Branko N. Huisa

Blood–Brain Barrier Permeability Abnormalities in Vascular Cognitive Impairment

Background and Purpose— Disruption of the blood–brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood–brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood–brain barrier permeability in vascular cognitive impairment. Method— We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems. Results— Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood–brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. Ki values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts. Conclusions— There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood–brain barrier damage and development of white matter hyperintensities.

Long-Term Blood–Brain Barrier Permeability Changes in Binswanger Disease

Background and Purpose— The blood–brain barrier (BBB) is disrupted in small vessel disease patients with lacunes and white matter hyperintensities (WMHs). The relationship of WMHs and regional BBB permeability changes has not been studied. We hypothesized that BBB disruption occurs in normal appearing WM and regions near the WMHs. To test the hypothesis, we repeated BBB permeability measurements in patients with extensive WMHs related to Binswanger disease. Methods— We selected a subset of 22 Binswanger disease subjects from a well-characterized larger prospective vascular cognitive impairment cohort. We used 16 age-matched controls for comparison. The abnormal WM permeability (WMP) was measured twice for several years using dynamic contrast–enhanced magnetic resonance imaging. WMP maps were constructed from voxels above a predetermined threshold. Scans from first and second visits were coregistered. WM was divided into 3 regions: normal appearing WM, WMH ring, and WMH core. The ring was defined as 2 mm on each side of the WMH border. WMP was calculated in each of the 3 specific regions. We used paired t test, ANOVA, and Fisher exact test to compare individual changes. Results— WMP was significantly higher in subjects than in controls (P<0.001). There was no correlation between WMH load and WMP. High permeability regions had minimal overlap between first and second scans. Nine percent of WMP was within the WMHs, 49% within the normal appearing WM, and 52% within the WMH ring (P<0.001; ANOVA). Conclusions— Increased BBB permeability in normal appearing WM and close to the WMH borders supports a relationship between BBB disruption and the development of WMHs.

Transcranial laser therapy for acute ischemic stroke: a pooled analysis of NEST-1 and NEST-2.

Background NeuroThera Effectiveness and Safety Trials (NEST) 1 and 2 have demonstrated safety of transcranial laser therapy (TLT) for human treatment in acute ischemic stroke. NEST 1 study suggested efficacy of TLT but the following NEST 2, despite strong signals, missed reaching significance on its primary efficacy endpoint. In order to assess efficacy in a larger cohort, a pooled analysis was therefore performed. Methods The two studies were first compared for heterogeneity, and then a pooled analysis was performed to assess overall safety and efficacy, and examined particular subgroups. The primary endpoint for the pooled analysis was dichotomized modified Rankin scale (mRS) 0–2 at 90 days. Results Efficacy analysis for the intention-to-treat population was based on a total of 778 patients. Baseline characteristics and prognostic factors were balanced between the two groups. The TLT group (n = 410) success rate measured by the dichotomized 90-day mRS was significantly higher compared with the sham group (n = 368) (P = 0·003, OR: 1·67, 95% CI: 1·19–2·35). The distribution of scores on the 90-day mRS was significantly different in TLT compared with sham (P = 0·0005 Cochran–Mantel–Haenszel). Subgroup analysis identified moderate strokes as a predictor of better treatment response. Conclusions This pooled analysis support the likelihood that transcranial laser therapy is effective for the treatment of acute ischemic stroke when initiated within 24 h of stroke onset. If ultimately confirmed, transcranial laser therapy will change management and improve outcomes of far more patients with acute ischemic stroke.

Atorvastatin in stroke: a review of SPARCL and subgroup analysis

Statin therapy in patients with cardiovascular disease is associated with reduced incidence of stroke. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial showed daily treatment with 80 mg of atorvastatin in patients with a recent stroke or transient ischemic attack (TIA) reduced the incidence of fatal or nonfatal stroke by 16%. Several post hoc analyses of different subgroups followed the SPARCL study. They have not revealed any significant differences when patients were sorted by age, sex, presence of carotid disease or type of stroke, with the exception of intracranial hemorrhage as the entry event. Lower low-density lipoprotein cholesterol levels in addition to possible neuroprotective mechanisms due to atorvastatin treatment correlate with improved risk reduction. Although not predefined subgroups and subject to an insufficient power, these post hoc studies have generated new clinical questions. However, clinicians should avoid denying therapy based on such subgroup analysis. At this point, the best evidence powerfully demonstrates stroke and TIA patients should be prescribed high dose statin therapy for secondary stroke prevention.

Assessment of Long-Term Outcomes for the STRokE DOC Telemedicine Trial

Telemedicine can provide stroke evaluations in locations with limited available expertise. The reliability of telestroke has been established. Decision making efficacy has been shown in the National Institutes of Healths STRokE DOC trial. No prospective trial has assessed long-term telestroke outcomes, however. In an institutional review board-approved trial (NCT00936455), we contacted patients originally enrolled in the STRokE DOC trial. A telephone script was used to verify consent. Patients were asked standardized questions regarding disposition, modified Rankin Scale (mRS) score, mortality, and recurrent stroke for 2 retrospective time points (6 and 12 months postevent) and one current time point. Blind was maintained. Primary outcome measures of mortality and percent mRS score of 0-1 [%mRS(0-1)] at 6 months are reported. Wilcoxons rank-sum test was used for continuous variables, and Fishers exact was used for categorical variables. Of the original 222 participants, 75 patients or surrogates could be contacted. Mean time from enrollment was 3.96 ± 1.0 years (range, 2.33-5.45 years). Mean National Institutes of Health Stroke Scale (NIHSS) score was 8 ± 7 (5 ± 8 for telephone; 12 ± 8 for telemedicine; P = .002). The rate of intravenous recombinant tissue plasminogen activator (rt-PA) use was 31%. Six-month %mRS(0-1) outcome was not different, at 42%. Mortality after imputation to the entire study sample also was not different, at 18%. There was no difference in the rate of recurrent stroke (P = .61). Some 85% of patients were home at 6 months. This study reports a good 6-month outcome for stroke patients evaluated by telemedicine or telephone. This design is limited by the time since original enrollment and resultant inability to contact participants. Although these findings can add to the limited data on telemedicine outcomes, a prospective trial is needed.

1H-MR spectroscopy metabolite levels correlate with executive function in vascular cognitive impairment

Background White matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy (1H-MRS) can identify ischaemic tissue, we hypothesised that MRS detectable brain metabolites would be superior to WMHs in predicting performance on neuropsychological tests. Methods 60 patients with suspected VCI underwent clinical, neuropsychological, MRI and CSF studies. They were diagnosed as having subcortical ischaemic vascular disease (SIVD), multiple infarcts, mixed dementia and leukoaraiosis. We measured brain metabolites in a white matter region above the lateral ventricles with 1H-MRS and WMH volume in this region and throughout the brain. Results We found a significant correlation between both total creatine (Cr) and N-acetylaspartyl compounds (NAA) and standardised neuropsychological test scores. Cr levels in white matter correlated significantly with executive function (p=0.001), attention (p=0.03) and overall T score (p=0.007). When lesion volume was added as a covariate, NAA also showed a significant correlation with executive function (p=0.003) and overall T score (p=0.015). Furthermore, while metabolite levels also correlated with total white matter lesion volume, adjusting the Cr levels for lesion volume did not diminish the strength of the association between Cr levels and neuropsychological scores. The lowest metabolite levels and neuropsychological scores were found in the SIVD group. Finally, lesion volume alone did not correlate significantly with any neuropsychological test score. Conclusion These results suggest that estimates of neurometabolite levels provide additional and useful information concerning cognitive function in VCI not obtainable by measurements of lesion load.

Diffusion-weighted Imaging–Fluid Attenuated Inversion Recovery Mismatch in Nocturnal Stroke Patients with Unknown Time of Onset

BACKGROUND More than a quarter of patients with ischemic stroke (IS) are excluded from thrombolysis because of an unknown time of symptom onset. Recent evidence suggests that a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) imaging could be used as a surrogate for the time of stroke onset. We compared used the DWI-FLAIR mismatch and the FLAIR/DWI ratio to estimate the time of onset in a group of patients with nocturnal strokes and unknown time of onset. METHODS We used a prospectively collected acute IS patient database with MRI as the initial imaging modality. Nineteen selected nocturnal stroke patients with unknown time of onset were compared with 22 patients who had an MRI scan within 6 hours from stroke onset (control A) and 19 patients who had an MRI scan between 6 and 12 hours (control B). DWI and FLAIR signal was rated as normal or abnormal. FLAIR/DWI ratio was calculated from independent DWI and FLAIR ischemic lesion volumes using semiautomatic software. RESULTS The DWI-FLAIR mismatch was different among groups (unknown 43.7%; control A 63.6%; control B 10.5%; Fisher-Freeman-Halton test; P = .001). There were significant differences in FLAIR/DWI ratio among the 3 groups (unknown 0.05 ± 0.12; control A 0.17 ± 0.15; control B 0.04 ± 0.06; Kruskal-Wallis test; P < .0001). Post-hoc pairwise comparisons revealed that FLAIR/DWI ratio from the unknown group was significantly different from the control B group (P = .0045) but not different from the control A group. DWI volumes were not different among the 3 groups. CONCLUSIONS A large proportion of patients with nocturnal IS and an unknown time of stroke initiation have a DWI-FLAIR mismatch, suggesting a recent onset of stroke.

Intravenous Tissue Plasminogen Activator for Patients with Minor Ischemic Stroke

BACKGROUND Patients with minor ischemic stroke (MIS) are frequently excluded from thrombolytic therapy. Denial of therapy to these patients, however, remains controversial. We compared outcomes in patients with MIS who received intravenous (IV) tissue plasminogen activator (t-PA) with those who were not treated. METHODS We selected adult patients with stroke onset within 3 hours from a prospectively collected stroke registry. MIS was defined as an admission National Institutes of Health Stroke Scale (NIHSS) score ≤ 5. The primary outcome was a 90-day modified Rankin scale (mRS) score of 0 to 1. Secondary outcomes were a Barthel index (BI) score ≥ 95 at 90 days, symptomatic intracranial hemorrhage (SICH), and death. Multivariable logistic regression was performed to determine the association between outcomes adjusting for age, history of diabetes, and NIHSS score at admission. Reasons for t-PA exclusion were obtained. RESULTS We identified 133 patients with MIS; 59 patients received IV t-PA. The NIHSS score (mean ± SD) at admission was higher in the t-PA treated group (3.4 ± 1.4 v 1.9 ± 1.3 in the untreated group; P < .0001). Other baseline characteristics were not significantly different between the 2 groups. At 90 days, 57.6% of patients in the t-PA group and 68.9% of patients in the untreated group had a mRS score of 0 to 1 (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.39-2.2; P = .87). A BI score of 95 to 100 was achieved in 75% of patients in the IV t-PA group versus 78.9% in the untreated group (OR 1.18, 95% CI 0.43-3.23; P = .74). There were 3 deaths (5.1%) in the IV t-PA group and 3 deaths (4.1%) in the control group. CONCLUSIONS In our sample, patients with MIS treated with IV t-PA have similar outcomes as patients not receiving thrombolysis. A randomized trial or larger observational study is needed confirm or reject these findings.

Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials

Objectives Vascular cognitive impairment (VCI) is a heterogeneous group of cerebrovascular diseases secondary to large and small vessel disease. We hypothesised that biomarkers obtained early in the disease could identify a homogeneous subpopulation with small vessel disease. Methods We obtained disease markers in 62 patients with VCI that included neurological findings, neuropsychological tests, multimodal MR and cerebrospinal fluid measurements of albumin ratio, matrix metalloproteinases (MMPs), amyloid-β1–42 and phosphorylated-τ181. Proton MR spectroscopic imaging showed ischaemic white matter and permeability of the blood-brain barrier (BBB) was measured with dynamic contrast-enhanced MRI. We constructed a 10-point Binswanger disease score (BDS) with subjective and objective disease markers. In addition, an objective set of biomarkers was used for an exploratory factor analysis (EFA) to select patients with BD. Patients were followed for an average of 2 years to obtain clinical consensus diagnoses. Results An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p<0.05; area under the curve (AUC)=0.79). EFA reduced nine objective biomarkers to four factors. The most predictive of BD was the factor containing the inflammatory biomarkers of increased BBB permeability, elevated albumin index and reduced MMP-2 index (factor 2; AUC=0.78). Both measures independently predicted a diagnosis of BD, and combining them improved the diagnostic accuracy. Conclusions Biomarkers predicted the diagnosis of the BD type of subcortical ischaemic vascular disease. Using pathophysiological biomarkers to select homogeneous groups of patients needs to be tested in targeted treatment trials.

Glycosylated Hemoglobin for Diagnosis of Prediabetes in Acute Ischemic Stroke Patients

BACKGROUND Prediabetes (PD) is an independent risk factor for stroke. The American Diabetes Association (ADA) has recently published new guidelines recommending glycosylated hemoglobin A1c (HbA1c) as a marker to diagnose diabetes and PD. Diagnosis of diabetes Mellitus (DM) is often made at the time of hospitalization for stroke. Less is known about identifying PD in acute ischemic stroke (AIS) patients. We aim to investigate the frequency of new-onset PD in the hospitalized AIS patients using the new ADA guidelines. METHODS We retrospectively studied 362 AIS patients from our local database. Stroke risk factors, type of stroke, and white matter hyperintensities (WMHs) were all collected. Based on the 2010 ADA guidelines, patients were classified as prediabetics, with HbA1c levels of 5.7%-6.4%; diabetics, with HbA1c levels more than 6.5%; and normoglycemic, HbA1c levels less than 5.7%. We used SAS 9.3 for analysis. RESULTS On admission, 279 (78%) AIS patients had HbA1c values collected. Stratifying by HbA1c, 113 (31%) AIS patients were given the diagnosis of DM and 109 (30%) were given the diagnosis of PD. From the 166 patients with no DM history, 53% had PD and 15% had DM. Patients with DM and PD were more likely to have hypertension (P<.001) and hyperlipidemia (P=.05). The likelihood of new-onset PD increased with age (P<.01). No differences were found by the type of stroke or WMH. CONCLUSION Diabetes and PD are highly prevalent in the hospitalized ischemic stroke (IS) patients. Our results suggest a need for routine HbA1c testing in all patients with IS. Further larger studies need to confirm these findings.