Faculty Bibliography

Objective: To study the rate of progression of multiple system atrophy (MSA) and assess for a potential ceiling effect of the Unified Multiple System Atrophy Rating Scale (UMSARS).
Background(s): Disease progression of MSA as measured by UMSARS varied significantly in natural history studies. Reported 1-year UMSARS-1 and UMSARS-2 progression rates ranged from 3.9 to 6.5 and 3.5 to 8.2 respectively. We hypothesize that this variability is due, at least in part, to differences in severity at enrollment and a potential ceiling effect in the scale, so that patients in more advanced stages may appear to worsen less, which would have important implications for clinical trial design.
Method(s): We analyzed the rate of change in the UMSARS in a large international cohort of well-characterized patients with a clinical diagnosis of possible or probable MSA enrolled in the Natural History Study of Synucleinopathies. Annualized progression rates were obtained using 2-year follow-up data.
Result(s): Three hundred and forty nine patients (61.4+/-7.9 years old) with MSA were enrolled. Disease duration was 4.5+/-5.1 years. 143 patients completed 1-year evaluations and 61 completed the 2-year evaluation. The 12-month progression rates were 5.4+/-5.1 for the UMSARS-I, 5.9+/-5.3 for the UMSARS-II, and 11.8+/-9.6 for the total score. The 24-month progression rates were 10.8+/-7.3 for the UMSARS-I, 12.2+/-7.9 for the UMSARSII, and 22.6+/-13.7 for the total score. Annualized progression rates were divided according to their baseline UMSARS-I and UMSARS II. There was a significant (p = 0.0153) inverse relationship between rate of progression and UMSARS-I at baseline. A similar, but not significant trend was observed with UMSARS-II at baseline.
Conclusion(s): The rate of progression as measured by UMSARS is influenced by the baseline disease severity. A possible ceiling effect should be considered when planning enrollment, power calculations, and outcome measures in clinical trials

OBJECTIVE:The carotid web (CW) is an underrecognized source of cryptogenic, embolic stroke in patients younger than 55 years of age, with up to 37% of these patients found to have CW on angiography. Currently, there are little data detailing the best treatment practices to reduce the risk of recurrent stroke in these patients. The authors describe their institutional surgical experience with patients treated via carotid endarterectomy (CEA) for a symptomatic internal carotid artery web. METHODS:A retrospective, observational cohort study was performed including all patients presenting to the authors' institution with CW. All patients who were screened underwent either carotid artery stenting (CAS) or CEA after presentation with ischemic stroke from January 2019 to February 2020. From this sample, patients with suggestive radiological features and pathologically confirmed CW who underwent CEA were identified. Patient demographics, medical histories, radiological images, surgical results, and clinical outcomes were collected and described using descriptive statistics. RESULTS:A total of 45 patients with symptomatic carotid lesions were treated at the authors' institution during the time period. Twenty patients underwent CAS, 1 of them for a CW. Twenty-five patients were treated via CEA, and of these, 6 presented with ischemic strokes ipsilateral to CWs, including 3 patients who presented with recurrent strokes. The mean patient age was 55 ± 12.6 years and 5 of 6 were women. CT angiography or digital subtraction angiography demonstrated the presence of CWs ipsilateral to the stroke in all patients. All patients underwent resection of CWs using CEA. There were no permanent procedural complications and no patients had stroke recurrence following intervention at the latest follow-up (mean 6.1 ± 4 months). One patient developed mild tongue deviation most likely related to retraction, with complete recovery at follow-up. CONCLUSIONS:CEA is a safe and feasible treatment for symptomatic carotid webs and should be considered a viable alternative to CAS in this patient population.

The development of painful diabetic neuropathy (PDN) is a common complication of chronic diabetes that can be associated with significant disability and healthcare costs. Prompt symptom identification and aggressive glycemic control is essential in controlling the development of neuropathic complications; however, adequate pain relief remains challenging and there are considerable unmet needs in this patient population. Although guidelines have been established regarding the pharmacological management of PDN, pain control is inadequate or refractory in a high proportion of patients. Pharmacotherapy with anticonvulsants (pregabalin, gabapentin) and antidepressants (duloxetine) are common first-line agents. The use of oral opioids is associated with considerable morbidity and mortality and can also lead to opioid-induced hyperalgesia. Their use is therefore discouraged. There is an emerging role for neuromodulation treatment modalities including intrathecal drug delivery, spinal cord stimulation, and dorsal root ganglion stimulation. Furthermore, consideration of holistic alternative therapies such as yoga and acupuncture may augment a multidisciplinary treatment approach. This aim of this review is to focus on the current management strategies for the treatment of PDN, with a discussion of treatment rationale and practical considerations for their implementation.

There has been a substantial rise in the number of women pursuing careers in neurology. However, research has shown that women in neurology have high rates of burnout with gender disparities in burnout and attrition in the field. Recently, there was a call from the NIH, including the National Institute of Neurological Disorders and Stroke, asking for input on factors that may limit or discourage grant applications from women. As the recipients of the highly coveted NIH career mentored awards (K awards) in headache medicine, we applaud the NIH for asking for gender-specific feedback and for raising awareness of research showing that female faculty on the Research Track are at an increased risk of departure. Using the NIH model for the Responsible Conduct of Research and the tenant of Nurturing the Fertile Environment, we discuss specific challenges in academic research that may contribute to gender differences in neurology research success. Although the rate of women conducting NIH-funded migraine research increased from 23% to 41% over the last 10 years, more women are currently in training compared with independence, with 6/6 of the NIH training grants but only 12/36 of the NIH research-level grants, held by women in fiscal years 2017-2019. We suggest concrete solutions to these challenges to ensure the success of women in research reaching independence.

OBJECTIVES/OBJECTIVE:To better understand the reasons medical students select or avoid a career in neurology by using a qualitative methodology to explore these factors, with the long-term objective of attracting more graduates to the field. METHODS:In 2017, 27 medical students and 15 residents participated in 5 focus groups, and 33 fourth-year medical students participated in semistructured individual interviews. Participants were asked predefined open-ended questions about specialty choice, experiences in their basic neuroscience course and neurology clerkship, and perceptions about the field. Interviews were audio recorded and transcribed. We used a flexible coding methodology to generate themes across groups and interviews. RESULTS:Four main analytical themes emerged: (1) early and broad clinical exposure allows students to "try on" neurology and experience the variety of career options; (2) preclerkship experiences and a strong neuroscience curriculum lay the foundation for interest in the field; (3) personal interactions with neurology providers may attract or deter students from considering the specialty; and (4) persistent stereotypes about neurologists, neurology patients, and treatment options harm student perceptions of neurology. CONCLUSION/CONCLUSIONS:Efforts to draw more students to neurology may benefit from focusing on clinical correlations during preclerkship neuroscience courses and offering earlier and more diverse clinical experiences, including hands-on responsibilities whenever possible. Finally, optimizing student interactions with faculty and residents and reinforcing the many positive aspects of neurology are likely to favorably affect student perceptions.

OBJECTIVE:<0.001). Rates of adverse events increased with the magnitude of D-dimer elevation; individuals with presenting D-dimer >2000 ng/mL had the highest risk of critical illness (66%), thrombotic event (37.8%), acute kidney injury (58.3%), and death (47%). CONCLUSIONS:Abnormal D-dimer was frequently observed at admission with COVID-19 and was associated with higher incidence of critical illness, thrombotic events, acute kidney injury, and death. The optimal management of patients with elevated D-dimer in COVID-19 requires further study.

The bacterial pathogen Mycobacterium tuberculosis is the leading cause of death by an infectious disease among humans. Here, we describe a previously uncharacterized M. tuberculosis protein, Rv0991c, as a molecular chaperone that is activated by oxidation. Rv0991c has homologs in most bacterial lineages and appears to function analogously to the well-characterized Escherichia coli redox-regulated chaperone Hsp33, despite a dissimilar protein sequence. Rv0991c is transcriptionally coregulated with hsp60 and hsp70 chaperone genes in M. tuberculosis, suggesting that Rv0991c functions with these chaperones in maintaining protein quality control. Supporting this hypothesis, we found that, like oxidized Hsp33, oxidized Rv0991c prevents the aggregation of a model unfolded protein in vitro and promotes its refolding by the M. tuberculosis Hsp70 chaperone system. Furthermore, Rv0991c interacts with DnaK and can associate with many other M. tuberculosis proteins. We therefore propose that Rv0991c, which we named "Ruc" (redox-regulated protein with unstructured C terminus), represents a founding member of a new chaperone family that protects M. tuberculosis and other species from proteotoxicity during oxidative stress.IMPORTANCEM. tuberculosis infections are responsible for more than 1 million deaths per year. Developing effective strategies to combat this disease requires a greater understanding of M. tuberculosis biology. As in all cells, protein quality control is essential for the viability of M. tuberculosis, which likely faces proteotoxic stress within a host. Here, we identify an M. tuberculosis protein, Ruc, that gains chaperone activity upon oxidation. Ruc represents a previously unrecognized family of redox-regulated chaperones found throughout the bacterial superkingdom. Additionally, we found that oxidized Ruc promotes the protein-folding activity of the essential M. tuberculosis Hsp70 chaperone system. This work contributes to a growing body of evidence that oxidative stress provides a particular strain on cellular protein stability.

BACKGROUND:Migraine treatment may mitigate migraine and associated pain in the perioperative period. OBJECTIVE:The aim of the study was to estimate the effect of perioperative acute and prophylactic migraine treatment on the risk of postoperative 30-day hospital readmission with an admitting diagnosis specifying any pain complaints among migraine patients. DESIGN/METHODS:Electronic health records were analysed for 21,932 adult migraine patients undergoing surgery between 2005 and 2017 at Beth Israel Deaconess Medical Center and Massachusetts General Hospital in Boston, Massachusetts, USA. METHODS:Perioperative abortive migraine treatment was defined as guideline-recommended medication (triptan, ergotamine, acetaminophen, nonsteroidal anti-inflammatory drug) prescription after surgery, within 30 days after discharge and prior readmission. Perioperatively continued prophylactic migraine treatment was defined as prescription both prior to surgery and perioperatively for recommended medications (beta-blockers, antidepressants, antiepileptics, onabotulinumtoxin A). RESULTS:Overall, 10,921 (49.8%) patients received a prescription for abortive migraine drugs. Of these, 1.2% and 1.5% of patients with and without such prescription were readmitted for pain, respectively. Patients with abortive treatment had lower odds of pain-related readmission (adjusted odds ratio 0.63 [95% confidence interval 0.49-0.81]). Prophylactic migraine treatment showed no effect on pain-related readmission independently of acute treatment (adjusted odds ratio 0.97 [95% confidence interval 0.72-1.32]). CONCLUSIONS:Migraine patients undergoing surgery with a perioperative prescription for abortive migraine drugs were at decreased risk of pain-related hospital readmission.