Faculty Bibliography

BACKGROUND:Infection has been associated with stroke in patients with left ventricular assist devices (LVAD); however, little data exist on the timing, type and mortality impact of infection-related stroke. METHODS:Prospectively collected data of HeartMate II (N = 332) and HeartWare (N = 70) LVAD patients from a single center were reviewed. Only strokes (ischemic or hemorrhagic) that occurred within 6 weeks following a LVAD infection were considered in analyses. The association between LVAD infections (wound, pump pocket, driveline and/or bloodstream infection [BSI]), specific pathogens and ischemic and hemorrhagic strokes was evaluated using multivariable logistic regression analysis. The impact of infection-related stroke on cumulative survival was assessed using Kaplan-Meier analysis. RESULTS:Of 402 patients, LVAD infection occurred in 158 (39%) including BSI in 107 (27%), driveline infection in 67 (17%), wound infection in 31 (8%) and pump pocket infection in 24 (6%). LVAD infection-related stroke occurred in 20/158 (13%) patients in a median of 4 days (0-36 days) from documented infection. In multivariable analysis, ischemic stroke was associated with wound infection (aOR 9.0, 95% CI 2.4-34.0, P = 0.001) and BSI (aOR 7.7, 95% CI 0.9-66.0, P = 0.064), and hemorrhagic stroke was associated with BSI in 100% of cases (P = 0.01). There was no association with driveline or pump pocket infection. The cumulative survival rate among patients with infection-related stroke was significantly lower compared to those with LVAD infection but no stroke (log-rank P < 0.001). There was a trend toward shorter stroke-free survival among patients with LVAD infection. CONCLUSIONS:LVAD infections, particularly BSI, are significantly associated with stroke, and infection-related stroke conferred significantly lower cumulative survival.

BACKGROUND:Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established. METHODS:To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study. RESULTS:PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement. CONCLUSIONS:Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.

The precise modulation of regional cerebral blood flow during neural activation is important for matching local energetic demand and supply and clearing brain metabolites. Here we discuss advances facilitated by high-resolution optical in vivo imaging techniques that for the first time have provided direct visualization of capillary blood flow and its modulation by neural activity. We focus primarily on studies of microvascular flow, mural cell control of vessel diameter, and oxygen level-dependent changes in red blood cell deformability. We also suggest methodological standards for best practices when studying microvascular perfusion, partly motivated by recent controversies about the precise location within the microvascular tree where neurovascular coupling is initiated, and the role of mural cells in the control of vasomotility.

PURPOSE/OBJECTIVE:To evaluate microsurgical trans-sylvian trans-ventricular anatomical hemispherectomy with regard to seizure outcome, risk of hydrocephalus, blood loss, and risk of chronic hemosiderosis in patients with intractable seizures selected for surgery using current preoperative assessment techniques. METHODS:Out of 86 patients who underwent hemispherectomy between February 2000 and April 2019, by a single surgeon, at a tertiary care referral center, 77 patients (ages 0.2-20 years; 40 females) who had an anatomical hemispherectomy were analyzed. Five of these were 'palliative' surgeries. One-stage anatomical hemispherectomy was performed in 55 children, two-stage anatomical hemispherectomy after extraoperative intracranial monitoring in 16, and six hemispherectomies were done following failed previous resection. Mean follow-up duration was 5.7 years (range 1-16.84 years). Forty-six patients had postoperative MRI scans. RESULTS:Ninety percent of children with non-palliative hemispherectomy achieved ILAE Class-1 outcome. Twenty-seven patients were no longer taking anticonvulsant medications. Surgical failures (n = 4) included one patient with previous meningoencephalitis, one with anti-GAD antibody encephalitis, one with idiopathic neonatal thalamic hemorrhage, and one with extensive tuberous sclerosis. There were no failures among patients with malformations of cortical development. Estimated average blood loss during surgery was 387 ml. Ten (21%) children developed hydrocephalus and required a shunt following one-stage hemispherectomy, whereas 10 (50%) patients developed hydrocephalus among those who had extraoperative intracranial monitoring. Only 20% of the shunts malfunctioned in the first year. Early malfunctions were related to the valve and later to fracture disconnection of the shunt. One patent had a traumatic subdural hematoma. None of the patients developed clinical signs of chronic 'superficial cerebral hemosiderosis' nor was there evidence of radiologically persistent chronic hemosiderosis in patients who had postoperative MRI imaging. CONCLUSION/CONCLUSIONS:Surgical results of anatomical hemispherectomy are excellent in carefully selected cases. Post-operative complications of hydrocephalus and intraoperative blood loss are comparable to those reported for hemispheric disconnective surgery (hemispherotomy). The rate of shunt malfunction was less than that reported for patients with hydrocephalus of other etiologies Absence of chronic 'superficial hemosiderosis', even on long-term follow-up, suggests that anatomical hemispherectomy should be revisited as a viable option in patients with intractable seizures and altered anatomy such as in malformations of cortical development, a group that has a reported high rate of seizure recurrence related to incomplete disconnection following hemispheric disconnective surgery.

OBJECTIVE:The natural history and long-term durability of Guglielmi detachable coil (GDC) embolization is still unknown. We hypothesize a stepwise decrease in durability of embolized cerebral aneurysms as stratified by the Modified Raymond-Roy Classification (MRRC). METHODS:First-time GDC-embolized cerebral aneurysms were retrospectively reviewed from 2004 to 2015. Loss of durability (LOD) was defined by change in aneurysm size or patency seen on serial radiographic follow-up. Kaplan-Meier survival analysis was performed to evaluate embolization durability. Multivariate Cox regression modeling was used to assess baseline aneurysm and patient characteristics for their effect on LOD. RESULTS:A total of 427 patients with 443 aneurysms met the inclusion criteria. Overall, 89 (21%) aneurysms met LOD criteria. Grade 1 aneurysms had statistically significantly greater durability than did all other MRRC grades. Grade 3b aneurysms had significantly worse durability than did all other aneurysm grades. There was no difference in durability between grade 2 and 3a aneurysms. Of aneurysms with LOD, 26 (29%) experienced worsening of MRRC grade. Thirty-five (24%) initial MRRC grade 2, 72 (45%) initial MRRC grade 3a, and 6 (22%) initial MRRC grade 3b aneurysms progressed to MRRC grade 1 without retreatment. In our multivariate analysis, only initial MRRC grade was statistically significantly associated with treatment durability (P < 0.001). CONCLUSIONS:MRRC grade is independently associated with first-time GDC-embolized cerebral aneurysm durability. Achieving MRRC grade 1 occlusion outcome is significantly associated with greater long-term GDC durability. Although few aneurysms experience further growth and/or recanalization, most incompletely obliterated aneurysms tend to remain stable over time or even progress to occlusion. Grading scales such as the MRRC are useful for characterizing aneurysm occlusion but may lack sensitivity and specificity for characterizing changes in aneurysm morphology over time.

BACKGROUND:Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE:This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS:A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS:Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS:BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Conus ateralbus is a cone snail endemic to the west side of the island of Sal, in the Cabo Verde Archipelago off West Africa. We describe the isolation and characterization of the first bioactive peptide from the venom of this species. This 30AA venom peptide is named conotoxin AtVIA (δ-conotoxin-like). An excitatory activity was manifested by the peptide on a majority of mouse lumbar dorsal root ganglion neurons. An analog of AtVIA with conservative changes on three amino acid residues at the C-terminal region was synthesized and this analog produced an identical effect on the mouse neurons. AtVIA has homology with δ-conotoxins from other worm-hunters, which include conserved sequence elements that are shared with δ-conotoxins from fish-hunting Conus. In contrast, there is no comparable sequence similarity with δ-conotoxins from the venoms of molluscivorous Conus species. A rationale for the potential presence of δ-conotoxins, that are potent in vertebrate systems in two different lineages of worm-hunting cone snails, is discussed.

OBJECTIVE:To obtain medical records, family interviews, and death-related reports of sudden unexpected death in epilepsy (SUDEP) cases to better understand SUDEP. METHODS:All cases referred to the North American SUDEP Registry (NASR) between October 2011 and June 2018 were reviewed; cause of death was determined by consensus review. Available medical records, death scene investigation reports, autopsy reports, and next-of-kin interviews were reviewed for all cases of SUDEP. Seizure type, EEG, MRI, and SUDEP classification were adjudicated by 2 epileptologists. RESULTS:There were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1-70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%. CONCLUSIONS:NASR participants commonly have clinical features that have been previously been associated with SUDEP risk such as young adult age, ASM nonadherence, and frequent GTCS. However, a sizeable minority of SUDEP occurred in patients thought to be treatment responsive or to have benign epilepsies. These results emphasize the importance of SUDEP education across the spectrum of epilepsy severities. We aim to make NASR data and biospecimens available for researchers to advance SUDEP understanding and prevention.

ABSTRACT/UNASSIGNED:Hypersomnolence is one of the more common symptoms reported after mild traumatic brain injury (TBI) and often one of the most difficult to treat. This case series presents a cohort of patients with TBI related hypersomnolence associated with a de novo autoimmune process that successfully resolved with pulse dose corticosteroid treatment. When associated with an autoimmune inflammatory process, corticosteroids may serve to stabilize the blood brain barrier leading to the successful and sustained resolution of TBI induced sleepiness.