Faculty Bibliography

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1^fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

OBJECTIVE:We sought to evaluate early clinical differences between cerebral arteriolosclerosis (pARTE), Alzheimer disease (pAD), and AD with arteriolosclerosis (ADARTE). METHODS:Using National Alzheimer's Coordinating Center neuropathology diagnoses, we defined pARTE (n=21), pAD (n=203), and ADARTE (n=158) groups. We compared demographics, medical history, psychometrics, neuropsychiatric symptoms, and apolipoprotein E (APOE) allele variants across neuropathology groups. Retrospective timepoints were first evaluation with Global Clinical Dementia Rating (CDR) score of 0.5 and 1.0, via the CDR Dementia Staging Instrument, corresponding to mild cognitive impairment (MCI) and mild dementia, respectively. RESULTS:In MCI, clinical differences were minimal but pARTE subjects were older, had later onset cognitive decline, and progressed less severely than pAD. In mild dementia, pAD subjects were younger and had earlier onset of decline. Neuropsychiatric (depression) and psychometric (Logical Memory Delayed Recall, Trails B) differences also emerged between the groups. In MCI, APOE4 associated with worse Logical Memory Delayed Recall in pAD and ADARTE. In mild dementia, APOE4 associated with better animal fluency in pAD, but with better Trails A performance and more neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire) in ADARTE. CONCLUSIONS:Differences between pARTE, pAD, and ADARTE emerge at mild dementia rather than MCI. APOE4 has varied cognitive and psychiatric impact dependent on neuropathology group and stage.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

The Non-Motor Symptoms Scale (NMSS) was developed and validated in 2007 as the first instrument for the comprehensive assessment of a range of non-motor symptoms in Parkinson's disease (PD). Thirteen years have elapsed since its introduction and extensive international validation with good psychometric attributes has been carried out. Here, we review the validation data of the NMSS and its cross-validity with other scales, and describe the key evidence derived from use of the NMSS in clinical studies. To date, over 100 clinical studies and trials have made use of it as an outcome measure, showing consistent and strong correlations between NMSS burden and health-related quality of life measures. Moreover, the scale has shown to be capable of detecting longitudinal changes in non-motor symptoms, where studies have shown differential changes over time of several of the NMSS domains. The scale has become a key outcome in several randomised clinical trials. Highlighting the prevalence and importance of non-motor symptoms to quality of life in patients with PD, the development of NMSS has also been useful in signposting clinical and biomarker based research addressing non-motor symptoms in PD.

Background and Purpose/UNASSIGNED:Hospital 30-day readmissions in patients with primary neurological problems are not well characterized. We sought to determine patient characteristics associated with readmission across 3 different inpatient neurology services at New York University Langone Hospital. Methods/UNASSIGNED:We retrospectively reviewed all 30-day readmissions from the General Neurology, Epilepsy, and Stroke services at NYULH Brooklyn and Manhattan campuses from 2016-2017 and compared them to a random sample of non-readmitted neurology patients. We used univariate analyses to compare demographics, clinical characteristics, disease specific metrics, and discharge factors of non-readmitted and readmitted groups and binomial logistic regression to examine specific variables with adjustment for confounders. Results/UNASSIGNED:We included 284 patients with 30-day readmissions and 306 control patients without readmissions matched by discharge location and service. After adjusting for confounders, we found that the following factors were associated with increased readmission risk: a recent hospital encounter increased risk for all services, increased number of medications at discharge, intensive care unit stay, higher length of stay, and prior history of seizure for the General Neurology Service, increased number of medications at discharge for the Epilepsy Service, and active malignancy and higher discharge modified Rankin Scale score for the Stroke Service. Conclusion/UNASSIGNED:This study identifies potential risk factors for readmission in patients across multiple neurology services. Further research is needed to establish whether these risk factors hold across multiple institutions.

OBJECTIVES/OBJECTIVE:To develop an assessment and recognition tool to identify elite athletes at risk for mental health symptoms and disorders. METHODS:We conducted narrative and systematic reviews about mental health symptoms and disorders in active and former elite athletes. The views of active and former elite athletes (N=360) on mental health symptoms in elite sports were retrieved through an electronic questionnaire. Our group identified the objective(s), target group(s) and approach of the mental health tools. For the assessment tool, we undertook a modified Delphi consensus process and used existing validated screening instruments. Both tools were compiled during two 2-day meeting. We also explored the appropriateness and preliminary reliability and validity of the assessment tool. SPORT MENTAL HEALTH ASSESSMENT TOOL 1 AND SPORT MENTAL HEALTH RECOGNITION TOOL 1: The International Olympic Committee Sport Mental Health Assessment Tool 1 (SMHAT-1) was developed for sports medicine physicians and other licensed/registered health professionals to assess elite athletes (defined as professional, Olympic, Paralympic or collegiate level; aged 16 years and older) potentially at risk for or already experiencing mental health symptoms and disorders. The SMHAT-1 consists of: (i) triage with an athlete-specific screening tool, (ii) six subsequent disorder-specific screening tools and (iii) a clinical assessment (and related management) by a sports medicine physician or licensed/registered mental health professional (eg, psychiatrist and psychologist). The International Olympic Committee Sport Mental Health Recognition Tool 1 (SMHRT-1) was developed for athletes and their entourage (eg, friends, fellow athletes, family and coaches). CONCLUSION/CONCLUSIONS:The SMHAT-1 and SMHRT-1 enable that mental health symptoms and disorders in elite athletes are recognised earlier than they otherwise would. These tools should facilitate the timely referral of those athletes in need for appropriate support and treatment.

Objective: A recent clinical trial with 0.7mg/kg/day of fenfluramine (FFA) showed 62.3% (IC 95%: -47.7%; -72.8%; p<0.001) reduction in convulsive seizure frequency (CSF) compared to placebo. However, the impact of the disease on the patient and their caregivers may depend on other variables. This alternative analysis value the impact of other results.
Method(s): After a baseline period of 6 weeks patients with DS ages 2 to 18 years, was randomized to FFA 0.7 or 0.2mg/kg/day or placebo added. Time to new event (time required to experience the same number of crisis as in the reference period [TTE]) was analyzed. Intervals without crisis and number of days without crisis was analyzed too.
Result(s): 119 patients with DS receiving FFA 0.7mg/kg/day; FFA0.2mg/kg/day; or placebo. TTE was significantly longer in active groups. Placebo: 6 weeks, FFA 0.2mg/kg/day:8 weeks and FFA 0.7mg/kg/day: >12 weeks (p<0.001; ~60% of patients in the FFA 0.7mg/kg/day group never reached their baseline seizure count and were censored). The number of days without crisis was higher in groups treated with FFA: 33 and 20 days without additional crisis counted in the active groups. The longest average without crisis was higher with FFA 0.7mg/kg/day (25 days; p<0.001) and FFA 0.2mg/kg/day (15 days; Px0.035) than with placebo (9.5 days).
Conclusion(s): FFA extended TTE and provided significantly more days without crisis and longer periods without crisis than placebo. Our analysis can help assess the ability of a treatment to reduce the burden of seizures in patients with SD and their caregivers

OBJECTIVE:To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach. DESIGN/METHODS:Genetic Association Cohort Study. METHODS:SETTING: Single-center study at an academic referral center. STUDY POPULATION/METHODS:164 patients with clinically diagnosed uveitis of the posterior segment. MAIN OUTCOME MEASURES/METHODS:Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling and in silico calculations were then used to rank and predict the functional consequences of key variants. RESULTS:A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis - such as NOD2 (Blau Syndrome) and CAPN5 NIV (Neovascular Inflammatory Vitreoretinopathy) - as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type. CONCLUSIONS:This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole exome sequencing can help diagnose non-syndromic uveitis patients harboring known variants for syndromic inflammatory diseases.