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Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA 2 DS 2 VASc=1) (or women with CHA 2 DS 2 VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these “low‐risk” patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low‐risk CHA 2 DS 2 VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA 2 DS 2 VASc=0, CHA 2 DS 2 VASc=1, females with a CHA 2 DS 2 VASc=2, and CHA 2 DS 2 VASc ≥2 in ORBIT‐AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA 2 DS 2 VASc ≥2 patients (84.2%), those with a CHA 2 DS 2 VASc=0 (60.3%), 1 (69.9%), and females with a CHA 2 DS 2 VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P <0.0001). Stroke rates were low overall and ranged from 0 per 100 patient‐years in those with CHA 2 DS 2 VASc=0, 0.8 (95% confidence interval [CI] [0.5–1.2]) in those with CHA 2 DS 2 VASc=1, 0.8 (95% CI [0.4–1.6]) in females with a CHA 2 DS 2 VASc score=2, and 1.7 (95% CI [1.6–1.9]) in CHA 2 DS 2 VASc ≥2. All‐cause mortality (per 100 patient‐years) was highest in females with a CHA 2 DS 2 VASc score=2 (1.4) (95% CI [0.8–2.3]), compared with patients with a CHA 2 DS 2 VASc=0 (0.2) (95% CI [0.1–1.0]), and CHA 2 DS 2 VASc=1 (1.0) (95% CI [0.7–1.4]), but lower than patients with a CHA 2 DS 2 VASc ≥2 (5.7) (95% CI [5.4–6.0]). Conclusion The majority of CHA 2 DS 2 VASc=0‐1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA 2 DS 2 VASc=0‐1 as well as among females with a CHA 2 DS 2 VASc score=2. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.

AbstractBackgroundGenetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine. We have previously found that in a postcesarean section cohort, the rate of hydromorphone formation was dependent on the genotype of CYP2D6 and that plasma hydromorphone, not hydrocodone, was predictive of pain relief.MethodBlood was obtained from a postcesarean cohort that were surveyed for pain response and common side effects. Plasma samples were genotyped for CYP3A4/5, and their hydrocodone concentrations were measured by LC-MS. R statistical software was used to check for differences in the outcomes due to CYP3A4/5 and CYP2D6, and a multivariate regression model was fit to determine factors associated with pain score.ResultsTwo-way ANOVA between CYP3A4/A5 and CYP2D6 phenotypes revealed that the former variants did not have a statistical significance on the outcomes, and only CYP2D6 phenotypes had a significant effect on total dosage (P = 0.041). Furthermore, a 3-way ANOVA analysis showed that CYP2D6 (P = 0.036) had a predictive effect on plasma hydromorphone concentrations, and CYP3A4/A5 did not have any effect on the measured outcomes.ConclusionsWith respect to total dosages in a cesarean section population, these results confirm that CYP2D6 phenotypes are predictors for plasma hydromorphone concentration and pain relief, but CYP3A4/A5 phenotypes have no influence on pain relief or on side effects.

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

SummaryAttention‐deficit/hyperactivity disorder (ADHD) is a common and challenging comorbidity affecting many children with epilepsy. A working group under the International League Against Epilepsy (ILAE) Pediatric Commission identified key questions on the identification and management of ADHD in children with epilepsy. Systematic reviews of the evidence to support approaches to these questions were collated and graded using criteria from the American Academy of Neurology Practice Parameter. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) requirements were followed, with PROSPERO registration (CRD42018094617). No increased risk of ADHD in boys with epilepsy compared to girls with epilepsy was found (Level A). Valproate use in pregnancy is associated with inattentiveness and hyperactivity in offspring (1 class I study), and children with intellectual and developmental disabilities are at increased risk of ADHD (Level A). Impact of early seizure onset on development of ADHD was unclear (Level U), but more evident with poor seizure control (Level B). ADHD screening should be performed from 6 years of age, or at diagnosis, and repeated annually (Level U) and reevaluated after change of antiepileptic drug (AED) (Level U). Diagnosis should involve health practitioners with expert training in ADHD (Level U). Use of the Strength and Difficulties Questionnaire screening tool is supported (Level B). Formal cognitive testing is strongly recommended in children with epilepsy who are struggling at school (Level U). Behavioral problems are more likely with polytherapy than monotherapy (Level C). Valproate can exacerbate attentional issues in children with childhood absence epilepsy (Level A). Methylphenidate is tolerated and effective in children with epilepsy (Level B). Limited evidence supports that atomoxetine is tolerated (Level C). Multidisciplinary involvement in transition and adult ADHD clinics is essential (Level U). In conclusion, although recommendations could be proposed for some of the study questions, this systematic review highlighted the need for more comprehensive and targeted large‐population prospective studies.

OBJECTIVES: We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE). METHODS: There were 775 children with a new diagnosis of epilepsy (&lt;3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012–2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities. RESULTS: Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed. CONCLUSIONS: Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group.

The clinical phenotype of leucine‐rich glioma‐inactivated protein 1 (LGI1) and contactin‐associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010–2017), 264 were seropositive for voltage‐gated potassium channel‐complex–IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell‐binding assay for LGI1‐IgG (n = 7), CASPR2‐IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473–480

Background Oral anticoagulation ( OAC ) reduces stroke risk in atrial fibrillation, but bleeding is a frequent side effect. The decision to discontinue or modify medication regimens in response to a bleeding event may differ according to bleeding site and severity. Methods and Results We used data from a large, national outpatient registry, ORBIT ‐ AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; 2010–2011), to evaluate event characteristics and OAC management following the first bleeding event occurring during follow‐up. Bleeding events were classified into 3 categories: (1) International Society of Thrombosis and Hemostasis major bleeding, (2) clinically relevant nonmajor bleeding requiring medical attention, and (3) nuisance bleeding not requiring medical attention (eg, bruising, hemorrhoidal bleeding). Of 9743 patients enrolled in ORBIT ‐ AF with follow‐up data, 510 (3.23/100 subject‐years) experienced a major bleed, 615 (3.90/100 subject‐years), experienced a clinically relevant nonmajor bleed, and 1558 (9.87/100 subject‐years) experienced a nuisance bleed, among first bleeds over 2 years. Nearly one third of patients (31.6%) discontinued OAC therapy following a major bleeding event, 12.7% following a clinically relevant nonmajor bleed, and 4.5% following a nuisance bleed. Compared with those who experienced a clinically relevant nonmajor or nuisance bleed, patients who experienced a major bleed were more likely to be black and female and to have a history of heart failure and stroke. Those who discontinued were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC therapy. Conclusions Overall, 1 in 3 patients who experienced a major bleed was no longer anticoagulated after the event. Those who discontinued OAC were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC .