Faculty Bibliography

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis.

Classic change blindness is the phenomenon where seemingly obvious changes that coincide with visual disruptions (such as blinks or brief blanks) go unnoticed by an attentive observer. Some early work into the causes of classic change blindness suggested that any pre-change stimulus representation is overwritten by a representation of the altered post-change stimulus, preventing change detection. However, recent work revealed that, even when observers do maintain memory representations of both the pre- and post-change stimulus states, they can still miss the change, suggesting that change blindness can also arise from a failure to compare the stored representations. Here, we studied slow change blindness, a related phenomenon that occurs even in the absence of visual disruptions when the change occurs sufficiently slowly, to determine whether it could be explained by conclusions from classic change blindness. Across three different slow change blindness experiments we found that observers who consistently failed to notice the change had access to at least two memory representations of the changing display. One representation was precise but short lived: a detailed representation of the more recent stimulus states, but fragile. The other representation lasted longer but was fairly general: stable but too coarse to differentiate the various stages of the change. These findings suggest that, although multiple representations are formed, the failure to compare hypotheses might not explain slow change blindness; even if a comparison were made, the representations would be too sparse (longer term stores) or too fragile (short-lived stores) for such comparison to inform about the change.

BACKGROUND:Acute myocardial injury is associated with poor outcomes in patients with acute ischemic stroke, but its prognostic significance in patients with spontaneous intracerebral hemorrhage remains unclear. We investigated whether acute myocardial injury and the direction of the cardiac troponin I (cTnI) change (rising versus falling) affect post-intracerebral hemorrhage outcomes. METHODS AND RESULTS/RESULTS:We re-analyzed the FAST (Factor-Seven-for-Acute-Hemorrhagic-Stroke) trial. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of >20%. Logistic regression tested for associations (1) between acute myocardial injury (presence versus absence) and poor outcome (modified Rankin Scale 4-6) and mortality at 15 and 90 days; (2) among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Among the 841 FAST participants, 785 patients were included. Acute myocardial injury was detected in 29% (n=227); 170 had rising cTnI. At 15 and 90 days, respectively, those with acute myocardial injury had higher odds of poor outcome (adjusted odds ratio) ([aOR] 2.3 [95% CI, 1.3-3.9]); and adjusted odds ratio 2.5 [95% CI, 1.6-3.9];, and higher odds of mortality (adjusted odds ratio 2.4 [95% CI, 1.4-4.3]; and adjusted odds ratio 2.2 [CI, 1.3-3.6]) than patients without. There was no interaction between FAST group assignment and myocardial injury, and associations between myocardial injury and outcomes were consistent across group assignments. Rising cTnI was associated with the highest risk of poor outcomes and mortality. CONCLUSIONS:In this secondary analysis of the FAST trial, acute myocardial injury was common and associated with poor outcomes. The direction of the cTnI change might provide additional risk stratification after intracerebral hemorrhage.

Glial cells in the peripheral nervous system (PNS), which arise from the neural crest, include axon-associated Schwann cells (SCs) in nerves, synapse-associated SCs at the neuromuscular junction, enteric glia, perikaryon-associated satellite cells in ganglia, and boundary cap cells at the border between the central nervous system (CNS) and the PNS. Here, we focus on axon-associated SCs. These SCs progress through a series of formative stages, which culminate in the generation of myelinating SCs that wrap large-caliber axons and of nonmyelinating (Remak) SCs that enclose multiple, small-caliber axons. In this work, we describe SC development, extrinsic signals from the axon and extracellular matrix (ECM) and the intracellular signaling pathways they activate that regulate SC development, and the morphogenesis and organization of myelinating SCs and the myelin sheath. We review the impact of SCs on the biology and integrity of axons and their emerging role in regulating peripheral nerve architecture. Finally, we explain how transcription and epigenetic factors control and fine-tune SC development and myelination.

PURPOSE/OBJECTIVE:Rasmussen syndrome (RS) is marked by progressive unihemispheric atrophy, resulting in hemiparesis, refractory epilepsy, and cognitive/language decline. Detailed diagnostic and treatment algorithms are currently lacking. We aimed to survey medical providers on their current practices in the diagnosis and treatment of RS. METHODS:A steering committee was formed to create the survey, which was disseminated to the international medical community. One hundred twelve surveys were completed. Descriptive statistics, as well as comparisons by level of experience, patient age group cared for, and geographic region using Fisher's exact test, were conducted. RESULTS:Analysis of cerebrospinal fluid (82 %) and serum (78 %) for autoimmune encephalitis (AE) are completed by most, while approximately one-third obtain genetic and metabolic studies in all patients (36 % and 38 %, respectively). Providers in US and Europe more readily pursue serum AE antibody panels (85 % and 85 %, respectively, versus 67 %, p = 0.019) and genetic testing (56 % and 47 %, respectively, versus 14 %, p < 0.001) than the rest of the world. Thirty-six percent proceed to biopsy in patients otherwise meeting diagnostic criteria, and US providers are more likely to suggest this than others (73 % versus 14-41 %, p < 0.001). Opinions differed on the prioritization of hemispherectomy/hemispherotomy versus immunotherapy in 14 clinical scenarios with various neurologic deficit severity provided. Preferred immunotherapy regimens also varied, with US providers more often choosing IVIG as first-line (67 %) compared to others (28 %-32 %, p = 0.030). Surgical standard of care was identified as functional hemispherectomy or hemispherotomy by 90 %. CONCLUSION/CONCLUSIONS:The survey highlights trends but also significant variations in clinical practice that can serve as targets for future research and expert consensus guidelines.

Sparse data exist on sex-related differences in extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest (rCA). We explored the role of sex on the utilization and outcomes of ECPR for rCA by retrospective analysis of the Extracorporeal Life Support Organization (ELSO) International Registry. The primary outcome was in-hospital mortality. Exploratory outcomes were discharge disposition and occurrence of any specific extracorporeal membrane oxygenation (ECMO) complications. From 1992 to 2020, a total of 7,460 adults with ECPR were identified: 30.5% women; 69.5% men; 55.9% Whites, 23.7% Asians, 8.9% Blacks, and 3.8% Hispanics. Women's age was 50.4 ± 16.9 years (mean ± standard deviation) and men's 54.7 ± 14.1 ( p < 0.001). Ischemic heart disease occurred in 14.6% women vs. 18.5% men ( p < 0.001). Overall, 28.5% survived at discharge, 30% women vs. 27.8% men ( p = 0.138). In the adjusted analysis, sex was not associated with in-hospital mortality (odds ratio [OR] = 0.93 [confidence interval {CI} = 0.80-1.08]; p = 0.374). Female sex was associated with decreased odds of neurologic, cardiovascular, and renal complications. Despite being younger and having fewer complications during ECMO, women had in-hospital mortality similar to men. Whether these findings are driven by biologic factors or disparities in health care warrants further investigation.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Despite the well-established efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's Disease (PD), there remains a subset of patients with only a moderate improvement in symptoms even with appropriate lead placement and optimal programming. In patients with persistent tremor or dyskinesias, one consideration is the addition of a second "rescue lead" to provide dual stimulation to primary and secondary targets to address the refractory component. This study aimed to assess all "rescue lead" cases from our institution and characterize the patients and their outcomes. METHODS:Records of all patients with PD treated at our institution between 2005 and 2023 were retrospectively reviewed. Clinical data of all patients treated with a second rescue lead to supplement a positive but inadequate initial DBS response were collected and reviewed. RESULTS:Of 670 patients with PD treated at our institution during the study period, 7 were managed with a rescue lead. All 7 were initially treated with STN DBS with a partial improvement in underlying symptoms, had confirmed appropriate lead placement, and underwent thorough programming. Four patients underwent rescue with a globus pallidus interna lead for persistent dyskinesias, all with subsequent improvement in their dyskinesias. Three patients had persistent tremors that were treated with a rescue ventrointermediate thalamus stimulation with subsequent improvement in tremor scores. There were no operative complications, and all patients tolerated dual stimulation. CONCLUSION/CONCLUSIONS:For a small subset of patients with PD with persistent dyskinesias or tremors after STN DBS despite optimized lead parameters and adequate lead placement, rescue lead placement offers an effective treatment option.