Outcome after stroke thrombolysis in patients >80 years treated within 3 hours vs >3–4.5 hours

ABSTRACT

Objective: To determine outcomes and risks of IV thrombolysis (IVT) in patients with acute ischemic stroke (AIS) >80 years of age within 3 hours compared to >3 to 4.5 hours recorded in the Safe Implementation of Treatment in Stroke (SITS) International Stroke Thrombolysis Registry.

Methods: A total of 14,240 (year 2003–2015) patients >80 years of age with AIS were treated with IVT ≤4.5 hours of stroke onset (3,558 in >3–4.5 hours). Of these, 8,658 (2,157 in >3–4.5 hours) were treated otherwise according to the European Summary of Product Characteristics (EU SmPC) criteria for alteplase. Outcomes were 3-month functional independence (modified Rankin Scale score 0–2), mortality, and symptomatic intracerebral hemorrhage (SICH)/SITS. Results were compared between the groups treated in >3 to 4.5 and ≤3 hours.

Results: Median age was 84 years; 61% were female in both groups. Median NIH Stroke Scale score was 12 vs 14 in the >3- to 4.5- and ≤3-hour group, respectively. Three-month functional independence was 34% vs 35% (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.69–0.89, p < 0.001); mortality was 31% vs 32% (aOR 1.10, 95% CI 0.97–1.25, p = 0.13); and SICH/SITS was 2.7% vs 1.6% (aOR 1.72, 95% CI 1.25–2.35, p = 0.001). In EU SmPC–compliant patients, 3-month functional independence was 36 vs 37% (aOR 0.79, 95% CI 0.68–0.92, p = 0.002), mortality was 29% vs 29.6% (aOR 1.10, 95% CI 0.95–1.28, p = 0.20), and SICH/SITS was 2.7% vs 1.6% (aOR 1.62, 95% CI 1.12–2.34, p = 0.01).

Conclusions: In this observational study, unselected patients >80 years of age treated with IVT after 3 hours vs earlier had a slightly higher rate of SICH and similar unadjusted functional outcome but poorer adjusted outcome. The absolute difference between the treatment groups is small, and elderly patients should not be denied IVT in the later time window solely because of age without other contraindications.

Neurology 2017

REM sleep behavior disorder is related to enteric neuropathology in Parkinson disease

ABSTRACT

Objective: To determine whether REM sleep behavior disorder (RBD) in Parkinson disease (PD) is associated with lesions and dysfunctions of the autonomic nervous system by evaluating enteric phosphorylated α-synuclein histopathology (PASH) and permeability.

Methods: A total of 45 patients with PD were included in this cross-sectional study. RBD was diagnosed on the basis of a standardized clinical interview and confirmed by polysomnography. For each patient, 5 biopsies were taken at the junction between the sigmoid and descending colon during the course of a rectosigmoidoscopy. For the detection of enteric PASH, 2 colonic biopsies were analyzed by immunohistochemistry with antibodies against phosphorylated α-synuclein and PGP9.5 in 43 patients (2 patients were excluded because only 1 biopsy was available). The paracellular permeability and transcellular permeability were evaluated by measuring sulfonic acid and horseradish peroxidase flux, respectively, in the 3 remaining biopsies mounted in Ussing chambers.

Results: Enteric PASH was more frequent in the subgroup of patients with PD with RBD compared to patients without RBD (18 of 28, 64.3%, vs 2 of 15, 13.3%, respectively, p < 0.01). No differences were observed in intestinal permeability between patients with PD with and without RBD.

Conclusions: Patients with PD and RBD have a greater frequency of synuclein pathology in the enteric nervous system, suggesting that RBD is associated with widespread synuclein neuropathology.

Neurology 2017

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs

ABSTRACT

Objective: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA).

Methods: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013.

Results: After a median of 33.3 months of follow-up (interquartile range 16.3–49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11–0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04–0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001).

Conclusion: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades.

ClinicalTrials.gov identifier: NCT00389181.

Classification of evidence: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Neurology 2017

Olfaction and incident Parkinson disease in US white and black older adults

ABSTRACT

Objective: To investigate olfaction in relation to incident Parkinson disease (PD) in US white and black older adults.

Methods: The study included 1,510 white (mean age 75.6 years) and 952 black (75.4 years) participants of the Health, Aging, and Body Composition study. We evaluated the olfaction of study participants with the Brief Smell Identification Test (BSIT) in 1999–2000. We retrospectively adjudicated PD cases identified through August 31, 2012, using multiple data sources. We used multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: During an average of 9.8 years of follow-up, we identified a total of 42 incident PD cases, including 30 white and 12 black participants. Overall, poor sense of smell, as indicated by a lower BSIT score, was associated with higher risk of PD. Compared with the highest tertile of BSIT (t3), the HR was 1.3 (95% CI 0.5–3.6) for the second tertile (t2) and 4.8 (95% CI 2.0–11.2) for the lowest tertile (t1) (p_trend < 0.00001). Further analyses revealed significant associations for incident PD in both the first 5 years of follow-up (HR_t1/[t2+t3] 4.2, 95% CI 1.7–10.8) and thereafter (HR_t1/[t2+t3] 4.1, 95% CI 1.7–9.8). This association appeared to be stronger in white (HR_t1/[t2+t3] 4.9, 95% CI 2.3–10.5) than in black participants (HR_t1/[t2+t3] 2.5, 95% CI 0.8–8.1), and in men (HR_t1/[t2+t3] 5.4, 95% CI 2.3–12.9) than in women (HR_t1/[t2+t3] 2.9, 95% CI 1.1–7.8).

Conclusions: Poor olfaction predicts PD in short and intermediate terms; the possibility of stronger associations among men and white participants warrants further investigation.

Neurology 2017

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease

ABSTRACT

Objective: To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD).

Methods: We examined self-reported and study partner–based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing.

Results: Self-reported SMC were greater in carriers than noncarriers (p = 0.02). Study partner–based SMC did not differ between groups (p = 0.21), but in carriers increased with age (r = 0.66, p < 0.001) and decreased with hippocampal volume (r = −0.35, p = 0.08).

Conclusions: Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset.

Neurology 2017

Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration

ABSTRACT

Objective: Whereas Alzheimer disease (AD) is associated with inner retina thinning visualized by spectral-domain optical coherence tomography (SD-OCT), we sought to determine if the retina has a distinguishing biomarker for frontotemporal degeneration (FTD).

Methods: Using a cross-sectional design, we examined retinal structure in 38 consecutively enrolled patients with FTD and 44 controls using a standard SD-OCT protocol. Retinal layers were segmented with the Iowa Reference Algorithm. Subgroups of highly predictive molecular pathology (tauopathy, TAR DNA–binding protein 43, unknown) were determined by clinical criteria, genetic markers, and a CSF biomarker (total tau: β-amyloid) to exclude presumed AD. We excluded eyes with poor image quality or confounding diseases. SD-OCT measures of patients (n = 46 eyes) and controls (n = 69 eyes) were compared using a generalized linear model accounting for intereye correlation, and correlations between retinal layer thicknesses and Mini-Mental State Examination (MMSE) were evaluated.

Results: Adjusting for age, sex, and race, patients with FTD had a thinner outer retina than controls (132 vs 142 μm, p = 0.004). Patients with FTD also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 μm, p = 0.003) and ellipsoid zone (EZ) (14.5 vs 15.1 μm, p = 0.009) than controls, but had similar thicknesses for inner retinal layers. The outer retina thickness of patients correlated with MMSE (Spearman r = 0.44, p = 0.03). The highly predictive tauopathy subgroup (n = 31 eyes) also had a thinner ONL (88.7 vs 97.4 μm, p = 0.01) and EZ (14.4 vs 15.1 μm, p = 0.01) than controls.

Conclusions: FTD is associated with outer retina thinning, and this thinning correlates with disease severity.

Neurology 2017

Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy

Abstract

Objective

The contribution of recurring seizures to the progression of epileptogenesis is debated. Seizure-induced brain damage is not conclusively demonstrated either in humans or in animal models of epilepsy. We evaluated the expression of brain injury biomarkers on postsurgical brain tissue obtained from 20 patients with frequent seizures and a long history of drug-resistant focal epilepsy.

Methods

The expression patterns of specific glial, neuronal, and inflammatory molecules were evaluated by immunohistochemistry in the core of type II focal cortical dysplasias (FCD-II), at the FCD boundary (perilesion), and in the adjacent normal-appearing area included in the epileptogenic region. We also analyzed surgical specimens from cryptogenic patients not presenting structural alterations at imaging.

Results

Astroglial and microglial activation, reduced neuronal density, perivascular CD3-positive T-lymphocyte clustering, and fibrinogen extravasation were demonstrated in the core of FCD-II lesions. No pathological immunoreactivity was observed outside the FCD-II or in cryptogenetic specimens, where the occurrence of interictal and ictal epileptiform activity was confirmed by either stereo-electroencephalography or intraoperative electrocorticography.

Interpretation

Recurrent seizures do not induce the expression of brain damage markers in nonlesional epileptogenic cortex studied in postsurgical tissue from cryptogenic and FCD patients. This evidence argues against the hypothesis that epileptiform activity per se contributes to focal brain injury, at least in the neocortical epilepsies considered here. 

Ann Neurol 2017