Epilepsy surgery in children under 3 years of age: surgical and developmental outcomes.

OBJECTIVE: Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS: This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors' institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS: The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS: Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.

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.

Transient water-electrolyte disturbance after hemispherotomy in young infants with epileptic encephalopathy.

PURPOSE: This study aimed to elucidate the clinical features of water-electrolyte disturbance (WED) as a sequela of hemispherotomy. METHODS: We performed a retrospective chart review to identify the clinical features of diabetes insipidus (DI) as a complication in < 12-month-old patients who underwent hemispherectomy or hemispherotomy for severe epilepsy between 2007 and 2018. Central DI was diagnosed if a patient developed polyuria (urine output > 5 mL/kg/h), abnormally high serum osmolality (> 300 mOsm/kg), high serum sodium level (> 150 mEq/L), either abnormally low urine specific gravity (< 1.005) or low urine osmolality (< 300 mOsm/kg) or both, and effective control of polyuria with arginine vasopressin (AVP). The clinical course of post-hemispherotomy WED, complications other than WED, and seizure outcomes were analyzed. RESULTS: The review identified that 3 of 23 infants developed WED. All patients developed polyuria within 2 days after surgery, with high serum osmolality and hypotonic urine; AVP was effective in treating these symptoms. The clinical course was compatible with central DI. Two patients subsequently developed hyponatremia in a biphasic or triphasic manner. All patients had multiple seizures that were probably related to WED. Two patients developed asymptomatic cerebral sinovenous thrombosis, possibly because of the surgical procedure and dehydration; anticoagulant treatment was provided. All patients were treated for WED for up to 2 months and had no residual pituitary dysfunction. CONCLUSION: Systemic complications other than intracranial ones can occur in patients who have undergone hemispherotomy. Perioperative systemic management of young infants undergoing this procedure should include careful water and electrolyte balance monitoring.

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.

Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background.

A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT.

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.

Outcome of vagus nerve stimulation for drug-resistant epilepsy: the first three years of a prospective Japanese registry.

Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug-resistant epilepsy, however, evidence for long-term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed.

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.

Surgical versus medical treatment for children with epileptic encephalopathy in infancy and early childhood: Results of an international multicenter cohort study in Far-East Asia (the FACE study).

OBJECTIVE: To compare the seizure and developmental outcomes in infants and young children with epileptic encephalopathy who have undergone surgical and medical treatments. METHODS: An international, multicenter, observational cohort study was undertaken. A total of 317 children aged <6 years, who had frequent disabling seizures despite intensive medical treatments, were registered. Among the enrolled children, 250 were treated medically (medical group), 31 underwent resective surgery (resective group), and 36 underwent palliative surgery [callosotomy (n=30) or vagal nerve stimulation (n=6); palliative group] on admission. Seizure and developmental outcomes were obtained for 230 children during the 3-year follow-up period. Cox proportional hazard model was used to adjust for clinical backgrounds among treatment groups when comparing the seizure-free survival rates. RESULTS: At the 3-year follow-up, seizure-free survival was 15.7%, 32.1%, and 52.4% in the medical, palliative, and resective groups, respectively. The adjusted hazard ratios for seizure recurrence in the resective and palliative groups versus the medical group were 0.43 (95% CI, 0.21-0.87, P=0.019) and 0.82 (95% CI, 0.46-1.46, P=0.50), respectively; the former was statistically significant. Regarding the developmental outcome, the mean DQs in the resective group increased significantly compared to those in the medical group during the follow-up (P<0.01). As for subgroup analysis, better seizure and development outcomes were demonstrated in the resective group compared to the medical group in children with nonsyndromic epilepsies (those to which no known epilepsy syndromes were applicable). SIGNIFICANCE: These results suggest that surgical treatments, particularly resective surgeries, are associated with better seizure and developmental outcomes compared with successive medical treatment. The present observations may facilitate the identification of infants and young children with epileptic encephalopathy who could benefit from surgery.

Characteristic expression of p57/Kip2 in balloon cells in focal cortical dysplasia.

Balloon cells are a pathognomonic cellular feature of various cortical malformations, including focal cortical dysplasia type IIb (FCD IIb), cortical tubers of tuberous sclerosis (TSC) and hemimegalencephaly (HME). In the present study, we investigated the immunohistochemical expression of p57/Kip2, a member of the Cip/Kip family of cyclin-dependent kinase inhibitory proteins, in balloon cells in surgical specimens taken from 26, 17 and six patients with FCD IIb, TSC and HME, respectively. Characteristic dot-like reactivity with a faint, intense, reticular and process-like pattern was confined to the proximal portion of the cytoplasmic processes of the cells. Immunoelectron microscopy revealed the p57/Kip2 reactivity on intermediate filaments in the proximal portion of the processes. The immunohistochemical profile appeared similar to that of CD34; however, a double immunofluorescence study demonstrated that no cells showed reactivity for both p57/Kip2 and CD34. The frequencies of the p57/Kip2-positive cells in FCD IIb and HME were significantly higher than those in TSC, suggesting that the balloon cells may be heterogeneous. These findings suggest some functional significance of the protein on the cytoplasmic processes of balloon cells and appear consistent with the notion that the cells are abnormally differentiated progenitor cells.

Two siblings with cortical dysplasia: Clinico-electroencephalographic features.

The older of two siblings began to have spasms and partial seizures at 1 month of age. Head magnetic resonance imaging showed an abnormal area in the left temporo-parieto-occipital region. Interictal electroencephalogram (EEG) showed a suppression-burst pattern. Adrenocorticotropic hormone stopped the spasms, but the seizures continued. Clonazepam, carbamazepine, zonisamide, and clobazam were ineffective. She underwent focal resection at age 8 months. Postoperatively, the seizures disappeared. Histopathologically, the lesion appeared to be focal cortical dysplasia type IIa. The younger sibling had spasms from birth. Head magnetic resonance imaging showed left hemi-megalencephaly. Interictal EEG showed a suppression-burst pattern. Phenobarbital, valproic acid, and zonisamide were ineffective. He underwent hemispherotomy at age 2 months and became seizure free. The histopathological features were consistent with those of hemi-megalencephaly. The siblings' EEG and clinical courses had some similarities. These siblings' conditions may have the same genetic background.

Research priorities in epilepsy for the Asia-Oceanian region.

The Asia-Oceanian region is the most populous region in the world. Although there has been substantial economic development and improvement in health services in recent years, epilepsy remains generally an underrecognized and understudied condition. To help promote research in the region, the Commission on Asian and Oceanian Affairs (CAOA) of the International League Against Epilepsy (ILAE) appointed the Research Task Force (RTF) to facilitate the development of research priorities for the region. Research that focuses on issues that are unique or of particular importance in the Asia-Oceanian region is encouraged, and that captures the impact of the dynamic socioeconomic changes taking place in the region is emphasized. Based on these considerations, we propose research "dimensions" as priorities within the Asia-Oceanian region. These are studies (1) that would lead to fuller appreciation of the health burden of epilepsy, particularly the treatment gap; (2) that would lead to better understanding of the causes of epilepsy; (3) that would alleviate the psychosocial consequences of epilepsy; (4) that would develop better therapies and improved therapeutic outcomes; and (5) that would improve the research infrastructure.

Complex regional pain syndrome in a 15-year-old girl successfully treated with continuous epidural anesthesia.

A 15-year-old girl developed severe pain in her right upper limb within a few days after she experienced an astatic epileptic seizure accompanied by falling on her right side. She was treated with fluid infusion through a cannula into her right hand. Swelling, mild flaring, and muscle weakness of the right arm subsequently appeared. Pharmacotherapy and stellate ganglion block were ineffective, and continuous epidural anesthesia was commenced 14 days after the falling event. The pain and accompanying symptoms completely disappeared within 5 days. Early treatment with continuous epidural anesthesia may be a promising option for the management of complex regional pain syndrome during childhood.

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.

[Epilepsy care network].

Build-up of community health coalition system is now an essential part of medicine. However, little attention has been paid to epilepsy care in Japan, which resulted in a chaotic and difficult situation to find epilepsy-care physicians in the community. The reason is that responsible medical specialty in charge has been ambiguous historically in Japan and a lack of post-in-charge in the government to plan epilepsy care system is aggravating this condition. To solve this issue, epilepsy care network connecting the primary, secondary and tertiary epilepsy care physicians should be established and open to the community. In this context, our Epilepsy Care Network-Japan was started on July 2012 proposing a new epilepsy care algorithm suitable for our complex medical community.

Hemimegalencephaly in a patient with coexisting trisomy 21 and hypomelanosis of Ito.

A male infant with trisomy 21 simultaneously showed clinical features of hypomelanosis of Ito and hemimegalencephaly, with related intractable epileptic seizures. The epileptic seizures were refractory to conventional antiepileptic drugs and persisted until the patient underwent functional hemispherotomy. It is well known that patients with hypomelanosis of Ito may also have cortical dysplasia and hemimegalencephaly and that approximately half of these patients have chromosomal abnormalities. However, to our knowledge, there is no previous report of a patient with trisomy 21 associated with hemimegalencephaly. Here, we describe a rare case of coexisting trisomy 21 and hypomelanosis of Ito, associated with hemimegalencephaly.

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.