Faculty Bibliography

A roundtable convened in July 2020 examined issues concerning respiratory support in amyotrophic lateral sclerosis (ALS), with reference to the potential for an early-phase orally administered medication that might either postpone the introduction of noninvasive ventilation (NIV) and/or enhance the benefits to be gained from it. Attention was also given to the impact of the COVID-19 pandemic on usual practice in the assessment and management of ALS-related respiratory difficulties. Implementation of NIV marks a step-change in clinical status for patients and a major increase in burden for caregivers. All means to ease this transition should be explored: an oral therapy that supported respiratory function and patients' independence and sense of well-being would aid discussions to facilitate the eventual successful introduction of NIV. Assessment of a candidate oral therapy that might support respiratory function in ALS patients would be aided by the development of improved patient-reported outcome measures for robust quantification of treatment effect and quality of life. Such instruments could also be used to monitor patients' status during the COVID-19 pandemic, averting some of the risks of face-to-face assessment plus the patient burden and costs of traditional methods. Several oral candidate therapies have recently failed to meet their primary endpoints in clinical trials. However, understanding of the underlying physiology and appropriate trial design have grown and will inform future developments in this field.

Current therapeutic development in amyotrophic lateral sclerosis (ALS) relies on individual randomized clinical trials to test a specific investigational product in a single patient population. This approach has intrinsic limitations, including cost, time, and lack of flexibility. Adaptive platform trials represent a novel approach to investigate several interventions for a single disease in a continuous manner. Already in use in oncology, this approach is now being employed more often in neurology. Here, we describe a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS, with the goal of rapidly identifying novel treatments, biomarkers, and trial endpoints. ANN NEUROL 2022;91:165-175.

Cytomegalovirus (CMV) disease is usually a mild and self-limiting disease in immunocompetent patients. Recent evidence shows that CMV infection may also develop in the setting of critical illness, burn and sepsis and is usually associated with increased mortality rate and prolonged ICU stay. This paper describes an 83-year-old female who was initially admitted as a case of community-acquired pneumonia-high risk but remained febrile with paucity of verbal output despite correction of pneumonia and other electrolyte derangements. MRI showed the presence of peculiar-appearing signal abnormalities in the interhemispheric region and the anterior frontal convexities which were suspected to represent secondarily infected fluid collections. On lumbar tap, viral cerebrospinal fluid (CSF) panel showed a positive result for CMV infection. The patient was then given ganciclovir for 14 days followed by valganciclovir for three months. The most notable improvement was noted with the lysis of fever several days after starting anti-viral treatment. Verbal output remained limited, yet, on repeat tap after completion of treatment, CMV viral panel is now negative.

Gait and balance abnormalities develop commonly in Parkinson's disease and are among the motor symptoms most disabling and refractory to dopaminergic or other treatments, including deep brain stimulation. Efforts to develop effective therapies are challenged by limited understanding of these complex disorders. There is a major need for novel and appropriately targeted research to expedite progress in this area. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society has charged a panel of experts in the field to consider the current knowledge gaps and determine the research routes with highest potential to generate groundbreaking data. © 2021 International Parkinson and Movement Disorder Society.

BACKGROUND:The dural vasculature plays a key role in several important conditions, including dural fistulas and subdural collections. While in vivo investigations of intrinsic dural arterial angioarchitecture are rare, no angiographic studies of dural venous drainage exist to our knowledge. OBJECTIVE:To describe methods by which dural venous drainage might be visualized with current angiographic equipment and technique, and to correlate our results with existing ex vivo literature. METHODS:Digital subtraction angiography and 3D angiography (rotational and Dyna CT) of dural neurovasculature were acquired in the context of subdural hematoma embolization and normal dura. Protocols for visualization of dural venous drainage were established, and findings correlated with ex vivo studies. RESULTS:Meningeal arteries supply both the skull and dura. Normal dural enhancement is accentuated by the presence of hypervascular membranes. Intrinsic meningeal veins/sinuses parallel outer layer arteries with well-known tram-tracking appearance. Dura adjacent to main arterial trunks drains via skull base foramina into the pterygopalatine venous plexus, or via emissary veins into the temporalis venous plexus. Dura near the sinuses drains into venous pouches adjacent to the sinus, before emptying into the sinus proper-possibly the same pouches implicated in the angioarchitecture of dural fistulas. Finally, posterior temporoparietal convexity dura, situated in a watershed-like region between middle and posterior meningeal territories, frequently empties into diploic and emissary veins of the skull. Wide variation in balance is expected between these three routes. Drainage patterns appear to correlate with venous embryologic investigations of Padget and ex vivo studies in adults. CONCLUSIONS:Continued attention to dural venous drainage may prove useful in the diagnosis and management of dural-based vascular diseases.

BACKGROUND:Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE:To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS:This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS:300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION/CONCLUSIONS:Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

Two studies examined genetic and environmental influences on traits proposed by the revised Reinforcement Sensitivity Theory (rRST) of personality. Both quantitative and molecular behavioral genetic methods were applied considering the effects of COMT, DRD2, HTR1A and TPH2 single nucleotide polymorphisms (SNPs). Study one included 274 monozygotic and 154 dizygotic twins for the quantitative behavioral study; and in study two there were 431 twins for the molecular genetic study. The Reinforcement Sensitivity Questionnaire was used to assess basic personality traits defined by the rRST. Univariate biometric modeling suggested that genetic influences accounted for 34-44% of variance of Behavioral Approach System (BAS), Behavioral Inhibition System (BIS) and Fight-Fligh-Freeze System. Molecular genetic analyses proposed the significant main effect of COMT SNP on the BAS and TPH2 SNP on the BIS, and pointed out epistatic effects of COMT x DRD2 on BAS and HTR1A x TPH2 on Fight. Results demonstrated substantial heritability for all rRST constructs, as well as for differences in the molecular genetic basis of both approach-related and avoidance-related dimensions.

The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.

COVID-19 has infected millions of people and upended the lives of most humans on the planet. Researchers from across the psychological sciences have sought to document and investigate the impact of COVID-19 in myriad ways, causing an explosion of research that is broad in scope, varied in methods, and challenging to consolidate. Because policy and practice aimed at helping people live healthier and happier lives requires insight from robust patterns of evidence, this article provides a rapid and thorough summary of high-quality studies available through early 2021 examining the mental-health consequences of living through the COVID-19 pandemic. Our review of the evidence indicates that anxiety, depression, and distress increased in the early months of the pandemic. Meanwhile, suicide rates, life satisfaction, and loneliness remained largely stable throughout the first year of the pandemic. In response to these insights, we present seven recommendations (one urgent, two short-term, and four ongoing) to support mental health during the pandemic and beyond.