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:The Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them. METHODS:We retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations. RESULTS:Comprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1. CONCLUSIONS:The proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

BACKGROUND:Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. METHODS:A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. RESULTS:The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. CONCLUSIONS:A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.

OBJECTIVES/OBJECTIVE:Nonhuman primates (NHPs) are model organisms for understanding the pathophysiology and treatment of epilepsy in humans, while data from human patients informs the diagnosis and treatment of NHP with seizures and epilepsy. We reviewed the literature and surveyed veterinarians at zoos and NHP research centers to (a) better define the range of seizures and epilepsy in NHP, (b) understand how NHPs can inform our knowledge of the pathophysiology and treatment of epilepsy in humans, and (c) identify gaps of knowledge and develop more effective guidelines to treat seizures and epilepsy in NHP. METHODS:We searched PrimateLit, PubMed, and Google Scholar for studies on experimental models of epilepsy in NHPs and on naturally occurring seizures and epilepsy in NHPs in captivity. In addition, we created a survey to assess methods to diagnose and treat epilepsy in NHPs. This survey was sent to 41 veterinarians at major international zoos and research facilities with NHP populations to study seizure phenomenology, diagnostic criteria for seizures and epilepsy, etiology, and antiseizure therapies in NHPs. RESULTS:We summarize the data from experimental and natural models of epilepsy in NHPs and case reports of epilepsy of unknown origin in captive primates. In addition, we present survey data collected from veterinarians at eight zoos and one research facility. Experimental data from NHP epilepsy models is abundant, whereas data from primates who develop epilepsy in the wild or in zoos is very limited, constraining our ability to advance evidence-based medicine. SIGNIFICANCE/CONCLUSIONS:Characterization of seizure or epilepsy models in NHPs will provide insights into mechanisms and new therapies that cannot be addressed by other animal models. NHP research will better inform species-specific diagnoses and outcomes.

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.

Hospital-acquired infections are common in neurointensive care units. We sought to review interventions which may reduce infection rates in neurocritically ill populations. We conducted a systematic review of studies targeting adult patients in neuro-intensive care units (neuro-ICUs) with an intervention designed to prevent ICU-acquired infections. Our outcome of interest was change in the prevalence or rates of infection between active and control arms of these studies. We excluded studies based on the following criteria: no English full-text version available; pediatric population; non-neurosciences ICU population; pre- or intraoperative methods to prevent infection; lack of discrete data for infection rates/prevalence; studies that were purely observational in nature and did not test an intervention; and studies performed in resource limited settings. We initially retrieved 3716 results by searching the following databases: PubMed/MEDLINE, EMBASE via Ovid, and Cochrane CENTRAL via Ovid. No date or language limits were used in the search. Computerized deduplication was conducted using EndNote followed by a confirmatory manual review resulting in 3414 citations. An additional 19 manuscripts were identified through review of references. The screening process followed a standard protocol, using two screeners at the title/abstract level to determine relevance and at the full-text level to determine eligibility for inclusion. The 3427 titles/abstracts were independently screened by two board-certified neurointensivists to determine relevance for full-text review, and 3248 were rejected. The remaining 179 abstracts were reviewed in full text using predetermined inclusion/exclusion criteria. Ultimately, 75 articles met our inclusion criteria and were utilized in the final analysis. The reviewed literature highlights the need for collaborative, multi-disciplinary, and multi-pronged approaches to reduce infections. Rates of VRI, SSI, VAP, CAUTI, and CLABSI can approach zero with persistence and a team-based approach.

BACKGROUND:Hematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH. METHODS:Primary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24 h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24 h of admission CT) were evaluated. HE was defined primarily as relative growth > 33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: > 6 mL, and > 33% or > 6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE. RESULTS:There were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (> 33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11-0.93; p = 0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as > 6 mL (adjusted OR 1.44; 95% CI 0.59-3.50; p = 0.41) or > 33% or > 6 mL (adjusted OR 0.71; 95% CI 0.29-1.70; p = 0.44). CONCLUSION/CONCLUSIONS:We identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

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:Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. METHODS:Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. RESULTS:in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. CONCLUSIONS:Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.