below AD thresholds at earlier ages for SEEG than SDE. AD and EIS thresholds were not affected by premedication. SIGNIFICANCE: SEEG and SDE have clinically relevant differences for functional brain mapping with electrical stimulation. Although evaluation of language and motor regions is comparable between SEEG and SDE, SEEG offers a higher likelihood of identifying sensory areas. A lower incidence of ADs and EISs, and a favorable relationship between functional and AD thresholds suggest superior safety and neurophysiologic validity for SEEG ESM than SDE ESM.

Stiripentol for Drug-Resistant Epilepsy Treatment in Tuberous Sclerosis Complex.

BACKGROUND: Drug-resistant epilepsy (DRE) is common in tuberous sclerosis complex (TSC). The role of stiripentol (STP) in seizure treatment in this population is not well understood. This study evaluates the efficacy and tolerability of STP in patients with TSC with DRE. METHODS: We performed a retrospective review of patients with TSC with DRE. Seizure frequencies at 1 month before (baseline) and 1, 3, 6, and 12 months after STP initiation were collected. RESULTS: Of the 1492 patients, 13 received STP and the number of patients with ≥50% seizure reduction at 1, 3, 6, and 12 months was 6/13 (46.2%), 4/13 (30.8%), 8/13 (61.5%), and 6/13 (46.2%), respectively. Six patients (46.2%) had favorable outcomes with persistent seizure reduction through 12 months. Their mean (±S.D.) percentage of seizure reduction at 1, 3, 6, and 12 months was 68.1 (±22.0), 71.3 (±23.2), 75.7 (±23.5), and 75.7 (±23.5), respectively. One patient had worsening seizures throughout the STP course. Three patients did not have seizure reduction until after 6 months, and 2 had initial seizure reduction before worsening. Younger age (P value <0.001), early STP treatment (P value <0.001), higher doses (P value = 0.004), and higher baseline seizure frequency (P value = 0.01) were associated with favorable outcomes. Side effects were seen in 85% of our cohort. CONCLUSIONS: About 46% of the patients had favorable outcomes. Younger age, early STP treatment, higher doses, and higher baseline seizure frequency were significantly associated with favorable outcomes.

Posterior Quadrant Disconnection Procedure for Intractable Epilepsy: A Case Series of 5 Young Pediatric Patients.

BACKGROUND: Posterior quadrant disconnection (PQD) has been described as a treatment for patients with refractory posterior quadrant subhemispheric epilepsy. Surgical outcomes are difficult to interpret because of limited literature. OBJECTIVE: To provide insight regarding the operative technique and postsurgical seizure freedom in young pediatric patients who underwent surgical disconnection for the treatment of posterior quadrant subhemispheric epilepsy at our institution. METHODS: The authors retrospectively analyzed a series of 5 patients who underwent PQD between 2019 and 2021. Charts were reviewed for preoperative workup including noninvasive/invasive testing, operative reports, and postoperative follow-up data which included degree of seizure freedom, completion of disconnection, and complications. RESULTS: Five patients were included in this series. The median age at seizure onset was 12 months (range 3-24 months), and the median age at surgery was 36 months (range 22-72 months). Histopathology confirmed focal cortical dysplasia in 3 of 5 patients (2 patients with type IB; 1 with type IIID). The average length of follow-up after surgery was 16.8 months (range 12-24 months). All patients underwent complete disconnection of the posterior quadrant without complications. Four of 5 patients (80%) had Engel score of I, while the remaining patient had an Engel score of IIB. CONCLUSION: Our early results demonstrate that complete PQD can be successful at providing excellent seizure freedom and functional outcomes in carefully selected young pediatric patients who have concordant seizure semiology, noninvasive/invasive testing, and imaging findings with primary seizure onset zone within the ipsilateral posterior quadrant. Meticulous surgical planning and thorough understanding of the surgical anatomy and technique are critical to achieving complete disconnection.

Clinical validation of magnetoencephalography network analysis for presurgical epilepsy evaluation.

OBJECTIVE: To clinically validate the connectivity-based magnetoencephalography (MEG) analyses to identify seizure onset zone (SOZ) with comparing to equivalent current dipole (ECD). METHODS: The ECD cluster was quantitatively analyzed by calculating the centroid of the cluster and maximum distance (the largest distance between all dipoles). The "primary hub" was determined by the highest eigencentrality. The distribution of nodes in the top 5% of eigenvector centrality values was quantified by generating the convex hull between each node. RESULTS: Thirty-one patients who underwent MEG, stereotactic-EEG, and focal surgery were included. The primary hub was significantly closer to the sEEG-defined SOZ compared to ECD (p = 0.009). The seizure freedom positive and negative predictive values of complete ECD cluster and primary hub resections did not significantly differ, although complete resection of the primary hub showed slightly better negative predictive value (ECD: 50.0% NPV, hub: 64.7% NPV). Both quantitative ECD and functional connectivity analyses suggested that spatially restricted dipole distributions and higher connectivity in a smaller region correlate with better seizure outcomes. CONCLUSIONS: Our findings suggest that MEG network analysis could be a valuable complement to the ECD methods. SIGNIFICANCE: The results of this study are an important step towards using non-invasive neurophysiologic recordings to accurately define the epileptic network.

Responsive neurostimulation device therapy in pediatric patients with complex medically refractory epilepsy.

OBJECTIVE: Pediatric epilepsy is characterized as drug resistant in 20%-30% of patients and defined as persistent seizures despite adequate treatment with two first-line antiepileptic medications. The American Academy of Neurology advocates surgical options earlier in the treatment of epilepsy to provide long-term seizure reduction. The new development of minimally invasive approaches has recently allowed for surgical options to patients not previously deemed surgical candidates. These may include patients with bilateral, deep, eloquent, or poorly localizing epileptogenic foci. To this end, responsive neurostimulation (RNS) is an FDA-approved closed-loop neuromodulation device for adjuvant treatment of adults with medically intractable epilepsy arising from one or multiple foci. METHODS: In this study, the authors describe their initial institutional experience with the use of RNS in pediatric patients with drug-resistant epilepsy. An IRB-approved retrospective review was conducted of 8 pediatric patients who underwent RNS implantation at Cincinnati Children's Hospital Medical Center between 2019 and 2021. RESULTS: Eight patients met the inclusion criteria for the study. The average age at the time of surgery was 14.7 years (range 8-18 years) with a mean follow-up of 16.5 months. All patients underwent invasive monitoring with stereo-EEG, subdural grid placement, or a combination of both. All patients had either bilateral or eloquent cortex targets. Trajectories were based on noninvasive (phase 1) and invasive (phase 2) seizure onset zone localization data. Four (50%) of the 8 patients underwent surgical intervention for epilepsy prior to RNS placement. RNS electrodes were placed with robot-assisted guidance in a hybrid operating room with intraoperative CT and electrocorticography. The authors demonstrated individualized RNS electrode trajectory and placement with targets in the amygdala/hippocampus, bilateral insula, bilateral parietal and occipital targets, and frontoparietal regions for a total of 14 implanted electrodes. One adverse event occurred, a wound infection requiring return to the operating room for removal of the RNS implant. All patients demonstrated a reduction in seizure frequency. All patients achieved > 50% reduction in seizure frequency at last follow-up. CONCLUSIONS: RNS implantation in carefully selected pediatric patients appears safe and efficacious in reducing seizure burden with a low rate of operative complications.

Improving Detection of Hippocampal Epileptiform Activity Using Magnetoencephalography.

PURPOSE: Magnetoencephalography (MEG) defines the spike-generating zone and provides targets for invasive monitoring with stereotactic electroencephalography. This retrospective, blinded, cross-sectional study determined whether MEG virtual sensors could identify hippocampal epileptiform activity. METHODS: Using MEG beamformer analysis, virtual sensors were manually placed in bilateral hippocampi and corresponding virtual sensor waveforms were analyzed for the presence of epileptiform activity. These findings were compared with hippocampal stereotactic electroencephalography in the same patients. Concordance was determined using sensitivity and specificity. RESULTS: Thirty patients (mean age 12.5 ± 5.9 years) and 35 hippocampi were included. Patients were also placed into subgroups based on conventional MEG analysis: temporal (n = 19), extratemporal (n = 10), and normal (n = 1). Overall, sensitivity and specificity were 57.9% and 50.0%, respectively (n = 35). Patients with temporal sources based on conventional MEG analysis had sensitivity and specificity of 80.0% and 36.4%, respectively (n = 21). Those with extratemporal sources based on conventional MEG had sensitivity and specificity of 42.9% and 80.0%, respectively (n = 12). CONCLUSIONS: When grouped by conventional MEG analysis, virtual sensors can be useful to confirm mesial temporal dipoles seen with conventional analysis. SIGNIFICANCE: This work may help support the use of MEG for the detection of epileptiform activity in the hippocampus and influence the planning of invasive electrode placement.

Subtraction ictal SPECT co-registered to MRI (SISCOM) patterns in children with temporal lobe epilepsy.

OBJECTIVE: We evaluated SISCOM patterns and their relationship with surgical outcome in children with temporal lobe epilepsy (TLE) who had undergone a temporal lobe surgery. METHODS: This was an observational study evaluating SISCOM patterns in 40 children with TLE. We classified SISCOM patterns into 4 categories; (i) unilateral anteromesial and/or anterolateral temporal pattern; (ii) unilateral anteromesial and/or anterolateral temporal plus posterior extension pattern; (iii) bilateral anteromesial and/or anterolateral temporal pattern; and (iv) atypical pattern. Determinants of SISCOM pattern and correlation between postoperative outcomes and SISCOM patterns were evaluated. RESULTS: Pattern (i), (ii), (iii), and (iv) were identified in 10 (25%), 14 (35%), 0 (0%), and 16 (40%) patients, respectively. There was no significant correlation between patterns and postoperative outcomes. SISCOM patterns significantly associated with the presence of hippocampal sclerosis and type of focal cortical dysplasia (p-value = 0.048 and 0.036, respectively). Patients with HS had 5 times the odds of having unilateral temporal pattern, compared to patients with other neuropathology (OR = 5, 95% CI 0.92 to 27.08). Patients with FCD type 2 had 9.71 times the odds of having atypical pattern, compared to patients with other types of FCD (OR = 9.71, 95% CI 0.92 to 103.04). Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcomes (p-value = 0.018 and 0.013, respectively). CONCLUSION: Three SISCOM patterns were seen. Patients with HS had increased odds of having unilateral temporal pattern while patients with FCD type 2 had increased odds of having atypical pattern. However, there was no significant correlation between SISCOM patterns and postoperative outcomes. Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcome. SIGNIFICANCE: This study shows that the distribution of SISCOM patterns and their relationship with postoperative outcomes in children with TLE are different from adult population. Besides, SISCOM may add only limited diagnostic and prognostic information in children with drug-resistant TLE undergoing epilepsy surgery. Further evaluation to identify patient populations that may benefit from SISCOM is desirable.

Neuropsychological outcomes after pediatric epilepsy surgery: Role of electrical stimulation language mapping.

PURPOSE: We studied the association between electrical stimulation mapping (ESM) with a visual naming task and post-operative neuropsychological outcomes after pediatric epilepsy surgery. METHODS: Children who underwent epilepsy surgery, having pre- and 1-year post-surgery neuropsychological evaluation (NPE) available, were included. NPE scores were transformed using principal components (PC) analysis. The relationship between post-surgical PC scores, adjusted for pre-surgery PC scores, and ESM was analyzed. Clinical variables influencing this relationship were also sought. RESULTS: One hundred and four children (89 patients >5 years-old, and 15 patients 3-5 years-old) were included. Among children >5 years-of-age, a significant effect of language ESM was observed on all 3 post-surgery PC scores adjusted for respective pre-surgery PC scores. Specifically, only 30 % patients who underwent language ESM had a decrease in PC1 scores ≥1-year after epilepsy surgery, compared to 68 % those who did not undergo language ESM (p = 0.001). Seizure outcomes, age at the time of surgery, predominant seizure type, and family history of epilepsy were other significant determinants of post-surgical PC scores including a change in PC scores from pre-surgery baseline. Combinations of pre-surgical variables were able to predict post-surgical PC scores with high specificity. In children aged 3-5 years, no significant effect of language ESM was seen on post-surgery PC scores adjusted for respective pre-surgery PC scores. CONCLUSIONS: Speech/language ESM should be performed more widely in patients >5 years-of-age undergoing epilepsy surgery. Also, more efficient brain mapping techniques and language paradigms are needed for younger children.

Impact of radiotracer injection latency and seizure duration on subtraction ictal SPECT co-registered to MRI (SISCOM) performance in children.

OBJECTIVE: We evaluated the impact of radiotracer injection latency and post-injection seizure duration on subtraction ictal SPECT co-registered to MRI (SISCOM) test performance in identifying the epileptogenic zone (EZ) in children with drug-resistant epilepsy who had undergone a resective epilepsy surgery. METHODS: SISCOM concordance with the EZ was retrospectively reviewed to evaluate its performance in 113 children. The impact of radiotracer injection latency and post-injection seizure duration was evaluated for their predictive value of SISCOM localization accuracy. RESULTS: The overall sensitivity and specificity of SISCOM in identifying an EZ was 64.8% (95%CI = 50.6-77.3) and 40.7% (95%CI = 28.1-54.3). The positive likelihood ratio and diagnostic odd ratio was 1.09 (95%CI = 0.80-1.48) and 1.26 (95%CI = 0.59-2.71), respectively. Logistic regression showed that injection latency and post-injection seizure duration did not significantly predict the probability of true positive SISCOM (p-value = 0.45 and 0.29, respectively). CONCLUSION: Radiotracer injection latency and post-injection seizure duration were not shown to have a statistical significant impact on SISCOM performance in identifying the EZ. SIGNIFICANCE: This study demonstrates that further study of factors contributing to the performance of SISCOM in EZ identification in children is needed.

Fosphenytoin pre-medication for pediatric extra-operative electrical stimulation brain mapping.

PURPOSE: We studied the effect of fosphenytoin (FOS) pre-medication on the incidence and thresholds of after-discharges (ADs), seizures, and functional responses during electrical stimulation mapping (ESM). METHODS: As individualized by the attending epileptologist, FOS was given intravenously at 2 mg-phenytoin-equivalents (PE)/kg/min or 150 mg-PE/min (whichever slower). Patients who received and did not receive FOS were compared for the incidence and thresholds of ADs, seizures, and functional responses. RESULTS: Before ESM, 40 and 82 patients respectively were pre-medicated/not pre-medicated with FOS. The incidence of ESM-induced seizures was significantly lower in FOS pre-medicated patients (22.5% vs. 42.7%, p = 0.044), whereas temporal language threshold was higher (9.2 vs. 6.5 mA, p = 0.032). FOS was more efficacious in preventing ESM-induced seizures in patients with symptomatogenic zone ipsilateral to the side of ESM. Although FOS dose had no significant effect on minimum language, minimum motor, or AD thresholds; seizure and temporal language thresholds showed trends approaching significance, intersecting at 12.2 mg-PE/kg. The incidence of ESM-induced seizures was significantly lower in those who received FOS at a dose of ≤12 mg/kg (9.1%) compared to those who did not receive any FOS (42.7%, p = 0.046), while the temporal language thresholds were not significantly different (6.3 vs. 6.5 mA, p = 0.897). CONCLUSIONS: This study provides class III evidence that FOS pre-medication before ESM decreases the incidence of ESM-induced seizures, but increases temporal language threshold. FOS pre-medication may thus be considered before ESM. Future studies should prospectively verify these observations and characterize dose-response relationships.