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Background: To review seizure outcomes in children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE) treated with the responsive neurostimulation (RNS) System., Methods: We retrospectively reviewed children (<21 years old) with TSC implanted with the RNS System at Texas Children's Hospital between July 2016 and May 2022., Results: Five patients meeting the search criteria were identified (all female). The median age of the RNS implantation was 13 years (range: 5 to 20 years). The median epilepsy duration before the RNS implantation was 13 years (range: 5 to 20 years). Surgeries before RNS implantation included vagus nerve stimulator placement (n = 2), left parietal resection (n = 1), and corpus callosotomy (n = 1). The median number of antiseizure medications tried before RNS was 8 (range: 5 to 12). The rationale for the RNS System implantation included seizure onset in eloquent cortex (n = 3) and multifocal seizures (n = 2). The maximum current density for each patient ranged between 1.8 and 3.5 μC/cm 2 , with an average daily stimulation of 2240 (range: 400 to 4200). There was an 86% median seizure reduction (range 0% to 99%) at a median follow-up duration of 25 months (range: 17 to 25 months). No patient experienced implantation or stimulation-related complications., Conclusions: We observed a favorable improvement in seizure frequency in pediatric patients with DRE secondary to TSC treated with the RNS System. The RNS System may be a safe and effective treatment for DRE in children with TSC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Surgery has become integral in treating children with tuberous sclerosis complex (TSC)-related drug-resistant epilepsy (DRE)., Objective: To describe outcomes of a multimodal diagnostic and therapeutic approach comprising invasive intracranial monitoring and surgical treatment and compare the complementary techniques of open resection and magnetic resonance-guided laser interstitial thermal therapy., Methods: Clinical and radiographic data were prospectively collected for pediatric patients undergoing surgical evaluation for TSC-related DRE at our tertiary academic hospital. Seizure freedom, developmental improvement, and Engel class were compared., Results: Thirty-eight patients (20 females) underwent treatment in January 2016 to April 2019. Thirty-five underwent phase II invasive monitoring with intracranial electrodes: 24 stereoencephalography, 9 craniotomy for grid/electrode placement, and 2 grids + stereoencephalography. With the multimodal approach, 33/38 patients (87%) achieved >50% seizure freedom of the targeted seizure type after initial treatment; 6/9 requiring secondary treatment and 2/2 requiring a third treatment achieved >50% freedom. The median Engel class was II at last follow-up (1.65 years), and 55% of patients were Engel class I/II. The mean age was lower for children undergoing open resection (2.4 vs 4.9 years, P = .04). Rates of >50% reduction in seizures (86% open resection vs 88% laser interstitial thermal therapy) and developmental improvement (86% open resection vs 83% magnetic resonance-guided laser interstitial thermal therapy) were similar., Conclusion: This hybrid approach of using both open surgical and minimally invasive techniques is safe and effective in treating DRE secondary to TSC. Clinical trials focused on treatment method with longer follow-up are needed to determine the optimal candidates for each approach and compare the treatment modalities more effectively., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background and Purpose: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC., Methods: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG)., Results: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features., Conclusions: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data., (© 2022 American Society of Neuroimaging.)

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations., Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required., Results: Only two changes were made to clinical diagnostic criteria reported in 2013: "multiple cortical tubers and/or radial migration lines" replaced the more general term "cortical dysplasias," and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals., Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Epilepsy occurs in nearly all patients with tuberous sclerosis and is often refractory to medical treatment. The definition of surgical candidacy in these patients has broadened in recent years due to philosophical and technological advances. The goals of surgery have shifted to focusing on quality of life and maximizing neurodevelopmental potential in patients unable to obtain seizure freedom. Novel diagnostic, ablative, and neuromodulatory techniques have been developed that may help patients that were previously considered inoperable to have an improved quality of life. In the coming years, it is expected that these techniques will be further refined and lead to an improvement of neurological prognosis in patients with tuberous sclerosis.

Background: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years., Methods: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures., Results: Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains., Conclusions: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal-dominant genetic syndrome marked by development of hamartomatous lesions arising from dysfunction of the mammalian target of rapamycin (mTOR) pathway. Although TSC remains a heterogeneous clinical entity, the recent inclusion of genetic diagnostic criteria reflects advancement in our understanding of its underlying etiopathogenesis. Abnormal cellular growth, differentiation, and migration result in multisystem sequelae, with neurologic manifestations of TSC representing the primary cause of morbidity and mortality for the majority of individuals. Modern imaging techniques aid in the diagnosis of TSC and guide treatment strategies by revealing central nervous system findings. Cortical tubers are the namesake lesion of the disorder and occur in up to 90% of cases, often exerting significant epileptogenic potential. Subependymal nodules are found in 80% of patients as calcified tumors lining the ependyma of the lateral ventricles. In some cases, these nodules are thought to progress to subependymal giant cell astrocytomas and may present with obstructive hydrocephalus. Retinal astrocytic hamartomas are also common, present in 50% of patients. Surgery remains the treatment of choice for large or symptomatic lesions, though clinical trials have highlighted a potential role for mTOR pathway antagonism. A multidisciplinary approach is necessary for achieving optimal patient outcomes., (© 2018 Wiley Periodicals, Inc.)

Introduction: Tuberous sclerosis is associated with three central nervous system pathologies: cortical/subcortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). Tubers are associated with epilepsy, which is often medication-resistant and often leads to resective surgery. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be effective reducing seizure burden in some patients with tuberous sclerosis complex (TSC)-related refractory epilepsy. mTORi have also been shown to be an alternative for surgery treating SEGAs. We describe several cases of resected tubers that contained SEGA tissue without an intraventricular SEGA., Methods: After institutional review board (IRB) protocol approval, we retrospectively reviewed the surgical-pathological data for all TSC patients who underwent cortical resections for treatment of refractory epilepsy at NYU Langone Medical Center and Tel Aviv Medical Center between 2003 and 2013. Data included demographics, epilepsy type, MRI characteristics, epilepsy outcome, and histopathological staining., Results: We reviewed cortical resections from 75 patients with complete pathological studies. In three patients, cortical lesions demonstrated histopathological findings consistent with a SEGA within the resected tuber tissue, with no intraventricular SEGA. All lesions were cortically based and none had any intraventricular extension. No patient had been treated before surgery with an mTORi. Two of the three patients remain Engel grade I-II. All lesions stained positive for glial fibrillary acidic protein (GFAP), synaptophysin, and neuronal nuclear antigen (NeuN)., Conclusion: This is the first description of cortical tubers harboring SEGA tissue. This observation though preliminary may suggest a subgroup of patients with intractable epilepsy in whom mTORi may be considered before surgical intervention.

Background: There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC)., Objective: We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery., Methods: A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery., Results: Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 ± 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1- and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom., Conclusion: In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber.

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers., Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic "microtubers". A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells., Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC.

Objectives: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC., Methods: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance)., Results: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder., Significance: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC., Methods: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics., Results: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002)., Significance: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Objective: Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism., Methods: Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens., Results: Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination., Significance: Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Object: Subependymal giant cell astrocytomas (SEGAs) are benign tumors, most commonly associated with tuberous sclerosis complex (TSC). The vast majority of these tumors arise from the lateral ependymal surface adjacent to the foramen of Monro, therefore potentially encroaching on one or both foramina, and resulting in obstructive hydrocephalus that necessitates surgical decompression. The indications for surgery, intraoperative considerations, and evolution of the authors' management paradigm are presented., Methods: Patients with TSC who underwent craniotomy for SEGA resection at New York University Langone Medical Center between January 1997 and March 2011 were identified. Preoperative imaging, clinical characteristics, management decisions, operative procedures, and outcomes were reviewed., Results: Eighteen patients with TSC underwent 22 primary tumor resections for SEGAs. The indication for surgery was meaningful radiographic tumor progression in 16 of 21 cases. The average age at the time of operation was 10.3 years. Average follow-up duration was 52 months (range 12-124 months). The operative approach was intrahemispheric-transcallosal in 16 cases, transcortical-transventricular in 5, and neuroendoscopic in 1. Nine tumors were on the right, 9 on the left, and 3 were bilateral. Gross-total resection was documented in 16 of 22 cases in our series, with radical subtotal resection achieved in 4 cases, and subtotal resection (STR) in 2 cases. Two patients had undergone ventriculoperitoneal shunt placement preoperatively and 7 patients required shunt placement after surgery for moderate to severe ventriculomegaly. Two patients experienced tumor progression requiring reoperation; both of these patients had initially undergone STR., Conclusions: The authors present their management strategy for TSC patients with SEGAs. Select patients underwent microsurgical resection of SEGAs with acceptable morbidity. Gross-total resection or radical STR was achieved in 90.9% of our series (20 of 22 primary tumor resections), with no recurrences in this group. Approximately half of our patient series required CSF diversionary procedures. There were no instances of permanent neurological morbidity associated with surgery.

Object: In patients with tuberous sclerosis complex (TSC), the tuber-to-brain proportion (TBP) is a marker of seizure severity and cognitive function. However, few studies have quantified the TBP. Furthermore, authors of these studies have measured the TBP at only a single time point, despite the fact that tuber cells were found to express proliferation markers, suggesting that they may be dynamic lesions. Authors of the present study used a semi-automated tuber segmentation program to determine whether the TBP changes over time., Methods: Axial FLAIR MR images were retrospectively identified for patients with TSC who had undergone imaging at the authors' institution between February 1998 and June 2009. Using FireVoxel software, the TBP was measured for each patient at a minimum interval of 2 years., Results: Twelve patients meeting the study inclusion criteria were identified. The mean TBP was 1.88% (range 0.38%-3.70%). Eight patients demonstrated minimal changes and 3 patients demonstrated small increases in TBP. The remaining patient exhibited a decrease of 1.00%, which correlated with a visible decrease in the size of 2 cerebellar lesions., Conclusions: Semi-automated brain segmentation is a valuable tool in the longitudinal study of tubers. A subset of patients with TSC, particularly those with cerebellar lesions, may exhibit changes in the TBP over time.

Since approximately 5-10% of the ~50,000 tuberous sclerosis complex (TSC) patients in the US are "MRI-negative," our goal was to test the hypothesis that they nevertheless exhibit metabolic abnormalities. To test this, we used proton MR spectroscopy to obtain and compare gray and white matter (GM and WM) levels of the neuronal marker, N-acetylaspartate (NAA), the glial marker, myo-inositol (mI), and its associated creatine (Cr), and choline (Cho) between two "MRI-negative" female TSC patients (ages 5 and 43 years) and their matched controls. The NAA, Cr, Cho and mI concentrations, 9.8, 6.3, 1.4, and 5.7 mM, in the pediatric control were similar to those of the patients, whereas the adult patient revealed a 17% WM NAA decrease and 16% WM Cho increase from their published means for healthy adults - both outside their respective 90% prediction intervals. These findings suggest that longer disease duration and/or TSC2 gene mutation may cause axonal dysfunction and demyelination., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Object: Tuberous sclerosis complex (TSC) brain pathology is characterized on MRI by cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. Seizures, the prominent feature of TSC, are frequently intractable to medical therapy and, in many patients, resection of tubers results in seizure control. However, in approximately 40% of patients, resection of tubers does not control seizures. This fact, as well as evidence from invasive electrophysiological recordings and experimental animal models, suggests that in patients with TSC, there may be extratuberal epileptogenic brain that does not display any apparent abnormality on conventional MRI. The authors hypothesized that high field strength MRI might uncover lesions not seen on conventional MRI in these patients., Methods: Institutional review board approval was obtained to scan 4 patients with TSC (ages 18-26 years) in a 7-T MR unit. Optimized 7-T sequences, including T1- and T2-weighted, FLAIR, SPACE FLAIR, T2*, and MPRAGE studies, were performed. Imaging studies were compared with identical sequences performed using a conventional 1.5-T MR scanner., Results: In all 4 patients, there was improved visualization of the findings demonstrated on conventional imaging. Importantly, new lesions were detected in all 4 patients, which were not well visualized with conventional MRI. Newly detected lesions included microtubers, radial glial signal abnormalities, subependymal nodules arising from the caudate nucleus, and caudate nucleus lesions., Conclusions: High field strength MRI detects previously uncharacterized lesions in patients with TSC and allows better detection and delineation of subtle abnormalities. In addition, the data demonstrate a compelling relationship between intraventricular lesions and the caudate nucleus. These data support previous electrophysiological and animal-model findings that demonstrate neurological pathology beyond the conventionally detected lesions in TSC.

Object: Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disorder resulting in hamartomas of several organs. Cortical tubers are the most prominent brain lesions in TSC. Treatment-resistant epilepsy often develops early in life in patients with TSC and is associated with severe intellectual and behavioral impairments. Seizures may remit following epilepsy surgery in selected cases, yet it remains unclear whether the tuber or the perituberal cortex is the source of seizure onset. In this study, the authors reviewed the onset of seizures in patients in whom depth electrodes had been placed within or adjacent to cortical tubers., Methods: After obtaining institutional review board approval, the authors retrospectively reviewed data from 12 pediatric patients with multifocal TSC and treatment-resistant epilepsy who had undergone invasive intracranial electroencephalographic monitoring. Tubers were identified on postimplantation MRI, and all depth electrodes were located. Depth electrode contacts were classified visually as either tuber/perituberal cortex or nontuber/nonperituberal cortex. Board-certified clinical neurophysiologists reviewed the seizures to identify all electrodes involved in the ictal onset., Results: Among 309 recorded seizures, 104 unique ictal onset patterns were identified. Of the 11 patients with electrodes recording in a tuber, 9 had seizure onsets involving the tuber. Similarly, of the 9 patients with perituberal recording electrodes, 7 had perituberal ictal onsets. Overall, there was no difference in the percentage of contacts involved in seizure onset between the tuber and perituberal cortex. In a subset of 7 patients in whom at least 1 depth electrode contact was within the tuber and 1 was in the perituberal cortex, there was no difference between the percentage of tuber and perituberal onsets., Conclusions: Findings demonstrated heterogeneity in the ictal onset patterns as well as involvement of the tuber and perituberal cortex within and between patients. Although the data are limited by the restricted region(s) sampled with intracranial electrodes, they do suggest that cortical hyperexcitability in TSC may derive from the tuber or surrounding cortex.

Object: Tuberous sclerosis complex (TSC) can manifest with 3 principal intracranial pathological entities: cortical tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). The authors analyzed the location and growth of intraventricular lesions in a large cohort of patients with TSC., Methods: After institutional review board protocol approval, the authors retrospectively reviewed brain MRI scans of TSC patients for whom at least 1 electronically stored cranial MRI study was available. Collected data included location, size, and growth over time of all intraventricular lesions., Results: The authors reviewed 560 scans in 103 patients, who harbored 496 intraventricular lesions. Of the 496 lesions, 157 lesions were located along the caudate-thalamic groove (CTG) in 88 patients. Twenty SEGAs were operated on. The remaining 339 lesions were distributed along the lateral ventricle, always in contact with the course of the caudate nucleus, and were presumed to be SENs. Twenty-two patients with more than 4 years of follow-up had 34 lesions along the CTG, of which 23 were stable in size and 11 grew. All other intraventricular lesions were stable. Seven-Tesla MRI showed the intimate association of SENs and the caudate nucleus in 1 patient., Conclusions: Intraventricular lesions in TSC patients are located throughout the lateral ventricular wall. Their location exclusively follows the course of the caudate nucleus. Only lesions along the CTG showed the potential to grow, and these were then identified as SEGAs. The remaining lesions were SENs. Understanding why these lesions develop in relation to the caudate nucleus may offer insights into therapy.

Object: Surgery is increasingly used to treat children with refractory epilepsy. Before surgery, the authors routinely evaluated the coagulation profile to identify coagulation abnormalities not established by personal and family history, physical examination, and routine screening tests., Methods: Thirty-nine consecutive children undergoing testing prior to epilepsy surgery were prospectively evaluated. The authors evaluated a detailed hematological history and an elaborative hematological panel including complete blood count, hepatic panel, anticoagulant levels, coagulation profile (prothrombin time, partial thromboplastin time, international normalized ratio, fibrinogen, thrombin time, von Willebrand antigen, ristocetin cofactor, factor VIII, and individual factor assays when indicated) and platelet aggregation studies (in the presence of adenosine diphosphate, epinephrine, collagen, and ristocetin). Patient variables included tuberous sclerosis complex (TSC), age at epilepsy onset, age at surgery, seizure frequency, number and type of antiepileptic drugs, recent or present ketogenic diet, and use of selective serotonin reuptake inhibitors., Results: Ten children (25.6%) had either coagulation or platelet function abnormalities. Abnormal coagulation was identified in 5 children, and abnormal platelet function was discovered in 6. A diagnosis of TSC was associated with a platelet function abnormality (p = 0.012), whereas children without TSC had a higher rate of coagulopathy (p = 0.041). None of the other characteristics reached statistical significance. In 2 patients (5.1%) with TSC and platelet aggregation abnormalities, the authors noted normal standard screening laboratory studies and an uneventful detailed personal and family history. One of these 2 patients developed a significant intraoperative bleeding complication., Conclusions: A preoperative screening with standard laboratory studies and detailed history may not be adequate to fully examine underlying coagulation abnormalities in children with refractory epilepsy. Platelet aggregation studies should be considered in patients with TSC.

Object: Many children with epilepsy and tuberous sclerosis complex (TSC) have multiple tubers on MR imaging and poorly localized/lateralized video electroencephalography (EEG) findings. Given the long-term risks associated with frequent seizures and multiple antiepileptic drugs, along with improved success in identifying focal epileptogenic zones in patients with multifocal lesions, the authors used bilateral intracranial EEG to lateralize the epileptogenic zone in patients with nonlateralizable noninvasive preoperative evaluations., Methods: A retrospective analysis from January 1, 1998, to June 30, 2008, identified 62 children with TSC who were presented at a surgical conference. Of the 52 patients undergoing diagnostic or therapeutic procedures during the study period, 20 underwent bilateral intracranial EEG. The presurgical testing results, intracranial EEG findings, surgical interventions, and outcomes were reviewed., Results: Fourteen of 20 patients had intracranial EEG findings consistent with a resectable epileptogenic zone. One patient is awaiting further resection. Five patients had findings consistent with a nonresectable epileptogenic zone, and 1 of these patients underwent a callosotomy. Seven patients had Engel Class I outcomes, 1 was Class II, 3 were Class III, and 3 were Class IV (mean follow-up 25 months)., Conclusions: Bilateral intracranial EEG can identify potential resectable seizure foci in nonlateralizable epilepsy in TSC. Although 6 of 20 patients did not undergo resection (1 patient is pending future resection), significant improvements in seizures (Engel Class I or II) were noted in 8 patients. In the authors' experience, this invasive monitoring provided a safe method for identifying the ictal onset zone.

Parents of children with tuberous sclerosis complex who underwent multistage resections for treatment of refractory seizures were offered a telephone questionnaire regarding quality of life (QOL) of child and family since surgery. Of 53 families, 39 responded. Age at epilepsy onset was birth to 3 months. Average duration of epilepsy before the first surgery was 5.1 years, and average age at surgery was 5.8. The average follow-up was 3.9. Seventy-seven percent had a >90% reduction in disabling seizures. In all outcome categories, 46-85% had at least a moderate improvement in QOL. There was a significant correlation between QOL variables and Engel outcome class. Despite the potential burden posed by the aggressive surgical approach, including multiple surgeries and long hospitalization periods, 94% of parents would choose the same course once again. We conclude that aggressive surgical treatment of tuberous sclerosis complex-related refractory seizures is associated with significant control of epilepsy as well as improved QOL for the patient and family., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Surgical resection of single, dominant, epileptogenic lesions in patients with tuberous sclerosis complex (TSC) is now accepted as an effective therapy. However, patients with symptomatic tubers in eloquent cortex are sometimes not offered surgery because of the concern for postoperative neurologic morbidity. In this study, we examine our results in children undergoing surgery for resection of tubers and associated seizure foci in rolandic and perirolandic cortex., Methods: Between 1998 and 2008, 52 pediatric patients (mean age 4 years) with TSC underwent epilepsy surgery at the NYU Comprehensive Epilepsy Center. Fifteen of these patients underwent multistage surgery for invasive mapping of seizure foci and surrounding functional cortex followed by resection of tubers/seizure foci in or near rolandic cortex. Data were retrospectively collected and neurologic outcomes were tabulated., Results: Postoperatively, four patients (27%) had either new hemiparesis or worsening of a preexisting hemiparesis. However, all patients were back to their neurologic baselines at 3-month follow-up, yielding no permanent postoperative deficits. The modified Engel outcome was class I in nine patients (60%), class II in three patients (20%), class III in two patients (13%), and class IV in one patient (7%) after 40 months mean follow-up., Discussion: Surgical resection of tubers and associated epileptogenic foci in rolandic and perirolandic cortex in children with TSC is feasible, with low neurologic morbidity, and yields good seizure control. These results suggest that tubers and perituberal epileptogenic foci can be safely resected even in eloquent regions because of reorganization of functional cortex or because these lesions contain no neurologic function.

Objective: The goal of the work described here was to assess the efficacy and safety of vagus nerve stimulation in a cohort of patients with tuberous sclerosis complex with refractory epilepsy. Furthermore, we examined the impact of vagus nerve stimulation failure on the ultimate outcome following subsequent intracranial epilepsy surgery., Methods: A retrospective review was performed on 19 patients with refractory epilepsy and TSC who underwent vagus nerve stimulator (VNS) implantation. There were 11 (58%) females and 8 (42%) males aged 2 to 44 years when the VNS was implanted (mean: 14.7+/-12 years). Twelve patients underwent primary VNS implantation after having failed a mean of 7.1 antiepileptic drugs. Two patients (17%) had generalized epilepsy, one had a single seizure focus, three (25%) had multifocal epilepsy, and six (50%) had multifocal and generalized epilepsy. Seven patients were referred for device removal and evaluation for intracranial procedures. One patient in the primary implantation group was lost to follow-up and excluded from outcome analysis., Results: All implantations and removals were performed without permanent complications. The duration of treatment for primary VNS implants varied from 8.5 months to 9.6 years (mean: 4.9 years). Mean seizure frequency significantly improved following VNS implantation (mean reduction: 72%, P<0.002). Two patients had Engel Class I (18%), one had Class II (9%), seven had Class III (64%), and one had Class IV (9%) outcome. Three patients with poor response to vagus nerve stimulation therapy at our center underwent resection of one or more seizure foci (Engel Class I, two patients; Engel Class III, one patient). Seven patients referred to our center for VNS removal and craniotomy underwent seizure focus resection (6) or corpus callosotomy (1) (Engel Class II: 2, Engel III: 2; Engel IV: 3). In total, 8 of 10 (80%) patients experienced improved seizure control following intracranial surgery (mean reduction: 65%, range: 0-100%, P<0.05)., Conclusions: VNS is a safe and effective treatment option for medically refractory epilepsy in patients with tuberous sclerosis complex. Nine of 11 patients (82%) experienced at least a 67% reduction in seizure burden. Lack of response to vagus nerve stimulation does not preclude subsequent improvement in seizure burden with intracranial epilepsy surgery.

Subependymal giant cell tumors (SGCTs) are observed in 5-20% of patients with tuberous sclerosis complex (TSC) but account for approximately 25% of neurological morbidity. The authors report the case of a 7-year-old girl with TSC and multiple cortical tubers who presented with worsening seizures in the context of the rapid growth of a cystic, calcified, extraventricular SGCT in the right frontal lobe, initially thought to represent a cortical tuber. The tumor and surrounding tubers were excised, and clinical seizures resolved. This is the first report of an extraventricular SGCT in a child with TSC outside the neonatal period.

Epilepsy surgery for medically refractory seizures among patients with tuberous sclerosis complex (TSC) is a well-accepted treatment option. Many epilepsy centers around the world have published their experience over the past several years, supporting the idea that the best seizure control is obtained when a single tuber and associated epileptogenic zone is documented and targeted surgically. Recent advances in imaging and physiological techniques that reveal the epileptogenic zone have been used successfully in children with TSC who are being evaluated for surgery. As a result, a number of different surgical strategies have emerged, each reflecting the experience, strengths, and referral biases of the individual treating teams. Experience suggests that some patients with TSC who present with seizures that are difficult to localize and do not meet the classic selection criteria for epilepsy surgery may, nevertheless, benefit from surgery. Tuberectomy alone is often not sufficient for obtaining seizure control. Intracranial electrode recordings performed in a large number of children with TSC undergoing epilepsy surgery have raised new questions about the relationship of the cortical tuber to the epileptogenic zone in TSC. A careful assessment of the risks and benefits of any surgical strategy, compared with those associated with continued refractory epilepsy, should be considered by the treating team in conjunction with the patient's family. Epilepsy surgery has not only benefited many children with TSC, but it also facilitates the understanding of epileptogenesis in TSC.

We describe diffuse glioma-like infiltrates in excised tubers in five out of forty Tuberous sclerosis complex (TSC) patients undergoing excision of a tuber at our institution within the last 10 years. All patients presented with refractory seizures. Resection specimens from four patients had the pathognomonic histologic features of neuroglial hamartomas (tubers) and in one case there was cortical microdysgenesis lacking cells typical of TSC. All lesions were associated with an infiltrate of atypical, mostly elongate, glioma-like small cells, which were immunoreactive for GFAP in three, and pS6 (a marker for activity of the mTOR pathway), in two cases. MAP-2 and CD34, were negative and MIB-1 (Ki67) immunostains ranged from <1-21%. Array-based comparative genomic hybridization revealed that these proliferative phenomena were associated with 21 different copy number aberrations in comparison with a tuber without atypical infiltrates. Postoperatively (follow-up period ranging from 8 to 34 months) none of the patients have any evidence of a glioma. We report that tubers resected for treatment of seizures are sometimes associated with glioma-like lesions, which are indistinguishable from infiltrating gliomas by morphology and immunohistochemistry. Genomic analysis with SNP arrays revealed copy number changes which may be associated with the pathogenesis of such infiltrates.

Purpose: Cortical tubers are epileptogenic lesions in patients with tuberous sclerosis complex (TSC). Giant cells and dysplastic neurons are pathological hallmarks of cortical tubers. Severe astrogliosis, which is invariably present in tubers, has attracted much less attention. We hypothesize that the development of astrogliosis in cortical tubers constitutes a primary pathology of astrocytes and is directly related to TSC 1/2 mutations., Methods: To begin to test this hypothesis, we performed immunohistochemical and electron microscopic analysis of brain tuber tissue resected from epileptic TSC patients. We compared alterations in tuber astrocytes to those found in other acute and chronic human epilepsy pathologies., Results: We found that astrogliosis in tubers is comprised of a mixture of "gliotic" and "reactive" astrocytes. The majority of tuber astrocytes are "gliotic" astrocytes that are morphologically and immunophenotypically similar to astrocytes in areas of gliosis in hippocampal sclerosis (HS). However, specific immunostaining features differentiate TSC gliosis from HS gliosis. "Reactive" tuber astrocytes are large-sized, vimentin positive cells in the vicinity of giant cells that show activation of the mammalian target of rapamycin (mTOR) pathway, consistent with mutated TSC gene function. These cells resemble acutely reactive human astrocytes seen in tissue resected from depth electrode implantation patients. Oligodendrocytes and NG2 expressing glial cells do not have any detectable alterations within tubers., Conclusion: We conclude that astrocytes are the type of glial cell selectively impacted in cortical tuber pathology. We propose that tubers may be dynamic lesions, with progression of astrocytes over time from "reactive" to "gliotic." Tuber astrogliosis in TSC may represent a genetic "model" of gliosis that is phenotypically similar to gliosis seen in acquired human pathologies.

Multicenter, retrospective analysis of 70 subjects with TSC following surgery for relief of epilepsy revealed significant associations between younger age at seizure onset, present/prior history of infantile spasms, interictal focality (bilateral versus unilateral), and absence of residual postoperative predominant tuber, and poorer postoperative outcome (p < 0.01). Ictal multifocality, mental retardation, and discordant EEG and MRI data showed a negative trend toward outcome, but were not significant.

Objective: Cortical tubers are a pathognomonic finding in some patients with tuberous sclerosis complex (TSC), and are believed to be epileptogenic foci. Surgery is an effective option in selected patients with TSC who are refractory to medical therapy. This article describes three patients with TSC who underwent three-stage epilepsy surgery at our center, with the intention of examining local electrophysiological changes after each stage of the procedure., Methods: Magnetic resonance images were obtained after initial implantation of electrodes and after resection and electrode reimplantation. These images were co-registered and overlaid. The intracranial grids were overlaid in a similar procedure and manually traced, and then added to the volumetric image. Mean spike counts were obtained for each patient and expressed in spikes per minute. Statistical analysis was performed on spike counts prior to and after resection., Results: All three patients displayed intense spiking in the regions around the dominant epileptogenic tuber. On tuber removal, spike counts diminished significantly. In each case, new areas of spiking emerged in regions remote from the tuber periphery after tuber resection, with the emergence of secondary ictal onset zones in the resection margin., Conclusion: This retrospective study highlights some common electrophysiological features among the patients examined. The observed epileptogenic activity and regions of ictal onset suggest that it may be the region of brain tissue surrounding the tuber that is responsible for the majority of epileptogenic activity in these patients.

Objective: Tuberous sclerosis complex (TSC) is associated with medically refractory epilepsy and developmental delay in children and usually results from cortical tubers. Seizures that begin in young patients are often refractory and may contribute to development delay. Functional outcome is improved when seizures are controlled at an early age. Previous reports have shown modest benefit from surgical resection of single tubers/seizure foci in older children; however, many children with TSC develop uncontrolled seizures before age 1. To identify patients who might benefit from surgery and to maximize outcome, we used a novel surgical approach in young children that consists of invasive intracranial monitoring, which is typically 3-staged and often bilateral., Methods: Of 110 consecutive children who underwent epilepsy surgery by a single surgeon in the past 6 years, 25 patients (9 boys and 16 girls) had TSC. At the time of their first surgery at our institution, they were a median age of 4.0 years. A total of 31 separate admissions for epilepsy surgery in these 25 patients were identified. Bilateral electrode placement was performed in 13 children whose seizures could not be lateralized definitively preoperatively, and 22 patients underwent 3-stage surgeries., Results: At 6 months or longer after the initial resection, 21 (84%) children were class I, 2 (8%) children were class II, and 2 (8%) children were class IV. At a mean follow-up of 28 months, 17 (68%) children were class I, 6 (24%) were class II, and 2 (8%) were class III. Four of the 5 children who initially were rejected as surgical candidates because of multifocality and who required initial bilateral electrode study are now seizure-free., Conclusions: This approach can help to identify both primary and secondary epileptogenic zones in young TSC patients with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery. Long-term follow-up will determine whether this approach has durable effects.

Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.

In Tuberous sclerosis complex (TSC), neurological dysfunction, usually in association with epilepsy, is responsible for the greatest degree of disease-related disability. Epilepsy surgery is increasingly recognized as a therapeutic option given the often medication-resistant nature of the disease. Seven subjects with medically refractory epilepsy associated with TSC, who underwent surgery at a tertiary care epilepsy center and in whom both preoperative and postoperative neuropsychological data were available, were examined. The Vineland Adaptive Behavior Scales, and in one case, the WISC-III were utilized. Postoperatively, the composite standard scores declined in six of the seven subjects, although for the most part this decline was quite modest (8 points or less in 5/6 subjects). The mean overall developmental/intellectual quotients were comparable across assessments (preoperative M = 55, SD = 20.3; postoperative M = 49 SD = 16.6). Good outcomes appeared to be related to seizure relief. Age estimates of developmental level indicated developmental progress in the majority of subjects in the current sample, and may yield greater clinical information for individuals with developmental delay than do standard scores.

Tuberous sclerosis complex is associated with medically refractory seizures and developmental delay in children. These epilepsies are often resistant to antiepileptic drugs, can be quite severe, and usually have a negative impact on the child's neurologic and cognitive development. It is believed that functional outcome is improved if seizures can be controlled at an early age. The surgical treatment of intractable epilepsy in children and adults with tuberous sclerosis complex has gained significant interest in recent years. Previously published studies have shown a potential benefit from resection of single tubers, with most of the results noted in relatively older children. All of these reports support the idea that if a single primary epileptogenic tuber or region can be identified, then a surgical approach is appropriate. However, most children with tuberous sclerosis complex have multiple potentially epileptogenic tubers, rendering localization challenging, and they are therefore rejected as possible surgical candidates. We have used a novel surgical approach using invasive intracranial monitoring, which is typically multistaged and bilateral. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in patients with tuberous sclerosis complex with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected patients. Long-term follow-up will determine whether this approach has durable effects. We await better methods for identifying the epileptogenic zone, both noninvasive and invasive.

Tuberous sclerosis complex (TSC) is associated with medically refractory seizures and developmental delay in children. These epilepsies are often resistant to antiepileptic drugs (AEDs), may be quite severe, and usually have a negative impact on the child's neurological and cognitive development. It is believed that functional outcome is improved if seizures can be controlled at an early age. The surgical treatment of intractable epilepsy in children and adults with TSC has gained significant interest in recent years. Previously published studies have shown a potential benefit from resection of single tubers, with most of the results noted in relatively older children. All of these reports support the idea that if a single primary epileptogenic tuber/region can be identified, then a surgical approach is appropriate. However, most children with TSC have multiple potentially epileptogenic tubers, rendering localization challenging, and they are therefore rejected as possible surgical candidates. We have utilized a novel surgical approach using invasive intracranial monitoring, which is typically multistaged and bilateral. Here we present an illustrative case of a young boy with TSC and medically refractory epilepsy who underwent a staged surgical approach. This multistage surgical approach has been useful in identifying both primary and secondary epileptogenic zones in TSC patients with multiple tubers. Multiple or bilateral seizure foci are not necessarily a contraindication to surgery in selected TSC patients. Long-term follow-up will determine whether this approach has durable effects. We await better methods for identifying the epileptogenic zone, both noninvasive and invasive.

p34cdc2, collapsin response mediator protein 4 (CRMP4), doublecortin (DCX), HuD, and NeuN expression was assessed in tuber (n = 16) and subependymal giant cell astrocytoma (SEGA; n = 6) specimens in tuberous sclerosis complex to define the developmental phenotype and lineage of giant cells (CGs) in these lesions. Many GCs exhibited HuD and NeuN immunolabeling suggesting a differentiated neural phenotype. Giant cells in tubers, SEGAs and subependymal nodules in the Eker rat model of TSC expressed CRMP4 and DCX. Tubers and SEGAs exhibit a heterogeneous profile of differentiation and may share a common cellular lineage. Tubers may contain a subpopulation of newly generated cells.

Refractory seizures are common in patients with tuberous sclerosis and can contribute to developmental delay and behavioral problems. Surgical intervention can reduce the seizure burden in selected patients with tuberous sclerosis and refractory epilepsy, thereby improving cognitive function, behavior, and quality of life. However, the risks of surgery are usually considered unacceptable when the epileptogenic focus lies over dominant hemisphere eloquent cortex or is multilobar. Multistage invasive monitoring can provide detailed data regarding the location and number of ictal foci and functional extraoperative mapping can precisely delineate the boundaries of eloquent areas of the brain. If independent ictal onsets are demonstrated, a staged surgical approach can allow a more aggressive yet safe procedure in selected patients. A combination of staged resection and multiple subpial transections may provide an opportunity to treat epileptogenic foci located over eloquent cortex. Bilateral staged resections can be used when independent bihemispheric foci are present in patients with tuberous sclerosis. This article presents two cases, one of which (case 2) was previously reported, on successful multistage surgical treatment of epileptogenic foci located over an eloquent cortex or in both hemispheres in children with tuberous sclerosis. This case is represented since there is additional follow-up available and the prior report was to a neurosurgical audience. This multistage approach permitted resection of epileptogenic foci that would traditionally have been considered inoperable.

On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland, to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program, and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. Here we summarize the outcomes from the extensive premeeting deliberations and final workshop recommendations, including (1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex, (2) the key gaps, needs, and challenges that hinder progress in tuberous sclerosis complex research, and (3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five to ten year time frame.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant. [ABSTRACT FROM AUTHOR]

Summary Purpose: Intracranial monitoring (IM) is a key diagnostic procedure for select patients with treatment-resistant epilepsy (TRE). Seizure focus resection may improve seizure control in both lesional and nonlesional TRE. IM itself is not considered to have therapeutic potential. We describe a cohort of patients with improved seizure control following IM without resective surgery. Methods: Over 12.5 years, 161 children underwent 496 surgeries including intracranial monitoring. We retrospectively reviewed the patients' charts, operative reports, and radiologic scans, under an institutional review board-approved protocol. Key Findings: Seventeen patients underwent only IM, without additional resective surgery, and seven had a dramatic improvement in their epilepsy; six of the seven patients are seizure-free (Engel class I), and one rarely has seizures (Engel class II). All seven patients had frequent seizures that led to IM: either daily (five patients) or 1-2 per week (two patients). The mean age (± standard deviation, SD) at seizure onset was 1.6 ± 1.3 years (range 0.5-4 years). Etiologies were tuberous sclerosis (3 patients), trauma (1 patient), and unknown (3 patients). Mean age at surgery (± SD) was 4.1 ± 2 years (range 1-7 years), and duration of epilepsy 2.5 ± 1.1 years (range 0.5-4 years). Duration of IM was 11.7 ± 5.6 days (5-19 days). Six patients had bilateral and one unilateral invasive electrodes. At last follow-up, four patients required fewer antiepileptic drugs (AEDs), one had the same medication but a higher dose, and two patients were taking additional AEDs. Follow-up was 30.6 ± 9.5 months (range 19-41 months). Significance: Although uncommon, patients with TRE may improve after IM alone. The explanation for this observation remains unclear; however, perioperative medications including steroids, direct cortical manipulation, or other factors may influence the epileptogenic network. [ABSTRACT FROM AUTHOR]

Abstract: Background: Tuberous sclerosis complex is an autosomal dominant disorder predisposing to the development of benign lesions in different body organs, mainly in the brain, kidney, liver, skin, heart, and lung. Subependymal giant cell astrocytomas are characteristic brain tumors that occur in 10% to 20% of tuberous sclerosis complex patients and are almost exclusively related to tuberous sclerosis complex. Subependymal giant cell astrocytomas usually grow slowly, but their progression ultimately leads to the occlusion of the foramen of Monro, with subsequent increased intracranial pressure and hydrocephalus, thus necessitating intervention. During recent years, secondary to improved understanding in the biological and genetic basis of tuberous sclerosis complex, mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of subependymal giant cell astrocytomas, becoming an alternative therapeutic option to surgery. Methods: In June 2012, an International Tuberous Sclerosis Complex Consensus Conference was convened, during which an expert panel revised the diagnostic criteria and considered treatment options for subependymal giant cell astrocytomas. This article summarizes the subpanel's recommendations regarding subependymal giant cell astrocytomas. Conclusions: Mammalian target of rapamycin inhibitors have been shown to be an effective treatment of various aspects of tuberous sclerosis complex, including subependymal giant cell astrocytomas. Both mammalian target of rapamycin inhibitors and surgery have a role in the treatment of subependymal giant cell astrocytomas. Various subependymal giant cell astrocytoma–related conditions favor a certain treatment. [Copyright &y& Elsevier]