Faculty Bibliography

There is currently a shortage of neurologists in the United States. Multiple efforts are underway to increase the strength of the neurology workforce. One potential approach is early exposure to neurology research and clinical care to pique interest and promote the specialty as a career choice. This study details the rewarding experience of working with undergraduate students, both in clinical research and clinical care. The logistics, benefits to students, and positive aspects for neurologists are outlined. Examples provided by undergraduate students who have participated in neurology research and clinical care are presented. The ultimate goals of this work are to encourage and inspire academic neurologists to involve undergraduate students in research and clinical care, to facilitate this process by outlining the steps needed to make this pairing successful, and to ultimately promote a pathway to build the neurology pipeline.

ABSTRACT/UNASSIGNED:Multifocal motor neuropathy with conduction block (MMN) and anti-myelin-associated glycoprotein (MAG) neuropathy are rare chronic acquired demyelinating neuropathies with distinct clinical and electrophysiological characteristics. These neuropathies are generally not known to coexist. This report describes a patient with long-standing MMN who subsequently developed clinical features of anti-MAG neuropathy. This suggests that subtypes of chronic inflammatory neuropathies may not be sharply defined. In addition, a presentation of MMN with anti-MAG titers may be a prognostic indicator of poor response to standard MMN treatment.

PURPOSE/OBJECTIVE:Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis. METHODS:/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses. RESULTS:Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings. CONCLUSION/CONCLUSIONS:/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.

The transformation of patient-clinician relationships with AI-based medical advice is discussed. many new tools are based on entirely new "˜black-box"™ AI-based technologies, whose inner workings are likely not fully understood by patients or clinicians. Most patients with Type 1 diabetes now use continuous glucose monitors and insulin pumps to tightly manage their disease. Their clinicians carefully review the data streams from both devices to recommend dosage adjustments. Recently new automated recommender systems to monitor and analyze food intake, insulin doses, physical activity, and other factors influencing glucose levels, and provide data-intensive, AI-based recommendations on how to titrate the regimen, are in different stages of FDA approval using "˜black box"™ technology, which is an alluring proposition for a clinical scenario that requires identification of meaningful patterns in complex and voluminous data.

Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

BACKGROUND:This survey assessed satisfaction with the practice environment among physicians who have completed fellowship training in critical care medicine (CCM) as recognized by the American Board of Anesthesiology (and are members of the American Society of Anesthesiology) and evaluated the perceived effectiveness of training programs in preparing fellows for critical care practice. METHODS:A cross-sectional online survey composed of 39 multiple choice and open-ended questions was administered between August and December 2018 to all members of the American Society of Anesthesiologists (ASA) who self-identified as being CCM trained. The survey instrument was developed and revised in an iterative fashion by ASA committee on CCM and the Society for Education in Anesthesia (SEA). Survey results were analyzed using a mixed-method approach. RESULTS:Three hundred fifty-three of the 1400 anesthesiologists who self-identified to the ASA as having CCM training (25.2%) completed the survey. Most were men (72.3%), board certified in CCM (98.7%), and had practiced a median of 5 years. Half of the respondents rated their training as "excellent." A total of 70.6% described currently working in academic centers with 53.6% providing care in open surgical intensive care units (ICUs). Most anesthesiologist intensivists (75%) spend at least 25% of their clinical time providing ICU care (versus clinical anesthesia). A total of 89% of the respondents were involved in educational activities, 60% reported being in administrative leadership roles, and 37% engaged in scholarly activity. Areas of dissatisfaction included fatigue, lack of collegiality or respect, lack of research training, decreased job satisfaction, and burnout. Analysis suggested moderate levels of job satisfaction (49%), work-life balance (52%), and high levels of burnout (74%). A significant contributor to burnout was with a perception of lack of respect (P = .005) in the work environment. Burnout was not significantly associated with gender or duration of practice. Qualitative analysis of the open-ended responses also identified these 3 variables as major themes. CONCLUSIONS:This survey of CCM-trained anesthesiologists described a high rate of board certification, practice in academic settings, and participation in resident education. Areas of dissatisfaction with an anesthesia/critical care practice included burnout, work/life balance, and lack of respect. These results may increase recruitment of anesthesiologists into critical care and inform strategies to improve satisfaction with anesthesia critical care practice, fellowship training.

ABSTRACT/UNASSIGNED:A collection of instructional videos that illustrate a step by step approach to tele-neuro-ophthalmology and neuro-otology visits. These videos provide instruction for patient preparation for their video visit, patient and provider interface with an electronic medical record associated video platform, digital applications to assist with vision testing, and practical advice for detailed remote neuro-ophthalmologic and neuro-otologic examinations.

OBJECTIVE:The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy. METHODS:Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy. RESULTS:Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively. SIGNIFICANCE/CONCLUSIONS:These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.

Homochirality of DNA and prevalent chirality of free and protein-bound amino acids in a living organism represents the challenge for modern biochemistry and neuroscience. The idea of an association between age-related disease, neurodegeneration, and racemization originated from the studies of fossils and cataract disease. Under the pressure of new results, this concept has a broader significance linking protein folding, aggregation, and disfunction to an organism's cognitive and behavioral functions. The integrity of cognitive function is provided by a delicate balance between the evolutionarily imposed molecular homo-chirality and the epigenetic/developmental impact of spontaneous and enzymatic racemization. The chirality of amino acids is the crucial player in the modulation the structure and function of proteins, lipids, and DNA. The collapse of homochirality by racemization is the result of the conformational phase transition. The racemization of protein-bound amino acids (spontaneous and enzymatic) occurs through thermal activation over the energy barrier or by the tunnel transfer effect under the energy barrier. The phase transition is achieved through the intermediate state, where the chirality of alpha carbon vanished. From a thermodynamic consideration, the system in the homo-chiral (single enantiomeric) state is characterized by a decreased level of entropy. The oscillating protein chirality is suggesting its distinct significance in the neurotransmission and flow of perceptual information, adaptive associative learning, and cognitive laterality. The common pathological hallmarks of neurodegenerative disorders include protein misfolding, aging, and the deposition of protease-resistant protein aggregates. Each of the landmarks is influenced by racemization. The brain region, cell type, and age-dependent racemization critically influence the functions of many intracellular, membrane-bound, and extracellular proteins including amyloid precursor protein (APP), TAU, PrP, Huntingtin, α-synuclein, myelin basic protein (MBP), and collagen. The amyloid cascade hypothesis in Alzheimer's disease (AD) coexists with the failure of amyloid beta (Aβ) targeting drug therapy. According to our view, racemization should be considered as a critical factor of protein conformation with the potential for inducing order, disorder, misfolding, aggregation, toxicity, and malfunctions.