Joshua Betz

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

BACKGROUND Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING National Institute of Neurological Disorders and Stroke.

Hearing loss and depression in older adults

TO THE EDITOR Hearing loss (HL) is a common, but underappreciated health issue affecting older adults. The functional consequences of HL for older adults are now surfacing in epidemiological studies demonstrating that HL may be independently associated with depression1 and loneliness.2 Compared to other medical co-morbidities, HL is more strongly associated with the development of depression in older adults.1 Whether hearing rehabilitative treatment may mitigate the possible effects of HL on depression remains unclear. We investigated the association of HL and hearing aid use with major depressive disorder (MDD)in a nationally representative study of older patients.

Association of Hearing Loss With Hospitalization and Burden of Disease in Older Adults

To the Editor Hearing loss (HL) is a chronic condition that affects nearly 2 of every 3 adults aged 70 or older in the US.1 Hearing loss has broader implications for older adults, being independently associated with poorer cognitive2 and physical functioning.3 Currently, the association of HL with other health economic outcomes, such as healthcare utilization, is unstudied. We investigated the association of HL with hospitalization and burden of disease in a nationally representative study of adults aged 70 and older.

Prognostic Value of Diffusion Tensor Imaging Parameters in Severe Traumatic Brain Injury

Diffusion tensor imaging (DTI) has recently emerged as a useful tool for assessing traumatic brain injury (TBI). In this study, the prognostic value of the relationship between DTI measures and the clinical status of severe TBI patients, both at the time of magnetic resonance imaging (MRI), and their discharge to acute TBI rehabilitation, was assessed. Patients (n=59) admitted to the trauma center with severe closed head injuries were retrospectively evaluated after approval from the institutions institutional review board, to determine the prognostic value of DTI measures. The relationship of DTI measures, including apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial (λ‖) and radial diffusivity (λ⊥) from the whole brain white matter, internal capsule, genu, splenium, and body of the corpus callosum, were compared with neurological status at MRI and at discharge to acute TBI rehabilitation. Whole brain white matter averages of ADC, λ‖, and λ⊥, and their coefficient of variation (CV) were significantly correlated with the Glasgow Coma Scale (GCS) score on the day of MRI. The average λ‖ was significantly correlated with GCS scores on the day of MRI in all measured brain regions. Outcomes were associated with whole brain white matter averages of ADC and λ‖, and the CVs of FA, ADC, λ‖, and λ⊥; and the averages and CVs of FA and λ‖ in all corpus callosum regions. The inclusion of regional and global DTI measures improved the accuracy of prognostic models, when adjusted for admission GCS score and age (p<0.05). Whole brain white matter and regional DTI measures are sensitive markers of TBI, and correlate with neurological status both at MRI and discharge to rehabilitation. The addition of DTI measures adjusted for age, gender, and admission GCS score significantly improved prognostic models.

Association of Hearing Impairment and Mortality in Older Adults

BACKGROUND Hearing impairment (HI) is highly prevalent in older adults and is associated with social isolation, depression, and risk of dementia. Whether HI is associated with broader downstream outcomes is unclear. We undertook this study to determine whether audiometric HI is associated with mortality in older adults. METHODS Prospective observational data from 1,958 adults ≥70 years of age from the Health, Aging, and Body Composition Study were analyzed using Cox proportional hazards regression. Participants were followed for 8 years after audiometric examination. Mortality was adjudicated by obtaining death certificates. Hearing was defined as the pure-tone average of hearing thresholds in decibels re: hearing level (dB HL) at frequencies from 0.5 to 4kHz. HI was defined as pure-tone average >25 dB HL in the better ear. RESULTS Of the 1,146 participants with HI, 492 (42.9%) died compared with 255 (31.4%) of the 812 with normal hearing (odds ratio = 1.64, 95% CI: 1.36-1.98). After adjustment for demographics and cardiovascular risk factors, HI was associated with a 20% increased mortality risk compared with normal hearing (hazard ratio = 1.20, 95% CI: 1.03-1.41). Confirmatory analyses treating HI as a continuous predictor yielded similar results, demonstrating a nonlinear increase in mortality risk with increasing HI (hazard ratio = 1.14, 95% CI: 1.00-1.29 per 10 dB of threshold elevation up to 35 dB HL). CONCLUSIONS HI in older adults is associated with increased mortality, independent of demographics and cardiovascular risk factors. Further research is necessary to understand the basis of this association and whether these pathways might be amenable to hearing rehabilitation.

Association Between Hearing Impairment and Self-Reported Difficulty in Physical Functioning

To determine whether hearing impairment, defined by using objective audiometry, is associated with multiple categories of self‐reported physical functioning in a cross‐sectional, nationally representative sample of older adults.

Association of Hearing Impairment with Declines in Physical Functioning and the Risk of Disability in Older Adults

BACKGROUND Identifying factors associated with functional declines in older adults is important given the aging of the population. We investigated if hearing impairment is independently associated with objectively measured declines in physical functioning in a community-based sample of older adults. METHODS Prospective observational study of 2,190 individuals from the Health, Aging, and Body Composition study. Participants were followed annually for up to 11 visits. Hearing was measured with pure-tone audiometry. Physical functioning and gait speed were measured with the Short Physical Performance Battery (SPPB). Incident disability and requirement for nursing care were assessed semiannually through self-report. RESULTS In a mixed-effects model, greater hearing impairment was associated with poorer physical functioning. At both Visit 1 and Visit 11, SPPB scores were lower in individuals with mild (10.14 [95% CI 10.04-10.25], p < .01; 7.35 [95% CI 7.12-7.58], p < .05) and moderate or greater hearing impairment (10.04 [95% CI 9.90-10.19], p < .01; 7.00 [95% CI 6.69-7.32], p < .01) than scores in normal hearing individuals (10.36 [95% CI 10.26-10.46]; 7.71 [95% CI 7.49-7.92]). We observed that women with moderate or greater hearing impairment had a 31% increased risk of incident disability (Hazard ratio [HR] =1.31 [95% CI 1.08-1.60], p < .01) and a 31% increased risk of incident nursing care requirement (HR = 1.31 [95% CI 1.05-1.62], p = .02) compared to women with normal hearing. CONCLUSIONS Hearing impairment is independently associated with poorer objective physical functioning in older adults, and a 31% increased risk for incident disability and need for nursing care in women.

Peripheral Hearing and Cognition: Evidence From the Staying Keen in Later Life (SKILL) Study.

Objectives: Research has increasingly suggested a consistent relationship between peripheral hearing and selected measures of cognition in older adults. However, other studies yield conflicting findings. The primary purpose of the present study was to further elucidate the relationship between peripheral hearing and three domains of cognition and one measure of global cognitive status. It was hypothesized that peripheral hearing loss would be significantly associated with poorer performance across measures of cognition, even after adjusting for documented risk factors. No study to date has examined the relationship between peripheral hearing and such an extensive array of cognitive measures. Design: Eight hundred ninety-four older adult participants from the Staying Keen in Later Life study cohort were eligible, agreed to participate, and completed the baseline evaluation. Inclusion criteria were minimal to include a sample of older adults with a wide range of sensory and cognitive abilities. Multiple linear regression analyses were conducted to evaluate the extent to which peripheral hearing predicted performance on a global measure of cognitive status, as well as multiple cognitive measures in the domains of speed of processing (Digit Symbol Substitution and Copy, Trail Making Test Part A, Letter and Pattern Comparison, and Useful Field of View), executive function (Trail Making Test Part B and Stroop Color-Word Interference Task), and memory (Digit Span, Spatial Span, and Hopkins Verbal Learning Test). Results: Peripheral hearing, measured as the three-frequency pure-tone average (PTA) in the better ear, accounted for a significant, but minimal, amount of the variance in measures of speed of processing, executive function, and memory, as well as global cognitive status. Alternative measures of hearing (i.e., three-frequency PTAs in the right and left ears and a bilateral, six-frequency PTA [three frequencies per ear]) yielded similar findings across measures of cognition and did not alter the study outcomes in any meaningful way. Conclusions: Consistent with literature suggesting a significant relationship between peripheral hearing and cognition, and in agreement with our hypothesis, peripheral hearing was significantly related to 10 of 11 measures of cognition that assessed processing speed, executive function, or memory, as well as global cognitive status. Although evidence, including the present results, suggests a relationship between peripheral hearing and cognition, little is known about the underlying mechanisms. Examination of these mechanisms is a critical need to direct appropriate treatment.

ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial.

Background and Purpose— Intracerebral hemorrhage (ICH) is a devastating disease without a proven therapy to improve long-term outcome. Considerable controversy about the role of surgery remains. Minimally invasive endoscopic surgery for ICH offers the potential of improved neurological outcome. Methods— We tested the hypothesis that intraoperative computerized tomographic image–guided endoscopic surgery is safe and effectively removes the majority of the hematoma rapidly. A prospective randomized controlled study was performed on 20 subjects (14 surgical and 4 medical) with primary ICH of >20 mL volume within 48 hours of ICH onset. We prospectively used a contemporaneous medical control cohort (n=36) from the MISTIE trial (Minimally Invasive Surgery and r-tPA for ICH Evacuation). We evaluated surgical safety and neurological outcomes at 6 months and 1 year. Results— The intraoperative computerized tomographic image–guided endoscopic surgery procedure resulted in immediate reduction of hemorrhagic volume by 68±21.6% (interquartile range 59–84.5) within 29 hours of hemorrhage onset. Surgery was successfully completed in all cases, with a mean operative time of 1.9 hours (interquartile range 1.5–2.2 hours). One surgically related bleed occurred peri-operatively, but no patient met surgical safety stopping threshold end points for intraoperative hemorrhage, infection, or death. The surgical intervention group had a greater percentage of patients with good neurological outcome (modified Rankin scale score 0–3) at 180 and 365 days as compared with medical control subjects (42.9% versus 23.7%; P=0.19). Conclusions— Early computerized tomographic image–guided endoscopic surgery is a safe and effective method to remove acute intracerebral hematomas, with a potential to enhance neurological recovery. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00224770.

Association of Hearing Impairment with Incident Frailty and Falls in Older Adults

Objective: We aimed to determine whether hearing impairment (HI) in older adults is associated with the development of frailty and falls. Method: Longitudinal analysis of observational data from the Health, Aging and Body Composition study of 2,000 participants aged 70 to 79 was conducted. Hearing was defined by the pure-tone-average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better hearing ear. Frailty was defined as a gait speed of <0.60 m/s and/or inability to rise from a chair without using arms. Falls were assessed annually by self-report. Results: Older adults with moderate-or-greater HI had a 63% increased risk of developing frailty (adjusted hazard ratio [HR] = 1.63, 95% confidence interval [CI] = [1.26, 2.12]) compared with normal-hearing individuals. Moderate-or-greater HI was significantly associated with a greater annual percent increase in odds of falling over time (9.7%, 95% CI = [7.0, 12.4] compared with normal hearing, 4.4%, 95% CI = [2.6, 6.2]). Discussion: HI is independently associated with the risk of frailty in older adults and with greater odds of falling over time.