Cortical Dysplasia Research Articles

DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature.

DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients. Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies. Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335). The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.

Focal Cortical Dysplasia: Diagnosis, Classification, and Treatment Options

AbstractFocal cortical dysplasias (FCDs) include a spectrum of anomalies of cortical development that consist in one or more areas with altered lamination and in some cases, neurons of abnormal morphology. Clinically, these structural anomalies led to arise of epilepsy, which is more often a focal, drug-resistant type with onset in pediatric or adolescent age. Occasionally, other symptoms have been reported in patients with FCDs, such as headache, movement disorders, and cognitive impairment. According to International League against Epilepsy scheme of 2011, three main subtypes of FCD can be distinguished, based of anatomopathological feature, radiological signs, and clinical expression. Magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography, and neurophysiology are the cornerstones of diagnosis, although their negativity cannot exclude FCD in symptomatic patients, especially in FCD type I which often is elusive. In MRI, the main finding is the irregularity of the cortical–subcortical signal, specifically reduction of cortical thickness and absence of clear demarcation between gray and white matters, which is strongly diagnostic for FCD. Epilepsy related to FCD is difficult to manage and until now there is not a clear direction for treatment's rules. FCD shows poor response to antiepileptic drugs (AEDs), and there is no evidence of some AED that has proved more efficacy than others in patients with FCDs. Considering genetical and pathophysiological recent acquisitions, mammalian target of rapamycin inhibitors may play a fundamental role in future treatment of FCDs, but nowadays, surgery still remains the main weapon, with 50% of patients who undergo neurosurgery.

Schizencephaly: Etiopathogenesis, Classification, Therapeutic, and Rehabilitative Approach

AbstractSchizencephaly is an uncommon anomaly in neuronal migration characterized by complete clefts that extend from the pia mater to the ependymal surface of the ventricular system. These clefts are encompassed by displaced gray matter and filled with cerebrospinal fluid. Typically, they are found most often in the frontal lobe or the area around the lateral sulcus and can occur on one or both sides. The size, location, and type of these clefts carry significant clinical and prognostic implications. Moreover, they are frequently associated with other central nervous system malformations, including the absence of the septum pellucidum, septo-optic dysplasia, optic nerve hypoplasia, pachygyria, polymicrogyria, cortical dysplasia, heterotopia, and dysplasia of the corpus callosum. Occurrence of schizencephaly is almost always sporadic but its etiopathogenesis is yet to be fully understood. Most likely environmental factors, including exposure to teratogens, viral infections, and maternal factors, operate jointly with genetic defects. To date COL4A1, EMX2, SHH, and SIX3 are the genes identified as possible pathogenetic target. It is interesting to notice that schizencephaly is commonly seen in abandoned or adopted children, as proof of causative effect of intrautero insults. Clinical presentations widely vary and symptoms include a spectrum of cognitive impairment, limb paresis/tetraparesis, and epileptic seizures either with early or late onset; anyway, none of these symptoms is ever-present and patients with schizencephaly can also have normal neurocognitive and motor development. Diagnostic gold standard for schizencephaly is magnetic resonance imaging, which allows to identify and characterize typical clefts. Treatment of schizencephaly is symptomatic and supportive and depends on the severity of morbidity resulting from the malformation. Therapy includes antiepileptic drugs, psychomotor rehabilitation, and in selected cases surgical approach.

Profile of adult -onset epilepsy in Zagazig university hospitals

BackgroundEpilepsy has many neurobiological consequences. This study aimed to identify the profile of adult patients with new onset epilepsy in our university hospitals as regarding clinical picture, etiology, cerebral imaging and electroencephalogram (EEG) correlation, comorbidities, management, drug therapy and seizure severity and quality of life. We recruited one hundred patients with adult onset epilepsy, and we assessed them clinically, radiologically, and electrophysiologically. We performed Liverpool Seizure Severity Scale (LSSS) to assess seizure severity and the Quality of Life In Epilepsy-10 Questionnaire (QOLIE-10) to assess quality of life of adult patients with new onset epilepsy.ResultsFifty-seven percent of the studied patients were males, and 43.0% were females with mean (± SD) of age was 52.83 (± 17.33), 13.0% of the studied patients had positive family history of epilepsy. 32.0% had focal epilepsy, and 68.0% had generalized epilepsy, 53% of patients had uncontrolled seizures, 49% of patients were on monotherapy, and 51.0% were on polytherapy. The mean (± SD) seizure frequency per month in the studied patients was 4.0 (± 3.15). Imaging abnormalities were found in 88% of studied patients. 43% of the studied patients had abnormal EEG. Post-traumatic epilepsy, focal cortical dysplasia and mesial temporal sclerosis were statistically significant higher in male patients than female patients. Arteriovenous malformations were significantly higher in females. Middle-aged adults’ group had hypertension more than other age groups, older adult age group had atrial fibrillation, coronary heart disease, diabetes mellitus and dyslipidemia more than other age groups. Young adults had migraine more than other age groups. Post-stroke epilepsy was higher in older adult and middle-aged adult groups more than young adult age group. Intracranial neoplasms were higher in older adult age group than other age groups. Patients with moderate, severe, and very severe LSSS score had significantly more frequent uncontrolled seizures, abnormal EEG and higher rate of polytherapy as compared to those with mild LSSS score. Patients with impaired quality of life had more seizure frequency, less seizure control, higher seizure severity, more EEG abnormalities and were mostly treated by AEDs polytherapy than those with average life quality.ConclusionsLevetiracetam was the most preferred drug for treating patients with adult-onset epilepsy (40%), whether used as monotherapy or in combination with other drugs. Seizure severity, and seizure frequency per month strongly impaired patients’ quality of life.

Advances of pathological research and classification in malformations of cortical development associated with refractory epilepsy

With rapid development of genetic testing techniques, neuroimaging and neuroelectrophysiological technologies, our understanding of malformations of cortical development continues to be deepened and updated. In particular, mutations in genes related to the mammalian target of rapamycin (mTOR) signaling pathway have been successively discovered in focal cortical dysplasia (FCD). At the same time, the classification consensus on FCD issued by the International League Against Epilepsy (ILAE) in 2011 has encountered problems and challenges in diagnostic practice. Therefore, in 2022, ILAE proposed an updated version of the FCD classification based on the progress in molecular genetics over the past decade. The main addition to the classification system is "white matter lesions, " and it is also suggested to integrate histopathological, neuroimaging, and molecular testing results for multi-level integrated diagnosis to achieve reliable, clinically relevant, and therapeutic targeted final diagnosis.

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C N-methyl-D-aspartate receptors.

Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate-gated N-methyl-D-aspartate receptors (NMDARs) has been demonstrated for germline defects in the TSC genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II. We used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C-mediated currents. Neurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory postsynaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time window between postnatal days P9 and P20. Somatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated neuronal NMDARs in neocortices of rat pups. The related and time-restricted local hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR-related brain disorders.

Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy

Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an MtorS2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.

Outcome of Epilepsy Surgery for Extratemporal Focal Cortical Dysplasia

Outcome of Epilepsy Surgery for Extratemporal Focal Cortical Dysplasia

The use of automated and AI-driven algorithms for the detection of hippocampal sclerosis and focal cortical dysplasia.

In drug-resistant epilepsy, magnetic resonance imaging (MRI) plays a central role in detecting lesions as it offers unmatched spatial resolution and whole-brain coverage. In addition, the last decade has witnessed continued developments in MRI-based computer-aided machine-learning techniques for improved diagnosis and prognosis. In this review, we focus on automated algorithms for the detection of hippocampal sclerosis and focal cortical dysplasia, particularly in cases deemed as MRI negative, with an emphasis on studies with histologically validated data. In addition, we discuss imaging-derived prognostic markers, including response to anti-seizure medication, post-surgical seizure outcome, and cognitive reserves. We also highlight the advantages and limitations of these approaches and discuss future directions toward person-centered care.

Pharmacological evaluation of E2730, a novel selective uncompetitive GAT1 inhibitor, on epileptiform activities in resected brain tissues from human focal cortical dysplasia ex vivo

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730—both as a single agent and in combination with CBZ—merits evaluation in clinical trials involving patients with FCD.

Spatial and temporal properties of intra-operatively recorded spikes and high frequency oscillations in focal cortical dysplasia

ObjectiveFocal cortical dysplasias (FCD) are characterized by distinct interictal spike patterns and high frequency oscillations (HFOs; ripples: 80–250 Hz; fast ripples: 250–500 Hz) in the intra-operative electrocorticogram (ioECoG). We studied the temporal relation between intra-operative spikes and HFOs and their relation to resected tissue in people with FCD with a favorable outcome. MethodsWe included patients who underwent ioECoG-tailored epilepsy surgery with pathology confirmed FCD and long-term Engel 1A outcome. Spikes and HFOs were automatically detected and visually checked in 1-minute pre-resection-ioECoG. Channels covering resected and non-resected tissue were compared using a logistic mixed model, assessing event numbers, co-occurrence ratios, and time-based properties. ResultsWe found pre-resection spikes, ripples in respectively 21 and 20 out of 22 patients. Channels covering resected tissue showed high numbers of spikes and HFOs, and high ratios of co-occurring events. Spikes, especially with ripples, have a relatively sharp rising flank with a long descending flank and early ripple onset over resected tissue. ConclusionsA combined analysis of event numbers, ratios, and temporal relationships between spikes and HFOs may aid identifying epileptic tissue in epilepsy surgery. SignificanceThis study shows a promising method for clinically relevant properties of events, closely associated with FCD.

Management of Anti-seizure Medication in Patients with Drug-resistant Focal Epilepsy Secondary to Focal Cortical Dysplasia Undergoing Epilepsy Surgery in Argentina (P10-1.016)

Management of Anti-seizure Medication in Patients with Drug-resistant Focal Epilepsy Secondary to Focal Cortical Dysplasia Undergoing Epilepsy Surgery in Argentina (P10-1.016)

Morphological and Electrophysiological Characterization of Balloon and Giant Cells in Pediatric Cortical Dysplasia Type IIB and Tuberous Sclerosis Complex (P1-1.002)

Morphological and Electrophysiological Characterization of Balloon and Giant Cells in Pediatric Cortical Dysplasia Type IIB and Tuberous Sclerosis Complex (P1-1.002)

Identification of a mosaic MTOR variant in purified neuronal DNA in a patient with focal cortical dysplasia using a novel depth electrode harvesting technique.

Recent studies have identified brain somatic variants as a cause of focal epilepsy. These studies relied on resected tissue from epilepsy surgery, which is not available in most patients. The use of trace tissue adherent to depth electrodes used for stereo electroencephalography (EEG) has been proposed as an alternative but is hampered by the low cell quality and contamination by nonbrain cells. Here, we use our improved depth electrode harvesting technique that purifies neuronal nuclei to achieve molecular diagnosis in a patient with focal cortical dysplasia (FCD). Depth electrode tips were collected, pooled by brain region and seizure onset zone, and nuclei were isolated and sorted using fluorescence-activated nuclei sorting (FANS). Somatic DNA was amplified from neuronal and astrocyte nuclei using primary template amplification followed by exome sequencing of neuronal DNA from the affected pool, unaffected pool, and saliva. The identified variant was validated using droplet digital polymerase chain reaction (PCR). An 11-year-old male with drug-resistant genetic-structural epilepsy due to left anterior insula FCD had seizures from age 3 years. Stereo EEG confirmed seizure onset in the left anterior insula. The two anterior insula electrodes were combined as the affected pool and three frontal electrodes as the unaffected pool. FANS isolated 140 neuronal nuclei from the affected and 245 neuronal nuclei from the unaffected pool. A novel somatic missense MTOR variant (p.Leu489Met, CADD score 23.7) was identified in the affected neuronal sample. Droplet digital PCR confirmed a mosaic gradient (variant allele frequency = .78% in affected neuronal sample; variant was absent in all other samples). Our findings confirm that harvesting neuronal DNA from depth electrodes followed by molecular analysis to identify brain somatic variants is feasible. Our novel method represents a significant improvement compared to the previous method by focusing the analysis on high-quality cells of the cell type of interest.

A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Development and prospective clinical validation of a convolutional neural network for automated detection and segmentation of focal cortical dysplasias

PurposeFocal cortical dysplasias (FCDs) are a leading cause of drug-resistant epilepsy. Early detection and resection of FCDs have favorable prognostic implications for postoperative seizure freedom. Despite advancements in imaging methods, FCD detection remains challenging. House et al. (2021) introduced a convolutional neural network (CNN) for automated FCD detection and segmentation, achieving a sensitivity of 77.8%. However, its clinical applicability was limited due to a low specificity of 5.5%. The objective of this study was to improve the CNN’s performance through data-driven training and algorithm optimization, followed by a prospective validation on daily-routine MRIs. Material and methodsA dataset of 300 3 T MRIs from daily clinical practice, including 3D T1 and FLAIR sequences, was prospectively compiled. The MRIs were visually evaluated by two neuroradiologists and underwent morphometric assessment by two epileptologists. The dataset included 30 FCD cases (11 female, mean age: 28.1 ± 10.1 years) and a control group of 150 normal cases (97 female, mean age: 32.8 ± 14.9 years), along with 120 non-FCD pathological cases (64 female, mean age: 38.4 ± 18.4 years). The dataset was divided into three subsets, each analyzed by the CNN. Subsequently, the CNN underwent a two-phase-training process, incorporating subset MRIs and expert-labeled FCD maps. This training employed both classical and continual learning techniques. The CNN’s performance was validated by comparing the baseline model with the trained models at two training levels. ResultsIn prospective validation, the best model trained using continual learning achieved a sensitivity of 90.0%, specificity of 70.0%, and accuracy of 72.0%, with an average of 0.41 false positive clusters detected per MRI. For FCD segmentation, an average Dice coefficient of 0.56 was attained. The model’s performance improved in each training phase while maintaining a high level of sensitivity. Continual learning outperformed classical learning in this regard. ConclusionsOur study presents a promising CNN for FCD detection and segmentation, exhibiting both high sensitivity and specificity. Furthermore, the model demonstrates continuous improvement with the inclusion of more clinical MRI data. We consider our CNN a valuable tool for automated, examiner-independent FCD detection in daily clinical practice, potentially addressing the underutilization of epilepsy surgery in drug-resistant focal epilepsy and thereby improving patient outcomes.

Spatial omics reveals molecular changes in focal cortical dysplasia type II

Focal cortical dysplasia (FCD) represents a group of diverse localized cortical lesions that are highly epileptogenic and occur due to abnormal brain development caused by genetic mutations, involving the mammalian target of rapamycin (mTOR). These somatic mutations lead to mosaicism in the affected brain, posing challenges to unravel the direct and indirect functional consequences of these mutations. To comprehensively characterize the impact of mTOR mutations on the brain, we employed here a multimodal approach in a preclinical mouse model of FCD type II (Rheb), focusing on spatial omics techniques to define the proteomic and lipidomic changes. Mass Spectrometry Imaging (MSI) combined with fluorescence imaging and label free proteomics, revealed insight into the brain's lipidome and proteome within the FCD type II affected region in the mouse model. MSI visualized disrupted neuronal migration and differential lipid distribution including a reduction in sulfatides in the FCD type II-affected region, which play a role in brain myelination. MSI-guided laser capture microdissection (LMD) was conducted on FCD type II and control regions, followed by label free proteomics, revealing changes in myelination pathways by oligodendrocytes. Surgical resections of FCD type IIb and postmortem human cortex were analyzed by bulk transcriptomics to unravel the interplay between genetic mutations and molecular changes in FCD type II. Our comparative analysis of protein pathways and enriched Gene Ontology pathways related to myelination in the FCD type II-affected mouse model and human FCD type IIb transcriptomics highlights the animal model's translational value. This dual approach, including mouse model proteomics and human transcriptomics strengthens our understanding of the functional consequences arising from somatic mutations in FCD type II, as well as the identification of pathways that may be used as therapeutic strategies in the future.

Potential of focal cortical dysplasia in migraine pathogenesis.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy.

Analysis of Predictive Factors in Surgical Treatment of Intractable Epilepsy Caused by Focal Cortical Dysplasia in Children

Objective: This study aims to analyze key factors affecting the surgical outcome of children with intractable epilepsy caused by focal cortical dysplasia, providing more effective clinical guidance. Methods: We conducted a study from March 2019 to February 2021, selecting 80 children with intractable epilepsy caused by focal cortical dysplasia who underwent surgical treatment. Comprehensive inclusion criteria were met. We collected general information and treatment outcomes before and after surgery, with a two-year postoperative follow-up. Patients were categorized into good and poor outcome groups based on outcomes. Various factors including pathological types, age of onset, seizure frequency, and extent of resection were selected as variables. Logistic regression analysis investigated predictive factors. Results: Engel class I included 53 cases, class II had 16 cases, class III had 9 cases, and class IV had 2 cases. Thus, 53 cases were in the good outcome group, and 27 in the poor outcome group. General data showed no significant differences between the groups (P > 0.05). Single-factor analysis revealed statistically significant risk factors: FCD classification, MRI results, age of onset, seizure frequency, and extent of resection (P < 0.05). Logistic multifactor analysis indicated seizure frequency. acute postoperative seizures (APSO) and extent of resection as independent influencing factors (P < 0.05). Conclusion: Seizure frequency, extent of resection, and APSO are key independent factors for surgical outcome in children with intractable epilepsy caused by focal cortical dysplasia. Clinicians should consider these factors when planning treatment to improve success rates and outcome, enhancing quality of life for affected children.

Responsive neurostimulation of thalamic nuclei for regional and multifocal drug-resistant epilepsy in children and young adults.

Responsive neurostimulation (RNS) is a US FDA-approved form of neuromodulation to treat patients with focal-onset drug-resistant epilepsy (DRE) who are ineligible for or whose condition is refractory to resection. However, the FDA approval only extends to use in patients with one or two epileptogenic foci. Recent literature has shown possible efficacy of thalamic RNS in patients with Lennox-Gastaut syndrome and multifocal epilepsy. The authors hypothesized that RNS of thalamic nuclei may be effective in seizure reduction for patients with multifocal or regionalized-onset DRE. The authors performed a retrospective chart review of all patients who had an RNS device managed at Texas Children's Hospital between July 2016 and September 2023, with at least one active electrode in the thalamic nuclei and ≥ 12 months of postimplantation follow-up. Information conveyed by the patient or their caregiver provided data on the change in the clinical seizure frequency, quality of life (QOL), and seizure severity between the preimplantation baseline visit and the last office visit (LOV). Thirteen patients (ages 8-24 years) were identified with active RNS leads in thalamic nuclei (11 centromedian and 2 anterior nucleus). At LOV, 46% of patients reported 50%-100% clinical seizure reduction (classified as responders), 15% reported 25%-49% reduction, and 38% reported < 25% reduction or no change. Additionally, 42% of patients reported subjective improvement in QOL and 58% reported improved seizure severity. Patients with focal cortical dysplasia (FCD) responded strongly: 3 of 5 (60%) reported ≥ 80% reduction in seizure burden and improvement in seizure severity and QOL. Patients with multifocal epilepsy and bilateral thalamocortical leads also did well, with all 3 reporting ≥ 50% reduction in seizures. RNS of thalamic nuclei shows promising results in reducing seizure burden for patients with multifocal or regional-onset DRE, particularly in a bilateral thalamocortical configuration or when addressing an underlying FCD.