Faculty Bibliography

The Uniform Determination of Death Act (UDDA) revision series in Neurology® originated in response to the Uniform Law Commission's plan to create a revised Uniform Determination of Death Act (rUDDA) to address contemporary controversies associated with brain death/death by neurologic criteria (BD/DNC) determination. This article contextualizes these, and other, controversies and reviews the extent to which they represent potential threats and impediments to the clinical practice of BD/DNC determination. It also explains the reasons that our rapidly evolving understanding of the brain's ability to recover from injury should not influence the clinical practice of BD/DNC determination. Finally, it explores the myriad ways in which the American Academy of Neurology has addressed potential threats and impediments to the clinical practice of BD/DNC determination and the implications potential changes to the UDDA may have on the future of the clinical practice of BD/DNC determination.

BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

According to a Bayesian framework, visual perception requires active interpretation of noisy sensory signals in light of prior information. One such mechanism, serial dependence, is thought to promote perceptual stability by assimilating current percepts with recent stimulus history. Combining a delayed orientation-adjustment paradigm with predictable (study 1) or unpredictable (study 2) task structure, we test two key predictions of this account in a novel context: first, that serial dependence should persist even in variable environments, and, second, that, within a given observer and context, this behavioral bias should be stable from one occasion to the next. Relying on data of 41 human volunteers and two separate experimental sessions, we confirm both hypotheses. Group-level, attractive serial dependence remained strong even in the face of volatile settings with multiple, unpredictable types of tasks, and, despite considerable interindividual variability, within-subject patterns of attractive and repulsive stimulus-history biases were highly stable from one experimental session to the next. In line with the hypothesized functional role of serial dependence, we propose that, together with previous work, our findings suggest the existence of a more general individual-specific fingerprint with which the past shapes current perception. Congruent with the Bayesian account, interindividual differences may then result from differential weighting of sensory evidence and prior information.

Although the fundamental principle behind the Uniform Determination of Death Act (UDDA), the equivalence of death by circulatory-respiratory and neurologic criteria, is accepted throughout the United States and much of the world, some families object to brain death/death by neurologic criteria. Clinicians struggle to address these objections. Some objections have been brought to court, particularly in the United States, leading to inconsistent outcomes and discussion about potential modifications to the UDDA to minimize ethical and legal controversies related to the determination of brain death/death by neurologic criteria.

To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host^1,2. The mammalian cell entry (MCE) proteins are important virulence factors in M. tuberculosis^1,3, where they are encoded by large gene clusters and have been implicated in the transport of fatty acids^4-7 and cholesterol^1,4,8 across the impermeable mycobacterial cell envelope. Very little is known about how cargos are transported across this barrier, and it remains unclear how the approximately ten proteins encoded by a mycobacterial mce gene cluster assemble to transport cargo across the cell envelope. Here we report the cryo-electron microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of Mycobacterium smegmatis-a non-pathogenic relative of M. tuberculosis. The structure reveals how the proteins of the Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the cell envelope. The Mce1 complex is dominated by a curved, needle-like domain that appears to be unrelated to previously described protein structures, and creates a protected hydrophobic pathway for lipid transport across the periplasm. Our structural data revealed the presence of a subunit of the Mce1 complex, which we identified using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a structural model for Mce1-mediated lipid import across the mycobacterial cell envelope.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

OBJECTIVE:Interventions for carotid occlusions are infrequently undertaken and the outcomes are poorly defined. We sought to study patients undergoing urgent carotid revascularization for symptomatic occlusions. METHODS:The Society for Vascular Surgery Vascular Quality Initiative database was queried from 2003 to 2020 to identify patients with carotid occlusions undergoing carotid endarterectomy (CEA). Only symptomatic patients undergoing urgent interventions within 24 hours of presentation were included. Patients were identified based on CT and MRI imaging. This cohort was compared to symptomatic patients undergoing urgent intervention for severe stenosis (≥80%). Primary endpoints were perioperative stroke, death, myocardial infarction (MI) and composite outcomes as defined by the SVS reporting guidelines. Patient characteristics were analyzed to determine predictors of perioperative mortality and neurological events. RESULTS:inhibitor (32.0%), aspirin (77.9%) and renin-angiotensin inhibitor (43.7%) preoperatively. When compared to patients undergoing urgent endarterectomy for severe stenosis (≥80%), those with symptomatic occlusion were well matched with regards to risk factors, but the severe stenosis cohort appeared better medically managed and less likely to present with cortical stroke symptoms. Perioperative outcomes were significantly worse for the carotid occlusion cohort, primarily driven by higher perioperative mortality (2.8% vs 0.9%, P<.001). The composite endpoint of stroke/death/MI was also significantly worse in the occlusion cohort (7.7% vs 4.9%, P=.014). On multivariate analysis, carotid occlusion was associated with increased mortality (OR, 3.028; 95% CI, 1.362-6.730; P=.007) and composite outcome of stroke, death, or MI (OR, 1.790; 95% CI, 1.135-2.822, P=.012). CONCLUSIONS:Revascularization for symptomatic carotid occlusion constitutes approximately 2% of carotid interventions captured in the VQI, affirming the rarity of this undertaking. These patients have acceptable rates of perioperative neurologic events but are at an elevated risk of overall perioperative adverse events, primarily driven by higher mortality, compared to those with severe stenosis. Carotid occlusion appears to be the most significant risk factor for the composite endpoint of perioperative stroke, death, or MI. While intervention for a symptomatic carotid occlusion may be performed with acceptable rate of perioperative complications, judicious patient selection is warranted in this high-risk cohort.