WNT pathway in focal cortical dysplasia compared to perilesional nonlesional tissue in refractory epilepsies.

BACKGROUND: Focal cortical dysplasia (FCD) is a malformation of cortical development that causes medical refractory seizures, and one of the main treatments may be surgical resection of the affected area of the brain. People affected by FCD may present with seizures of variable severity since childhood. Despite many medical treatments available, only surgery can offer cure. The pathophysiology of the disease is not yet understood; however, it is known that several gene alterations may play a role. The WNT/ß-catenin pathway is closely related to the control and balance of cell proliferation and differentiation in the central nervous system. The aim of this study was to explore genes related to the WNT/ß-catenin pathway in lesional and perilesional brain tissue in patients with FCD type II. METHODS: Dysplastic and perilesional tissue from the primary dysplastic lesion of patients with FCD type IIa were obtained from two patients who underwent surgical treatment. The analysis of the relative expression of genes was performed by a qRT-PCR array (super array) containing 84 genes related to the WNT pathway. RESULTS: Our results suggest the existence of molecular alteration in some genes of the WNT pathway in tissue with dysplastic lesions and of perilesional tissue. We call this tissue of normal-appearing adjacent cortex (NAAC). Of all genes analyzed, a large number of genes show similar behavior between injured, perilesional and control tissues. However, some genes have similar characteristics between the perilesional and lesional tissue and are different from the control brain tissue, presenting the perilesional tissue as a molecularly altered material. CONCLUSION: Our results suggest that the perilesional area after surgical resection of tissue with cortical dysplasia presents molecular changes that may play a role in the recurrence of seizures in these patients. The perilesional tissue should receive expanded attention beyond the somatic mutations described and associated with FCD, such as mTOR, for example, to new signaling pathways that may play a crucial role in seizure recurrence.

The ILAE consensus classification of focal cortical dysplasia: An update proposed by an ad hoc task force of the ILAE diagnostic methods commission.

Ongoing challenges in diagnosing focal cortical dysplasia (FCD) mandate continuous research and consensus agreement to improve disease definition and classification. An International League Against Epilepsy (ILAE) Task Force (TF) reviewed the FCD classification of 2011 to identify existing gaps and provide a timely update. The following methodology was applied to achieve this goal: a survey of published literature indexed with ((Focal Cortical Dysplasia) AND (epilepsy)) between 01/01/2012 and 06/30/2021 (n = 1349) in PubMed identified the knowledge gained since 2012 and new developments in the field. An online survey consulted the ILAE community about the current use of the FCD classification scheme with 367 people answering. The TF performed an iterative clinico-pathological and genetic agreement study to objectively measure the diagnostic gap in blood/brain samples from 22 patients suspicious for FCD and submitted to epilepsy surgery. The literature confirmed new molecular-genetic characterizations involving the mechanistic Target Of Rapamycin (mTOR) pathway in FCD type II (FCDII), and SLC35A2 in mild malformations of cortical development (mMCDs) with oligodendroglial hyperplasia (MOGHE). The electro-clinical-imaging phenotypes and surgical outcomes were better defined and validated for FCDII. Little new information was acquired on clinical, histopathological, or genetic characteristics of FCD type I (FCDI) and FCD type III (FCDIII). The survey identified mMCDs, FCDI, and genetic characterization as fields for improvement in an updated classification. Our iterative clinico-pathological and genetic agreement study confirmed the importance of immunohistochemical staining, neuroimaging, and genetic tests to improve the diagnostic yield. The TF proposes to include mMCDs, MOGHE, and "no definite FCD on histopathology" as new categories in the updated FCD classification. The histopathological classification can be further augmented by advanced neuroimaging and genetic studies to comprehensively diagnose FCD subtypes; these different levels should then be integrated into a multi-layered diagnostic scheme. This update may help to foster multidisciplinary efforts toward a better understanding of FCD and the development of novel targeted treatment options.

Drebrin expression patterns in patients with refractory temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. METHODS: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. RESULTS: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. SIGNIFICANCE: Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.

Dysplastic Cerebellar Epilepsy: Complete Seizure Control Following Resection of a Ganglioglioma.

Subcortical epilepsy has been a controversial issue, partially settled by evidence showing seizure generation in hypothalamic hamartomas and also by reports of seizures caused by cerebellar lesions. We report 4-year-old girl with right hemifacial seizures and autonomic phenomena, in whom MRI showed an irregular mass in the right cerebellar peduncle. Despite several unremarkable video-EEG recordings, seizure origin in the lesion was hypothesized. Complete resection was feasible, histopathology showed a ganglioglioma, and she has been seizure free for 3 years. A fine line separates these developmental tumors from focal cortical dysplasia, and the homogeneous presentation of this entity led us to propose the terminology dysplastic cerebellar epilepsy.

Cerebral cavernous malformations in the setting of focal epilepsies: pathological findings, clinical characteristics, and surgical treatment principles.

Cavernous cerebral malformations (CCMs) are a well-defined epilepsy-associated pathology. They represent lesions/conglomerates of abnormally configured vessels leading to seizures either as a result of physiological changes affecting the cerebral cortex immediately surrounding the CCM (an epileptogenic mechanism that is relevant for both temporal and extratemporal lesions), or as a result of promoting epileptogenicity in remote but anatomo-functionally connected brain regions (a mechanism that is particularly relevant for temporal lobe lesions). This review details the pathological findings in CCMs and discusses the mechanisms of epileptogenicity in this context. The bulk of the review will focus on therapeutic strategies. Medical therapy using antiepileptic drugs is recommended as a first-line therapy, but surgical removal of the CCM with the surrounding cortex should be pursued if seizures prove to be drug resistant. Early timing of the resection and complete removal of any associated epileptic pathology are critical for best outcomes. In addition to reviewing the available data from prior series, we present original research from two specialized epilepsy centers targeted at answering particularly pressing clinical questions mainly related to the ideal timing and extent of surgery. Further research is needed to define the best surgical strategies in patients with temporal lobe CCMs and structurally normal hippocampi.

An 18-year follow-up of seizure outcome after surgery for temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVES: To evaluate the very long-term clinical outcome of surgery for mesial temporal lobe epilepsy and unilateral hippocampal sclerosis (MTLE/HS) without atypical features. The impact of surgical technique and postoperative reduction of medication on this outcome was investigated. DESIGN: Prospective longitudinal cohort follow-up study for up to18 years. SETTING: Epilepsy surgery centre in a university hospital. PATIENTS: 108 patients who underwent unilateral MTLE/HS. INTERVENTION: Surgery for MTLE/HS. MAIN OUTCOME MEASURE: Engel classification (I). Clinical evaluations were based on systematic interviews in person or by phone. Kaplan-Maier survival curves estimated the probability of remaining seizure free. The impact of medication management in the postoperative outcome was analysed using Cox regression. RESULTS: The probability of remaining completely seizure-free at 12 and 18 years after MTLE/HS surgery was 65% and 62%, respectively. The risk of having any recurrence was 22% during the first 24 months and increased 1.4% per year afterwards. Type of surgical technique (selective amygdalohippocampectomy vs anterior temporal lobectomy) did not impact on outcome. Remaining on antiepileptic drugs and history of generalised clonic seizure diminished the probability of remaining seizure free. CONCLUSIONS: MTLE/HS surgery is able to keep patients seizure free for almost up to two decades. Removal of the neocortex besides the mesial portion of the temporal lobe does not lead to better chances of seizure control. These findings are applicable to the typical unilateral MTLE/HS syndrome and cannot be generalised for all types of TLE. Future longitudinal randomised controlled studies are needed to replicate these findings.

Developmental tumors and adjacent cortical dysplasia: single or dual pathology?

Developmental tumors often lead to refractory partial seizures and constitute a well-defined, surgically remediable epilepsy syndrome. Dysplastic features are often associated with these tumors, and their significance carries both practical and conceptual relevance. If associated focal cortical dysplasia (FCD) relates to the extent of the epileptogenic tissue, then presurgical evaluation and surgical strategies should target both the tumor and the surrounding dyslaminated cortex. Furthermore, the association has been included in the recently revised classification of FCD and the epileptogenicity of this associated dysplastic tissue is crucial to validate such revision. In addition to the possibility of representing dual pathology, the association of developmental tumors and adjacent dysplasia may instead represent a single developmental lesion with distinct parts distributed along a histopathologic continuum. Moreover, the possibility that this adjacent dyslamination is of minor epileptogenic relevance should also be entertained. Surgical data show that complete resection of the solid tumors and immediately adjacent tissue harboring satellites may disrupt epileptogenic networks and lead to high rates of seizure freedom, challenging the epileptogenic relevance of more extensive adjacent dyslaminated cortex. Whether the latter is a primary or secondary abnormality and whether dyslaminated cortex in the context of a second lesion may produce seizures after complete resection of the main lesion is still to be proven.

Immediate improvement of motor function after epilepsy surgery in congenital hemiparesis.

Hemispherectomy often leads to a loss of contralateral hand function. In some children with congenital hemiparesis, however, paretic hand function remains unchanged. An immediate improvement of hand function has never been reported. A 17-year-old boy with congenital hemiparesis and therapy-refractory seizures due to a large infarction in the territory of the middle cerebral artery underwent epilepsy surgery. Intraoperatively, electrical cortical stimulation of the affected hemisphere demonstrated preserved motor projections from the sensorimotor cortex to the (contralateral) paretic hand. A frontoparietal resection was performed, which included a complete disconnection of all motor projections originating in the sensorimotor cortex of the affected hemisphere. Surprisingly, the paretic hand showed a significant functional improvement immediately after the operation. This observation demonstrates that, in congenital hemiparesis, crossed motor projections from the affected hemisphere are not always beneficial, but can be dysfunctional, interfering with ipsilateral motor control over the paretic hand by the contralesional hemisphere.

Temporal patterns and mechanisms of epilepsy surgery failure.

Epilepsy surgery is an accepted treatment option in patients with medically refractory focal epilepsy. Despite various advances in recording and localization noninvasive and invasive techniques (including electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetoencephalography (MEG), subdural grids, depth electrodes, and so on), the seizure outcome following surgical resection remains suboptimal in a significant number of patients. The availability of long-term outcome data on an increasing number of patients suggests two major temporal patterns of seizure recurrence (early vs. late) that implicate the following two different mechanisms for seizure recurrence: (1) a failure to either define/resect the epileptogenic zone, and (2) the nonstatic nature of epilepsy as a disease through the persistence of proepileptic cortical pathology. We describe the temporal patterns of epilepsy surgery failures and discuss their potential clinical, histopathologic, genetic, and molecular mechanisms. In addition, we review predictors of successful surgical interventions and analyze the natural history of epilepsy following surgical intervention. We hypothesize that the acute/early postoperative failures are due to errors in localizing and/or resecting the epileptic focus, whereas late recurrences are likely due to development/maturation of a new and active epileptic focus (de novo epileptogenesis).

Bilateral perisylvian ulegyria: an under-recognized, surgically remediable epileptic syndrome.

PURPOSE: Interest in the association of epilepsy and pseudobulbar palsy was rekindled since the identification through magnetic resonance imaging (MRI) of bilateral perisylvian polymicrogyria (PMG). Seizures are often intractable, but resective epilepsy surgery has not been recommended. However, a similar clinical picture can be encountered in patients with bilateral perisylvian destructive lesions, which fit the description of ulegyria (ULG). We report a series of patients with epilepsy and pseudobulbar palsy due to bilateral perisylvian ULG (BP-ULG), show that hippocampal sclerosis (HS) is often associated and highlight the fact that in this entity, unlike in malformative bilateral perisylvian PMG, seizures may be surgically treated. METHODS: The motor, cognitive, epileptologic, and imaging features of 12 patients with perisylvian ULG followed at three institutions are described. For patients with refractory seizures, we detail extracranial and intracranial electrographic recordings, surgical strategies, histopathologic analyses of the resected tissue, and outcome of surgical treatment. Descriptive statistics were used for quantitative and categorical variables. Student's t-test was used to compare means, and a p < 0.05 was considered significant. KEY FINDINGS: Pseudobulbar palsy and mental retardation were present in all patients with symmetrical BP-ULG. Five had refractory seizures. There was no relationship between the severity of the pseudobulbar palsy or of the mental retardation and the degree of seizure control with medication. The five patients in whom seizures were refractory to medication had significantly earlier age of onset and longer duration of epilepsy (p < 0.05). Dual pathology with associated unilateral HS was present in four. One patient with dual pathology had a temporolimbic electroclinical picture and had an anterior temporal lobectomy (ATL) based upon noninvasive evaluation. The other four had ictal semiology suggesting involvement of both temporolimbic and perisylvian cortex. Intracranial electroencephalography (EEG) showed concomitant seizure onset in the anterior temporal region and in the ipsilateral ULG in three of the four with dual pathology and in the ulegyric cortex in the one without HS. Resection guided by a combination of semiology, MRI, and extra and intracranial EEG led to complete seizure control in two and almost complete seizure control (Engel class II) in two other patients. The only surgical failure was an isolated ATL in a patient with dual pathology, and concomitant seizure onset in both lesions according to semiology and intracranial EEG. SIGNIFICANCE: Our findings suggest that BP-ULG mimics the clinical features of bilateral perisylvian PMG. In patients with refractory seizures, recognition of this entity should lead to consideration of resective surgery despite the bilateral ULG.

Resting-state fMRI in patients with refractory epilepsy with and without drop attacks: exploring the connectivity of sensorimotor cortex.

OBJECTIVE: Patients with multifocal or generalized epilepsies manifesting with drop attacks have severe refractory seizures and significant cognitive and behavioural abnormalities. It is unclear to what extent these features relate to network abnormalities and how networks in sensorimotor cortex differ from those in patients with refractory focal epilepsies. Thus, in this study we sought to provide preliminary data on connectivity of sensorimotor cortex in patients with epileptic drop attacks, in comparison to patients with focal refractory epilepsies. METHODS: Resting-state fMRI (rs-fMRI) data was available for 5 patients with epileptic drop attacks and 15 with refractory focal epilepsies undergoing presurgical evaluation. Functional connectivity was analyzed with a seed-based protocol, with primary seeds placed at the precentral gyrus, the postcentral gyrus and the premotor cortex. For each seed, the subjects' timeseries were extracted and transformed to Z scores. Between-group analysis was then performed using the 3dttest+ + AFNI program. RESULTS: Two clusters of reduced connectivity in the group with drop attacks (DA group) in relation to those with focal epilepsies were found in the between-group analysis: the precentral seed showed reduced connectivity in the surrounding motor area, and the postcentral seed, reduced connectivity with the ipsilateral posterior cingulate gyrus. In the intra-group analyses, sensorimotor and premotor networks were abnormal in the DA group, whereas patients with focal epilepsies had the usual connectivity maps with each seed. CONCLUSION: This pilot study shows differences in the cerebral connectivity in the sensorimotor cortex of patients with generalized epilepsies and drop attacks which should be further explored to better understand the biological bases of the seizure generation and cognitive changes in these people.

Extended resection for seizure control of pure motor strip focal cortical dysplasia during awake craniotomy: illustrative case.

BACKGROUND: Focal cortical dysplasias (FCD) represent highly intrinsically epileptogenic lesions that require complete resection for seizure control. Resection of pure motor strip FCD can be challenging. Effective control of postoperative seizures is crucial and extending the boundaries of resection in an eloquent zone remains controversial. OBSERVATIONS: The authors report a 52-year-old right-handed male with refractory epilepsy. The seizure phenotype was a focal crisis with preserved awareness and a clonic motor onset of right-hemibody. Epilepsy surgery protocol demonstrated a left pure motor strip FCD and a full-awake resective procedure with motor brain mapping was performed. Further resection of surgical boundaries monitoring function along intraoperative motor tasks with no direct electrical stimulation corroborated by intraoperative-neuromonitorization was completed as the final part of the surgery. In the follow-up period of 3-years, the patient has an Engel-IB seizure-control with mild distal lower limb palsy and no gate compromise. LESSONS: This report represents one of the few cases with pure motor strip FCD resection. In a scenario similar to this case, the authors consider that this variation can be useful to improve seizure control and the quality of life of these patients by extending the resection of a more extensive epileptogenic zone minimizing functional damage.

Control of drop attacks with selective posterior callosotomy: Anatomical and prognostic data.

OBJECTIVE: In a previous proof of concept study, selective posterior callosotomy achieved similar degree of control of drop attacks as total callosotomy, while sparing prefrontal interconnectivity. The present study aims to confirm this finding in a larger cohort and to provide anatomical and prognostic data. METHODS: Fifty-one patients with refractory drop attacks had selective posterior callosotomy and prospective follow up for a mean of 6.4 years. Twenty-seven patients had post-operative magnetic resonance imaging (MRI) and 18 had tractography (DTI) of remaining callosal fibers. Pre and postoperative falls were quantified and correlated with demographic, clinical and imaging data. RESULTS: Mean monthly frequency of drop attacks had a 95 % reduction, from 297 before to 16 after the procedure. Forty- one patients (80 %) had either complete or greater than 90 % control of the epileptic falls. Age and duration of epilepsy at surgery correlated with outcome (p values, respectively, 0.042 and 0.005). Mean index of callosal section along the posterior-to-anterior axis was 53.5 %. Extending the posterior section anterior to the midbody of the corpus callosum did not correlate with seizure control (p 0.91), providing fibers interconnecting the primary motor (M1) and caudal supplementary motor areas (SMA) were sectioned. Only one patient had a notable surgical complication which resolved in two days. CONCLUSIONS: This level III cohort study with objective outcome assessment confirms that selective posterior callosotomy is safe and effective to control epileptic falls. Younger patients with smaller duration of epilepsy have better results. A posterior section contemplating the splenium, isthmus and posterior half of the body (posterior midbody) seems sufficient to achieve complete or almost complete control of drop attacks.

A novel scale for suspicion of psychogenic nonepileptic seizures: development and accuracy.

OBJECTIVE: The differential diagnosis between epileptic and psychogenic nonepileptic seizures (PNES) is challenging, yet suspicion of PNES is crucial to rethink treatment strategies and select patients for diagnostic confirmation through video EEG (VEEG). We developed a novel scale to prospectively suspect PNES. METHODS: First, we developed a 51-item scale in two steps, based upon literature review and panel expert opinion. A pilot study verified the applicability of the instrument, followed by a prospective evaluation of 158 patients (66.5% women, mean age 33 years) who were diagnosed for prolonged VEEG. Only epileptic seizures were recorded in 103 patients, and the other 55 had either isolated PNES or both types of seizures. Statistical procedures identified 15 items scored between 0 and 3 that best discriminated patients with and without PNES, with a high degree of consistency. RESULTS: Internal consistency reliability of the scale for suspicion of PNES was 0.77 with Cronbach's Alpha Coefficient and 0.95 with Rasch Item Reliability Index, and performance did not differ according to the patient's gender. For a cut-off score of 20 (of 45) points, area under the curve was 0.92 (95% IC: 0.87-0.96), with an accuracy of 87%, sensitivity of 89%, specificity of 85%, positive predictive value of 77%, and negative predictive value of 94% (95% IC) for a diagnosis of PNES. CONCLUSIONS: The scale for suspicion of PNES (SS-PNES) has high accuracy to a reliable suspicion of PNES, helping with the interpretation of apparent seizure refractoriness, reframing treatment strategies, and streamlining referral for prolonged VEEG.

Selective Posterior Callosotomy for Treatment of Epileptic Drop Attacks: Video Documentation of the Surgical Technique: 2-Dimensional Operative Video.

This is a surgical technique video of selective posterior callosotomy (SPC), a novel surgical procedure to alleviate refractory epileptic drop attacks.1 Departing from traditional approaches aiming the anterior half or the entire callosum, SPC sections the posterior half of the callosum sparing prefrontal connectivity.1 Drop attacks are generalized epileptic seizures characterized by sudden falls.1 These seizures are often seen in diffuse brain pathology associated with generalized or multifocal epilepsies, whose electroencephalogram (EEG) "fingerprint" is bilaterally synchronous epileptic discharges.1 Sectioning the callosum to control drop attacks follows the rationale that the rapid synchronization of discharges between motor and premotor regions of both hemispheres is the basis.1 The standard approach to callosotomies always contemplated the anterior fibers of the callosum.2 Literature reports that anterior sections lead to unsatisfactory control of drop attacks, and results are improved when extended into a total callosotomy.2,3 This evidence coupled with diffusion tensor imaging (DTI) findings showing that motor and premotor fibers actually cross through posterior half of the callosum led us to hypothesize that selective section of the posterior half of the callosum would section all relevant motor fibers and control drop attacks to a similar extent to total callosotomies, with the advantage of sparing prefrontal interconnectivity3 and no split-brain syndrome. Both our series, one retrospective, followed by a new prospective study have confirmed SPC to be a safe procedure, leading to complete or greater than 90% control of epileptic falls in 85% of patients.1 The video presented here was recorded during a selective posterior callosotomy performed on a 13-yr-old girl who had hundreds of uncontrollable drop attacks per day. Falls were completely controlled with significant gains in psychomotor development and cognition, after 5 yr of follow-up. The patient provided signed consent to the surgical procedure, video acquisition, photo acquisition, and storage at operations, and the publication of this material.

Neuropsychiatric features of the coexistence of epilepsy and psychogenic nonepileptic seizures.

OBJECTIVE: To investigate demographic, epidemiologic and psychiatric features suggestive of the coexistence epilepsy (ES) and psychogenic nonepileptic seizures (PNES) that may contribute to precocious suspicion of the association. METHODS: In this exploratory study, all patients older than 16 years admitted to prolonged video-electroencephalogram monitoring were evaluated about demographic, epileptological and psychiatric features. Detailed psychiatric assessment using M.I.N.I.-plus 5.0, Beck Anxiety Inventory, Beck Depression Inventory and the Childhood Trauma Questionnaire (CTQ) was performed. Data were collected previous to the final diagnosis and patients with ES-only, PNES-only or coexistence of ES/PNES were compared. RESULTS: Of 122 patients admitted to epilepsy monitoring unit, 86 patients were included and 25 (29%) had PNES. Twelve (14%) had PNES-only, 13 (15%) had ES/PNES and the remaining 61 (71%) had only ES. A coexistence of ES and PNES was associated with clinical report of more than one seizure type (p˂0.001), nonspecific white matter hyperintensities on MRI (p < .001) and a past of psychotic disorder (p = .005). In addition, these patients had significantly more emotional abuse and neglect (p < .002 and 0.001, respectively). Somatization (including conversion disorder) was the most common diagnosis in patients with PNES- only (83%) and co-existing of PNES and ES (69.2%), differentiating both from ES-only patients (p < .001). CONCLUSION: The high prevalence of this coexistence ES/PNES in this study reinforces a need to properly investigate PNES, especially in patients with confirmed ES who become refractory to medical treatment with antiepileptic drugs. The neuropsychiatric assessment may help to diagnostic suspicion and in the planning of therapeutic interventions.

Callosotopy: leg motor connections illustrated by fiber dissection.

Precise anatomical knowledge of the structure of the corpus callosum is important in split-brain research and during neurosurgical procedures sectioning the callosum. According to the classic literature, commissural fibers connecting the motor cortex are situated in the anterior part of the corpus callosum. On the other hand, more recent imaging studies using diffusion tensor imaging indicate a more posterior topography of callosal fibers connecting motor areas. Topographical knowledge is especially critical when performing disconnective callosotomies in epilepsy patients who experience sudden loss of leg motor control, so-called epileptic drop attacks. In the current study, we aim to precisely delineate the topography of the leg motor connections of the corpus callosum. Of 20 hemispheres obtained at autopsy, 16 were dissected according to Klingler's fiber dissection technique to study the course and topography of callosal fibers connecting the most medial part of the precentral gyrus. Fibers originating from the anterior bank of the central sulcus were invariably found to be located in the isthmus of the corpus callosum, and no leg motor fibers were found in the anterior part of the callosum. The current results suggest that the disconnection of the pre-splenial fibers, located in the posterior one-third of the corpus callosum, is paramount in obtaining a good outcome after callosotomy.

Induced pluripotent stem cells from patients with focal cortical dysplasia and refractory epilepsy.

Focal cortical dysplasia (FCD) is caused by numerous alterations, which can be divided into abnormalities of the cortical architecture and cytological variations; however, the exact etiology of FCD remains unknown. The generation of induced pluripotent stem cells (iPSCs) from the cells of patients with neurological diseases, and their subsequent tissue­specific differentiation, serves as an invaluable source for testing and studying the initial development and subsequent progression of diseases associated with the central nervous system. A total of 2 patients demonstrating seizures refractory to drug treatment, characterized as FCD Type IIb, were enrolled in the present study. Fibroblasts were isolated from residual skin fragments obtained from surgical treatment and from brain samples obtained during surgical resection. iPSCs were generated following exposure of fibroblasts to viral vectors containing POU class 5 homeobox 1 (OCT4), sex determining region Y­box 2 (SOX2), Kruppel­like factor 4 and c­MYC genes, and were characterized by immunohistochemical staining for the pluripotent markers homeobox protein NANOG, SOX2, OCT4, TRA1­60 and TRA1­81. The brain samples were tested with antibodies against protein kinase B (AKT), phosphorylated­AKT, mechanistic target of rapamycin (mTOR) and phosphorylated­mTOR. Analysis of the AKT/mTOR pathway revealed a statistically significant difference between the cerebral tissues of the two patients, which were of different ages (45 and 12 years old). Clones with the morphological features of embryonic cells were detected on the 13th day and were characterized following three subcultures. The positive staining characteristics of the embryonic cells confirmed the successful generation of iPSCs derived from the patients' fibroblasts. Therefore, the present study presents a method to obtain a useful cellular source that may help to understand embryonic brain development associated with FCD.