Patricia Desmond

Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison

BACKGROUND Psychotic disorders, such as schizophrenia, are associated with neuroanatomical abnormalities, but whether these predate the onset of symptoms or develop progressively over the course of illness is unclear. We investigated this issue with MRI to study people with prodromal symptoms who are at ultra high-risk for the development of psychosis. METHODS We did two comparisons, cross-sectional and longitudinal. For the cross-sectional comparison, 75 people with prodromal signs of psychosis were scanned with MRI. After at least 12 months of follow-up, 23 (31%) had developed psychosis and 52 (69%) had not. Baseline MRI data from these two subgroups were compared. For the longitudinal comparison, 21 of the ultra high-risk individuals were scanned again with MRI after at least 12 months. Ten of these had developed psychosis and 11 had not. MRI data from baseline and follow-up were compared within each group of people. FINDINGS In the cross-sectional comparison, compared with people who did not develop psychosis, those who did develop the disorder had less grey matter in the right medial temporal, lateral temporal, and inferior frontal cortex, and in the cingulate cortex bilaterally. In the longitudinal comparison, when re-scanned, individuals who had developed psychosis showed a reduction in grey matter in the left parahippocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In those who had not become psychotic, longitudinal changes were restricted to the cerebellum. INTERPRETATION Some of the grey-matter abnormalities associated with psychotic disorders predate the onset of frank symptoms, whereas others appear in association with their first expression.

Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial

BACKGROUND Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). METHODS We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. FINDINGS We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Students t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxons test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. INTERPRETATION Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.

Persistent Poststroke Hyperglycemia Is Independently Associated With Infarct Expansion and Worse Clinical Outcome

BACKGROUND AND PURPOSE Hyperglycemia at the time of ischemic stroke is associated with increased mortality and morbidity. Animal studies suggest that infarct expansion may be responsible. The influence of persisting hyperglycemia after stroke has not previously been examined. We measured the blood glucose profile after acute ischemic stroke and correlated it with infarct volume changes using T2- and diffusion-weighted MRI. METHODS We recruited 25 subjects within 24 hours of ischemic stroke symptoms. Continuous glucose monitoring was performed with a glucose monitoring device (CGMS), and 4-hour capillary glucose levels (BGL) were measured for 72 hours after admission. MRI and clinical assessments were performed at acute (median, 15 hours), subacute (median, 5 days), and outcome (median, 85 days) time points. RESULTS Mean CGMS glucose and mean BGL glucose correlated with infarct volume change between acute and subacute diffusion-weighted MRI (r>or=0.60, P<0.01), acute and outcome MRI (r=0.56, P=0.01), outcome National Institutes of Health Stroke Scale (NIHSS; r>or=0.53, P<0.02), and outcome modified Rankin Scale (mRS; r>or=0.53, P=0.02). Acute and final infarct volume change and outcome NIHSS and mRS were significantly higher in patients with mean CGMS or mean BGL glucose >or=7 mmol/L. Multiple regression analysis indicated that both mean CGMS and BGL glucose levels >or=7 mmol/L were independently associated with increased final infarct volume change. CONCLUSIONS Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with worse functional outcome. There is an urgent need to study normalization of blood glucose after stroke.

Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study.

Controversy exists whether acute hyperglycemia is causally associated with worse stroke outcome or simply reflects a more severe stroke. In reversible ischemia models, hyperglycemia is associated with lactic acidosis and conversion of penumbral tissue to infarction. However, the relationship between hyperglycemia, lactic acidosis, and stroke outcome has not been explored in humans. Sixty‐three acute stroke patients were prospectively evaluated with serial diffusion‐weighted and perfusion‐weighted magnetic resonance imaging and acute blood glucose measurements. Patients with hypoperfused at‐risk tissue were identified by acute perfusion‐diffusion lesion mismatch. As a substudy, acute and subacute magnetic resonance spectroscopy was performed in the 33 most recent patients to assess the relationship between acute blood glucose and lactate production in the ischemic region. In 40 of 63 patients with acute perfusion‐diffusion mismatch, acute hyperglycemia was correlated with reduced salvage of mismatch tissue from infarction, greater final infarct size, and worse functional outcome. These correlations were independent of baseline stroke severity, lesion size, and diabetic status. Furthermore, higher acute blood glucose in patients with perfusion‐diffusion mismatch was associated with greater acute‐subacute lactate production, which, in turn, was independently associated with reduced salvage of mismatch tissue. In contrast, acute blood glucose levels in nonmismatch patients did not independently correlate with outcome measures, nor was there any acute‐subacute increase in lactate in this group. Acute hyperglycemia increases brain lactate production and facilitates conversion of hypoperfused at‐risk tissue into infarction, which may adversely affect stroke outcome. These findings support the need for randomized controlled trials of aggressive glycemic control in acute stroke.

Diffusion- and perfusion-weighted MRI response to thrombolysis in Stroke

Diffusion‐ and perfusion‐weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub‐6‐hour stroke patients using serial diffusion‐ and perfusion‐weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub‐6‐hour ischemic stroke patients studied serially with diffusion‐ and perfusion‐weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion‐weighted imaging–diffusion‐weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs −25% in controls). Despite similar baseline diffusion‐weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm3 vs 56cm3 in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of ≥7 points. The natural evolution of acute perfusion‐weighted imaging–diffusion‐weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion‐ and perfusion‐weighted imaging in selecting and monitoring patients for thrombolytic therapy.

Pathophysiological Topography of Acute Ischemia by Combined Diffusion-Weighted and Perfusion MRI

BACKGROUND AND PURPOSE Combined echoplanar MRI diffusion-weighted imaging (DWI), perfusion imaging (PI), and magnetic resonance angiography (MRA) can be used to visualize acute brain ischemia and predict lesion evolution and functional outcome. The appearance of a larger lesion by PI than by DWI quantitatively defines a mismatch of potential clinical importance. Qualitative lesion variations exist in the topographic concordance of this mismatch. We examined both the topographic heterogeneity and relative frequency of mismatched patterns in acute stroke using these MRI techniques. METHODS Acute DWI, PI, and MRA studies of 34 prospectively recruited patients with supratentorial ischemic lesions scanned within 24 hours of stroke onset (range 2.5 to 23.3 hours, 12 patients <6 hours) were analyzed. RESULTS Ischemic lesions were predominantly in the middle cerebral artery (MCA) territory (94%), with DWI lesions most commonly affecting the insular region. Mismatched patterns with PI lesion larger than DWI lesion occurred in 21 patients (62% overall), in all 4 patients imaged within 3 hours, and in 44% of patients imaged after 18 hours. A patient with a large PI but no DWI lesion and severe clinical deficit at 2.5 hours after stroke onset recovered completely. Regional variations in DWI and PI lesion loci were found, inferring site of proximal MCA occlusion, embolic pathogenesis, and regional arterial reperfusion. CONCLUSIONS Analysis of the topographic concordance of PI and DWI lesions in acute stroke reveals regional PI lesions without concomitant DWI lesions, which do not necessarily progress to infarction but may suggest stroke pathogenesis and site of current arterial occlusion. Location of DWI lesions may suggest an earlier site of arterial occlusion and regions of maximal perfusion deficit.

Neuropsychological and structural brain changes in anorexia nervosa before and after refeeding

The neuropsychological performance and Magnetic Resonance Imaging (MRI) brain appearance of a consecutive series of 46 in-patients with anorexia nervosa (AN) was compared with that of 41 normal-weight controls. The groups were matched for sex, age, estimated pre-morbid intelligence and education. AN patients who had gained at least 10% of their body weight were retested and rescanned. Controls were retested after a similar interval. The AN group performed significantly worse than the controls on tasks measuring attention, visuospatial ability and memory. On tasks assessing flexibility and learning, no group differences were evident although an examination of deficits in individuals revealed that more anorexics were impaired on both. Following treatment, the AN group improved relative to the control group only on those tasks assessing attention. Comparison of MRI measures showed a significant proportion of anorexics had enlarged lateral ventricles and dilated sulci on both cortical and cerebellar surfaces, but no dilatation was evident for the third and fourth ventricular measures. Improvements were found after treatment on some of the radiological measures but many differences remained. Relationships between morphological brain changes and cognitive impairments were weak. Lower weight, but not duration of illness, was associated with poorer performance on tasks assessing flexibility/inhibition and memory, and with greater MRI ventricular size.

Identification of Major Ischemic Change Diffusion-Weighted Imaging Versus Computed Tomography

BACKGROUND AND PURPOSE Thrombolytic therapy is not recommended in patients with CT changes of recent major infarction, which has been defined as reduced attenuation or cerebral edema involving >33% of the middle cerebral artery territory (European Cooperative Acute Stroke Study [ECASS] criteria). Diffusion-weighted imaging (DWI) is more sensitive than CT in detecting acute ischemia, and the combination of DWI, MR perfusion imaging, and MR angiography provides additional information from a single examination. We sought to determine whether DWI could identify the presence and extent of major ischemia as well as CT in hyperacute stroke patients. METHODS Seventeen suspected hemispheric stroke patients were studied with both CT and DWI within 6 hours of symptom onset. None received thrombolytic therapy. The scans were examined separately by 2 neuroradiologists in a blinded fashion for ischemic change and cerebral edema, graded as normal, <33%, or >33% of the MCA territory. Final diagnosis of stroke was determined with the use of standard clinical criteria and T2-weighted imaging at day 90. RESULTS Sixteen of 17 patients had a final diagnosis of stroke. Acute ischemic changes were seen in all 16 on DWI (100% sensitivity) and in 12 of 16 on CT (75% sensitivity). DWI identified all 6 patients with major ischemia on CT, with excellent agreement between the 2 imaging techniques (kappa=0.88). One patient eligible for thrombolysis on the ECASS CT criteria had major ischemia on DWI. CONCLUSIONS DWI is more sensitive than CT in the identification of acute ischemia and can visualize major ischemia more easily than CT.

Serial Study of Apparent Diffusion Coefficient and Anisotropy in Patients With Acute Stroke

BACKGROUND AND PURPOSE We sought to characterize the evolution of apparent diffusion coefficient (ADC) and apparent diffusion anisotropy (ADA) in acute stroke and to evaluate their roles in predicting stroke evolution and outcome. METHODS We studied 26 stroke patients acutely (<24 hours), subacutely (3 to 5 days), and at outcome (3 months). Ratios of the ADC and ADA within a region of infarction and the normal contralateral region were evaluated and compared with the Canadian Neurological Scale, Barthel Index, and Rankin Scale. RESULTS Heterogeneity in ADC and ADA evolution was observed not only between patients but also within individual lesions. Three patterns of ADA evolution were observed: (1) elevated ADA acutely and subacutely; (2) elevated ADA acutely and reduced ADA subacutely; and (3) reduced ADA acutely and subacutely. At outcome, reduced ADA with elevated ADC was observed generally. We identified 3 phases of diffusion abnormalities: (1) reduced ADC and elevated ADA; (2) reduced ADC and reduced ADA; and (3) elevated ADC and reduced ADA. The ADA ratios within 12 hours correlated with the acute Canadian Neurological Scale (r=0.46, P=0.06), subacute Canadian Neurological Scale (r=0.55, P=0.02), outcome Barthel Index (r=0.62, P=0.01), and Rankin Scale (r=-0.77, P<0.0005) scores. CONCLUSIONS Combined ADC and ADA provide differential patterns of stroke evolution. Early ADA changes reflect cellular alterations in acute ischemia and may provide a potential marker to predict stroke outcome.

Cerebral Blood Flow Is the Optimal CT Perfusion Parameter for Assessing Infarct Core

Background and Purpose— CT perfusion (CTP) is widely and rapidly accessible for imaging acute ischemic stroke but has limited validation. Cerebral blood volume (CBV) has been proposed as the best predictor of infarct core. We tested CBV against other common CTP parameters using contemporaneous diffusion MRI. Methods— Patients with acute ischemic stroke <6 hours after onset had CTP and diffusion MRI <1 hour apart, before any reperfusion therapies. CTP maps of time to peak (TTP), absolute and relative CBV, cerebral blood flow (CBF), mean transit time (MTT), and time to peak of the deconvolved tissue residue function (Tmax) were generated. The diffusion lesion was manually outlined to its maximal visual extent. Receiver operating characteristic (ROC) analysis area under the curve (AUC) was used to quantify the correspondence of each perfusion parameter to the coregistered diffusion-weighted imaging lesion. Optimal thresholds were determined (Youden index). Results— In analysis of 98 CTP slabs (54 patients, median onset to CT 190 minutes, median CT to MR 30 minutes), relative CBF performed best (AUC, 0.79; 95% CI, 0.77–81), significantly better than absolute CBV (AUC, 0.74; 95% CI, 0.73–0.76). The optimal threshold was <31% of mean contralateral CBF. Specificity was reduced by low CBF/CBV in noninfarcted white matter in cases with reduced contrast bolus intensity and leukoaraiosis. Conclusions— In contrast to previous reports, CBF corresponded with the acute diffusion-weighted imaging lesion better than CBV, although no single threshold avoids detection of false-positive regions in unaffected white matter. This relates to low signal-to-noise ratio in CTP maps and emphasizes the need for optimized acquisition and postprocessing.