Farrah J. Mateen

Neurological Injury in Adults Treated With Extracorporeal Membrane Oxygenation

BACKGROUND Extracorporeal membrane oxygenation (ECMO) may be urgently used as a last resort form of life support when all other treatment options for potentially reversible cardiopulmonary injury have failed. OBJECTIVE To examine the range and frequency of neurological injury in ECMO-treated adults. DESIGN Retrospective clinicopathological cohort study. SETTING Mayo Clinic, Rochester, Minnesota. PATIENTS A prospectively collected registry of all patients 15 years or older treated with ECMO for 12 or more hours from January 2002 to April 2010. INTERVENTION Patients were analyzed for potential risk factors for neurological events and death using logistic regression and Cox proportional hazards models. MAIN OUTCOME MEASURES Neurological diagnosis and/or death. RESULTS A total of 87 adults were treated (35 female [40%]; median age, 54 years [interquartile range, 31]; mean duration of ECMO, 91 hours [interquartile range, 100]; overall survival >7 days after ECMO, 52%). Neurological events occurred in 42 patients who received ECMO (50%; 95% confidence interval [CI], 39%-61%). Diagnoses included subarachnoid hemorrhage, ischemic watershed infarctions, hypoxic-ischemic encephalopathy, unexplained coma, and brain death. Death in patients who received ECMO who did not require antecedent cardiopulmonary resuscitation was associated with increased age (odds ratio, 1.24 per decade; 95% CI, 1.03-1.50; P = .02) and lower minimum arterial oxygen pressure (odds ratio, 0.79; 95% CI, 0.68-0.92; P = .03). Although stroke was rarely diagnosed clinically, 9 of 10 brains studied at autopsy demonstrated hypoxic-ischemic and hemorrhagic lesions of vascular origin. CONCLUSION Severe neurological sequelae occur frequently in adult ECMO-treated patients with otherwise reversible cardiopulmonary injury (conservative estimate, 50%) and include a range of potentially fatal neurological diagnoses that may be due to the precipitating event and/or ECMO treatment.

Progressive Multifocal Leukoencephalopathy in Transplant Recipients

Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), a rare demyelinating disorder caused by oligodendrocyte destruction by JC virus.

Air pollution as an emerging global risk factor for stroke.

AMBIENT AIR POLLUTION EXPOSURE IS CONSIDERED AN important factor associated with mortality worldwide. In high-income countries, air pollution was associated with 2.5% of all deaths (eighth leading risk factor for mortality). Increasing evidence suggests that the highest proportion of air pollution–related deaths, especially those related to particulate matter (PM), are not pulmonary related as might be speculated, but are due to cardiovascular causes. The American Heart Association concluded in an updated scientific statement that the overall evidence is consistent with PM playing a causal role in cardiovascular morbidity and mortality. Although adverse cardiopulmonary outcomes have been the focus of most recent studies, air pollution–related stroke has received less attention. This relationship may represent a serious and increasing burden to populations, particularly in the developing world, and merits further attention on global research and public policy agendas. Air pollution consists of a heterogeneous mixture of PM and gases (eg, ozone, carbon monoxide). Fossil fuel combustion (eg, traffic, power generation, industry) is a major source; however, indoor pollutants and the burning of biomass fuels are also significant contributors in many countries. Early studies, including analyses of the Great London Fog of 1952, a renowned pollution episode of the 20th century, found an increased risk of stroke deaths attributable to a short-term extreme rise in air pollution. This relationship continues to be demonstrated even at lower levels. In most cases, exposure to each pollutant reported, including gases and particles of varying sizes, is associated with an increased risk of cerebrovascular events. Numerous between-study differences exist, including demographic characteristics, measured pollutants, temporal risk associations, and the ascertainment of stroke and stroke outcomes, making direct comparisons difficult. However, the relative risk for stroke-related mortality may reach 2.04 for a 21.3 μg/m-increase in same-day PM10 levels (elderly individuals in Seoul, South Korea), whereas the incidence rate increase for stroke hospitalizations may reach 13% (95% confidence interval [CI], 4%-22%) when previous-day PM10 levels are greater than 30 μg/m vs less than 15 μg/m (in Sweden). In general, the risk of stroke appears to be greater for ischemic stroke compared with hemorrhagic stroke, and the association with PM is at least as strong as with gaseous pollutants. In a prospective study that evaluated both stroke and heart disease outcomes in women, long-term exposure to air pollution was associated with an increased risk for a cerbrovascular disease event (odds ratio, 1.35; 95% CI, 1.081.68) that was comparable with that for myocardial infarction (odds ratio, 1.06; 95% CI, 0.85-1.34) and all coronary disease events (odds ratio, 1.21; 95% CI, 1.08-1.68). However, some studies did not report a significant association between air pollution exposure and stroke risk. These studies suggested that the pollutant composition may be less harmful in some regions, some populations may be less susceptible, or that methodological differences (pollutant levels, study designs or power) could affect the reported strokeexposure association. A variety of noncausal factors may also explain the different effects of air pollution on stroke compared with heart disease incidence. Stroke is more heterogeneous in nature (ischemic, hemorrhagic) and etiology (embolic, thrombotic), has no simple diagnostic biomarker, and involves costly confirmatory imaging. These factors may limit risk measurements for individual air pollutants and stroke using large national registries and community studies. Studies frequently consider hemorrhagic stroke and ischemic stroke as a single outcome although the risk profile and outcomes of hemorrhagic and ischemic stroke are distinct. Studies from countries with higher air pollutant levels (Taiwan, China, South Korea) and comparatively lower air pollutant levels (Finland, Canada) demonstrate that shortterm exposures are associated with a higher risk of stroke. For example, in the US Medicare population, elderly patients experienced an increase in stroke hospitalization on the same day of exposure to higher PM levels. In contrast, fewer prospective studies have reported stroke risk associated with longer-term PM exposures. One study showed fatal and total stroke risks associated with PM exposures were higher over the several years of follow-up than typically reported by shorter-term analyses. This suggests that for any

Statistical normalization techniques for magnetic resonance imaging

While computed tomography and other imaging techniques are measured in absolute units with physical meaning, magnetic resonance images are expressed in arbitrary units that are difficult to interpret and differ between study visits and subjects. Much work in the image processing literature on intensity normalization has focused on histogram matching and other histogram mapping techniques, with little emphasis on normalizing images to have biologically interpretable units. Furthermore, there are no formalized principles or goals for the crucial comparability of image intensities within and across subjects. To address this, we propose a set of criteria necessary for the normalization of images. We further propose simple and robust biologically motivated normalization techniques for multisequence brain imaging that have the same interpretation across acquisitions and satisfy the proposed criteria. We compare the performance of different normalization methods in thousands of images of patients with Alzheimers disease, hundreds of patients with multiple sclerosis, and hundreds of healthy subjects obtained in several different studies at dozens of imaging centers.

HIV-associated opportunistic infections of the CNS

Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus, malnutrition, and the effects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic infections remain a serious burden worldwide. Most opportunistic infections can be recognised by a combination of characteristic clinical and radiological features and are treatable, but some important challenges remain in the diagnosis and management of HIV-associated opportunistic infections.

Long-term cognitive outcomes following out-of-hospital cardiac arrest A population-based study

Objective: To report the neurologic outcomes in long-term survivors of out-of-hospital cardiac arrest with ventricular fibrillation as the presenting rhythm (OHCA VF) at a population level. Methods: All adults who experienced OHCA VF in Olmsted County, MN, from 1990 to 2008, survived more than 6 months postarrest, and were alive at the time of study recruitment were invited to participate in structured neuropsychological testing and a neurologic examination. Cognitive test results were compared to the normal population using the Mayos Older Adults Normative Studies. Linear regression models were fit to evaluate each neuropsychological test result in relation to call-to-shock time, sex, age at cardiac arrest, time elapsed since event, witnessed vs unwitnessed arrest, and administration of bystander cardiopulmonary resuscitation. Results: Of 332 OHCA VF arrests, 140 people (42.2%, 95% confidence interval 36.9%–47.5%) survived to discharge. No patient entered a minimally conscious or permanent vegetative state. Long-term survivors (n = 47, median survival 7.8 years postarrest) had lower scores on measures of long-term memory and learning efficiency (p = 0.001) but higher than average scores on verbal IQ (p = 0.001). Nearly all survivors were functionally independent and scored high on the Mini-Mental State Examination (MMSE) (median Barthel Index 100/100, median MMSE 29/30). Conclusions: Long-term survivors of OHCA VF have long-term memory deficits compared to the normal population at the same age and education level. These findings provide a baseline for cognitive outcomes studies of OHCA VF as new techniques are developed to improve survival.

Outcomes of Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 90 Years or Older

Although age is a major risk factor for stroke, physicians are often reluctant to use thrombolytic agents in those who are very old. No published study provides detailed information on the use of intravenous tissue plasminogen activator (tPA) in patients aged 90 years or older. We retrospectively reviewed the use of intravenous tPA for patients 90 years or older who were admitted with acute ischemic stroke to the hospital at 4 academic centers from March 1, 1999, to March 1, 2008. We reviewed the clinical features of the patients at presentation, complications, and outcomes. Twenty-two patients (11 women; median age, 93 years; range, 90-101 years) were identified who had received intravenous tPA for symptoms of acute ischemic stroke (average time to treatment, 143 minutes; range, 90-180 minutes; no tPA protocol violations; mean National Institutes of Health Stroke Scale score, 15; range, 5-28). Nearly all patients were highly functional at baseline (median modified Rankin Scale [mRS] score, 1; median Barthel Index score, 95), and all but one performed the activities of daily living with little or no assistance before stroke. By the 30-day follow-up, 2 patients (9%) had a favorable outcome (mRS score, 0-2) and 2 (9%) had moderate disability (mRS score, 3). Most patients died (n=10) or experienced severe disability, defined as an mRS score of 4 or 5 (n=5). Asymptomatic intracerebral hemorrhage occurred in 3 patients (14%) and was nonfatal. Most patients aged 90 years or older who received intravenous tPA for acute ischemic stroke had poor 30-day functional outcomes or died. Intravenous tPA treatment in this age group does not improve the outcome of ischemic stroke.

OASIS is Automated Statistical Inference for Segmentation, with applications to multiple sclerosis lesion segmentation in MRI☆

Magnetic resonance imaging (MRI) can be used to detect lesions in the brains of multiple sclerosis (MS) patients and is essential for diagnosing the disease and monitoring its progression. In practice, lesion load is often quantified by either manual or semi-automated segmentation of MRI, which is time-consuming, costly, and associated with large inter- and intra-observer variability. We propose OASIS is Automated Statistical Inference for Segmentation (OASIS), an automated statistical method for segmenting MS lesions in MRI studies. We use logistic regression models incorporating multiple MRI modalities to estimate voxel-level probabilities of lesion presence. Intensity-normalized T1-weighted, T2-weighted, fluid-attenuated inversion recovery and proton density volumes from 131 MRI studies (98 MS subjects, 33 healthy subjects) with manual lesion segmentations were used to train and validate our model. Within this set, OASIS detected lesions with a partial area under the receiver operating characteristic curve for clinically relevant false positive rates of 1% and below of 0.59% (95% CI; [0.50%, 0.67%]) at the voxel level. An experienced MS neuroradiologist compared these segmentations to those produced by LesionTOADS, an image segmentation software that provides segmentation of both lesions and normal brain structures. For lesions, OASIS out-performed LesionTOADS in 74% (95% CI: [65%, 82%]) of cases for the 98 MS subjects. To further validate the method, we applied OASIS to 169 MRI studies acquired at a separate center. The neuroradiologist again compared the OASIS segmentations to those from LesionTOADS. For lesions, OASIS ranked higher than LesionTOADS in 77% (95% CI: [71%, 83%]) of cases. For a randomly selected subset of 50 of these studies, one additional radiologist and one neurologist also scored the images. Within this set, the neuroradiologist ranked OASIS higher than LesionTOADS in 76% (95% CI: [64%, 88%]) of cases, the neurologist 66% (95% CI: [52%, 78%]) and the radiologist 52% (95% CI: [38%, 66%]). OASIS obtains the estimated probability for each voxel to be part of a lesion by weighting each imaging modality with coefficient weights. These coefficients are explicit, obtained using standard model fitting techniques, and can be reused in other imaging studies. This fully automated method allows sensitive and specific detection of lesion presence and may be rapidly applied to large collections of images.

Hypertension prevalence and Framingham risk score stratification in a large HIV-positive cohort in Uganda.

Background: To report the prevalence of hypertension and projected 10-year absolute risk of acute cardiovascular disease in a large prospectively followed cohort of HIV-positive youth and adults beginning antiretroviral therapy in sub-Saharan Africa. Methods: HIV-positive individuals seeking HIV treatment, ages 13 years and older, were assessed for repeated blood pressure measurements over the first year following initiation of antiretroviral therapy, including serum total cholesterol, high-density lipoprotein, CD4 cell count and related clinical and laboratory measurements. Outcomes include hypertension, defined according to the 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure categories, and Framingham Risk Score based 10-year cardiovascular disease risk estimates. Results: Five thousand, five hundred and sixty-three patients had at least two blood pressure measurements on at least two separate occasions during the first year of antiretroviral therapy [median age of therapy initiation 34, first and third quartile (Q1–Q3) 28–40 years, 1841 (33.1%) men, baseline CD4 cell count 161 cells/&mgr;l (Q1–Q3 72–231 cells/&mgr;l]. Hypertension was diagnosed in 1551 patients [27.9%, 95% confidence interval (CI) 26.7– 29.1] including 786 (14.1%, 95% CI 13.2–15.1) who met criteria for stage 2 hypertension. The age-standardized prevalence for Ugandans aged 13 or more was 24.8% (95% CI 23.8–26.1). Among those with complete laboratory studies (n = 1102), nearly all women were in the 10% or less 10-year Framingham Risk Score category, but 20% of men were at at least 10% or more long-term risk of acute cardiovascular disease. Conclusion: : Efforts to combine HIV treatment with vascular disease risk factor prevention and management are urgently needed to address noncommunicable disease multimorbidity in HIV-positive persons in sub-Saharan Africa, particularly in men.

Neurologic disorders incidence in HIV+ vs HIV− men Multicenter AIDS Cohort Study, 1996–2011

Objective: To study the incidence and pattern of neurologic disorders in a large cohort of HIV-positive men, compared with HIV-negative men, in the era of highly active antiretroviral therapy (HAART). Methods: The Multicenter AIDS Cohort Study is a prospective study of men who have sex with men enrolled in 4 cities in the United States. We compared HIV-positive vs HIV-negative men for incidence and category of neurologic diagnoses in the HAART era (July 1, 1996, to last known follow-up or death, on or before July 1, 2011). Results: There were 3,945 participants alive during the HAART era (2,083 HIV negative, 1,776 HIV positive, and 86 who became infected with HIV during the study period) including 3,427 who were older than 40 years of age. Median age at first neurologic diagnosis among all participants alive in the HAART era was lower in HAART-treated HIV-positive vs HIV-negative men (48 vs 57 years of age, p < 0.001). Incidence of neurologic diagnoses was higher in HAART-treated HIV-positive vs HIV-negative men (younger than 40 years: 11.4 vs 0 diagnoses per 1,000 person-years [p < 0.001]; 40–49 years: 11.6 vs 2.0 [p < 0.001]; 50–60 years: 15.1 vs 3.0 [p < 0.001]; older than 60 years: 17.0 vs 5.7 [p < 0.01]). Excess neurologic disease was found in the categories of nervous system infections (p < 0.001), dementia (p < 0.001), seizures/epilepsy (p < 0.01), and peripheral nervous system disorders (p < 0.001), but not stroke (p = 0.60). Conclusions: HIV-positive men receiving HAART have a higher burden of neurologic disease than HIV-negative men and develop neurologic disease at younger ages.