Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders.

PURPOSE: Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability. METHODS: By international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro. RESULTS: In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION: By identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.

An Educational Workshop to Improve Neurology Resident Understanding of Burnout, Substance Abuse, and Mood Disorders.

Introduction: Burnout, substance abuse, and mood disorders are prevalent among neurology residents. Increased recognition of concerning behaviors might encourage more access to mental health resources and reduce burnout. Methods: We created an educational resource reviewing burnout, substance abuse, and mood disorders for neurology residents. This resource included an online module (control) and a role-play scenario offered only to one cohort (intervention). Online surveys assessed knowledge as well as confidence in the ability to recognize concerning behaviors. A practical assessment using a previously published "Stressed Resident" video was also conducted among resident cohorts. Results: Of neurology residents, 18 participated in the activity, with nine in the control group and nine in the intervention group. In the postvideo survey, the residents who participated in a role-play activity outperformed a control cohort of their peers when identifying signs of burnout, mood disorders, and substance abuse portrayed in the video (84% vs. 72%; t test, p = .01). Residents indicated increased confidence in the ability to recognize symptoms of maladaptive stress as well as identify resources for themselves and peers. Participants demonstrated no difference in knowledge-based questions scores on pre- and postactivity assessments. Discussion: Our educational resource improved resident ability to recognize signs of maladaptive stress and to identify residents that are a risk to patient safety. The activity is easy to implement and can be easily adapted outside neurology. Limited sample sizes may limit the ability to demonstrate this tool's impact on knowledge of burnout, substance abuse, and mood disorders.

Capturing Initial Understanding and Impressions of Surgical Therapy for Parkinson's Disease.

Background: Deep Brain Stimulation (DBS) is an underutilized surgical therapy for Parkinson's Disease (PD). Both physician and patient hesitancies have been described as potential barriers to DBS, but the specifics of patient perceptions of DBS have not been well-characterized in the general PD population. Objective: To characterize the understanding and impressions of surgical therapy in PD patients prior to formal surgical evaluation. Methods: A 30-question survey assessing impressions of surgical therapy for PD and understanding of DBS for PD was administered to PD patients seen at an urban movement disorders clinic. Results: One hundred and two patients completed the survey. When asked if they would undergo a hypothetical risk-free, curative brain surgery for PD, 98 patients responded "yes." Patients were more agreeable to "reversible," "minimally-invasive," and "incisionless" surgery. 51.2% thought DBS is an "effective" treatment for PD, 76.6% thought it was "invasive," and 18.3% thought it was "reversible." 45.2% reported fear of being awake during DBS surgery. Regarding costs, 52.4% were concerned that DBS was "very expensive" or "not covered by insurance." Initial source of information and perceived treatment effectiveness were not associated with concerns about DBS effectiveness or threats to normality. Negative perceptions of past surgery were associated with concerns about DBS altering mood and personality. Conclusion: Overall, patients expressed concerns regarding procedural efficacy, invasiveness, cost, and irreversibility-independent of the original source of information. Future studies are required to allow us to better understand the impact of these initial findings on DBS hesitancy and underutilization.

Innovations in on-demand audio education: Beyond trending.

The evolution of broadcast audio has been rapidly changing over the past 10-15 years with the advent of podcasts in the early 2000s. As with other media, podcast audio has been adapted for use within medical and specifically neurology education in the form of the Neurology Podcast since 2007. As podcasts were an initial step in the field of on-demand media, further technological evolution has resulted in increasing customization of a listener's audio experience. We believe a historical inflection point has been reached with the increasingly mainstream adoption of virtual assistant technology which allows for consumption of brief on-demand self-curated audio productions. As editors of the Neurology Podcast, we have introduced a new audio product to this technological landscape, the Neurology Minute. In doing so, we hope that curated on-demand educational audio will become a part of the daily routine of many practicing neurologists as we move into this new technological age.

Digitized spiral analysis may be a potential biomarker for brachial dystonia.

INTRODUCTION: Objective measures for detection and quantification of dystonic movements may guide both diagnosis and clinical monitoring. Digitized spiral analysis is a non-invasive method used to assess upper limb motor control in movement disorders and may have utility in dystonia. We aimed to determine if digitized spiral analysis can distinguish dystonia subjects from controls, and evaluated correlation with a validated clinical rating scale. METHODS: Kinematic, dynamic, and spatial attributes of Archimedean spirals drawn with an inking pen on a digitizing tablet were compared for participants with brachial dystonia and either Tor1A (DYT1) (n = 15) or THAP1 (DYT6) mutations (n = 12) and age and gender matched controls (n = 27) using Receiver Operator Characteristics (ROC) analysis. Spiral indices including an overall degree of severity (DoS) were also calculated and correlated with clinical severity ratings as measured by the Burke-Fahn-Marsden scale. RESULTS: Dystonia spirals had significantly higher severity scores as well as higher measures of spiral irregularity compared to controls. ROC analysis demonstrated that the DoS score had good discriminative ability to distinguish dystonia spirals from controls, with an Area Under the Curve (AUC) of 0.87. Measures of spiral irregularity correlated with validated clinical rates of dystonia severity in the analyzed arm, with one particular index, Residue of Theta vs R, showing the highest correlation (r = 0.55, p = 0.005). CONCLUSION: Digitized spiral analysis may be a promising non-invasive method to objectively quantify brachial dystonia. It may also be a useful way to monitor subtle changes in dystonia severity over time not captured with current clinical rating scales.

Cerebrotendinous Xanthomatosis ataxia responsive to CDCA and Riluzole.

Cerebrotendinous Xanthomatosis (CTX) is a rare genetic disorder due to mutations in the CYP27A1 gene resulting in both systemic and neurologic manifestations from accumulation and deposition of cholestanol in tissues. Chenodeoxycholic Acid (CDCA) is the standard medical therapy, resulting in decreased cholestanol synthesis, however, neurologic improvement is typically not seen. Riluzole may have a symptomatic benefit in ataxia from a presumed protective effect on Purkinje cells. To date, there are no reports of symptomatic improvement in CTX related ataxia following treatment with Riluzole. We report the case of a 45 year old woman diagnosed with CTX-related cerebellar ataxia. Therapy with CDCA and Riluzole resulted in quantifiable improvement on the Scale for the Assessment and Rating of Ataxia (SARA). Thus, in addition to the standard therapy with CDCA, the addition of Riluzole may have some therapeutic benefits for ataxia caused by CTX. Further controlled studies are needed.

Burnout, career satisfaction, and well-being among US neurology residents and fellows in 2016.

OBJECTIVE: To study prevalence of and factors contributing to burnout, career satisfaction, and well-being in US neurology residents and fellows. METHODS: A total of 938 US American Academy of Neurology member neurology residents and fellows were surveyed using standardized measures of burnout, career satisfaction, and well-being from January 19 to March 21, 2016. RESULTS: Response rate was 37.7% (354/938); about 2/3 of responders were residents and 1/3 were fellows. Median age of participants was 32 years and 51.1% were female. Seventy-three percent of residents and 55% of fellows had at least one symptom of burnout, the difference largely related to higher scores for depersonalization among residents. For residents, greater satisfaction with work-life balance, meaning in work, and older age were associated with lower risk of burnout; for fellows, greater satisfaction with work-life balance and effective support staff were associated with lower risk of burnout. Trainees experiencing burnout were less likely to report career satisfaction. Career satisfaction was more likely among those reporting meaning in work and more likely for those working in the Midwest compared with the Northeast region. CONCLUSIONS: Burnout is common in neurology residents and fellows. Lack of work-life balance and lack of meaning in work were associated with reduced career satisfaction and increased risk of burnout. These results should inform approaches to reduce burnout and promote career satisfaction and well-being in US neurology trainees.

Trouble crossing the bridge: altered interhemispheric communication of emotional images in anxiety.

Worry is thought to involve a strategy of cognitive avoidance, in which internal verbalization acts to suppress threatening emotional imagery. This study tested the hypothesis that worry-prone individuals would exhibit patterns of between-hemisphere communication that reflect cognitive avoidance. Specifically, the hypothesis predicted slower transfer of threatening images from the left to the right hemisphere among worriers. Event-related potential (ERP) measures of interhemispheric transfer time supported this prediction. Left-to-right hemisphere transfer times for angry faces were relatively slower for individuals scoring high in self-reported worry compared with those scoring low, whereas transfer of happy and neutral faces did not differ between groups. These results suggest that altered interhemispheric communication may constitute one mechanism of cognitive avoidance in worry.

Anxiety and error monitoring: increased error sensitivity or altered expectations?

This study tested the prediction that the error-related negativity (ERN), a physiological measure of error monitoring, would be enhanced in anxious individuals, particularly in conditions with threatening cues. Participants made gender judgments about faces whose expressions were either happy, angry, or neutral. Replicating prior studies, midline scalp negativities were greater following errors than following correct responses. In addition, state anxiety interacted with facial expression to predict ERN amplitudes. Counter to predictions, participants high in state anxiety displayed smaller ERNs for angry-face blocks and larger ERNs for happy-face blocks, compared to less anxious participants. These results are inconsistent with the simple notion that anxiety enhances error sensitivity globally. Rather, we interpret the findings within an expectancy violation framework, in which anxious participants have altered expectations for success and failure in the context of happy and angry facial cues, with greater ERN amplitudes when expectations are violated.