In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

Although chronic vagus nerve stimulation (VNS) is an established treatment for medically-intractable childhood epilepsy, there is considerable heterogeneity in seizure response and little data are available to pre-operatively identify patients who may benefit from treatment. Since the therapeutic effect of VNS may be mediated by afferent projections to the thalamus, we tested the hypothesis that intrinsic thalamocortical connectivity is associated with seizure response following chronic VNS in children with epilepsy. Twenty-one children (ages 5–21 years) with medically-intractable epilepsy underwent resting-state fMRI prior to implantation of VNS. Ten received sedation, while 11 did not. Whole brain connectivity to thalamic regions of interest was performed. Multivariate generalized linear models were used to correlate resting-state data with seizure outcomes, while adjusting for age and sedation status. A supervised support vector machine (SVM) algorithm was used to classify response to chronic VNS on the basis of intrinsic connectivity. Of the 21 subjects, 11 (52%) had 50% or greater improvement in seizure control after VNS. Enhanced connectivity of the thalami to the anterior cingulate cortex (ACC) and left insula was associated with greater VNS efficacy. Within our test cohort, SVM correctly classified response to chronic VNS with 86% accuracy. In an external cohort of 8 children, the predictive model correctly classified the seizure response with 88% accuracy. We find that enhanced intrinsic connectivity within thalamocortical circuitry is associated with seizure response following VNS. These results encourage the study of intrinsic connectivity to inform neural network-based, personalized treatment decisions for children with intractable epilepsy.

SUMMARYObjective: We observed several children with medically resistant epilepsy demonstrating focal positron emission tomography (PET) hypermetabolism, a finding rarely reported and of questionable significance. We therefore retrospectively reviewed the incidence of hypermetabolic PET, and its relationship to electroencephalography (EEG) and magnetic resonance imaging (MRI) findings, and to the outcome of epilepsy surgery. Methods: We retrospectively reviewed 498 PET brain studies in patients with medically resistant childhood epilepsy for evidence of hypermetabolism. In patients with PET hypermetabolism, we correlated metabolic abnormality with the scalp EEG and MRI findings. In a subset of patients who underwent surgical resection, we further correlated the PET findings with histopathologic and surgical outcomes. Results: Focal PET hypermetabolism was identified in 33 (6.6%) of 498 studies. The region of hypermetabolism correlated with a spike count of ≥10 per minute in 26 of 32 concomitant scalp EEG studies and 18 of 21 lesions evident on MRI. In 17 patients who underwent surgical resection, PET hypermetabolism further correlated with regions revealing almost continuous epileptiform discharges on the intracranial EEG and with histopathologically malformative tissue. At a minimum follow-up of 1 year postsurgery (median 33 months), 7 (50%) of 14 patients had Engel's class I outcome, 4 patients had class II, and 2 had class III outcome, whereas one patient was unchanged. At last follow-up, seizure freedom was noted in five of seven patients with focal PET hypermetabolism alone versus three of eight patients with PET hypometabolism. Significance: Focal PET hypermetabolism is associated with high spike frequency on scalp EEG and can occur in the absence of ictal events during the peri-injection period. Correlation with intracranial EEG usually corroborates the highly epileptogenic pathophysiologic state. Cortical malformations constitute the most common pathologic substrate, and resection of the hypermetabolic PET region may facilitate favorable outcomes. These observations indicate that focal PET hypermetabolism is an important marker of the epileptogenic zone and may represent its epicenter. KEY WORDS: Intractable childhood epilepsy, High spike count, Resection of hypermetabolic PET region, Epilepsy surgery outcome, Epicenter of epileptogenic zone.

Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics.

Continuous EEG monitoring is used with increasing frequency in critically ill children to provide insight into brain function and to identify electrographic seizures. EEG monitoring use often impacts clinical management, most often by identifying electrographic seizures and status epilepticus. Most electrographic seizures have no clinical correlate, and thus would not be identified without EEG monitoring. There is increasing data that electrographic seizures and electrographic status epilepticus are associated with worse outcome. Seizure identification efficiency may be improved by further development of quantitative EEG trends. This review describes the clinical impact of EEG data, the epidemiology of electrographic seizures and status epilepticus, the impact of electrographic seizures on outcome, the utility of quantitative EEG trends for seizure identification, and practical considerations regarding EEG monitoring.

SUMMARYObjective: The aim of this study was to investigate the utility of three-dimensional electroencephalography source imaging (3D-ESI) with low-resolution electroencephalographic data in the pediatric noninvasive presurgical evaluation, and to compare the findings with positron emission tomography (PET) and ictal single-photon emission computed tomography (iSPECT). Methods: We retrospectively selected 60 patients from a database of 594 patients who underwent excisional surgery for drug-resistant epilepsy. Patients were <18 years at time of surgery, had at least one presurgical volumetric brain magnetic resonance imaging (MRI), and at least 1 year of outcome data. 3D-ESI was performed with NeuroScan software CURRY V.7.0. For each patient the surgical resection was planned utilizing 3D-ESI as an adjunctive tool to supplement MRI and electrocorticographic data. Our analyses addressed three critical variables: pathology (focal cortical dysplasia vs. other pathologies), imaging (MRI negative vs. positive cases), and surgery (temporal resection vs. extratemporal and multilobar resections). We also compared the localizing utility and surgical outcome of 3D-ESI findings with PET, iSPECT, and the colocalized surgical resection. Statistical analyses were performed using the Statistical Package for the Social Sciences, Version 20. Results: Mean age at surgery was 11.18 years (range 1-18 years). 3D-ESI showed a strong correlation with the surgical resection cavity (65.0%), particularly within the temporal lobe. 3D-ESI demonstrated better localization in MRI-negative cases (78.6%), which was not statistically significant. 3D-ESI also correlated with a superior surgical outcome profile compared to PET and iSPECT. Significance: Our findings demonstrate that 3D-ESI data obtained with low-resolution electroencephalography achieves reasonably accurate noninvasive localization of epileptic spikes in pediatric focal epilepsy, especially in temporal lobe and MRI-negative cases, and is comparable to iSPECT and PET. Given its lesser expense and lack of radiation exposure, 3D-ESI is a useful and efficient tool for evaluating surgical candidacy in pediatric epilepsy surgery centers, particularly if PET and iSPECT are unavailable.

Purpose: Reverse-transcriptase PCR (RT-PCR) assays for carcinoembryonic antigen (CEA) have been described to identify lymph node micrometastases. These assays are not quantitative and can be confounded by false-positive results. The purpose of this study was to determine whether quantification of CEA in lymph nodes could more readily identify clinically relevant groups.Experimental Design: Specimens included 400 lymph nodes from 64 patients undergoing colon resections. Specimens were tested by immunohistochemistry and by RT-PCR using nested primers for CEA. Specimens from 59 patients that were positive by nested RT-PCR were further quantified by detection of CEA mRNA fluorescence increase at a threshold PCR cycle.Results

Consideration of iron-chelation (IC) in transfusion-dependent patients is recommended in most clinicalpractice guidelines on myelodysplastic syndromes (MDS). The financial impact of IC on health-care systems is predicted through economic modeling, but an analysis based on actual prevalence is lacking. Here, we have investigated the potential drug-costs and need for IC in a cohort of 189 United Kingdom-based MDS patients diagnosed from 2000 to 2010. Patients with low or intermediate-1 IPSS scores were identified as eligible for IC if 24 red cell units (RCU) had been transfused over 12 consecutive months or the transfusion-intensity averaged 2 RCU per month. Drug-costs were calculated from the time patients qualified for IC until death or last follow-up. In 159 patients with low/intermediate-1 MDS, survival was superior with a low IPSS score (P 5 0.014), age <70 years (P 5 0.043), transfusion-independence at diagnosis (P 5 0.0056) and transfusion-intensity of <2 RCU per month (P 5 0.009). Reflecting the time elapsed since diagnosis, longer survival was observed with a cumulative red cell load of 75 U (P 5 0.046). By logistic-regression analysis, transfusion-intensity independently predicted survival (P 5 0.0035) in low and intermediate-1 risk MDS patients. Forty-one patients fulfilled criteria for consideration of IC. Of these, 6 patients died within 1 month; 35 patients survived for a median of 16 months (range 1-61). Had patients commenced IC, the anticipated drug-costs alone would have been $526,880-$2,064,800 over 10 years. The lack of association between cumulative transfusion-load and survival calls for a prospective evaluation of the cost-utility of IC in patients surviving long-term, to enable evidencebased recommendations in MDS management. Am. J. Hematol. 86:406-410, 2011. V