Faculty Bibliography

BACKGROUND:Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. RESULTS:Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. CONCLUSIONS:We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

Background and Purpose- Trials have shown potential clinical benefit for minimally invasive clot evacuation of intracerebral hemorrhage (ICH). Prior research showing an association between ICH size and functional outcome did not fully address the spectrum of hematoma volumes seen after clot evacuation. Methods- In this secondary analysis of the MISTIE III trial (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III), we included patients randomized to the surgical arm. The primary outcome was good outcome (modified Rankin Scale score 0-3 at 1 year from study enrollment). The primary predictors were the end-of-treatment (EoT) ICH and intraventricular hemorrhage volumes and an end-of-treatment ICH stratification scale called the EoT ICH volume score. Results- In 246 patients, the end-of-treatment computed tomography was performed an average of 5 days from onset. For patients with good versus poor outcomes, the mean end-of-treatment ICH and intraventricular hemorrhage volumes were 12.9 versus 18.0 mL (P=0.002) and 0.5 versus 2.3 mL (P<0.001), respectively. The probability of a good outcome decreased from 73% for EoT ICH volume 3 (<5 mL) to 28% for EoT ICH volume 0 (>20 mL; P=0.001). Conclusion s-After surgical clot evacuation, both ICH and intraventricular hemorrhage volumes have a strong association with good neurological outcome. The EoT ICH volume score needs independent verification, but such an approach could be used for prognostication and therapeutic planning.

Background Mobile stroke units (MSUs) reduce time to intravenous thrombolysis in acute ischemic stroke. Whether this advantage exists in densely populated urban areas with many proximate hospitals is unclear. Methods and Results We evaluated patients from the METRONOME (Metropolitan New York Mobile Stroke) registry with suspected acute ischemic stroke who were transported by a bi-institutional MSU operating in Manhattan, New York, from October 2016 to September 2017. The comparison group included patients transported to our hospitals via conventional ambulance for acute ischemic stroke during the same hours of MSU operation (Monday to Friday, 9 am to 5 pm). Our exposure was MSU care, and our primary outcome was dispatch-to-thrombolysis time. We estimated mean differences in the primary outcome between both groups, adjusting for clinical, demographic, and geographic factors, including numbers of nearby designated stroke centers and population density. We identified 66 patients treated or transported by MSU and 19 patients transported by conventional ambulance. Patients receiving MSU care had significantly shorter dispatch-to-thrombolysis time than patients receiving conventional care (mean: 61.2 versus 91.6 minutes; P=0.001). Compared with patients receiving conventional care, patients receiving MSU care were significantly more likely to be picked up closer to a higher mean number of designated stroke centers in a 2.0-mile radius (4.8 versus 2.7, P=0.002). In multivariable analysis, MSU care was associated with a mean decrease in dispatch-to-thrombolysis time of 29.7 minutes (95% CI, 6.9-52.5) compared with conventional care. Conclusions In a densely populated urban area with a high number of intermediary stroke centers, MSU care was associated with substantially quicker time to thrombolysis compared with conventional ambulance care.

BACKGROUND AND PURPOSE/OBJECTIVE:Early neurologic improvement (ENI) in patients treated with alteplase has been shown to correlate with functional outcome. However, the definition of ENI remains controversial and has varied across studies. We hypothesized that ENI defined as a percentage change in the National Institute of Health Stroke Scale (NIHSS) score (percent change NIHSS score) at 24-hours would better correlate with favorable outcomes at 3 months than ENI defined as the change in NIHSS score (delta NIHSS score) at 24 hours. METHODS:Retrospective analysis of prospectively collected single-center quality improvement data was performed of all acute ischemic stroke (AIS) patients treated with alteplase. We examined delta NIHSS score and percent change NIHSS score in unadjusted and adjusted logistic regression models as predictors of a favorable outcome at 3 months (defined as mRS 0-1). RESULTS:Among 586 patients who met the inclusion criteria, 194 (33.1%) had a favorable outcome at 3 months. In fully adjusted models, both delta NIHSS score (OR per point decrease 1.27; 95% confidence interval [CI] 1.19-1.36) and percent change NIHSS score (OR per 10 percent decrease 1.17; 95% CI 1.12-1.22) were associated with favorable functional outcome at 3 months. Receiver operating characteristic (ROC) curve comparison showed that the area under the ROC curve for percent change NIHSS score (.755) was greater than delta NIHSS score (.613) or admission NIHSS (.694). CONCLUSIONS:Percentage change in NIHSS score may be a better surrogate marker of ENI and functional outcome in AIS patients after receiving acute thrombolytic therapy. More studies are needed to confirm our findings.

PURPOSE/OBJECTIVE:To examine associations between fluctuating consciousness and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) assessments in stroke patients compared to non-neurological patients. MATERIALS AND METHODS/METHODS:We linked all recorded CAM-ICU assessments with corresponding Richmond Agitation Sedation Scale (RASS) measurements in patients with stroke or sepsis from a single-center ICU database. Fluctuating consciousness was defined by RASS variability using standard deviations (SD) over 24-h periods; regression analyses were performed to determine associations with RASS variability and CAM-ICU rating. RESULTS:We identified 16,509 paired daily summaries of CAM-ICU and RASS measurements in 546 stroke patients and 1586 sepsis patients. Stroke patients had higher odds of positive (OR 4.2, 95% CI 3.3-5.5) and "unable to assess" (UTA; OR 5.2, 95% CI 4.0-6.8) CAM-ICU ratings compared to sepsis patients, and CAM-ICU-positive and UTA assessment-days had higher RASS variability than CAM-ICU-negative assessment-days, especially in stroke patients. Based on model-implied associations of RASS variability (OR 2.0 per semi-IQR-difference in RASS-SD, 95% CI 1.7-2.2) and stroke diagnosis (OR 2.7, 95% CI 2.0-3.7) with CAM-ICU-positive assessments, over one-third of probable delirium cases among stroke patients were potentially missed by the CAM-ICU. CONCLUSIONS:Post-stroke delirium may frequently go undetected by the CAM-ICU, even in the setting of fluctuating consciousness.

BACKGROUND:The practice of ≥24 h of bed rest after acute ischemic stroke thrombolysis is common among hospitals, but its value compared to shorter periods of bed rest is unknown. METHODS:Consecutive adult patients with a diagnosis of ischemic stroke who had received intravenous thrombolysis treatment from 1/1/2010 until 4/13/2016, identified from the local ischemic stroke registry, were included. Standard practice bed rest for ≥24 h, the protocol prior to 1/27/2014, was retrospectively compared with standard practice bed rest for ≥12 h, the protocol after that date. The primary outcome was favorable discharge location (defined as home, home with services, or acute rehabilitation). Secondary outcome measures included incidence of pneumonia, NIHSS at discharge, and length of stay. RESULTS:392 patients were identified (203 in the ≥24 h group, 189 in the ≥12 h group). There was no significant difference in favorable discharge outcome in the ≥24 h bed rest protocol compared with the ≥12 h bed rest protocol in multivariable logistic regression analysis (76.2% vs. 70.9%, adjusted OR 1.20 CI 0.71-2.03). Compared with the ≥24 h bed rest group, pneumonia rates (8.3% versus 1.6%, adjusted OR 0.12 CI 0.03-0.55), median discharge NIHSS (3 versus 2, adjusted p = .034), and mean length of stay (5.4 versus 3.5 days, adjusted p = .006) were lower in the ≥12 h bed rest group. CONCLUSION/CONCLUSIONS:Compared with ≥24 h bed rest, ≥12 h bed rest after acute ischemic stroke reperfusion therapy appeared to be similar. A non-inferiority randomized trial is needed to verify these findings.

Background and Purpose- American Heart Association guidelines recommend obtaining baseline troponin in all patients with acute ischemic stroke. Yet, there is a paucity of data on the prevalence of baseline troponin elevation and specifically its diagnostic yield for acute myocardial infarction (AMI) in patients presenting within the time window for thrombolysis. Methods- We retrospectively analyzed 1072 consecutive patients admitted for acute ischemic stroke or transient ischemic attack, who presented within 4.5 hours of last known well (LKW). Patients who had baseline cardiac troponin I (bcTnI) obtained within 72 hours from LKW (n=525) were included in the study. Multivariable logistic regression was conducted to determine factors independently related to an elevated bcTnI (>0.04 ng/mL). We calculated the area under receiver operator curves, sensitivity, and specificity, to determine the diagnostic accuracy of (i) the bcTnI for AMI stratified by the time to assessment and (ii) the best time cutoff for obtaining bcTnI. Results- Among included subjects, the median time from LKW to the bcTnI was 3.8 hours and 113 (21.5%) subjects had an elevated bcTnI. Assessment of bcTnI within 4.5 hours from LKW was significantly more often associated with normal values as compared to assessment between 4.5 and 72 hours (61.7% versus 38.3%; P=0.001). Fifteen (2.9%) patients were diagnosed with AMI. After adjustment for pertinent confounders, time to bcTnI assessment was independently associated with AMI (odds ratio, 1.04 [95% CI, 1.02-1.07] P=0.001). When stratified by time, bcTnI assessed within 4.5 hours had a sensitivity of 25% and specificity of 83.7% for AMI, whereas bcTnI assessment between 4.5 and 72 hours was associated with a sensitivity of 90.9% and specificity of 74.8%. Conclusions- Assessment of bcTnI after 4.5 hours from LKW was associated with greater diagnostic accuracy than testing within 4.5 hours. This information may inform routine clinical practice.

PURPOSE OF REVIEW/OBJECTIVE:Cryptogenic stroke describes a subset of ischemic stroke for which no cause can be found despite a structured investigation. There are a number of putative mechanisms of cryptogenic ischemic stroke including a covert structural cardiac lesion, paroxysmal atrial fibrillation, hypercoagulable state or undiagnosed malignancy. Because many of these proposed mechanisms are embolic - and based on studies of thrombus history showing commonalities between thrombus composition between cardioembolic and cryptogenic strokes - the concept of embolic stroke of undetermined source (ESUS) (Hart et al. Lancet Neurol. 13(4):429-38, 2014; Stroke. 48(4):867-72, 2017) has been proposed to describe cryptogenic strokes that may warrant systemic anticoagulation. In this review, we discuss the phenomena of cryptogenic stroke, ESUS and a proposed management pathway. RECENT FINDINGS/RESULTS:1. The concept of ESUS was proposed in 2014 as a potentially useful therapeutic entity. Two recent trials - NAVIGATE-ESUS (Hart et al. N Engl J Med. 378(23):2191-201, 2018) and RESPECT-ESUS (Diener 2018) were proposed based on this concept. They were negative for their primary endpoint and for the secondary endpoint of ischemic stroke recurrence. Post-hoc analysis of the WARSS trial (Longstreth et al. Stroke. 44(3):714-9, 2013) suggested that people with elevated pro-BNP benefited from systemic anticoagulation whereas those with a normal pro-BNP did not. This led to the hypothesis that a subgroup of patients at higher risk for embolism from the left atrium would benefit from anticoagulation, even if the WARSS trial was negative for the primary endpoint. Thus, the ARCADIA trial (Kamel et al. Int J Stroke. 14(2):207-14, 2019) was proposed - a randomized, active-control, multi-center trial comparing apixaban with aspirin for secondary stroke prevention in patients with ESUS and biomarkers of left atrial cardiopathy. This trial is actively recruiting. 2. Carotid web - an intimal form of fibromuscular dysplasia - has come to increased prominence in the literature as a cause of embolic stroke. It is a non-stenosis, non-atherosclerotic lesion in the posterior wall of the internal carotid artery that leads to pooling with stasis of blood distal to the lesion and, as a consequence, embolic stroke. It is not usually detected by a standard stroke workup as it masquerades as non-calcified atherosclerosis and does not cause hemodynamically significant stenosis. There have been two major recent papers - a meta-analysis in Stroke (Zhang et al. Stroke. 49(12):2872-6, 2018) and narrative review in JAMA Neurology (Kim et al. JAMA Neurol. 2018) - that addressed this topic. Cryptogenic stroke describes a stroke for which no cause has been found. ESUS is a more precisely-defined entity that mandates a specific workup and implicates remote embolism as a cause of stroke. In ESUS, the options for further investigation include long-term cardiac monitoring, transesophageal echocardiography, investigation for occult malignancy or arterial hypercoagulability. Options for management include anti-platelet therapy (the current standard of care), empiric anticoagulation or enrollment in to a clinical trial examining the use of NOACs compared with aspirin for secondary prevention (such as ARCADIA or ATTICUS). In a person less than 60 years old with ESUS and a patent foramen ovale the risk of a recurrent stroke is low but recent trials have suggested that percutaneous device closure reduces this risk further with an acceptable complication rate.