Mechanistic Target of Rapamycin Pathway in Epileptic Disorders

The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.

Mechanistic Target of Rapamycin Pathway in Epileptic Disorders

The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.

Taxonomic classify framework for malformation of cortical development / 中华实用儿科临床杂志

Malformation of cortical development (MCD) is an important cause of children's intellectual motor development disorder and refractory epilepsy.The classification of MCD is very complex,whether from the dimensions of embryonic development,genetic regulation abnormality or tissue structure characteristics.This article is mainly based on an updated version of Barkovich's MCD classification.This framework help clinic to understand various types of MCD,search its genetic causes,and select appropriate surgical treatment for some treatable refractory epilepsy with MCD.

Mild malformation of cortical development with oligodendroglial hyperplasia: a new pathological subtype of frontal lobe epilepsy / 中华神经科杂志

Objective To analyze the clinical and histology characteristics of a patient with frontal lobe epilepsy diagnosed with mild malformation of cortical development with oligodendroglial hyperplasia, and to recognize the new neuropathological entity. Methods Clinical history, seizure types, neuroimaging, electroencephalography as well as macroscope, histology and immunohistochemistry characteristics were collected from a frontal lobe epilepsy patient and were compared with cases from literature. Results It was a female patient aged 16 years with 12 years history of epilepsy. The seizures manifested as episodes of conscious loss with automatism including grope and voice lasting for seconds. About 10 episodes a day were found and sometimes with secondary generalized tonic-clonic seizures. MRI showed blurring of grey-white matter interface in left orbital frontal cortex. Video-encephalography revealed left frontal lobe origin of seizures. So left prefrontal lobe was removed. Histology showed almost normal cortex neuropil and neurons. Blurring of grey-white interface in some area with patches of proliferation of oligodendrocytes in the corresponding sub-cortical white matter was found. The density of oligodendrocytes was significantly higher in sub-cortical than in deep white matter both shown in HE and Oligo-2 staining. Obvious oligodendrocytes increase and satellite phenomenon in deep cortical layer as well as increased ectopic neurons in sub-cortical white matter were found in the lesion. In proliferation area, there were some nuclei stained with Ki-67, but not as high as tumor. Subsequent follow up for two years proved the operation efficacy and benign prognosis. Conclusions There are special and undiscovered histopathological entities in epilepsy etiology. Although known as grey matter disease, white matter pathology plays an important role in epilepsy pathophysiology which needs further research.

Characteristics of fetal anomalies detected on the third trimester ultrasound scan / 中华围产医学杂志

Objective To investigate the categories of fetal anomalies detected by ultrasound scan in the third trimester.Methods From January 1,2012 to December 31,2013,492 singleton fetuses were found to have structural abnormalities on the first,second or third trimester ultrasound scan in the Peking University First Hospital,only 50 (10.2％) fetuses were detected on the third trimester (≥ 28 weeks of gestation) with no abnormalities detected on the first and second trimester scan,were enrolled.The categories of the fetal structural abnormalities were analyzed.Results The age of the mothers of the 50 fetuses with structural abnormalities was (35.7± 5.2) years (26-43 years) with an average gestation of (32.4±2.8) weeks (28.6-36.8 weeks).These abnormalities were seen in the central nervous system (42％,21/50),digestive system (28％,14/50),urinary system (16％,8/50),cardiovascular system (8％,4/50),respiratory system (4％,2/50) and facial structures (2％,1/50).Intrauterine death occurred in one case and 49 mothers had a live birth.After birth,14 neonates were normal,five needed further treatment,three cases were complicated by other abnormalities,23 had no dysfunction but need follow-up and four were lost to follow-up.Six of the 20 (30％) fetuses with central nervous system abnormalities and 2/4 fetuses with cardiovascular system abnormalities had an adverse prognosis,while 1/12 and 2/7 fetuses with digestive and urinary system abnormalities had an adverse prognosis.Conclusions The central nervous system and cardiovascular system should be examined in priority during the third trimester ultrasound scan.

Displasias corticales como causa de epilepsia y sus representaciones en las imágenes: [revisión] / Cortical dysplasia as a cause of epilepsy and its images respresentation: [review]

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures, which are clinically classified as generalized or partial. Approximately, 30 percent of patients with partial epilepsy is refractory to medical treatment. Within the refractory group we must discard the presence of cortical dysplasia as an underlying cause of the crisis. Cortical dysplasias are a type of malformations of cortical development (MCD) that are increasingly recognized as a cause of refractory epilepsy. From the radiological point of view this kind of pathology is of particular interest since imaging manifestations can be subtle or may show completely normal examinations. The aim of this paper is to review the literature, describing the imaging appearance of the normal cortical development, the classifications of cortical malformations, mainly cortical dysplasias, by highlighting the most frequent radiological signs. We also examine the current role of positron emission tomography (PET) in epilepsy, which in conjunction with magnetic resonance imaging findings and electrophysiological studies are used to define a possible surgical treatment. Through this treatment we expect to be provided with details of histopathological alterations found in the surgical specimen to be compared to the radiographic changes revealed in the pre-surgical study.

La epilepsia es una alteración neurológica crónica caracterizada por crisis convulsivas recurrentes y espontáneas, que clínicamente se clasifican como generalizadas o parciales, dentro de las cuales aproximadamente el 30 por ciento de los pacientes con epilepsia parcial son refractarios al tratamiento médico. Dentro del grupo refractario debemos descartar la presencia de una displasia cortical como causa subyacente de las crisis. Las displasias corticales son un tipo de malformaciones del desarrollo cortical que en forma cada vez más frecuente se reconocen como causante de epilepsia refractaria. Desde el punto de vista radiológico, este tipo de patología tiene especial interés debido a que las manifestaciones imaginológicas pueden ser sutiles o presentar exámenes completamente normales. El objetivo de este artículo es realizar una revisión de la literatura, describiendo el desarrollo cortical normal con su aspecto en imágenes, las clasificaciones de las malformaciones corticales y en especial de las displasias corticales, destacando los signos radiológicos más frecuentes. Además revisaremos el rol en la actualidad de la Tomografía por Emisión de Positrones (PET) en epilepsia, que en conjunto con las imágenes por resonancia magnética y los estudios electrofisiológicos se utilizan para definir un eventual tratamiento quirúrgico, el que una vez realizado nos da detalles del análisis de las alteraciones histopatológicas en la pieza quirúrgica versus las alteraciones radiológicas visualizadas en el estudio pre-quirúrgico.

Cortical Dysplasia and Microdysgenesis; Correlations between Clinical Feaures, Neuroimaging and Electrophysiology after Lobectomy for Intractable Epilepsy in Children / 대한소아신경학회지

PURPOSE: The diagnosis of cortical dysplasia(CD) and microdysgenesis(MD) is valuable because they often cause childhood intractable epilepsy. This study is to analyze clinical manifestations, EEG findings, and imaging features based on the pathologic diagnosis(cortical dysplasia and microdysgenesis) in childhood intractable epilepsy with surgical treatment. METHODS: We performed retrospective studies and analyzed 27 patients with MCD diagnosed by pathologic findings after brain lobectomy for intractable epilepsy from October 2003 to September 2006 in our hospital. We compared their clinical characteristics, EEGs, neuroimaging studies including MRI, and FDG-PET. We analyzed the locations of malformations of cortical development(MCD). The surgical outcomes were reviewed. RESULTS: There were no pathognomonic seizure types or EEG findings for microdysgenesis. The clinical and EEG features of microdysgenesis were similar to those of cortical dysplasia. Only 6(37 percent) out of 16 microdysgenesis patients showed normal MRI findings and also 2(18 percent) out of 10 cortical dysplasia patients showed normal MRI findings. The most common location of MCD was frontal lobe in both of the groups, followed by temporal lobe. 10(63%) out of 16 microdysgenesis patients and 9 (90%) out of 10 cortical dysplasia patients became seizure free. The locations of MCD was not related to the prognosis of the outcomes. All the patients who had had developmental delay showed improvement in development after the surgery. CONCLUSION: There were no significant differences in gender, seizure onset age, duration of seizures, seizure types, EEG findings, and MCD locations between CD and MD. The seizure outcomes were better in CD than in MD. All the patients whose pre- and post-oprative developmental status were compared showed developmental improvement.

The efficacy of ketogenic diet in childhood intractable epilepsy with malformation of cortical development / 소아과

PURPOSE: Malformation of cortical development(MCD) constitutes an important etiology of intractable epilepsy and is considered an indication for surgical treatments, though their efficacy is limited and variable depending on MCD's location or distribution. Ketogenic diets are widely known to be effective, but as little study has been made concerning their efficacy on epilepsy with MCD, we evaluated the efficacy of ketogenic diets on MCD patients compared with that of epileptic surgery, which is more invasive. METHODS: We performed retrospective studies and analyse on 30 patients with MCD diagnosed by brain MRI and treated with ketogenic diets for intractable epilepsy since 1998, checking decreases in their seizure episodes after starting the diets. RESULTS: Cortical dysplasia was observed in 24(80.0 percent) patients as the most common type of MCD. Also, MCD was observed in unilateral hemisphere most commonly, in 23(76.7 percent) patients; it was observed in both hemispheres in 7(23.3 percent) patients. Nine(30.0 percent) out of 30 patients became seizure-free after starting ketogenic diets, and 14(46.7 percent) patients experienced 50 percent seizure reductions as well. Age of starting the diet or the duration of epilepsy period before starting showed no statistical relationship with the efficacy of the diet. Though the younger the patient and the longer the treatment the more effective the diet seemed to be, there was no statistical correlation between them. The location of MCD showed no significance neither. CONCLUSION: Considering various limits and invasiveness of surgical treatment, a ketogenic diet could be a good tool in treating children with intractable epilepsy with MCD.

Clinical and Electrophysiologic Characteristics of Malformation of Cortical Development with Childhood Epilepsy / 대한간질학회지

PURPOSE: To evaluate the clinical and electrophysiological characteristics of malformation of cortical development (MCD) with epilepsy. METHOD: We studied clinical and electroencephalographic (EEG) features of 54 childhood epilepsy patients with MCD diagnosed by magnetic resonance imaging (MRI) and pathologic examinations. RESULTS: 1) Bilateral diffuse MCD's were in 5 patients, bilateral focal MCD's were in 8, unilateral diffuse MCD's in 7, and unilateral focal MCD's were noted in 34 patients. 2) Partial seizures were manifested in 35 patients, and 4 of them evolve to infantile spasm (IS), isolated IS was noted in 15 cases, and generalized seizures were noticed in 2 cases 3) Asymmetric EEG backgraound slowing was noted in 30 patients, and 29 patients (96.7%) had MCD's in abnormal side of brain. 4) Polymorphic slowing was noted in 36 patients, and 28 cases (77.8%) had MCD's in those area. 5) Sensitivity of partial epileptiform discharges (ED's) for MCD was 79.6%, but specificity was 68.5%. 6) Localized paroxysmal fast activity was noted in 16 cases (29.6%), and specificity for MCD was 90.7%. 7) Spindle shaped fast activity was noted in 8 patients (14.8%), and its specificity was 100%. 8) Thirty-one cases (57.4%) were intractable to antiepileptic drugs (AED's). Seventeen cases of them were treated by ketogenic diet, and 12 patients (66.7%) were completely controlled. Among 12 cases of surgical resection, 11 patients (91.7%) became seizure free for 6 months to 2 years. 9) In pathologically confirmed cases, EEG sensitivity for MCD lesion was 100%, but sensitivity of MRI was 69.2%. CONCLUSION: EEG is most sensitive diagnostic tool for MCD in childhood epilepsy. and many of intractable epilepsy could be controlled by ketogenic diet and surgery.