Russell T. Shinohara

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.

Automatic lesion incidence estimation and detection in multiple sclerosis using multisequence longitudinal MRI.

BACKGROUND AND PURPOSE: Detecting incidence and enlargement of lesions is essential in monitoring the progression of MS. In clinical trials, lesion load is observed by manually segmenting and comparing serial MR images, which is time consuming, costly, and prone to inter- and intraobserver variability. Subtracting images from consecutive time points nulls stable lesions, leaving only new lesion activity. We propose SuBLIME, an automated method for segmenting incident lesion voxels. MATERIALS AND METHODS: We used logistic regression models incorporating multiple MR imaging sequences and subtraction images from consecutive longitudinal studies to estimate voxel-level probabilities of lesion incidence. We used T1-weighted, T2-weighted, FLAIR, and PD volumes from a total of 110 MR imaging studies from 10 subjects. RESULTS: To assess the performance of the model, we assigned 5 subjects to a training set and the remaining 5 to a validation set. With SuBLIME, lesion incidence is detected and delineated in the validation set with an AUC of 99% (95% CI [97%, 100%]) at the voxel level. CONCLUSIONS: This fully automated and computationally fast method allows sensitive and specific detection of lesion incidence that can be applied to large collections of images. Using the explicit form of the statistical model, SuBLIME can easily be adapted to cases when more or fewer imaging sequences are available.

Population-Wide Principal Component-Based Quantification of Blood-Brain-Barrier Dynamics in Multiple Sclerosis

The processes by which new white matter lesions in multiple sclerosis (MS) develop are only partially understood. Much of this understanding has come through magnetic resonance imaging (MRI) of the human brain. One of the hallmarks of new lesion development in MS is enhancement on T(1)-weighted MRI scans following the intravenous administration of a gadolinium-based contrast agent that shortens the longitudinal relaxation time of the tissue. Visible enhancement on the MRI results from the opening of the blood-brain barrier and reveals areas of active inflammation. The incidence and number of existing enhancing lesions are common outcome measures used in MS treatment clinical trials. Dynamic-contrast-enhanced MRI (DCE-MRI) can estimate the rate at which contrast agents pass from the plasma to MS lesions. In this paper, we develop a principal component-based framework for the analysis of these data that provides biologically meaningful quantification of blood-brain-barrier opening in new MS lesions. To accomplish this, we use functional principal components analysis to study directions of variation in the voxel-level time series of intensities both within and across subjects. The analysis reveals and allows quantification of typical spatiotemporal enhancement patterns in acute MS lesions, providing measures of magnitude, rate, shape (ring-like vs. nodular), and dynamics (centrifugal vs. centripetal). Across 10 subjects with relapsing-remitting and primary progressive MS, we found subjects to have between 0 and 12 gadolinium-enhancing lesions, the majority of which enhanced centripetally. We quantified the spatiotemporal behavior within each of these lesions using novel measures. Further application of these techniques will determine the extent to which these lesion measures can predict or track response to therapy or long-term prognosis in this disorder.

Postoperative mortality after surgery for brain tumors by patient insurance status in the United States.

OBJECTIVE To examine whether being uninsured is associated with higher in-hospital postoperative mortality when undergoing surgery in the United States for a brain tumor. DESIGN Retrospective cohort study using the Nationwide Inpatient Sample, January 1, 1999, through December 31, 2008. SETTING The Nationwide Inpatient Sample contains all inpatient records from a stratified sample of 20% of hospitals in 37 states. PATIENTS A total of 28,581 patients, aged 18 to 65 years, who underwent craniotomy for a brain tumor. Three groups were studied: Medicaid recipients and privately insured and uninsured patients. MAIN OUTCOME MEASURE The main outcome measure was in-hospital postoperative death. Associations between this outcome and insurance status were examined within the full cohort and within the subset of patients with no comorbidity using Cox proportional hazards models. These models were stratified by hospital to control for any clustering effects that could arise from differing access to care. RESULTS In the unadjusted analysis, the mortality rate for privately insured patients was 1.3% (95% CI, 1.1%-1.4%) compared with 2.6% for uninsured patients (95% CI, 1.9%-3.3%; P < .001) and 2.3% for Medicaid recipients (95% CI, 1.8%-2.8%; P < .001). After adjusting for patient characteristics and stratifying by hospital in patients with no comorbidity, uninsured patients still had a higher risk of experiencing in-hospital death (hazard ratio, 2.62; 95% CI, 1.11-6.14; P = .03) compared with privately insured patients. In this adjusted analysis, the disparity was not conclusively present in Medicaid recipients (hazard ratio, 2.03; 95% CI, 0.97-4.23; P = .06). CONCLUSIONS Uninsured patients who underwent craniotomy for a brain tumor experienced the highest in-hospital mortality. Differences in overall health do not fully account for this disparity.

Guillain–Barré Syndrome in India: Population-based validation of the Brighton criteria

OBJECTIVE Case definitions of GBS were recently developed in response to the 2009 H1N1 vaccination programme but have undergone limited field testing. We validate the sensitivity of the Brighton Working Group case definitions for Guillain-Barré Syndrome (GBS) using a population-based cohort in India. METHODS The National Polio Surveillance Unit of India actively collects all cases of acute flaccid paralysis (AFP) in children <15 years old, including cases of GBS. Cases of GBS with available cerebrospinal fluid (CSF) and nerve conduction studies (NCS) results, neurological examination, clinical history, and exclusion of related diagnoses were selected (2002-2003). Relevant data were abstracted and entered into a central database. Sensitivity of the Brighton GBS criteria for level 3 of diagnostic certainty which requires no clinical laboratory testing, level 2 which employs CSF or NCS, and level 1 which employs both, were calculated. RESULTS 79 cases of GBS (mean age 6.5 years, range 4.0-14.5; 39% female) met the case definition. GBS cases were ascending (79%), symmetrical (85%), and bilateral (100%); involving lower extremity hypotonia (86%) and weakness (100%), upper extremity hypotonia (62%) and weakness (80%), areflexia/hyporeflexia (88%), respiratory muscles (22%), bulbar muscles (22%), and cranial nerves (13%). Four limbs were involved in 80% of cases. Mean time to maximal weakness was 5.2 days (range 0.5-30 days) with nadir GBS disability scores of 3 (7%), 4 (67%), 5 (15%), 6 (10%), or unclear (1%). CSF (mean time to lumbar puncture 29 days) was normal in 29% with cytoalbuminologic dissociation in 65% (mean protein 105 mg/dL, range 10-1000; mean cell count 11/μL, range 0-220, n=4 with >50 cells/μL). Significant improvement occurred in 73% whereas death (9%) occurred 6-29 days after sensorimotor symptom onset. The majority of cases (86%) fulfilled Brighton level 3, level 2 (84%), and level 1 (62%) of diagnostic certainty. CONCLUSION The diagnosis of GBS can be made using Brighton Working Group criteria in India with moderate to high sensitivity. Brighton Working Group case definitions are a plausible standard for capturing a majority of cases of GBS in field operations in low income settings during AFP surveillance.

Oral and inactivated poliovirus vaccines in the newborn: A review

BACKGROUND Oral poliovirus vaccine (OPV) remains the vaccine-of-choice for routine immunization and supplemental immunization activities (SIAs) to eradicate poliomyelitis globally. Recent data from India suggested lower than expected immunogenicity of an OPV birth dose, prompting a review of the immunogenicity of OPV or inactivated poliovirus vaccine (IPV) when administered at birth. METHODS We evaluated the seroconversion and reported adverse events among infants given a single birth dose (given ≤7 days of life) of OPV or IPV through a systematic review of published articles and conference abstracts from 1959 to 2011 in any language found on PubMed, Google Scholar, or reference lists of selected articles. RESULTS 25 articles from 13 countries published between 1959 and 2011 documented seroconversion rates in newborns following an OPV dose given within the first seven days of life. There were 10 studies that measured seroconversion rates between 4 and 8 weeks of a single birth dose of TOPV, using an umbilical cord blood draw at the time of birth to establish baseline antibody levels. The percentage of newborns who seroconverted at 8 weeks range from 6-42% for poliovirus type 1, 2-63% for type 2, and 1-35% for type 3. For mOPV type 1, seroconversion ranged from 10 to 76%; mOPV type 3, the range was 12-58%; and for the one study reporting bOPV, it was 20% for type 1 and 7% for type 3. There were four studies of IPV in newborns with a seroconversion rate of 8-100% for serotype 1, 15-100% for serotype 2, and 15-94% for serotype 3, measured at 4-6 weeks of life. No serious adverse events related to newborn OPV or IPV dosing were reported, including no cases of acute flaccid paralysis. CONCLUSIONS There is great variability of the immunogenicity of a birth dose of OPV for reasons largely unknown. Our review confirms the utility of a birth dose of OPV, particularly in countries where early induction of polio immunity is imperative. IPV has higher seroconversion rates in newborns and may be a superior choice in countries which can afford IPV, but there have been few studies of an IPV dose for newborns.

Designs combining instrumental variables with case-control: estimating principal strata causal effects.

The instrumental variables framework is commonly used for the estimation of causal effects from cohort samples. However, the combination of instrumental variables with more efficient designs such as case-control sampling requires new methodological consideration. For example, as the use of Mendelian randomization studies is increasing and the cost of genotyping and gene expression data can be high, the analysis of data gathered from more cost-effective sampling designs is of prime interest. We show that the standard instrumental variables analysis does not appropriately estimate the causal effects of interest when the instrumental variables design is combined with the case-control design. We also propose a method that can estimate the causal effects in such combined designs. We illustrate the method with a study in oncology.

Injury Deaths among People with Epilepsy in Rural Bangladesh: A Retrospective Population-Based Study

BACKGROUND Accidental death in people with epilepsy (PWE) has been described in high income settings where the relative risk of death is known to be higher than in the standard population. Population-based studies of injury deaths among PWE in developing countries are uncommon. METHODS A population-based verbal autopsy study in Matlab, Bangladesh, performed at a health and demographic surveillance system site (mean population 223,886 in 142 villages), was used to assess the possible causes of all deaths. All cases of accidental injury (2005-2008) were evaluated and compared between people with and without a diagnosis of epilepsy. RESULTS There were 12 accidental deaths among PWE (8 females, age range 12-58 years old) out of a total of 316 deaths due to accidental injuries (3.8% of all injury deaths). Causes of mortality were drowning (n=10) and burns (n=2). The proportion of deaths due to drowning among PWE was significantly higher than that of the standard population (83% (10/12) vs. 7% (21/304), relative risk 12.6 (95% CI, 7.7-20.7, p<0.0001)). Mortality due to injury in PWE occurred at a younger age compared to people without epilepsy (mean difference 20.7 years (95% CI 6.7, 34.3), p<0.004). CONCLUSIONS There is a high proportion of accidental deaths due to drowning in PWE in Bangladesh compared to the standard population. Given the risk of seasonal flooding and low level of formal education, programs targeting water safety for PWE at all ages should be emphasized, appropriate for level of ability.

A broad symmetry criterion for nonparametric validity of parametrically based tests in randomized trials.

Pilot phases of a randomized clinical trial often suggest that a parametric model may be an accurate description of the trials longitudinal trajectories. However, parametric models are often not used for fear that they may invalidate tests of null hypotheses of equality between the experimental groups. Existing work has shown that when, for some types of data, certain parametric models are used, the validity for testing the null is preserved even if the parametric models are incorrect. Here, we provide a broader and easier to check characterization of parametric models that can be used to (i) preserve nonparametric validity of testing the null hypothesis, i.e., even when the models are incorrect, and (ii) increase power compared to the non- or semiparametric bounds when the models are close to correct. We demonstrate our results in a clinical trial of depression in Alzheimers patients.

Population-Wide Model-Free Quantification of Blood-Brain-Barrier Dynamics in Multiple Sclerosis

The processes by which new white matter lesions in multiple sclerosis (MS) develop are only partially understood. Recently developed lesions tend to enhance on magnetic resonance imaging (MRI) scans following the intravenous administration of a contrast agent. In this paper, we develop a model-free framework for the analysis of these data that provides biologically meaningful quantification of this blood-brain barrier opening.