Dose-dependent Effects of Cacao Polyphenol Intake on Lipid Metabolism in Rats.

Cacao polyphenols (CPs) are known to suppress the oxidation of low-density lipoprotein and cholesterol absorption. Herein, we examined the impact of CP on the lipid metabolism in rats fed CP-rich chocolate, by analyzing liver weight and histology, via hematoxylin-eosin staining. The high-CP group had significantly lighter livers than the CP-free group. Histologically, the high-CP group showed significantly lower liver fat accumulation than the CP-free group. These results suggest that CPs prevent liver fat accumulation, being potentially useful against obesity and related diseases.

Deep Brain Stimulation for Refractory Tourette Syndrome: Electrode Position and Clinical Outcome.

The efficacy of deep brain stimulation (DBS) for refractory Tourette syndrome (TS) is accepted, but whether the efficacy of DBS treatment in the Japanese population is equivalent to those reported internationally and whether adverse effects are comparable are not yet known. This study evaluated the clinical practice and outcome of DBS for TS in a Japanese institution. This study included 25 consecutive patients with refractory TS treated with thalamic centromedian-parafascicular nucleus DBS. The severity of tics was evaluated with the Yale Global Tic Severity Scale (YGTSS) before surgery, at 1 year after surgery, and at the last follow-up of 3 years or more after surgery. The occurrence of adverse events, active contact locations, and stimulation conditions were also evaluated. YGTSS tic severity score decreased by average 45.2% at 1 year, and by 56.6% at the last follow-up. The reduction was significant for all aspects of the scores including motor tics, phonic tics, and impairment. The mean coordinates of active contacts were 7.62 mm lateral to the midline, 3.28 mm posterior to the midcommissural point, and 3.41 mm above anterior commissure-posterior commissure plane. Efficacy and stimulation conditions were equivalent to international reports. The stimulation-induced side effects included dysarthria (32.0%) and paresthesia (12.0%). Device infection occurred in three patients (12.0%) as a surgical complication. The DBS device was removed because of infection in two patients. DBS is an effective treatment for refractory TS, although careful indication is necessary because of the surgical risks and unknown long-term outcome.

Cognitive and developmental outcomes after pediatric insular epilepsy surgery for focal cortical dysplasia.

OBJECTIVE: Cognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula. METHODS: A review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3-13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction). RESULTS: The mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1-3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors. CONCLUSIONS: Resection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.

Deep slow nasal respiration with tight lip closure for immediate attenuation of severe tics.

BACKGROUND: Severe intractable tics, which are associated with Tourette syndrome and chronic tic disorder (TS/CTD), severely affect the quality of life. Common less-invasive treatments are often unable to attenuate tics with deep brain stimulation currently being the only effective treatment. We aimed to assess the anti-tic effect of deep slow nasal respiration with tight lip closure using patients with TS/CTD. METHODS: We retrospectively analyzed 10 consecutive patients (9 men, 1 woman; 23-41 years old). We instructed the patients to perform the procedure for 120 s and to obtain a video recording of before and during the procedure. The videos were used to count tics and determine lip competency or incompetency. The counted tics were rated using the modified Rush Video Rating Scale. RESULTS: Compared with before the procedure, there were significantly lower frequencies of motor and phonic tics, as well as video scored, during the procedure. Eight patients presented with lip incompetency before the procedure and none after the procedure (P = 0.041). There were no side effects associated with the procedure. CONCLUSION: Our findings indicate that deep slow nasal respiration with tight lip closure ameliorates tics in patients with TS/CTD. In accordance with our results, lip opening and oral breathing could be causes of tics, in addition to heritability. Therefore, this novel procedure could improve tics. Furthermore, our findings could contribute toward the development of tic treatments and elucidate their pathophysiology regarding the reward system, hypersensitivity, autonomic nerves, and nasal airway.

Altered Expression of Astrocyte-Related Receptors and Channels Correlates With Epileptogenesis in Hippocampal Sclerosis.

BACKGROUND: Hippocampal sclerosis (HS) is one of the major causes of intractable epilepsy. Astrogliosis in epileptic brain is a peculiar condition showing epileptogenesis and is thought to be different from the other pathological conditions. The aim of this study is to investigate the altered expression of astrocytic receptors, which contribute to neurotransmission in the synapse, and channels in HS lesions. METHODS: We performed immunohistochemical and immunoblotting analyses of the P2RY1, P2RY2, P2RY4, Kir4.1, Kv4.2, mGluR1, and mGluR5 receptors and channels with the brain samples of 20 HS patients and 4 controls and evaluated the ratio of immunopositive cells and those expression levels. RESULTS: The ratio of each immunopositive cell per glial fibrillary acidic protein-positive astrocytes and the expression levels of all 7 astrocytic receptors and channels in HS lesions were significantly increased. We previously described unique astrogliosis in epileptic lesions similar to what was observed in this study. CONCLUSION: This phenomenon is considered to trigger activation of the related signaling pathways and then contribute to epileptogenesis. Thus, astrocytes in epileptic lesion may show self-hyperexcitability and contribute to epileptogenesis through the endogenous astrocytic receptors and channels. These findings may suggest novel astrocytic receptor-related targets for the pharmacological treatment of epilepsy.

Sensory phenomena and obsessive-compulsive symptoms in Tourette syndrome following deep brain stimulation: Two case reports.

Here, we assess sensory phenomena (SP) and obsessive-compulsive symptoms (OCS) in two patients with refractory Tourette syndrome (TS) before and after deep brain stimulation (DBS) targeting the centromedian-parafascicular complex (CM-Pfc)-ventral oral nuclei of the bilateral thalami. Based on changes in these clinical features, we also aimed to elucidate useful information regarding the use of DBS in TS. We administered the Yale Global Tic Severity Scale (YGTSS) to assess tics, the Premonitory Urge for Tics Scale (PUTS) for premonitory urges, the University of São Paulo Sensory Phenomena Scale (USP-SPS) for broader SP, the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) for OCS, and the Global Assessment of Functioning (GAF) scale for global functioning. We report on two male patients who showed consistent improvement in tics, premonitory urges, and global functioning two years after DBS. In contrast, there were differences between the patients in broader SP, including "just right" perceptions, and OCS. Our results suggest that systematic assessment of a wide range of SP and OCS dimensions is necessary to elucidate the usefulness of DBS in TS.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events. Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Surgical strategy to avoid ischemic complications of the pyramidal tract in resective epilepsy surgery of the insula: technical case report.

Surgical treatment of the insula is notorious for its high probability of motor complications, particularly when resecting the superoposterior part. Ischemic damage to the pyramidal tract in the corona radiata has been regarded as the cause of these complications, resulting from occlusion of the perforating arteries to the pyramidal tract through the insular cortex. The authors describe a strategy in which a small piece of gray matter is spared at the bottom of the periinsular sulcus, where the perforating arteries pass en route to the pyramidal tract, in order to avoid these complications. This method was successfully applied in 3 patients harboring focal cortical dysplasia in the posterior insula and frontoparietal operculum surrounding the periinsular sulcus. None of the patients developed permanent postoperative motor deficits, and seizure control was achieved in all 3 cases. The method described in this paper can be adopted for functional preservation of the pyramidal tract in the corona radiata when resecting epileptogenic pathologies involving insular and opercular regions.

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay.

The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.

Vertical parasagittal hemispherotomy for Sturge-Weber syndrome in early infancy: case report and literature review.

INTRODUCTION: The authors here present a rare case of a 3-month-old infant with unilateral Sturge-Weber syndrome (SWS) who had excellent seizure control and no aggravation of previous existed neurological deficits after vertical parasagittal hemispherotomy (VPH). To our knowledge, this patient with SWS was the youngest one who received VPH. CASE DESCRIPTION: The use of VPH results in a successful treatment of intractable epilepsy in a patient with seizure onset in early infancy. At follow-up, the patient's neurodevelopmental status has been improved since the surgery. DISCUSSION: It is generally accepted that early-onset seizures in children with SWS are associated with worse neurological and developmental outcomes. However, when surgical treatment should be considered and how it should be performed remain a longstanding controversy. We promote early surgery in children with SWS and early-onset epilepsy. CONCLUSION: We suggest that VPH may be a useful adjuvant in the management of SWS with refractory epilepsy in early infancy and this procedure carries low neurological risk.

The International Deep Brain Stimulation Registry and Database for Gilles de la Tourette Syndrome: How Does It Work?

Tourette Syndrome (TS) is a neuropsychiatric disease characterized by a combination of motor and vocal tics. Deep brain stimulation (DBS), already widely utilized for Parkinson's disease and other movement disorders, is an emerging therapy for select and severe cases of TS that are resistant to medication and behavioral therapy. Over the last two decades, DBS has been used experimentally to manage severe TS cases. The results of case reports and small case series have been variable but in general positive. The reported interventions have, however, been variable, and there remain non-standardized selection criteria, various brain targets, differences in hardware, as well as variability in the programming parameters utilized. DBS centers perform only a handful of TS DBS cases each year, making large-scale outcomes difficult to study and to interpret. These limitations, coupled with the variable effect of surgery, and the overall small numbers of TS patients with DBS worldwide, have delayed regulatory agency approval (e.g., FDA and equivalent agencies around the world). The Tourette Association of America, in response to the worldwide need for a more organized and collaborative effort, launched an international TS DBS registry and database. The main goal of the project has been to share data, uncover best practices, improve outcomes, and to provide critical information to regulatory agencies. The international registry and database has improved the communication and collaboration among TS DBS centers worldwide. In this paper we will review some of the key operation details for the international TS DBS database and registry.

Tourette syndrome deep brain stimulation: a review and updated recommendations.

Deep brain stimulation (DBS) may improve disabling tics in severely affected medication and behaviorally resistant Tourette syndrome (TS). Here we review all reported cases of TS DBS and provide updated recommendations for selection, assessment, and management of potential TS DBS cases based on the literature and implantation experience. Candidates should have a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM V) diagnosis of TS with severe motor and vocal tics, which despite exhaustive medical and behavioral treatment trials result in significant impairment. Deep brain stimulation should be offered to patients only by experienced DBS centers after evaluation by a multidisciplinary team. Rigorous preoperative and postoperative outcome measures of tics and associated comorbidities should be used. Tics and comorbid neuropsychiatric conditions should be optimally treated per current expert standards, and tics should be the major cause of disability. Psychogenic tics, embellishment, and malingering should be recognized and addressed. We have removed the previously suggested 25-year-old age limit, with the specification that a multidisciplinary team approach for screening is employed. A local ethics committee or institutional review board should be consulted for consideration of cases involving persons younger than 18 years of age, as well as in cases with urgent indications. Tourette syndrome patients represent a unique and complex population, and studies reveal a higher risk for post-DBS complications. Successes and failures have been reported for multiple brain targets; however, the optimal surgical approach remains unknown. Tourette syndrome DBS, though still evolving, is a promising approach for a subset of medication refractory and severely affected patients.

Expression of astrocyte-related receptors in cortical dysplasia with intractable epilepsy.

Epilepsy is one of the major neurologic diseases, and astrocytes play important roles in epileptogenesis. To investigate possible roles of astrocyte-related receptors in patients with intractable epilepsy associated with focal cortical dysplasia (FCD) and other conditions, we examined resected epileptic foci from 31 patients, including 23 with FCD type I, IIa, or IIb, 5 with tuberous sclerosis complex, and 3 with low-grade astrocytoma. Control samples were from 21 autopsied brains of patients without epilepsy or neurologic deficits and 5 patients with pathologic gliosis without epilepsy. Immunohistochemical and immunoblot analyses with antibodies against purinergic receptor subtypes P2RY1, P2RY2, P2RY4, potassium channels Kv4.2 and Kir4.1, and metabotropic receptor subtypes mGluR1 and mGluR5 were performed. Anti-glial fibrillary acidic protein, anti-NeuN, and anti-CD68 immunostaining was used to identify astrocytes, neurons, and microglia, respectively. Most glial fibrillary acidic protein-immunopositive astrocyte cells in the brain samples from patients with epilepsy were P2RY1-, P2RY2-, P2RY4-, Kv4.2-, Kir4.1-, mGluR1-, and mGluR5-positive, whereas samples from controls and pathologic gliosis showed lower expression levels of these astrocyte-related receptors. Our findings suggest that, although these receptors are necessary for astrocyte transmission, formation of the neuron-glia network, and other physiologic functions, overexpression in the brains of patients with intractable epilepsy may be associated with activation of intracellular and glio-neuronal signaling pathways that contribute to epileptogenesis.

Persistent verbal and behavioral deficits after resection of the left supplementary motor area in epilepsy surgery.

An 8-year-old boy underwent a resection for focal cortical dysplasia at the left supplementary motor area (SMA) for the treatment of intractable epilepsy. The manifestations of SMA syndrome, such as transient mutism and right hemiparesis, resolved within a few weeks. Verbal disfluency and impaired executive function, accompanied by impulsivity and distractibility, persisted for more than 12months. The verbal and behavioral problems caused serious difficulties in the school life of the patient, until they became less evident at 18months after surgery. Tractography performed 18months after surgery revealed a defect in the subportion of fronto-parietal association fibers within the left superior longitudinal fascicles. Verbal influency can persist with unusually long duration after resection of SMA during childhood. Although not discernible on the routine neuroimaging, white matter damage beneath the SMA region could result in serious disabilities in executive function. These complications should be recognized for the prediction and assessment of deficits in children after surgical intervention involving this region.

Long-term developmental outcome after early hemispherotomy for hemimegalencephaly in infants with epileptic encephalopathy.

This study aimed to identify the effect of early hemispherotomy on development in a consecutive series of 12 infants with hemimegalencephaly (HME) demonstrating epileptic encephalopathy. Mean age at onset was 20.4 days (range, 1-140), mean age at surgery was 4.3 months (range, 2-9), and mean follow-up time was 78.8 months (range, 36-121). Eleven patients had a history of early infantile epileptic encephalopathy. Vertical parasagittal hemispherotomy was performed without mortality or severe morbidities. At follow-up, seizure freedom was obtained in 8 patients (66.7%), who showed significantly higher postoperative developmental quotient (DQ) (mean, 31.3; range, 7-61) than those with seizures (mean, 5.5; range, 3-8) (p=0.02). Within the seizure-free group, postoperative DQ correlated with preoperative seizure duration (r=-0.811, p=0.01). Our results showed that shorter seizure duration during early infancy could provide better postoperative DQ in infants with HME and epileptic encephalopathy.

Surgical management of cortical dysplasia in infancy and early childhood.

PURPOSE: To describe operative procedures, seizure control and complications of surgery for cortical dysplasia (CD) causing intractable epilepsy in infancy and early childhood. METHODS: Fifty-six consecutive children (less than 6years old) underwent resective epilepsy surgery for CD from December 2000 to August 2011. Age at surgery ranged from 2 to 69months (mean 23months) and the follow-up was from 1 to 11years (mean 4years 4months). RESULTS: Half of the children underwent surgery during infancy at an age less than 10months, and the majority (80%) of these infants needed extensive surgical procedures, such as hemispherotomy and multi-lobar disconnection. Seizure free (ILAE class 1) outcome was obtained in 66% of the cases (class 1a; 55%): 85% with focal resection (n=13), 50% with lobar resection (n=18), 71% with multilobar disconnection (n=7) and 67% with hemispherotomy (n=18). Peri-ventricular and insular structures were resected in 23% of focal and 61% of lobar resections. Repeated surgery was performed in 9 children and 5 (56%) became seizure free. Histological subtypes included hemimegalencephaly (16 patients), polymicrogyria (5 patients), and FCD type I (6 patients), type IIA (19 patients), type IIB (10 patients). Polymicrogyria had the worst seizure outcome compared to other pathologies. Surgical complications included 1 post-operative hydrocephalus, 1 chronic subdural hematoma, 2 intracranial cysts, and 1 case of meningitis. No mortality or severe morbidities occurred. CONCLUSIONS: Early surgical intervention in children with CD and intractable seizures in infancy and early childhood can yield favorable seizure outcome without mortality or severe morbidities although younger children often need extensive surgical procedures.

Posterior disconnection in early infancy to treat intractable epilepsy with multilobar cortical dysplasia: three case report.

Extensive multilobar cortical dysplasias occasionally occur in children and can induce seizure onset in early infancy, causing severe epileptic encephalopathy. Surgical interventions in early infancy, such as disconnection of large parts of the brain, are challenging because of the degree of invasiveness and carry greater risks in infants compared with older children. Here we report the successful treatment of intractable epilepsy with multilobar cortical dysplasias in the posterior cortex by posterior disconnection in three infants (age 3 months). The patients showed good postoperative recovery and exhibited excellent seizure control at follow-up evaluation within a year after surgery. Developmental catch-up was also achieved and no early complications have been detected to date. Use of the posterior disconnection technique for early-stage extensive multilobar cortical dysplasias can result in good seizure control and developmental progress with little perioperative morbidity. However, the efficacy of this surgical technique needs to be verified with long-term follow up after surgery.

Late-onset epilepsy in children with acute febrile encephalopathy with prolonged convulsions: A clinical and encephalographic study.

The aim of this study is to analyze the characteristics of epilepsies as the sequelae of acute febrile encephalopathy with prolonged convulsions during childhood. Sixteen patients (M:F=9:7) aged 2-13years (mean 6.1years) with history of febrile acute encephalopathy were retrospectively reviewed. These patients experienced febrile encephalopathy at the age of 11months to 4years, with 11 individuals presenting with findings of a biphasic clinical course (n=5), frontal predominant (n=8) lesions, and/or reduced diffusivity in the cerebral white matter on magnetic resonance imaging (MRI; n=3). The remaining 5 patients had unilateral lesions that manifested the phenotype of hemiconvulsion-hemiplegia-epilepsy syndrome (HHES). Epilepsy emerged with a latent period of 2months to 2years after the acute phase of febrile encephalopathy. Head nodding or spasm with subsequent motion arrest and brief tonic seizures were the main seizure phenotypes. Ictal records of epileptic seizures were available in 9 patients. Epileptiform discharges with a focal or uneven distribution appeared at the seizure onset and lasted less than 1s in all patients; these were followed by either generalized attenuation or fast activity in 8 patients with head nodding, spasm, or brief tonic seizures, and by localized fast activity in 1 patient with versive tonic seizures. Notably, the seizure onset area was often located outside the severe lesions on MRI, i.e., in the parietal areas in patients with frontal predominant lesions, and in the spared hemisphere of HHES. Although phenobarbital, zonisamide, carbamazepine, clobazam, clonazepam, and clorazepate were partially effective in some patients, daily seizures persisted in 11 patients. Callosotomy was performed in 2 patients, and beneficial effects were observed in both. These characteristics suggested a broad distribution of augmented excitability in these patients, resulting in the rapid propagation of epileptic activity in the initial phase of ictal phenomena. Thus, this study investigates the most severe subgroup of epilepsy following febrile acute encephalopathy and provides the basis for further exploration of the pathogenesis and treatment of characteristic seizures in this population.