Faculty Bibliography

STUDY OBJECTIVES/OBJECTIVE:Pediatric insomnia is a widespread problem and especially difficult to manage in children with neurodevelopmental disorders. There are currently no US Food and Drug Administration-approved medications to use once first-line therapy fails. The objective of this study was to evaluate the efficacy and tolerability of doxepin in pediatric patients. METHODS:This is a retrospective single-center chart review of children and adolescents (2-17 years of age) whose sleep failed to improve with behavioral intervention and melatonin who were then trialed on doxepin. Treatment was initiated at a median starting dose of 2 mg and slowly escalated to a median maintenance dose of 10 mg. Improvement in sleep was recorded using a 4-point Likert scale reported by parents on follow-up visits. RESULTS:A total of 29 patients were included in the analysis. Mean follow-up duration was 6.5 ± 3.5 months. Of 29 patients, 4 (13.8%) patients discontinued doxepin because of lack of efficacy or side effects. Eight (27.6%) patients showed significant improvement of their insomnia, 8 (27.6%) showed moderate improvement, 10 (34.5%) showed mild improvement, and 3 (10.3%) showed minimal to no improvement on treatment with doxepin (P < .05) Only 2 patients (6.9%) experienced adverse effects in the form of behavioral side effects (aggression) and enuresis. CONCLUSIONS:Results of our studies suggest that low-dose doxepin is both effective and well tolerated in pediatric patients with insomnia.

Caregivers of individuals with intellectual and developmental disabilities and epilepsy such as Dravet syndrome (DS) must navigate a complex web of state and community services through the transition from child-centered to adult-oriented healthcare. This study examined barriers to successful transition from the caregivers' perspective. Primary caregivers of teenagers or adults with DS who had contemplated or completed transition to adult care were eligible. A three-week, asynchronous, web-based focus group was conducted on Facebook. Data were analyzed in an iterative process based on a Grounded Theory approach. Participants reviewed findings for accuracy. Transition success was defined by how well it ensured adequate care for the child when caregivers became unable to provide it. Existing transition programs were described as "not for our kids." All caregivers reported that transition programs began too late. Challenges to identifying suitable providers were formidable, with 71% of adult patients still being seen by pediatric neurologists. Many adult physicians lacked a general knowledge of DS, yet caregivers perceived that adult physicians were unwilling to listen to caregivers, and few were comfortable accommodating patients with intellectual disabilities and challenging behaviors. Community programs often excluded patients with DS, and rural healthcare disparities created additional barriers. Analysis produced recommendations for improving the transition process including the creation of a certified Transition Navigator position in the clinical setting. The limitations of this focus group analysis include possible selection bias, but our study identified key issues and pathways to improve the transition process for patients with DS and their caregivers.

The natural history of idiopathic Parkinson's disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.

BACKGROUND/UNASSIGNED:Dietary intervention in multiple sclerosis carries potential therapeutic implications. While studies utilizing animal models of multiple sclerosis (MS) have demonstrated intriguing findings, well-designed clinical trials are few in number. OBJECTIVE/UNASSIGNED:The objective of this study is to review the animal model and clinical literature regarding dietary factors in experimental autoimmune encephalitis (EAE) and MS. METHODS/UNASSIGNED:This manuscript provides a comprehensive review of current animal model and clinical knowledge related to dietary factors in MS. RESULTS/UNASSIGNED:While there is currently little data for any specific diet in MS, there is growing evidence that certain dietary factors may influence the disease. CONCLUSIONS/UNASSIGNED:Definitive information regarding dietary factors as a modifiable risk factor in MS will require larger randomized clinical trials.

Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.

BACKGROUND:The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. OBJECTIVE:To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). METHODS:The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. RESULTS:A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. CONCLUSION/CONCLUSIONS:There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

BACKGROUND:Little data exists on outcomes of mechanical thrombectomy (MT) in nonagenarians. We aimed to compare the procedural and discharge outcomes of MT for acute ischemic stroke (AIS) in nonagenarians versus younger patients. METHODS:Procedural outcomes and discharge disposition were compared in propensity score-matched groups of nonagenarians versus patients aged≤69 with AIS who underwent MT. Patients aged 70-89 were excluded in order to compare nonagenarians to a younger cohort that most closely approximates the age of patients in the seminal MT trials. Good discharge disposition was defined as a discharge to home or acute rehabilitation. RESULTS:Of 3010 AIS patients, 46/297(16%) nonagenarians underwent MT compared to 159/1337(12%) aged≤69 (P = 0.091). Of 78 propensity score-matched patients (N = 39 ≥90, N = 39 ≤69), the median admission NIHSS was 22 versus 20, median ASPECTS was 9 versus 9, pre-stroke mRS<4 was 82% versus 87%, 18% versus 8% received IV tPA, and mTICI≥2b was 90% versus 90%, respectively (all P>0.05). Revascularization time (569 versus 372 min), door to groin puncture time (82 versus 71 min) and groin puncture to revascularization times (39 versus 24 min) were similar in between nonagenarians and ≤69, respectively (both P>0.05). Symptomatic ICH (2.6% versus 10.3%; p = 0.165) and in-hospital death rates (10% vs 26%; p = 0.077) trended lower among nonagenarians versus aged≤69. Good discharge disposition occurred in 44% of nonagenarians versus 51% aged≤69 years (p = 0.496). CONCLUSIONS:In propensity score analysis, 90% of nonagenarians achieved successful recanalization and almost half (44%) were discharged to home/acute rehabilitation, which was similar to a younger (aged≤69 years) cohort.

BACKGROUND AND PURPOSE/OBJECTIVE:Understanding factors associated with ischemic stroke despite therapeutic anticoagulation is an important goal to improve stroke prevention strategies in patients with atrial fibrillation (AF). We aim to determine factors associated with therapeutic or supratherapeutic anticoagulation status at the time of ischemic stroke in patients with AF. METHODS:The Initiation of Anticoagulation after Cardioembolic stroke (IAC) study is a multicenter study pooling data from stroke registries of eight comprehensive stroke centers across the United States. Consecutive patients hospitalized with acute ischemic stroke in the setting of AF were included in the IAC cohort. For this study, we only included patients who reported taking warfarin at the time of the ischemic stroke. Patients not on anticoagulation and patients who reported use of a direct oral anticoagulant were excluded. Analyses were stratified based on therapeutic (INR ≥2) versus subtherapeutic (INR <2) anticoagulation status. We used binary logistic regression models to determine factors independently associated with anticoagulation status after adjustment for pertinent confounders. In particular, we sought to determine whether atherosclerosis with 50% or more luminal narrowing in an artery supplying the infarct (a marker for a competing atherosclerotic mechanism) and small stroke size (≤ 10 mL; implying a competing small vessel disease mechanism) related to anticoagulant status. RESULTS:Of the 2084 patients enrolled in the IAC study, 382 patients met the inclusion criteria. The mean age was 77.4 ± 10.9 years and 52.4% (200/382) were women. A total of 222 (58.1%) subjects presented with subtherapeutic INR. In adjusted models, small stroke size (OR 1.74 95% CI 1.10-2.76, p = 0.019) and atherosclerosis with 50% or more narrowing in an artery supplying the infarct (OR 1.96 95% CI 1.06-3.63, p = 0.031) were independently associated with INR ≥2 at the time of their index stroke. CONCLUSION/CONCLUSIONS:Small stroke size (≤ 10 ml) and ipsilateral atherosclerosis with 50% or more narrowing may indicate a competing stroke mechanism. There may be important opportunities to improve stroke prevention strategies for patients with AF by targeting additional ischemic stroke mechanisms to improve patient outcomes.