Results of a National Delphi consensus on the outpatient management of pediatric psychogenic nonepileptic seizures in the United States.

BACKGROUND AND OBJECTIVES: The purpose of this study was to develop national consensus based on expert opinion on the optimal outpatient care model of pediatric psychogenic nonepileptic seizures (PNES). METHODS: A core working group (CWG) within the PNES special interest group of the Pediatric Epilepsy Research Consortium was established. The CWG developed a rigorous scoring rubric to select experts in pediatric PNES within the United States of America and a three-round Delphi study was conducted to assess consensus on key components of the management of pediatric PNES in the outpatient setting. RESULTS: Eighteen experts representing neurology, psychology, psychiatry, social work and nursing participated in the study. Strong consensus was reached that the multidisciplinary clinic (MDC) model is the gold standard for the outpatient management of pediatric PNES. Consensus was obtained that a neurologist, psychologist and social worker are essential members of the MDC and in the setting of unlimited resources, psychiatry and nursing are also recommended. Further consensus was established on the roles of specific personnel, structure of the clinic, billing practices, trainee inclusion, patient inclusion and exclusion, and end of visit management. While consensus was reached that a new term should be developed for this diagnosis, consensus was not reached on the ideal term. DISCUSSION: Expert consensus was established for the multidisciplinary management of pediatric PNES in the outpatient setting. Specific recommendations were provided that can facilitate the development and implementation of MDCs in other institutions. Further prospective studies are warranted to validate this practice model.

La Crosse Virus Neuroinvasive Disease in Children: A Contemporary Analysis of Clinical/Neurobehavioral Outcomes and Predictors of Disease Severity.

BACKGROUND: La Crosse virus (LACV) is the most common neuroinvasive arboviral infection in children in the United States. However, data regarding predictors of disease severity and neurologic outcome are limited. Additionally, long-term neurologic and neurobehavioral outcomes remain relatively sparse. METHODS: This was a single-center, retrospective cohort study, followed by recruitment for a cross-sectional analysis of long-term neurobehavioral outcomes, among children aged 0-18 years with proven or probable LACV neuroinvasive disease (LACV-ND) between January 2009 and December 2018. Case ascertainment was assured by International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes cross-referenced with laboratory results detecting LACV. Demographics, diagnostics, radiographs, and outcomes were evaluated. Recruitment of patients with prior diagnosis of LACV-ND occurred from January 2020 to March 2020, with assessment performed by validated pediatric questionnaires. RESULTS: One-hundred fifty-two children (83 males; median age, 8 years [interquartile range, 5-11.5 years]) were diagnosed with proven (n = 61 [47%]) and probable (n = 91 [60%]) LACV-ND. Sixty-five patients (43%) had severe disease. Altered mental status (AMS) (odds ratio [OR], 6.36 [95% confidence interval {CI}, 2.03-19.95]; P = .0002) and seizures at presentation (OR, 10.31 [95% CI, 3.45-30.86]; P = .0001) were independent predictors of severe disease. Epileptiform discharges on electroencephalogram (EEG) were independently associated with epilepsy diagnosis at follow-up (OR, 13.45 [95% CI, 1.4-128.77]; P = .024). Fifty-four patients were recruited for long-term neurobehavioral follow-up, with frequent abnormal assessments identified (19%-54%) irrespective of disease severity. CONCLUSIONS: Severe disease was observed frequently among children with LACV-ND. Seizures and AMS at presentation were independent predictors of severe disease. EEG may help determine long-term epilepsy risk. Long-term neurobehavioral issues are frequent and likely underrecognized among children with LACV-ND.

Status Epilepticus.

Status epilepticus is a neurologic emergency defined as a seizure that lasts longer than 5 minutes. This is the most common neurologic emergency in children, and it is associated with significant morbidity and mortality. Initial seizure management focuses on stabilization of the patient, followed by medication to terminate the seizure. Benzodiazepines, levetiracetam, fosphenytoin, valproic acid and other antiseizure medications can effectively halt status epilepticus. There is a narrow but important differential diagnosis, including prolonged psychogenic nonepileptic seizure, status dystonicus, and nonconvulsive status epilepticus. Focused laboratory testing, neuroimaging, and electroencephalography can be useful in the evaluation of status epilepticus. Sequelae include focal neurologic deficits, cognitive impairment, and behavioral problems. Pediatricians play an important role in the early recognition and treatment of status epilepticus, thereby preventing the acute and chronic harm that can be associated with status epilepticus.

Education Research: Educating Child Neurology Residents About Psychogenic Nonepileptic Seizures: A Needs Assessment.

Background and Objectives: Psychogenic nonepileptic seizures (PNES) are difficult to differentiate from epileptic seizures (ES) even for neurologists who see these conditions frequently. This difficulty is due to overlapping semiologic findings between the 2 diagnoses. Previous studies have shown that trainees, including neurology trainees, are not accurate in differentiating PNES from ES. Neurologists often find the communication of PNES difficult. Despite these challenges, most programs do not have formal curricula for teaching PNES, and there are no standards for residency curricula in this topic. The aim of this study was to understand the gaps in resident education on PNES. Methods: This study was accomplished through a needs assessment of current pediatric neurology residents and residency program directors (PDs). Two unique surveys were distributed, 1 for child neurology trainees and 1 for PDs. Questions were designed to understand trainees' self-reported knowledge, confidence, current education received, and desired teaching. Similarly for PDs, questions were designed to assess the state of education on PNES at their programs, sufficiency of education, and their desire for standardized curriculum. Results: Sixty-eight trainees and 21 PDs responded to the survey. Approximately one-quarter of trainees reported neutral to low levels of confidence and 38% reported neutral to low levels of knowledge in caring for patients with PNES. Trainees reported that directing patients with PNES to appropriate management was the most challenging aspect of care, followed by communicating the diagnosis, with 60% and 46% reporting difficulty, respectively. Only 21% of residents felt their current PNES education needs no improvement. One-fifth of PDs felt their current PNES education is not sufficient, and all reported they would incorporate a standardized curriculum. Trainees reported preferring to learn about this topic through lectures and simulation, while PDs preferred online modules and simulation. Discussion: While residents and PDs report high confidence and knowledge in treating pediatric patients with PNES, respondents felt improvement is needed to their curricula regarding this topic. Multiple learning methods are preferred, with emphasis on communicating the diagnosis and management of patients once the diagnosis has been made. PDs desire a standardized curriculum and would incorporate one into their programs. Findings of this study could be used to create a national curriculum.

Brief Report: Psychogenic Nonepileptic Events in Pediatric Patients with Autism or Intellectual Disability.

This is a retrospective case series of pediatric patients referred to the psychogenic nonepileptic events clinic (PNEE) who had comorbid diagnoses of autism spectrum disorder (ASD) or intellectual disability (ID). We describe 15 patients, nine with ASD and six with ID who had a telephone visit follow-up at 12 months. There were higher rates of male gender (40%) and comorbid epilepsy (53%) compared to the larger PNEE cohort. Eleven patients were available for follow-up and ten patients had improvement in events or were event-free. We report that patients with ASD or ID can develop PNEE and experience improvement from events.

Creating a New Set of Milestones for the Clinical Neurophysiology Fellowship.

INTRODUCTION: The Accreditation Council for Graduate Medical Education and the American Board of Psychiatry and Neurology first developed milestones for the clinical neurophysiology (CNP) fellowship in 2015. The milestones provide a comprehensive evaluation of the fellow's development based on six domains of competency. Here, we describe the development of a new set of milestones for CNP fellowship with level 1 as the incoming level, level 4 as the goal for graduation, and level 5 as the aspirational level that may not be achieved. METHODS: Committee members were nominated or volunteered to participate in the milestones update. Milestone development began with the creation of a shared mental model of the ideal skills and knowledge a graduating CNP fellow should attain. RESULTS: The CNP committee met virtually 7 times for a total of 14 meeting hours. Nine Patient Care and five Medical Knowledge milestones evolved from the seven Patient Care and six Medical Knowledge milestones that were in the first iteration. The committee incorporated 11 "Harmonized Milestones" into the revision and a supplemental guide was created. CONCLUSIONS: The revised Accreditation Council for Graduate Medical Education milestones for CNP fellowship contain important updates that program directors should review against their curricula to identify any gaps in learning. Program leadership should take note of two new Patient Care milestones for telemedicine and intraoperative monitoring. Clinical neurophysiology fellowships are not designed to provide level 4 competency across all milestones. The revised milestones should be viewed within the context of an individual program's goals.

Validating Coding for the Identification of Pediatric Treatment Resistant Epilepsy Patients.

The International Classification of Diseases (ICD) system includes sub codes to indicate that an individual with epilepsy is treatment resistant. These codes would be a valuable tool to identify individuals for quality improvement and population health, as well as for recruitment into clinical trials. However, the accuracy of these codes is unclear. We performed a single center cross sectional study to understand the accuracy of ICD codes for treatment resistant epilepsy. We identified 344 individuals, roughly half with treatment resistant epilepsy The ICD code had a sensitivity of 90% (147 of 164) and specificity of 86% (155 of 180). The miscoding of children with refractory epilepsy was attributed to the following reasons: 5 patients had epilepsy surgery, 4 had absence epilepsy, 4 patients were seen by different providers, and 1 patient was most recently seen in movement disorders clinic. ICD codes accurately identify children with treatment resistant epilepsy.

Long-term Risks of Recurrent Febrile Seizures.

Investigators from Denmark at Aarhus University studied the long-term risk of epilepsy, psychiatric disorders, and mortality among children with recurrent febrile seizures.

Fluorinated acid amplifiers for EUV lithography.

Five new compounds were synthesized for use as acid amplifiers in EUV (13.5 nm) photoresists. Four compounds act as acid amplifiers and decompose by autocatalytic kinetics to generate fluorinated sulfonic acids, essential for the simultaneous improvement of resolution, sensitivity, and line edge roughness (LER) in EUV photoresists. The decomposition rates were studied using (19)F NMR in the presence and absence of 1.2 equiv of tri-tert-butylpyridine. Three acid amplifiers decomposed 490, 1360, and 1430 times faster without base than with base. Preliminary lithographic evaluations show that cis-1-methyl-2-(4-(trifluoromethyl)phenylsulfonyloxy)cyclohexyl acetate simultaneously improves the resolution, LER, and sensitivity of an EUV photoresist.

Safety and Efficacy of Supratherapeutic Doses of Clobazam.

Clobazam is a commonly used long-acting benzodiazepine approved by the US Food and Drug Administration (FDA) to treat seizures associated with Lennox Gastaut syndrome. The FDA approved maximum dosage of clobazam is 1 mg/kg/d or a total of 40 mg a day. Many providers exceed this dosage but there is limited data on the safety, tolerability, and efficacy of supratherapeutic doses. We reviewed retrospective data at our institution and compared patients on supratherapeutic doses to patients on therapeutic doses. A total of 133 patients met inclusion criteria (65 supratherapeutic, 67 therapeutic). There was no statistically significant difference in terms of seizure control, health care utilization, or side effects between patients on supratherapeutic doses and those on therapeutic doses. This study lends further support to the safety and tolerability of supratherapuetic doses of clobazam.

Preparation, separation, and characterization of ruthenium(II) thiocyanate linkage isomers.

The reaction of [(p-cym)Ru(bpy)Cl](+) (p-cym = eta(6)-p-cymene; bpy = 2,2'-bipyridine) with SCN(-) gives a mixture of the linkage isomers [(p-cym)Ru(bpy)(SCN)](+) and [(p-cym)Ru(bpy)(NCS)](+). The linkage isomers were efficiently separated by column chromatography on Hg(NO3)2-coated Al2O3. Both isomers were fully characterized by elemental analysis, (1)H NMR and IR spectroscopy, and X-ray crystallography. The equilibrium constant for the conversion of the S-bound to the N-bound isomer was determined to be 0.29(4) in methanol-d4 and 0.74(7) in acetone-d6, respectively, at 50 degrees C. Kinetic data for the linkage isomerization reaction are also reported.

Inadequate Regulation Contributes to Mislabeled Online Cannabidiol Products.

Researchers from the University of Pennsylvania, Veterans Affairs San Diego, RTI international, Americans for Safe Access, Palo Alto University and Johns Hopkins University analyzed the content of 84 cannabidiol (CBD) products purchased on the internet and compared the results to their advertised concentrations.

Opinion and Special Articles: Neurology education at US osteopathic medical schools.

Osteopathic medical schools have a longstanding tradition of training primary care physicians (PCP). Neurologic symptoms are common in the PCP's office and there is an undersupply of neurologists in the United States. It is therefore crucial for osteopathic medical students to have a strong foundation in clinical neurology. Despite the importance, a mere 6% of osteopathic medical schools have required neurology clerkships. Furthermore, exposure to neurology in medical school through required clerkships has been correlated with matching into neurology residency. As osteopathic medical schools continue to expand, it will become increasingly important to emphasize the American Academy Neurology's published guidelines for a core clerkship curriculum. Practicing neurologists should take an active role in encouraging osteopathic medical schools to adopt these guidelines.

Synthesis, characterization, and reactivity of [Ru(bpy)(CH3CN)3(NO2)]PF6, a synthon for [Ru(bpy)(L3)NO2] complexes.

We report a high yield, two-step synthesis of fac-[Ru(bpy)(CH3CN)3NO2]PF6 from the known complex [(p-cym)Ru(bpy)Cl]PF6 (p-cym = eta(6)-p-cymene). [(p-cym)Ru(bpy)NO2]PF6 is prepared by reacting [(p-cymene)Ru(bpy)Cl]PF6 with AgNO3/KNO2 or AgNO2. The 15NO2 analogue is prepared using K15NO2. Displacement of p-cymene from [(p-cym)Ru(bpy)NO2]PF6 by acetonitrile gives [Ru(bpy)(CH3CN)3NO2]PF6. The new complexes [(p-cym)Ru(bpy)NO2]PF6 and fac-[Ru(bpy)(CH3CN)3NO2]PF6 have been fully characterized by 1H and 15N NMR, IR, elemental analysis, and single-crystal structure determination. Reaction of [Ru(bpy)(CH3CN)3NO2]PF6 with the appropriate ligands gives the new complexes [Ru(bpy)(Tp)NO2] (Tp = HB(pz)3-, pz = 1-pyrazolyl), [Ru(bpy)(Tpm)NO2]PF6 (Tpm = HC(pz)3), and the previously prepared [Ru(bpy)(trpy)NO2]PF6 (trpy = 2,2',6',2' '-terpyridine). Reaction of the nitro complexes with HPF6 gives the new nitrosyl complexes [Ru(bpy)TpNO][PF6]2 and [Ru(bpy)(Tpm)NO][PF6]3. All complexes were prepared with 15N-labeled nitro or nitrosyl groups. The nitro and nitrosyl complexes were characterized by 1H and 15N NMR and IR spectroscopy, elemental analysis, cyclic voltammetry, and single-crystal structure determination for [Ru(bpy)TpNO][PF6]2. For the nitro complexes, a linear correlation is observed between the nitro 15N NMR chemical shift and 1/nu(asym), where nu(asym) is the asymmetric stretching frequency of the nitro group.

Ligand substitution, pH dependent deoxygenation, and linkage isomerization reactions of the 2,2'-bipyridinetetranitroruthenate dianion.

The reaction of the [Ru(bpy)(NO(2))(4)](2-) (bpy = 2,2'-bipyridine) ion in aqueous solutions produces two different nitrosyl complexes, depending on the pH of the solution. At acidic pH, complex cis,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) was isolated. At neutral or basic pH, [Ru(bpy)(NO(2))(4)](2-) reacts to give cis,trans-Ru(bpy)(NO(2))(2)(NO)(OH). Both new complexes were fully characterized by elemental analysis and UV-vis, IR, (1)H NMR, and (15)N NMR spectroscopy. A single-crystal X-ray structure of cis,trans-Ru(bpy)(NO(2))(2)(NO)(OH) was also obtained. cis,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) isomerizes in acetone or water solution to give a mixture of the trans,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) and cis,cis-Ru(bpy)(ONO)(2)(NO(2))(NO) linkage isomers as determined by (1)H and (15)N NMR spectroscopy. A single-crystal X-ray structure of a solid solution of cis,cis-Ru(bpy)(ONO)(2)(NO(2))(NO)/trans,cis-Ru(bpy)(NO(2))(2)(ONO)(NO) was also obtained. This pair of isomers is the first crystallographically characterized compound with nitro, nitrito, and nitrosyl ligands. The kinetic studies of the Ru-NO(2) --> Ru-NO conversion reactions of [Ru(bpy)(NO(2))(4)](2)(-) in buffered solutions from pH 3 to pH 9 complement previous studies of the reverse reaction. The reactions are first order in [Ru(bpy)(NO(2))(4)](2-). At high pH, the reaction is independent of the concentration of H(+) while, at low pH, the reaction is first order in the concentration of H(+). The rate determining step of the high pH reaction involves breakage of the Ru-NO(2) bond while, at low pH, the mechanism involves a rapid reversible protonation of a NO(2) ligand followed by the rate determining loss of hydroxide to produce a nitrosyl ligand.