Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Neuropsychological Changes in Patients Undergoing Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND: Evaluation of differences in neuropsychological outcomes in patients undergoing surgical clipping (SC) vs endovascular coiling (EC) for unruptured cerebral aneurysms is essential in guiding patients seeking treatment of asymptomatic cerebral aneurysms. OBJECTIVE: To perform a prospective longitudinal analysis of neuropsychological outcomes in patients who underwent microsurgery or coiling for unruptured cerebral aneurysms. METHODS: SC (50 patients), EC (35 patients), and healthy controls (43 individuals) were included. A detailed neuropsychological evaluation was performed at baseline and at 2 wk, 3 mo, 6 mo, and 12 mo. Student's t-test was utilized for comparing neuropsychological outcomes among the 3 groups. A mixed-effects model allowed for evaluation of neuropsychological outcome changes among the groups over time. RESULTS: Both the SC and EC groups had nonsignificant differences in procedure-related complications. SC patients had the greatest initial declines in short-term memory, fine motor control, and executive functioning; however, these patients also recovered to a greater degree in neuropsychological functionality. Over the next year, all groups achieved similar neuropsychological outcomes with no significant differences among groups. CONCLUSION: Whereas the initial decline in neuropsychological functioning was greater for SC patients, 1 yr after treatment there was no significant difference in neuropsychological outcome among the SC, EC, and healthy control groups.

Executive Functioning at Baseline Prospectively Predicts Depression Treatment Response.

OBJECTIVE: Existing cognitive and clinical predictors of treatment response to date are not of sufficient strength to meaningfully impact treatment decision making and are not readily employed in clinical settings. This study investigated whether clinical and cognitive markers used in a tertiary care clinic could predict response to usual treatment over a period of 4 to 6 months in a sample of 75 depressed adults. METHODS: Patients (N = 384) were sequentially tested in 2 half-day clinics as part of a quality improvement project at an outpatient tertiary care center between August 2003 and September 2007; additional subjects evaluated in the clinic between 2007 and 2009 were also included. Diagnosis was according to DSM-IV-TR criteria and completed by residents and attending faculty. Test scores obtained at intake visits on a computerized neuropsychological screening battery were the Parametric Go/No-Go task and Facial Emotion Perception Task. Treatment outcome was assessed using 9-item Patient Health Questionnaire (PHQ-9) self-ratings at follow-up (n = 75). Usual treatment included psychotropic medication and psychotherapy. Decline in PHQ-9 scores was predicted on the basis of baseline PHQ-9 score and education, with neuropsychological variables entered in the second step. RESULTS: PHQ-9 scores declined by 46% at follow-up (56% responders). Using 2-step multiple regression, baseline PHQ-9 score (P ≤ .05) and education (P ≤ .01) were significant step 1 predictors of percent change in PHQ-9 follow-up scores. In step 2 of the model, faster processing speed with interference resolution (go reaction time) independently explained a significant amount of variance over and above variables in step 1 (12% of variance, P < .01), while other cognitive and affective skills did not. This 2-step model accounted for 28% of the variance in treatment change in PHQ-9 scores. Processing speed with interference resolution also accounted for 12% variance in treatment and follow-up attrition. CONCLUSIONS: Use of executive functioning assessments in clinics may help identify individuals with cognitive weaknesses at risk for not responding to standard treatments.

Very Early Administration of Progesterone Does Not Improve Neuropsychological Outcomes in Subjects with Moderate to Severe Traumatic Brain Injury.

A Phase III, double-blind, placebo-controlled trial (ProTECT III) found that administration of progesterone did not reduce mortality or improve functional outcome as measured by the Glasgow Outcome Scale Extended (GOSE) in subjects with moderate to severe traumatic brain injury. We conducted a secondary analysis of neuropsychological outcomes to evaluate whether progesterone is associated with improved recovery of cognitive and motor functioning. ProTECT III was conducted at 49 level I trauma centers in the United States. Adults with moderate to severe TBI were randomized to receive intravenous progesterone or placebo within 4 h of injury for a total of 4 days. At 6 months, subjects underwent evaluation of memory, attention, executive functioning, language, and fine motor coordination/dexterity. Chi-square analysis revealed no significant difference in the proportion of subjects (263/280 progesterone, 283/295 placebo) with Galveston Orientation and Amnesia Test scores ≥75. Analyses of covariance did not reveal significant treatment effects for memory (Buschke immediate recall, p = 0.53; delayed recall, p = 0.94), attention (Trails A speed, p = 0.81 and errors, p = 0.22; Digit Span Forward length, p = 0.66), executive functioning (Trails B speed, p = 0.97 and errors, p = 0.93; Digit Span Backward length, p = 0.60), language (timed phonemic fluency, p = 0.05), and fine motor coordination/dexterity (Grooved Pegboard dominant hand time, p = 0.75 and peg drops, p = 0.59; nondominant hand time, p = 0.74 and peg drops, p = 0.61). Pearson Product Moment Correlations demonstrated significant (p < 0.001) associations between better neuropsychological performance and higher GOSE scores. Similar to the ProTECT III trial's results of the primary outcome, the secondary outcomes do not provide evidence of a neuroprotective effect of progesterone.

Very early administration of progesterone for acute traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams.

OBJECTIVES: The objective was to evaluate safety of intravenous (IV) tissue plasminogen activator (tPA) delivered without dedicated thrombolytic stroke teams. METHODS: This was a retrospective, observational study of patients treated between 1996 and 2005 at four southeastern Michigan hospital emergency departments (EDs) with a prospectively defined comparison to the National Institute of Neurological Disorders and Stroke (NINDS) tPA stroke study cohort. Main outcome measures were mortality, intracerebral hemorrhage (ICH), systemic hemorrhage, neurologic recovery, and guideline violations. RESULTS: A total of 273 consecutive stroke patients were treated by 95 emergency physicians (EPs) using guidelines and local neurology resources. One-year mortality was 27.8%. Unadjusted Cox model relative risk (RR) of mortality compared to the NINDS tPA treatment and placebo groups was 1.20 (95% confidence interval [CI] = 0.87 to 1.64) and 1.04 (95% CI = 0.76 to 1.41), respectively. The rate of significant ICH by computed tomography (CT) criteria was 6.6% (odds ratio [OR] = 1.03, 95% CI = 0.56 to 1.90 compared to the NINDS tPA treatment group). The proportions of symptomatic ICH by two other prespecified sets of clinical criteria were 4.8 and 7.0%. The rate of any ICH within 36 hours of treatment was 9.9% (RR = 0.94, 95% CI = 0.58 to 1.51 compared to the NINDS tPA group). The occurrence of major systemic hemorrhage (requiring transfusion) was 1.1%. Functional recovery by the modified Rankin Scale score (mRS = 0 to 2) at discharge occurred in 38% of patients with a premorbid disability mRS < 2. Guideline deviations occurred in the ED in 26% of patients and in 25% of patients following admission. CONCLUSIONS: In these EDs there was no evidence of increased risk with respect to mortality, ICH, systemic hemorrhage, or worsened functional outcome when tPA was administered without dedicated thrombolytic stroke teams. Additional effort is needed to improve guideline compliance.

Lack of association between pretreatment neurology consultation and subsequent protocol deviation in tissue plasminogen activator-treated patients with stroke.

BACKGROUND AND PURPOSE: We evaluated the hypothesis that consultation with neurology would be associated with fewer protocol deviations in tissue plasminogen activator-treated patients with stroke. METHODS: A retrospective analysis of consecutive tissue plasminogen activator-treated patients with acute patients was performed. Using chi(2) tests, the proportion of patients with a protocol deviation was calculated and compared between those with evidence of a neurology consultation and those without. Logistic regression was then used to determine the OR for protocol deviation at the same time as controlling for clinical presentation covariates. RESULTS: Two hundred seventy-three subjects were included. Protocol deviation rates did not significantly differ between those with (44%) and those without (41%) a consultation. The adjusted OR for deviation comparing any consultation versus nonconsultation was 1.25 (95% CI: 0.58 to 2.68). There was no statistically significant difference between symptomatic intracranial hemorrhage and in-hospital mortality rates between the groups. The proportion of patients with pretreatment deviations not related to timing was low in both the consultation (9.7%) and nonconsultation groups (8.1%). CONCLUSIONS: Neurological consultation was not found to be associated with decreased protocol deviations in this cohort, although the high proportion of deviations with and without consultation suggests that quality improvement is needed. Most observed pretreatment deviations were attributable to timing. As acute stroke care becomes more efficient and additional methods in reducing door-to-treatment times are sought, models in which emergency physicians direct the initial phase of treatment may merit further consideration.

Lack of association between hyperglycaemia at arrival and clinical outcomes in acute stroke patients treated with tissue plasminogen activator.

RATIONALE: Hyperglycaemia is associated with adverse outcomes in some studies of acute ischaemic stroke. AIMS: We hypothesised that in thrombolytic-treated stroke patients, hyperglycaemia would be independently associated with haemorrhagic transformation and unfavourable outcome. DESIGN: Consecutive rt-PA-treated acute ischaemic stroke patients presenting to four emergency departments were analysed. Associations of initial blood glucose and survival to hospital discharge, symptomatic intracerebral haemorrhage, any form of intracerebral haemorrhage, and disability at hospital discharge were determined. Potentially confounding factors of age, National Institutes of Health Stroke Scale, and smoking were analysed by univariate logistic regression and those with P<0.3 included in the multivariate model. STUDY OUTCOME: In 268 patients, initial glucose values ranged from 62 to 507 mg/dl (mean 131). Elevated glucose at arrival was not significantly associated with any adverse clinical outcomes. A trend towards higher mortality in hyperglycaemic patients (odds ratio 1.71 per 100 mg/dl increase in glucose, 95% confidence interval 0.92-3.13, P=0.08) was seen, but is of unclear significance, and was not corroborated by effects on discharge disability, symptomatic intracerebral haemorrhage or intracerebral haemorrhage. CONCLUSIONS: Thrombolytic-treated stroke patients with hyperglycaemia at presentation did not have significantly worse outcomes than others in this cohort. These data fail to confirm previously described associations seen in similarly sized studies. Further study of these associations and their magnitude are necessary to better define the relationship between serum glucose and outcome in thrombolytic-treated acute ischaemic stroke.

Resource utilization and outcome at a university versus a community teaching hospital in tPA treated stroke patients: a retrospective cohort study.

BACKGROUND: Comparing patterns of resource utilization between hospitals is often complicated by biases in community and patient populations. Stroke patients treated with tissue plasminogen activator (tPA) provide a particularly homogenous population for comparison because of strict eligibility criteria for treatment. We tested whether resource utilization would be similar in this homogenous population between two hospitals located in a single Midwestern US community by comparing use of diagnostic testing and associated outcomes following treatment with t-PA. METHODS: Medical records from 206 consecutive intravenous t-PA-treated stroke patients from two teaching hospitals (one university, one community-based) were reviewed. Patient demographics, clinical characteristics and outcome were analyzed, as were the frequency of use of CT, MRI, MRA, echocardiography, angiography, and EEG. RESULTS: Seventy-nine and 127 stroke patients received t-PA at the university and community hospitals, respectively. The two patient populations were demographically similar. There were no differences in stroke severity. All outcomes were similar at both hospitals. Utilization of CT scans, and non-invasive carotid and cardiac imaging studies were similar at both hospitals; however, brain MR, TEE, and catheter angiography were used more frequently at the university hospital. EEG was obtained more often at the community hospital. CONCLUSIONS: Utilization of advanced brain imaging and invasive diagnostic testing was greater at the university hospital, but was not associated with improved clinical outcomes. This could not be explained on the basis of stroke severity or patient characteristics. This variation of practice suggests substantial opportunities exist to reduce costs and improve efficiency of diagnostic resource use as well as reduce patient exposure to risk from diagnostic procedures.

Preliminary effects of pagoclone, a partial GABA(A) agonist, on neuropsychological performance.

Pagoclone is a novel cyclopyrrolone that acts as a partial GABA(A) receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals' performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use.

Surgeons outperform normative controls on neuropsychologic tests, but age-related decay of skills persists.

BACKGROUND: The present study was undertaken to determine if psychomotor and visual-spatial abilities improve as a result of surgical training or are enhanced at baseline in those individuals choosing a surgical career. METHODS: Medical students entering a surgical field and practicing surgeons performed a series of neuropsychologic tests. Performance was compared between surgeon groups, as well as with normative aged-matched controls. RESULTS: An age-related decline was noted in the performance of all exercises, with the medical student group outperforming the midcareer surgeons, who in turn outperformed the senior surgeons. Interestingly, however, all 3 groups significantly outperformed their normative control groups on some or all tasks. CONCLUSIONS: Improved visual memory and psychomotor performance compared with normative controls appears to be present at baseline rather than resulting from surgical training. Decline in performance with age is observed, however, and this should be considered when an older surgeon is learning new visually complex procedures.

The sensitivity and psychometric properties of a brief computer-based cognitive screening battery in a depression clinic.

At present, there is poor accuracy in assessing cognitive and vegetative symptoms in depression using clinician or self-rated measures, suggesting the need for development of standardized tasks to assess these functions. The current study assessed the psychometric properties and diagnostic specificity of a brief neuropsychological screening battery designed to assess core signs of depression; psychomotor retardation, attention and executive functioning difficulties, and impaired emotion perception within an outpatient psychiatry setting. Three hundred eighty-four patients with mood disorders and 77 healthy volunteers participated. A large percentage of patients met diagnostic criteria for Major Depressive Disorder alone (49%) or with another comorbid psychiatric disorder (24%). A brief, 25-min battery of computer-based tests was administered to control participants and patients measuring the constructs of inhibitory control, attention, visual perception, and both executive and visual processing speed. The patient groups performed significantly worse than the control group regardless of diagnosis on visual perception and attention accuracy and processing speed factors. Surprisingly, the anxiety disorder group performed better than several other psychiatric disorder groups in inhibitory control accuracy. Developing valid and reliable measures of cognitive signs in mood disorders creates excellent opportunities for tracking cognitive status prior to initiation of treatment, and allows for reliable retest following treatment.

Recovery of cognitive function after surgery for aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Abnormalities in neurocognitive function are common after surgery for aneurysmal subarachnoid hemorrhage, even among patients with good functional outcomes. The time course of neurocognitive recovery, along with the long-term effects of mild intraoperative hypothermia (33 degrees C) and aneurysm location, is unknown. We determined these in a subset of subarachnoid hemorrhage patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST). METHODS: We performed a longitudinal, multicenter, prospective, blinded study of adult IHAST patients with a Glasgow Outcome Score=1 or 2 (independent function), 3 months postsurgery and a matched control group (n=45). Subjects were tested with a 5-test cognitive function battery and standard neurological evaluations at 3, 9 and 15 months postsurgery. The primary outcome measure was a composite score on cognitive test performance. RESULTS: There were 303 IHAST patients available for inclusion: 218 eligible, 185 enrolled (89 hypothermic, 96 normothermic). Significant cognitive improvement was noted from 3 to 9 (P<0.001) and 3 to 15 (P<0.001) months in both hypothermic and normothermic groups, even after adjusting for practice effects observed in the control group. No significant change was identified between 9 and 15 months. Neither mild hypothermia nor aneurysm location (anterior communicating artery versus others) had a significant effect on recovery over time or frequency of cognitive impairment. Compared with control group, the frequency of cognitive impairment (Z score <-1.96) in all patients at 3, 9 and 15 months was 36%, 26% and 23%, respectively. CONCLUSIONS: In this population, cognitive improvement continued beyond 3 months, with a plateau between 9 and 15 months. This was not affected by the use of intraoperative hypothermia or anatomical location of aneurysm.

Use of death certificates to study ethnic-specific mortality.

OBJECTIVES: The Hispanic population in the United States represents more than 40 million individuals, with Mexican Americans (MA) as the largest subgroup. To assess the utility of death certificates and medical records as the source of race/ethnicity data for epidemiologic studies, we compared self-reported race/ ethnicity to race/ethnicity recorded on death certificates and medical records in a bi-ethnic, non-immigrant U.S. community with a significant MA population. METHODS: This study utilized data collected from a subset of 1,856 participants of the Brain Attack Surveillance in Corpus Christi (BASIC) project. In-person interviews were conducted to determine self-reported race/ethnicity. Of those interviewed, 480 subsequently expired. Using self-reported race/ethnicity as the gold standard, we determined percent agreement, sensitivity, and specificity of the death certificate and medical record. RESULTS: Of the 480 subjects, 259 self-reported their race/ethnicity as non-Hispanic white (NHW), 195 self-reported as MA, and 26 self-reported as non-Hispanic black. Median age was 78.5 years and 55.8% were female. Percent agreement between self-reported race/ethnicity and race/ethnicity recorded on the death certificate and medical record was 97.1% and 96.3% respectively. Five percent of MAs were misclassified as NHW on their death certificates and 3% on their medical records. CONCLUSIONS: Results indicated that Hispanic designation recorded on death certificates and medical records in this community was largely consistent with that of self-report. This study suggests that vital statistics data in non-immigrant U.S. Hispanic communities can be used with confidence to investigate ethnic-specific aspects of disease and mortality. Similar studies in other multi-racial communities should be conducted to confirm and generalize these results.

A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam.

INTRODUCTION: The effects of any drug treatment on cognitive function are typically studied in groups of subjects. Observations made about the behavior of the drug, in the study sample, are then generalized to the population from which the sample was drawn. However, the magnitude and pharmacodynamic qualities of the response to many central nervous system-active drugs are known to vary in the population. Therefore, it is useful to consider statistical models for the detection of cognitive change in response to a drug treatment in individual subjects. MATERIALS AND METHODS: In this report, we first outline the statistical assumptions and requirements for the reliable estimation of clinically relevant individual change in cognition. We then used the sedative benzodiazepine, alprazolam, as a pharmacologic challenge in healthy volunteer subjects to test our statistical model, using a parallel groups placebo-controlled study design. After treatment, the nature and severity of alprazolam-induced cognitive change was determined for each individual. RESULTS: Our proposed method and analysis showed an excellent sensitivity and specificity for alprazolam-related cognitive deterioration in individuals. DISCUSSION AND CONCLUSIONS: These findings, although preliminary, suggest that statistically reliable decisions about the effects of sedative drugs on cognition can be made for individuals.

A method for determining the magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of two different doses alprazolam.

While there is no doubt that benzodiazepine administration leads to transient cognitive impairment in healthy adults, the nature and magnitude of such impairment has not been well described. The cognitive effects of a single dose of alprazolam 0.5 and 1 mg were therefore assessed in 36 healthy adults on measures of psychomotor function, visual attention, working memory, planning and learning in a double-blind parallel-groups study. Measures of these different cognitive functions were selected on the basis of their brevity and because they yielded distributions of performance data that were without skew, floor or ceiling effects of range restriction (i.e. normal distributions). With data satisfying the assumptions for parametric analysis, measures of effect size could be computed in addition to significance testing, thus allowing for direct and meaningful comparison between the different performance measures used. Alprazolam 0.5 mg reduced only the speed of attentional performance although the magnitude of this reduction was large (d = 0.8). At 1.0 mg, impairments in psychomotor function, equivalent to that seen for attentional function at the lower dose, were observed. In addition, moderate (d approx = 0.5) impairments in working memory, and learning also became obvious. When considered together, these results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also become impaired, and it is likely that the combination of these led to the observed moderate impairments in higher level executive and memory processes. The current study also illustrates a method for directly comparing the magnitude of change in cognitive function between measures with different performance metrics.