Faculty Bibliography

INTRODUCTION/BACKGROUND:We explored regional brain atrophy patterns and their clinical correlates in dementia with Lewy bodies (DLB). METHODS:In this multicentre study, we included a total of 333 patients with DLB, 352 patients with Alzheimer's disease (AD), and 233 normal controls and used medial temporal lobe atrophy, posterior atrophy, and frontal atrophy (GCA-F) visual rating scales. Patients were classified according to four atrophy patterns. RESULTS:Patients with DLB had higher scores on all the three atrophy scales than healthy controls but had less medial temporal lobe atrophy than those with AD (all P-values < .001). A signature hippocampal-sparing pattern of regional atrophy was observed in DLB. The magnetic resonance imaging measures showed 65% ability to discriminate between DLB and AD and marginally contributed to the discrimination over and above the core clinical features. DISCUSSION/CONCLUSIONS:The most common pattern of atrophy of DLB was hippocampal-sparing. Future studies should explore whether comorbid AD pathology underlies the atrophy patterns seen in DLB.

INTRODUCTION/BACKGROUND:In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS:Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS:In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION/CONCLUSIONS:SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.

OBJECTIVE:Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS:Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS:This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE/CONCLUSIONS:In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Background/UNASSIGNED:The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. Purpose/UNASSIGNED:In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. Methods/UNASSIGNED:In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. Results/UNASSIGNED:A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24-2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74-2.04)). Conclusions/UNASSIGNED:After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

OBJECTIVES/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. METHODS:Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C- reactive protein, yearly frequency of hyper-adrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. RESULTS:Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body Mass Index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower Inspiratory Capacity (IC) (42.7% predicted vs 62.8% predicted; p=0.04). CONCLUSIONS:Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.

Background and Purpose- It is uncertain whether heart transplantation decreases the risk of stroke. The objective of our study was to determine whether heart transplantation is associated with a decreased risk of subsequent stroke among patients with heart failure awaiting transplantation. Methods- We performed a retrospective cohort study using administrative data from New York, California, and Florida between 2005 and 2015. Individuals with heart failure awaiting heart transplantation were identified using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for heart failure in combination with code V49.83 for awaiting organ transplant status. Individuals with prior stroke were excluded. Our primary exposure variable was heart transplantation, modeled as a time-varying covariate and defined by procedure code 37.51. The primary outcome was stroke, defined as the composite of ischemic and hemorrhagic stroke. Survival statistics were used to calculate stroke incidence, and Cox proportional hazards analysis was used to determine the association between heart transplantation and stroke while adjusting for demographics, stroke risk factors, Elixhauser comorbidities, and implantation of a left ventricular assist device. Results- We identified 7848 patients with heart failure awaiting heart transplantation, of whom 1068 (13.6%) underwent heart transplantation. During a mean follow-up of 2.7 years, we identified 428 strokes. The annual incidence of stroke was 0.7% (95% CI, 0.5%-1.0%) after heart transplantation versus 2.4% (95% CI, 2.2%-2.6%) among those awaiting heart transplantation. After adjustment for potential confounders, heart transplantation was associated with a lower risk of stroke (hazard ratio, 0.4; 95% CI, 0.2-0.6). Conclusions- Heart transplantation is associated with a decreased risk of stroke among patients with heart failure awaiting transplantation.

AIM:device in patients with recurrent glioblastoma (rGBM). MATERIALS & METHODS:) that uses a magnetic field to penetrate tissues to alter specific biologic functions within cells. Patients with rGBM were treated with Voyager alone (V) or Voyager in combination with standard of care (V + SoC). Safety and clinical utility were assessed every 2-4 months. RESULTS:Data from the first 11 patients treated are reported here. Median progression-free survival was 10 weeks in the V arm and 16 weeks in the V + SoC arm. Median overall survival was 16 months in V arm and 11 months in the V + SoC arm. No serious adverse events associated with the device were reported. CONCLUSION:These data suggest that the Voyager is safe and feasible for the treatment of rGBM.

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

PURPOSE/OBJECTIVE:To assess the potential biologic significance of variations in burst-suppression patterns (BSPs) after cardiac arrest in relation to recovery of consciousness. In the context of recent theoretical models of BSP, bursting frequency may be representative of underlying network dynamics; discontinuous activation of membrane potential during impaired cellular energetics may promote neuronal rescue. METHODS:We reviewed a database of 73 comatose post-cardiac arrest patients who underwent therapeutic hypothermia to assess for the presence of BSP and clinical outcomes. In a subsample of patients with BSP (n = 14), spectral content of burst and suppression periods were quantified using multitaper method. RESULTS:Burst-suppression pattern was seen in 45/73 (61%) patients. Comparable numbers of patients with (31.1%) and without (35.7%) BSP regained consciousness by the time of hospital discharge. In addition, in two unique cases, BSP initially resolved and then spontaneously reemerged after completion of therapeutic hypothermia and cessation of sedative medications. Both patients recovered consciousness. Spectral analysis of bursts in all patients regaining consciousness (n = 6) showed a prominent theta frequency (5-7 Hz) feature, but not in age-matched patients with induced BSP who did not recover consciousness (n = 8). CONCLUSIONS:The prognostic implications of BSP after hypoxic brain injury may vary based on the intrinsic properties of the underlying brain state itself. The presence of theta activity within bursts may index potential viability of neuronal networks underlying recovery of consciousness; emergence of spontaneous BSP in some cases may indicate an innate neuroprotective mechanism. This study highlights the need for better characterization of various BSP patterns after cardiac arrest.