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Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies.

The development of seizures in epilepsy syndromes associated with malformations of cortical development (MCDs) has traditionally been attributed to intrinsic cortical alterations resulting from abnormal network excitability. However, recent analyses at single-cell resolution of human brain samples from MCD patients have indicated the possible involvement of adaptive immunity in the pathogenesis of these disorders. By exploiting the MethylAzoxyMethanol (MAM)/pilocarpine (MP) rat model of drug-resistant epilepsy associated with MCD, we show here that the occurrence of status epilepticus and subsequent spontaneous recurrent seizures in the malformed, but not in the normal brain, are associated with the outbreak of a destructive autoimmune response with encephalitis-like features, involving components of both cell-mediated and humoral immune responses. The MP brain is characterized by blood-brain barrier dysfunction, marked and persisting CD8+ T cell invasion of the brain parenchyma, meningeal B cell accumulation, and complement-dependent cytotoxicity mediated by antineuronal antibodies. Furthermore, the therapeutic treatment of MP rats with the immunomodulatory drug fingolimod promotes both antiepileptogenic and neuroprotective effects. Collectively, these data show that the MP rat could serve as a translational model of epileptogenic cortical malformations associated with a central nervous system autoimmune response. This work indicates that a preexisting brain maldevelopment predisposes to a secondary autoimmune response, which acts as a precipitating factor for epilepsy and suggests immune intervention as a therapeutic option to be further explored in epileptic syndromes associated with MCDs. [ABSTRACT FROM AUTHOR]

Background: TUBA1A is a gene responsible for encoding alpha-tubulin, a protein involved in forming and organizing microtubules. Pathogenic variants of these genes lead to the occurrence of a wide spectrum of complex brain malformations known as tubulinopathies, including polymicrogyria, pachygyria, lissencephaly, basal ganglia dysmorphism, and subcortical band heterotopia. Clinically, the pathogenic changes in these genes primarily manifest as intellectual disability, motor deficits, and epilepsy. Materials and methods: We present the case of a 6-year-old patient diagnosed in our clinic with geneticstructural focal epilepsy, associated with a brain malformation - tubulinopathy with a pathogenic variant in the TUBA1A gene and central hypothyroidism with a pathogenic hemizygous variant in the IRS4 gene. Discussion: It's noteworthy that in the case of our patient, suspicion of a cerebral developmental anomaly arose in utero, but imaging investigations at that time were limited due to the challenging visualization of brain structures. The complete clinical picture emerged concomitantly with the patient's neurological development, determining the subsequent performance of more extensive clinical and imaging investigations. The diagnosis of brain malformations currently relies on both cerebral neuroimaging, which highlights the structural alteration, and the extensive implementation of genetic testing, which can establish etiology. [ABSTRACT FROM AUTHOR]

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Brain malformations cause cognitive disability and seizures in both human and animal models. Highly laminated structures such as the neocortex and cerebellum are vulnerable to malformation, affecting lamination and neuronal connectivity as well as causing heterotopia. The objective of the present study was to determine if sporadic neocortical and/or cerebellar malformations in C57BL/6J mice are correlated with reduced seizure threshold. The inhaled chemi-convulsant flurothyl was used to induce generalized, tonic-clonic seizures in male and female C57BL/6J mice, and the time to seizure onset was recorded as a functional correlate of brain excitability changes. Following seizures, mice were euthanized, and brains were extracted for histology. Cryosections of the neocortex and cerebellar vermis were stained and examined for the presence of molecular layer heterotopia as previously described in C57BL/6J mice. Over 60% of mice had neocortical and/or cerebellar heterotopia. No sex differences were observed in the prevalence of malformations. Significantly reduced seizure onset time was observed dependent on sex and the type of malformation present. These results raise important questions regarding the presence of malformations in C57BL/6J mice used in the study of brain development, epilepsy, and many other diseases of the nervous system. [ABSTRACT FROM AUTHOR]

Copyright of Medicina (Buenos Aires) is the property of Medicina (Buenos Aires) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. Neuroimaging analysis revealed four main cerebral phenotypes—hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment. [ABSTRACT FROM AUTHOR]

Brain malformations cause cognitive disability and seizures in both human and animal models. Highly laminated structures such as the neocortex and cerebellum are vulnerable to malformation, affecting lamination and neuronal connectivity as well as causing heterotopia. The objective of the present study was to determine if sporadic neocortical and/or cerebellar malformations in C57BL/6J mice are correlated with reduced seizure threshold. The inhaled chemi-convulsant flurothyl was used to induce generalized, tonic-clonic seizures in male and female C57BL/6J mice, and the time to seizure onset was recorded as a functional correlate of brain excitability changes. Following seizures, mice were euthanized, and brains were extracted for histology. Cryosections of the neocortex and cerebellar vermis were stained and examined for the presence of molecular layer heterotopia as previously described in C57BL/6J mice. Over 60% of mice had neocortical and/or cerebellar heterotopia. No sex differences were observed in the prevalence of malformations. Significantly reduced seizure onset time was observed dependent on sex and the type of malformation present. These results raise important questions regarding the presence of malformations in C57BL/6J mice used in the study of brain development, epilepsy, and many other diseases of the nervous system.

The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS‐Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS‐Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS‐Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic‐like behaviors in NS‐Pten KO mice. [ABSTRACT FROM AUTHOR]

Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22-9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250-500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.

In the present study, we characterized the effects of bath application of the proconvulsant drug 4-aminopyridine (4-AP) alone or in combination with GABAA and/or GABAB receptor antagonists, in cortical dysplasia (CD type I and CD type IIa/b), tuberous sclerosis complex (TSC), and non-CD cortical tissue samples from pediatric epilepsy surgery patients. Whole-cell patch clamp recordings in current and voltage clamp modes were obtained from cortical pyramidal neurons (CPNs), interneurons, and balloon/giant cells. In pyramidal neurons, bath application of 4-AP produced an increase in spontaneous synaptic activity as well as rhythmic membrane oscillations. In current clamp mode, these oscillations were generally depolarizing or biphasic and were accompanied by increased membrane conductance. In interneurons, membrane oscillations were consistently depolarizing and accompanied by bursts of action potentials. In a subset of balloon/giant cells from CD type IIb and TSC cases, respectively, 4-AP induced very low-amplitude, slow membrane oscillations that echoed the rhythmic oscillations from pyramidal neurons and interneurons. Bicuculline reduced the amplitude of membrane oscillations induced by 4-AP, indicating that they were mediated principally by GABAA receptors. 4-AP alone or in combination with bicuculline increased cortical excitability but did not induce seizure-like discharges. Ictal activity was observed in pyramidal neurons and interneurons from CD and TSC cases only when phaclofen, a GABAB receptor antagonist, was added to the 4-AP and bicuculline solution. These results emphasize the critical and permissive role of GABAB receptors in the transition to an ictal state in pediatric CD tissue and highlight the importance of these receptors as a potential therapeutic target in pediatric epilepsy.

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20 years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

Beta-tubulin (TUBB) protein is one of the components of the microtubule cytoskeleton that plays a critical role in the central nervous system. Genetic variants of TUBB cause cortical dysplasia, a developmental brain defect implicated in axonal guidance and the neuron migration. In this study, we assess pathogenic variants (Q15K, Y222F, M299V, V353I, and E401K) of TUBB protein and compared with non-pathogenic variant G235S to determine their impact on protein dynamic to cause cortical dysplasia. Among the analyzed variants, Q15K, Y222F, M299V, and E401K were noticed to have deleterious effect. Then, variant structures were modeled and their affinity with their known cofactor Guanosine-5'-triphosphate (GTP) was assessed which showed diverse binding energies ranged between (-7.436 to -6.950 kcal/mol) for the variants compared to wild-type (-7.428 kcal/mol). Finally, the molecular dynamics simulation of each variant was investigated which showed difference in trajectory between the pathogenic and non-pathogenic variant. Our analysis suggests change in amino acid residue of TUBB structure has notably affects the protein flexibility and their interactions with known cofactor. Overall, our findings provide insight on the relationship between TUBB variants and their structural dynamics that may cause diverse effects leading to cortical dysplasia. [ABSTRACT FROM AUTHOR]

Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2 , which encodes the UDP-galactose transporter. We developed a mouse model to investigate how disruption of this transporter leads to a malformation of cortical development. We used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of male and female fetal mice to model mosaic expression. Mosaic Slc35a2 knockout was verified through next-generation sequencing and immunohistochemistry of GFP-labelled transfected cells. Histology of brain tissue in mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing, increased afterhyperpolarisation duration and reduced burst-firing when compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotor activity. We successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability, increase epileptiform activity and cause hyperactivity in mosaic mice. Our mouse model provides an opportunity to further investigate the disease mechanisms that contribute to MOGHE and facilitate the development of precision therapies. • A mouse model of MOGHE was generated by cortical mosaic Slc35a2 knockout. • Slc35a2 mosaicism causes increased network-level epileptiform activity. • Excitatory neuron dendritic arborisation is altered by Slc35a2 knockout. • Electrophysiological recordings from knockout neurons reveal decreased excitability. [ABSTRACT FROM AUTHOR]

Brain somatic variants in SLC35A2, an intracellular UDP-galactose transporter, are commonly identified mutations associated with drug-resistant neocortical epilepsy and developmental brain malformations, including focal cortical dysplasia type I and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). However, the causal effects of altered SLC35A2 function on cortical development remain untested. We hypothesized that focal Slc35a2 knockout (KO) or knockdown (KD) in the developing mouse cortex would disrupt cortical development and change network excitability. Through two independent studies, we used in utero electroporation (IUE) to introduce CRISPR/Cas9/targeted guide RNAs or short-hairpin RNAs into the embryonic mouse brain at day 14.5–15.5 to achieve Slc35a2 KO or KD, respectively, from neural precursor cells. Slc35a2 KO or KD caused disrupted radial migration of electroporated neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, importantly suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects of Slc35a2 mutations. Adult KO mice were implanted with EEG electrodes for 72-hour continuous recording. Spontaneous seizures were not observed in focal Slc35a2 KO mice, but there was reduced seizure threshold following pentylenetetrazol injection. Here we demonstrate that focal Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration and that KO leads to reduced seizure threshold. Together these results demonstrate a direct causal role for SLC35A2 in cortical development. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between the anatomical features of schizencephaly and characteristics of epilepsy.Methods: We retrospectively evaluated patients diagnosed with schizencephaly using brain magnetic resonance imaging. Seizure outcomes were evaluated as drug-resistant epilepsy and frequent seizures (more than once a month) during the previous year. Development of epilepsy, seizure outcomes, and clinical variables were compared according to the anatomical features of schizencephaly, such as cleft type, size, bilaterality, presence of cortical dysplasia, and temporal lobe involvement.Results: Of the 76 patients with schizencephaly-related epilepsy, 28 (36.8%) had open lip clefts, and 13 (17.1%) had bilateral clefts. The development of epilepsy was related to a larger cleft size and the presence of cortical dysplasia. The patients with medium-to-large clefts were younger at seizure onset than those with small clefts (9.7±7.8 vs. 20.8±10.4 years). Among the 64 patients whose outcomes were evaluated, 31 (48.4%) had drug-resistant epilepsy, and 21 (32.8%) met our definition of frequent seizures. In the univariate analysis, open lip, larger clefts, and the presence of cortical dysplasia were associated with poor seizure outcomes. Even after adjustment for covariates, open lip clefts were significantly related to drug-resistant epilepsy (odds ratio=13.036, P=0.001) and frequent seizures (odds ratio=7.682, P=0.008).Conclusion: Open lip clefts were associated with poor seizure outcomes. Further, a larger cleft was related to an earlier development of epilepsy. The anatomical features of schizencephaly should be considered in the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Background: Patients with temporal lobe epilepsy are subjected to standard temporal lobectomy wherever indicated. This is performed using a reverse question mark flap and a standard frontotemporal craniotomy. We describe the technique of minitemporal craniotomy (3 × 3cms) for temporal lobe epilepsy (TLE) and analyze the clinical outcomes of patients operated using this approach.Objectives: To describe the technique of minitemporal craniotomy for TLE without navigation guidance and to analyze the clinical outcomes of patients operated using this approach.Materials and Method: This was a retrospective analysis of all consecutive TLE cases operated at our institute from 2014 to 2019, via minitemporal craniotomy, using surface landmarks only without navigation guidance. The surgical technique, indications for surgery, and their clinical outcomes were analyzed.Results: A total number of 48 patients underwent surgery for TLE. There were no complications except three patients who had transient hemiparesis. The average duration of hospital stay was 4 days following surgery. Out of 28 patients with mesial temporal sclerosis, 22 (82%) had international league against epilepsy, Class I seizure outcome, 4 (12.5%) had Class II outcome and 2 (5.5%) had Class III outcome. 9 patients with dysembryoplastic neurectodermal tumor (DNET), 4 gangliogliomas, 2 neurocystecercosis (NCC), all had Class I outcome. Out of the five patients with MTS and associated anterior temporal focal cortical dysplasia (FCD), four (80%) had a Class I outcome, whereas one (20%) had Class II outcome.Conclusion: Utilizing surface anatomical landmarks, minitemporal craniotomy can be performed in even peripheral centers without neuronavigation, with good cosmesis, seizure outcomes. [ABSTRACT FROM AUTHOR]

ObjectivePolymicrogyria (PMG) is a malformation of cortical development characterized by formation of an excessive number of small gyri. Sixty percent to 85% of patients with PMG have epilepsy that is refractory to medication, but surgical options are usually limited. We characterize a cohort of patient with polymicrogyria who underwent epilepsy surgery and document seizure outcomes.MethodsA retrospective study of all patients with PMG who underwent epilepsy surgery (focal seizure foci resection and/or hemispherectomy) at our center was performed by review of all clinical data related to their treatment.ResultsWe identified 12 patients (7 males and 5 female) with mean age of 18 (ranging from 3 months to 44 years) at time of surgery. Mean age at seizure onset was 8 years, with the majority (83%) having childhood onset. Six patients had focal, five had multifocal, and one patient had diffuse PMG. Perisylvian PMG was the most common pattern seen on magnetic resonance imaging (MRI). Eight patients had other cortical malformations including hemimegalencephaly and cortical dysplasia. Scalp electroencephalography (EEG) often showed diffuse epileptic discharges that poorly lateralized but were focal on intracranial electrocorticography (ECoG). Eight patients underwent seizure foci resection and four underwent hemispherectomy. Mean follow-up was 7 years (ranging from one to 19 years). Six patients (50%) were seizure-free at last follow-up. One patient had rare seizures (Engel class II). Three patients were Engel class III, having either decreased seizure frequency or severity, and two patients were Engel class IV. Gross total resection of the PMG cortex trended toward good seizure control.SignificanceOur study shows that even in patients with extensive or bilateral PMG malformations, some may still be good candidates for surgery because the epileptogenic zone may involve only a portion of the malformation. Intracranial ECoG can provide additional localizing information compared to scalp EEG in guiding resection of epileptogenic foci.

The study aimed to investigate the clinical implications and natural history of primary intraparenchymal lesions in patients with neurofibromatosis type 2. Radiological findings of 15 neurofibromatosis type 2 cases were retrospectively collected. Twenty-seven primary intraparenchymal lesions were observed in 7 out of 15 patients (47%). Cortical/subcortical T2 hyperintense lesions and enlarged Virchow–Robin spaces were the most common findings in five and four patients, respectively. During the follow-up period (median 84 months), one new primary intraparenchymal lesion was identified and increased lesions were observed in two cases on contrast-enhanced MRI. Surgical resection was performed in one case pathologically diagnosed with atypical meningioma. Twenty-five other lesions without contrast enhancement presented no apparent growth during follow-up. Although most primary intraparenchymal lesions are benign, a subset of cases would present newly developed or increased lesions on contrast-enhanced MRI. Careful monitoring is necessary for such cases, and pathological confirmation should be considered. [ABSTRACT FROM AUTHOR]

Copyright of Pamukkale Medical Journal is the property of Pamukkale Journal of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Refractory epilepsy is a complex case of epileptic disease. The quantitative analysis of fluorodeoxyglucose positron emission tomography (FDG-PET) images complements visual assessment and helps localize the epileptogenic zone (EZ) for better curative treatment. Statistical parametric mapping (SPM) and its computational anatomy toolbox (SPM-CAT) are two commonly applied tools in neuroimaging analysis. This study compares SPM and SPM-CAT with different parameters to find the optimal approach for localizing EZ in refractory epilepsy. The current study enrolled 45 subjects, including 25 refractory epilepsy patients and 20 healthy controls. All of the 25 patients underwent surgical operations. Pathological results and the postoperative outcome evaluation by the Engel scale were likewise presented. SPM and SPM-CAT were used to assess FDG-PET images with three different uncorrected p -values and the corresponding cluster sizes (k), as in voxels in the cluster, namely p < 0.0002, k > 25; p < 0.001, k > 100; p < 0.005, and k > 200. When combining three settings, SPM and SPM-CAT yielded overall positive finding scores of 96.0% (24/25) and 100.0% (25/25) respectively. However, for the individual setting, SPM-CAT achieved the diverse positive finding scores of 96.0% (24/25), 96.0% (24/25), and 88.0% (22/24), which are higher than those of SPM [88.0% (22/25), 76.0% (19/25), and 72.0% (18/25)]. SPM and SPM-CAT localized EZ correctly with 28.0% (7/25) and 64.0% (16/25), respectively. SPM-CAT with parameter settings p < 0.0002 and k > 25 yielded a correct localization at 56.0% (14/25), which is slightly higher than that for the other two settings (48.0 and 20.0%). Moderate concordance was found between the confirmed and pre-surgical EZs, identified by SPM-CAT (kappa value = 0.5). Hence, SPM-CAT is more efficient than SPM in localizing EZ for refractory epilepsy by quantitative analysis of FDG-PET images. SPM-CAT with the setting of p < 0.0002 and k > 25 might perform as an objective complementary tool to the visual assessment for EZ localization. [ABSTRACT FROM AUTHOR]

Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

Refractory epilepsy is a complex case of epileptic disease. The quantitative analysis of fluorodeoxyglucose positron emission tomography (FDG-PET) images complements visual assessment and helps localize the epileptogenic zone (EZ) for better curative treatment. Statistical parametric mapping (SPM) and its computational anatomy toolbox (SPM-CAT) are two commonly applied tools in neuroimaging analysis. This study compares SPM and SPM-CAT with different parameters to find the optimal approach for localizing EZ in refractory epilepsy. The current study enrolled 45 subjects, including 25 refractory epilepsy patients and 20 healthy controls. All of the 25 patients underwent surgical operations. Pathological results and the postoperative outcome evaluation by the Engel scale were likewise presented. SPM and SPM-CAT were used to assess FDG-PET images with three different uncorrected p-values and the corresponding cluster sizes (k), as in voxels in the cluster, namely p < 0.0002, k > 25; p < 0.001, k > 100; p < 0.005, and k > 200. When combining three settings, SPM and SPM-CAT yielded overall positive finding scores of 96.0% (24/25) and 100.0% (25/25) respectively. However, for the individual setting, SPM-CAT achieved the diverse positive finding scores of 96.0% (24/25), 96.0% (24/25), and 88.0% (22/24), which are higher than those of SPM [88.0% (22/25), 76.0% (19/25), and 72.0% (18/25)]. SPM and SPM-CAT localized EZ correctly with 28.0% (7/25) and 64.0% (16/25), respectively. SPM-CAT with parameter settings p < 0.0002 and k > 25 yielded a correct localization at 56.0% (14/25), which is slightly higher than that for the other two settings (48.0 and 20.0%). Moderate concordance was found between the confirmed and pre-surgical EZs, identified by SPM-CAT (kappa value = 0.5). Hence, SPM-CAT is more efficient than SPM in localizing EZ for refractory epilepsy by quantitative analysis of FDG-PET images. SPM-CAT with the setting of p < 0.0002 and k > 25 might perform as an objective complementary tool to the visual assessment for EZ localization.

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

Spontaneous pacemaker γ-aminobutyric acid (GABA) receptor-mediated synaptic activity (PGA) occurs in a subset of tissue samples from pediatric epilepsy surgery patients. In the present study, based on single-cell electrophysiological recordings from 120 cases, we describe the etiologies, cell types, and primary electrophysiological features of PGA. Cells displaying PGA occurred more frequently in the areas of greatest anatomical abnormality in cases of focal cortical dysplasia (CD), often associated with hemimegalencephaly (HME), and only rarely in non-CD etiologies. PGA was characterized by rhythmic synaptic events (5-10Hz) and was observed in normal-like, dysmorphic cytomegalic, and immature pyramidal neurons. PGA was action potential-dependent, mediated by GABAA receptors, and unaffected by antagonism of glutamate receptors. We propose that PGA is a unique electrophysiological characteristic associated with CD and HME. It could represent an abnormal signal that may contribute to epileptogenesis in malformed postnatal cortex by facilitating pyramidal neuron synchrony.

ObjectThe object of this study was to determine if etiology and age at surgery were linked with fevers and altered white blood cell and CSF laboratory values after cerebral hemispherectomy.MethodsSeizure etiologies (n = 76) were classified into hemimegalencephaly (HME), cortical dysplasia (CD), infarcts (stroke), Rasmussen encephalitis (RE), history of infections, and Sturge-Weber syndrome (SWS) and were compared with clinical variables, maximum daily temperature (Tmax), and blood and CSF studies through Day 12 posthemispherectomy.ResultsThe Tmax on Days 2-4 and 9-12 postsurgery were higher for HME and RE cases than for stroke cases. Patients with RE showed positive correlations, whereas those with SWS had negative correlations between Tmax and age at surgery. Blood WBC counts on postsurgery Days 3, 6, and 9-12 were higher in the HME and CD cases than in the stroke and RE cases. The percentage of blood polymorphonuclear cells (%bloodPMNs) was higher in the RE cases than in the HME, CD, and SWS cases. The RE, HME, and CD cases showed positive correlations between %bloodPMNs and age at surgery. The percentage of blood monocytes (%bloodMono) was higher in the patients with HME than in those with stroke or RE. The HME and CD cases showed negative correlations between %bloodMono and age at surgery. The CSF red blood cell counts were higher in the RE than in the CD and stroke cases. The percentage of CSF monocytes was higher in patients with CD than in those with stroke and RE. The percentage of CSF lymphocytes positively correlated with age at surgery.ConclusionsSeizure etiology and age at surgery were associated with developing fevers and altered blood and CSF values after pediatric cerebral hemispherectomy. These findings indicate that besides infections, other clinical variables have an impact on developing fevers and abnormal laboratory values posthemispherectomy. Cultures appear to be the most reliable predictor of infections.

Cortical dysplasia (CD) is a common cause of drug-resistant epilepsy. Increasing studies have implicated innate immunity in CD with epilepsy. However, it is unclear whether innate immune factors induce epileptogenic CD. Here, we injected recombinant human high mobility group box 1 (rHMGB1) into embryonic rat ventricles to determine whether rHMGB1 can induce epileptogenic CD with pathophysiological characteristics similar to those of human CD. Compared with controls and 0.1 μg rHMGB1-treated rats, the cortical organization was severely disrupted in the 0.2 μg rHMGB1-treated rats, and microgyria and heterotopia also emerged; additionally, disoriented and deformed neurons were observed in the cortical lesions and heterotopias. Subcortical heterotopia appeared in the white matter and the gray–white junction of the 0.2 μg rHMGB1-treated rats. Moreover, there was decreased number of neurons in layer V–VI and an increased number of astrocytes in layer I and V of the cortical lesions. And the HMGB1 antagonist dexmedetomidine alleviated the changes induced by rHMGB1. Further, we found that TLR4 and NF-κB were increased after rHMGB1 administration. In addition, the excitatory receptors, N-methyl-D-aspartate receptor 1 (NR1), 2A (NR2A), and 2B (NR2B) immunoreactivity were increased, and immunoreactivity of excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2) were reduced in 0.2 μg rHMGB1-treated rats compared with controls. While there were no differences in the glutamic acid decarboxylase 65/67 (GAD65/67) immunoreactivity between the two groups. These results indicate that the excitation of cortical lesions was significantly increased. Furthermore, electroencephalogram (EEG) showed a shorter latency of seizure onset and a higher incidence of status epilepticus in the 0.2 μg rHMGB1-treated rats; the frequency and amplitude of EEG were higher in the treated rats than controls. Intriguingly, spontaneous electrographic seizure discharges were detected in the 0.2 μg rHMGB1-treated rats after 5 months of age, and spike-wave discharges of approximately 8 Hz were the most significantly increased synchronous propagated waves throughout the general brain cortex. Taken together, these findings indicate that rHMGB1 exposure during pregnancy could contribute to the development of epileptogenic CD, which mimicked some pathophysiological characteristics of human CD.

Laser interstitial thermal therapy (LITT) has become a popular tool in the treatment of tumors and epilepsy. While most commonly used for the treatment of mesial temporal lobe epilepsy, it can be used as a minimally invasive option for the treatment of any seizure focus but has very rarely been discussed in the setting of cortical dysplasia. Here, we discuss the case of a 5-year-old girl with medically refractory epilepsy secondary to a right medial orbital gyrus and gyrus rectus cortical dysplasia successfully treated with LITT. After confirmation of seizure focus using stereo electroencephalography (SEEG), the patient underwent thermal ablation of the focus through an eyebrow incision with use of a single laser fiber. She has been seizure-free 6 months postoperatively, only on one anti-seizure medication, with normal EEG. The use of LITT in this case was successful because of the cylindrical shape of the cortical dysplasia, making it easily accessible via a single laser fiber in the absence of a yet to develop fontal sinus. While open resection would have also been appropriate, the use of LITT provided a minimally invasive alternative approach that allowed for an excellent outcome with limited risks. [ABSTRACT FROM AUTHOR]

The neocortex, the most recently evolved brain region in mammals, is characterized by its unique areal and laminar organization. Distinct cortical layers and areas can be identified by the presence of graded expression of transcription factors and molecular determinants defining neuronal identity. However, little is known about the expression of key master genes orchestrating human cortical development. In this study, we explored the expression dynamics of NR2F1 and SOX2, key cortical genes whose mutations in human patients cause severe neurodevelopmental syndromes. We focused on physiological conditions, spanning from mid-late gestational ages to adulthood in unaffected specimens, but also investigated gene expression in a pathological context, a developmental cortical malformation termed focal cortical dysplasia (FCD). We found that NR2F1 follows an antero-dorsallow to postero-ventralhigh gradient as in the murine cortex, suggesting high evolutionary conservation. While SOX2 is mainly expressed in neural progenitors next to the ventricular surface, NR2F1 is found in both mitotic progenitors and post-mitotic neurons at GW18. Interestingly, both proteins are highly co-expressed in basal radial glia progenitors of the outer sub-ventricular zone (OSVZ), a proliferative region known to contribute to cortical expansion and complexity in humans. Later on, SOX2 becomes largely restricted to astrocytes and oligodendrocytes although it is also detected in scattered mature interneurons. Differently, NR2F1 maintains its distinct neuronal expression during the whole process of cortical development. Notably, we report here high levels of NR2F1 in dysmorphic neurons and NR2F1 and SOX2 in balloon cells of surgical samples from patients with FCD, suggesting their potential use in the histopathological characterization of this dysplasia. [ABSTRACT FROM AUTHOR]

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8‐year‐old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole‐exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously‐reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum “KIF2A syndrome” with variable severity. [ABSTRACT FROM AUTHOR]

Epilepsy affects ~5 out of every 10,000 children per year. Up to one-third of these children have medically refractory epilepsy, with limited to no options for improved seizure control. mTOR, a ubiquitous 289 kDa serine/threonine kinase in the phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) family, is dysregulated in a number of human diseases, including tuberous sclerosis complex (TSC) and epilepsy. In cell models of epilepsy and TSC, rapamycin, an mTOR inhibitor, has been shown to decrease seizure frequency and duration, and positively affect cell growth and morphology. Rapamycin has also been shown to prevent or improve epilepsy and prolong survival in animal models of TSC. To date, clinical studies looking at the effects of mTOR inhibitors on the reduction of seizures have mainly focused on patients with TSC. Everolimus (Novartis Pharmaceuticals), a chemically modified rapamycin derivative, has been shown to reduce seizure frequency with reasonable safety and tolerability. Mutations in mTOR or the mTOR pathway have been found in hemimegalencephaly (HME) and focal cortical dysplasias (FCDs), both of which are highly correlated with medically refractory epilepsy. Given the evidence to date, a logical next step is to investigate the role of mTOR inhibitors in the treatment of children with medically refractory non-TSC epilepsy, particularly those children who have also failed resective surgery.

ObjectThe authors sought to determine if clinical epilepsy variables, maximum daily temperature (Tmax), and blood and CSF findings were associated with the risk of developing hydrocephalus after first-time resection-disconnection hemispherectomy.MethodsPatients who underwent cerebral hemispherectomy in whom a standardized perioperative protocol was used, including the use of ventriculostomies (n = 79), were classified into those who developed and those who did not develop hydrocephalus requiring CSF shunts. The authors compared these 2 groups for clinical variables, Tmax, and blood and CSF studies through postoperative Day 12.ResultsIn this cohort, 30% of the patients required CSF shunts, of which 8% developed late hydrocephalus up to 3 years posthemispherectomy. Multivariate analysis found that etiology was associated with developing posthemispherectomy hydrocephalus. Higher shunt rates were observed for patients with hemimegalencephaly (40%; n = 15) and a history of CNS infection (100%; n = 4) compared with cortical dysplasia (17%; n = 23) and Rasmussen encephalitis (17%; n = 12). In univariate analysis, other factors associated with developing hydrocephalus were elevated maximum daily temperatures, elevated white blood cell counts, decreased CSF protein, and increased CSF red blood cell counts.ConclusionsThe findings of the study indicate that etiology was the factor most strongly associated with developing posthemispherectomy hydrocephalus. These findings suggest that there are variable mechanisms for developing hydrocephalus after cerebral hemispherectomy depending on the procedure, and in resection-disconnection operations the mechanism may involve changes in CSF bulk flow that varies by histopathology.

Schizencephaly is a rare malformation of cortical development characterized by congenital clefts extending from the pial surface to the lateral ventricle that are lined by heterotopic gray matter. The clinical presentation is variable and can include motor or cognitive impairment and epilepsy. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, or maternal trauma. Reported genetic causes include chromosomal aneuploidy, EMX2 mutations, and possible autosomal recessive familial cases based on recurrence in siblings. In an effort to identify risk factors for schizencephaly, we conducted a survey of 48 parents or primary caretakers of patients with schizencephaly born between 1983 and 2004. We discovered that young maternal age, lack of prenatal care, and alcohol use were all significantly associated with risk of schizencephaly. Our results suggest that there are important nongenetic, intrauterine events that predispose to schizencephaly.

• Seventy-seven percent of infants with posterior quadrant dysplasia experienced seizure freedom after posterior quadrantectomy. • The preoperative hyperconnectivity on the nonsurgical side improved postoperatively to the same level as that in normal infants. • A better long-term neurodevelopment entailed a stronger postoperative connectivity on the nonsurgical side. To reveal whether neurodevelopmental outcome of infants after epilepsy surgery can be quantitatively assessed by electroencephalography (EEG) functional connectivity analysis. We enrolled 13 infants with posterior quadrant dysplasia aged <2 years who were treated using posterior quadrantectomy and 21 age-matched infants. EEG was performed both before and one year after surgery. Developmental quotient (DQ) was assessed both before and 3 years after surgery. The phase lag index (PLI) of three different pairs of electrodes in the nonsurgical hemisphere, i.e., the anterior short distance (ASD), posterior short distance (PSD), and long distance (LD) pairs, were calculated as indices of brain connectivity. The relationship between the PLI and DQ was evaluated. Overall, 77% infants experienced seizure freedom after surgery. The beta- and gamma- range PLI of PSD pairs increased preoperatively. All these pairs normalized postoperatively. Simple linear regression analysis revealed a significant relationship between the postoperative DQ and the postoperative beta-band PLI of ASD pairs. Preoperative abnormal hyper-connectivity was normalized to the control level after surgery. The postoperative hyperconnectivity was associated with long-term neurodevelopmental improvement. PLI quantifies neurodevelopmental improvements after posterior quadrantectomy. [ABSTRACT FROM AUTHOR]

The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually associated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical disorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may independently cause the predisposition to epilepsy and comorbid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.

Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

In the present study, we characterized the effects of bath application of the proconvulsant drug 4-aminopyridine (4-AP) alone or in combination with GABAA and/or GABAB receptor antagonists, in cortical dysplasia (CD type I and CD type IIa/b), tuberous sclerosis complex (TSC), and non-CD cortical tissue samples from pediatric epilepsy surgery patients. Whole-cell patch clamp recordings in current and voltage clamp modes were obtained from cortical pyramidal neurons (CPNs), interneurons, and balloon/giant cells. In pyramidal neurons, bath application of 4-AP produced an increase in spontaneous synaptic activity as well as rhythmic membrane oscillations. In current clamp mode, these oscillations were generally depolarizing or biphasic and were accompanied by increased membrane conductance. In interneurons, membrane oscillations were consistently depolarizing and accompanied by bursts of action potentials. In a subset of balloon/giant cells from CD type IIb and TSC cases, respectively, 4-AP induced very low-amplitude, slow membrane oscillations that echoed the rhythmic oscillations from pyramidal neurons and interneurons. Bicuculline reduced the amplitude of membrane oscillations induced by 4-AP, indicating that they were mediated principally by GABAA receptors. 4-AP alone or in combination with bicuculline increased cortical excitability but did not induce seizure-like discharges. Ictal activity was observed in pyramidal neurons and interneurons from CD and TSC cases only when phaclofen, a GABAB receptor antagonist, was added to the 4-AP and bicuculline solution. These results emphasize the critical and permissive role of GABAB receptors in the transition to an ictal state in pediatric CD tissue and highlight the importance of these receptors as a potential therapeutic target in pediatric epilepsy.

Pathological high-frequency oscillations (HFOs), specifically fast ripples (FRs, >250 Hz), are pathognomonic of an active epileptogenic zone. However, the origin of FRs remains unknown. Here we explored the correlation between FRs recorded with intraoperative pre-resection electrocorticography (ECoG) and spontaneous synaptic activity recorded ex vivo from cortical tissue samples resected for the treatment of pharmacoresistant epilepsy. The cohort included 47 children (ages 0.22–9.99 yr) with focal cortical dysplasias (CD types I and II), tuberous sclerosis complex (TSC) and non-CD pathologies. Whole-cell patch clamp recordings were obtained from pyramidal neurons and interneurons in cortical regions that were positive or negative for pathological HFOs, defined as FR band oscillations (250–500 Hz) at ECoG. The frequency of spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and IPSCs, respectively) was compared between HFO+ and HFO- regions. Regardless of pathological substrate, regions positive for FRs displayed significantly increased frequencies of sIPSCs compared with regions negative for FRs. In contrast, the frequency of sEPSCs was similar in both regions. In about one third of cases (n = 17), pacemaker GABA synaptic activity (PGA) was observed. In the vast majority (n = 15), PGA occurred in HFO+ areas. Further, fast-spiking interneurons displayed signs of hyperexcitability exclusively in HFO+ areas. These results indicate that, in pediatric epilepsy patients, increased GABA synaptic activity is associated with interictal FRs in the epileptogenic zone and suggest an active role of GABAergic interneurons in the generation of pathological HFOs. Increased GABA synaptic activity could serve to dampen excessive excitability of cortical pyramidal neurons in the epileptogenic zone, but it could also promote neuronal network synchrony.

Antiepileptic drug-resistance is a major health problem in patients with cortical dysplasia (CD). Whether drug-resistant epilepsy is associated with progressive brain damage is still debated. We previously generated a rat model of acquired CD, the methylazoxymethanol-pilocarpine (MP) rat, in which the occurrence of status epilepticus and subsequent spontaneous seizures induce progressive brain damage (Nobili et al., 2015). The present study tested the outcome of early-chronic carbamazepine (CBZ) administration on both seizure activity and brain damage in MP rats. We took advantage of the non-invasive CBZ-in-food administration protocol, established by Ali (2012), which proved effective in suppressing generalized convulsive seizures in kainic acid rat model of epilepsy. MP rats were treated immediately after the onset of the first spontaneous seizure with 300 mg/kg/day CBZ formulated in pellets for a two-months-trial. CBZ-treated rats were continuously video-monitored to detect seizure activity and were compared with untreated epileptic MP rats. Despite CBZ serum levels in treated rats were within the suggested therapeutic range for humans, CBZ affected spontaneous convulsive seizures in 2 out of 10 treated rats (responders), whereas the remaining animals (non-responders) did not show any difference when compared to untreated MP rats. Histological analysis revealed cortical thinning paralleled by robust staining of Fluoro-Jade+ (FJ+) degenerating neurons and diffuse tissue necrosis in CBZ-non-responder vs CBZ-responder rats. Data reported here suggest that MP rat model represents suitable experimental setting where to investigate mechanisms of CD-related drug-resistant epilepsy and to verify if modulation of seizures, with appropriate treatment, may reduce seizure-induced brain damage.

Objective: Focal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation and a prevalent cause of surgically amenable epilepsy. While cellular and molecular biology data suggest that FCD lesional characteristics lie along a spectrum, this notion remains to be verified in vivo. We tested the hypothesis that machine learning applied to MRI captures FCD lesional variability at a mesoscopic scale. Methods: We studied 46 patients with histologically verified FCD Type II and 35 age- and sex-matched healthy controls. We applied consensus clustering, an unsupervised learning technique that identifies stable clusters based on bootstrap-aggregation, to 3 T multicontrast MRI (T1-weighted MRI and FLAIR) features of FCD normalized with respect to distributions in controls. Results: Lesions were parcellated into four classes with distinct structural profiles variably expressed within and across patients: Class-1 with isolated white matter (WM) damage; Class-2 combining grey matter (GM) and WM alterations; Class-3 with isolated GM damage; Class-4 with GM-WM interface anomalies. Class membership was replicated in two independent datasets. Classes with GM anomalies impacted local function (resting-state fMRI derived ALFF), while those with abnormal WM affected large-scale connectivity (assessed by degree centrality). Overall, MRI classes reflected typical histopathological FCD characteristics: Class-1 was associated with severe WM gliosis and interface blurring, Class-2 with severe GM dyslamination and moderate WM gliosis, Class-3 with moderate GM gliosis, Class-4 with mild interface blurring. A detection algorithm trained on class-informed data outperformed a class-naïve paradigm. Significance: Machine learning applied to widely available MRI contrasts uncovers FCD Type II variability at a mesoscopic scale and identifies tissue classes with distinct structural dimensions, functional and histopathological profiles. Integrating in vivo staging of FCD traits with automated lesion detection is likely to inform the development of novel personalized treatments.