Miriam M. Morales

Thrombolytic Therapy for Patients Who Wake-Up With Stroke

Background and Purpose— Approximately 25% of ischemic stroke patients awaken with their deficits. The last-seen-normal time is defined as the time the patient went to sleep, which places these patients outside the window for thrombolysis. The purpose of this study was to describe our center’s experience with off-label, compassionate thrombolysis for wake-up stroke (WUS) patients. Methods— A retrospective review of our database identified 3 groups of ischemic stroke patients: (1) WUS treated with thrombolysis; (2) nontreated WUS; and (3) 0- to 3-hour intravenous tissue plasminogen activator-treated patients. Safety and clinical outcome measures were symptomatic intracerebral hemorrhage, excellent outcome (discharge modified Rankin score, 0–1), favorable outcome (modified Rankin score, 0–2), and mortality. Outcome measures were controlled for baseline NIHSS using logistic regression. Results— Forty-six thrombolysed and 34 nonthrombolysed WUS patients were identified. Sixty-one percent (28/46) of the treated WUS patients underwent intravenous thrombolysis alone whereas 30% (14/46) were given only intra-arterial thrombolysis. Four patients received both intravenous and intra-arterial thrombolysis (9%). Two symptomatic intracerebral hemorrhages occurred in treated WUS (4.3%). Controlling for NIHSS imbalance, treated WUS had higher rates of excellent (14% vs 6%; P=0.06) and favorable outcome (28% vs 13%; P=0.006), but higher mortality (15% vs 0%) compared to nontreated WUS. A second comparison controlling for baseline NIHSS between treated WUS and 174 intravenous tissue plasminogen activator patients treated within 3 hours of symptoms showed no significant differences in safety and clinical outcomes. Conclusion— Thrombolysis may be safe in WUS patients. Our center’s experience supports considering a prospective, randomized trial to assess the safety and outcome of thrombolysis for this specific patient population.

Can comprehensive stroke centers erase the 'weekend effect'?

Background: Prior epidemiological work has shown higher mortality in ischemic stroke patients admitted on weekends, which has been termed the ‘weekend effect’. Our aim was to assess stroke patient outcomes in order to determine the significance of the ‘weekend effect’ at 2 comprehensive stroke centers. Methods: Consecutive stroke patients were identified using prospective databases. Patients were categorized into 4 groups: intracerebral hemorrhage (ICH group), ischemic strokes not treated with IV t-PA (intravenous tissue plasminogen activator; IS group), acute ischemic strokes treated with IV t-PA (AIS-TPA group), and transient ischemic attack (TIA group). Weekend admission was defined as the period from Friday, 17:01, to Monday, 08:59. Patients treated beyond the 3-hour window, receiving intra-arterial therapy, or enrolled in nonobservational clinical trials were excluded. Patient demographics, NIHSS scores, and admission glucose levels were examined. Adverse events, poor functional outcome (modified Rankin scale, mRS, 3–6), and mortality were compared. Results: A total of 2,211 patients were included (1,407 site 1, 804 site 2). Thirty-six percent (800/2,211) arrived on a weekend. No significant differences were found in the ICH, IS, AIS-TPA, or TIA groups with respect to the rate of symptomatic ICH, mRS on discharge, discharge disposition, 90-day mRS, or 90-day mortality when comparing weekend and weekday groups. Using multivariate logistic regression to adjust for site, age, admission NIHSS, and blood glucose, weekend admission was not a significant independent predictive factor for in-hospital mortality in all strokes (OR = 1.10, 95% CI 0.74–1.63, p = 0.631). Conclusions: Our results suggest that comprehensive stroke centers (CSC) may ameliorate the ‘weekend effect’ in stroke patients. These results may be due to 24/7 availability of stroke specialists, advanced neuroimaging, or ongoing training and surveillance of specialized nursing care available at CSC. While encouraging, these results require confirmation in prospective studies.

Identifying Patients at High Risk for Poor Outcome After Intra-Arterial Therapy for Acute Ischemic Stroke

BACKGROUND AND PURPOSE Intra-arterial recanalization therapy (IAT) is increasingly used for acute stroke. Despite high rates of recanalization, the outcome is variable. We attempted to identify predictors of outcome that will enable better patient selection for IAT. METHODS All patients who underwent IAT at the University of Texas Houston Stroke Center were reviewed. Poor outcome was defined as modified Rankin Scale score 4 to 6 on hospital discharge. Findings were validated in an independent data set of 175 patients from the University of California at Los Angeles Stroke Center. RESULTS One hundred ninety patients were identified. Mean age was 62 years and median baseline National Institutes of Health Stroke Scale score was 0.18. Recanalization rate was 75%, symptomatic hemorrhage rate was 6%, and poor outcome rate was 66%. Variables associated with poor outcome were: age, baseline National Institutes of Health Stroke Scale, admission glucose, diabetes, heart disease, previous stroke, and the absence of mismatch on the pretreatment MRI. Logistic regression identified 3 variables independently associated with poor outcome: age (P=0.049; OR, 1.028), National Institutes of Health Stroke Scale (P=0.013; OR, 1.084), and admission glucose (P=0.031; OR, 1.011). Using these data, we devised the Houston IAT score: 1 point for age >75 years; 1 for National Institutes of Health Stroke Scale score >18, and 1 point for glucose >150 mg/dL (range, 0 to 3 mg/dL). The percentage of poor outcome by Houston IAT score was: score of 0, 44%; 1, 67%; 2, 97%; and 3, 100%. Recanalization rates were similar across the scores (P=0.4). Applying Houston IAT to the external cohort showed comparable trends in outcome and nearly identical rates in the Houston IAT therapy 3 tier. CONCLUSIONS The Houston IAT score estimates the chances of poor outcome after IAT, even with recanalization. It may be useful in comparing cohorts of patients and when assessing the results of clinical trials.

The IVH Score: A novel tool for estimating intraventricular hemorrhage volume: Clinical and research implications

Objective:Intraventricular extension of intracerebral hemorrhage (IVH) is an independent predictor of poor outcome. IVH volume may be important in outcome prediction and management; however, it is difficult to measure routinely. Design and Patients:We reviewed the charts and computed tomographies of a cohort of consecutive patients with IVH. The cohort was divided into two groups: index and validation by random sampling. IVH and intracerebral hemorrhage (ICH) volume were measured manually in all patients. IVH was also graded using a simple classification system termed IVH score (IVHS). Clinical outcome was determined by the modified Rankin Scale (mRS) at discharge and in-hospital death. Poor outcome was defined as mRS 4–6. Main Results:One hundred seventy-five patients were analyzed, 92 in the index group and 83 in the validation group. Exponential regression yielded the following formula for estimating IVH volume (mL): eÎVHS/5 (R2 = .75, p < 0.001). The IVH estimation formula was then verified in the validation group (R2 = .8, p < 0.001). The following correlations with mRS were obtained: IVH volume R = .305; ICH volume R = .468; total volume {lsqb;TV{rsqb; R = .571 (p < 0.001 for all three correlations). Partial correlation of TV with mRS controlling for ICH volume yielded R = .3 for TV (p < 0.001). Logistic regression model comparing ICH and TV association with poor outcome yielded the following: ICH odds ratio = 5.2, 95% confidence interval 2.3–11.6, p < 0.001; TV odds ratio = 41.6, 95% confidence interval 9.6–180.6, p < 0.001. Substituting TV for ICH volume in the ICH score resulted in a significant increase in the specificity from 64% to 87% for predicting mortality. Conclusions:IVHS enables clinicians to rapidly estimate IVH volume. The addition of IVH to ICH volume increases its predictive power for poor outcome and mortality significantly. IVHS and TV may be used in clinical practice and clinical trials of patients with ICH.

Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

Rationale Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. Aims The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. Study Design This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. Outcomes The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Is the drip-and-ship approach to delivering thrombolysis for acute ischemic stroke safe?

BACKGROUND The drip-and-ship method of treating stroke patients may increase the use of tissue plasminogen activator (t-PA) in community hospitals. OBJECTIVE The safety and early outcomes of patients treated with t-PA for acute ischemic stroke (AIS) by the drip-and-ship method were compared to patients directly treated at a stroke center. METHODS The charts of all patients who were treated with intravenous (i.v.) t-PA at outside hospitals under the remote guidance of our stroke team and were then transferred to our facility were reviewed. Baseline NIHSS (National Institutes of Health Stroke Scale) scores, onset-to-treatment (OTT), and arrival-to-treatment (ATT) times were abstracted. The rates of in-hospital mortality, symptomatic hemorrhage (sICH), early excellent outcome (modified Rankin Scale [mRS] ≤ 1), and early good outcome (discharge home or to inpatient rehabilitation) were determined. RESULTS One hundred sixteen patients met inclusion criteria. Eighty-four (72.4%) were treated within 3 h of symptom onset. The median estimated NIHSS score was 9.5 (range 3-27). The median OTT time was 150 min, and the median ATT was 85 min. These patients had an in-hospital mortality rate of 10.7% and sICH rate of 6%. Thirty percent of patients had an early excellent outcome and 75% were discharged to home or inpatient rehabilitation. When these outcome rates were compared with those observed in patients treated directly at our stroke center, there were no statistical differences. CONCLUSIONS In this small retrospective study, drip-and-ship management of delivering i.v. t-PA for AIS patients did not seem to compromise safety. However, a large prospective study comparing drip-and-ship management to routine care is needed to validate the safety of this approach to treatment.

Effect of Ingested Interferon-α on β-Cell Function in Children With New-Onset Type 1 Diabetes

OBJECTIVE To evaluate the safety and efficacy of ingested human recombinant interferon-α (hrIFN-α) for preservation of β-cell function in young patients with recent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS Subjects aged 3–25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-α at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal. RESULTS Individuals in the placebo group (n = 30) lost 56 ± 29% of their C-peptide secretion from 0 to 12 months, expressed as area under the curve (AUC) in response to a mixed meal. In contrast, children treated with hrIFN-α lost 29 ± 54 and 48 ± 35% (for 5,000 [n = 27] and 30,000 units [n = 31], respectively, P = 0.028, ANOVA adjusted for age, baseline C-peptide AUC, and study site). Bonferroni post hoc analyses for placebo versus 5,000 units and placebo versus 30,000 units demonstrated that the overall trend was determined by the 5,000-unit treatment group. Adverse events occurred at similar rates in all treatment groups. CONCLUSIONS Ingested hrIFN-α was safe at the doses used. Patients in the 5,000-unit hrIFN-α treatment group maintained more β-cell function 1 year after study enrollment than individuals in the placebo group, whereas this effect was not observed in patients who received 30,000 units hrIFN-α. Further studies of low-dose ingested hrIFN-α in new-onset type 1 diabetes are needed to confirm this effect.

Recovery after ischemic stroke: criteria for good outcome by level of disability at day 7.

Background: Ischemic stroke is a leading cause of morbidity. Assessing the chances of recovery is critical to optimize poststroke care. Methods: We used a cohort of patients from the Virtual International Stroke Trial Archive that participated in acute stroke trials (control arm) and were followed for 90 days. The cohort was grouped by day 7 (D7) modified Rankin scale (mRS) scores. Variables that were associated with good outcome (mRS 0–2 at 90 days) in the univariate analysis were entered into a logistic regression model to determine the independent good outcome criteria for each D7 mRS tier. Results: We analyzed 1,798 patients. The independent good outcome criteria identified for different mRS tiers were: D7 mRS of 3: age ≤70, 0–2 vascular risk factors, D7 NIH Stroke Scale (NIHSS) arm strength ≤1, D7 NIHSS language score = 0; D7 mRS of 4: age ≤70, male, D7 NIHSS facial palsy ≤1, D7 NIHSS visual = 0, D7 NIHSS leg strength ≤1, D7 NIHSS dysarthria = 0; D7 mRS of 5: age ≤70, IV tPA treatment, D7 NIHSS dysarthria = 0, D7 NIHSS leg strength ≤2. For each mRS tier, we observed a graded increase in the percentage of the primary and secondary end points with increase in the number of criteria. Conclusions: We identified clinical variables that predict good outcome, are specific to each day 7 mRS tier, and enable easy and informative assessment of the patient’s likelihood of achieving varying degrees of recovery at day 90. These results may be useful in both clinical practice and research but require validation in an independent patient cohort.

Bio-equivalence of IM and SQ H.P. Acthar® Gel

OBJECTIVE IM Acthar Gel (Acthar) is a natural-source ACTH used for the treatment of MS exacerbations. It is not known if subcutaneous (SQ) administration of Acthar is equivalent to IM administration or if lower doses of Acthar would provide comparable serum cortisol responses. METHODS We compared IM and SQ administration of Acthar to explore bio-equivalency between the two routes of administration. RESULTS Our results show that SQ administration of Acthar is bio-equivalent to IM administration. Both 20 and 80 units of Acthar, respectively, show bio-equivalency after SQ and IM administration. However, 20 units of Acthar do not provide comparable stimulation of the adrenal cortex compared to 80 units, administered either SQ or IM. CONCLUSIONS Bio-equivalency between IM and SQ administration may allow the use of SQ Acthar.

Predicting the need for hospital admission of TIA patients

BACKGROUND It is unknown which patient will benefit most from hospital admission after transient ischemic attack (TIA). Our aim was to define predictors of a positive hospital outcome. METHODS We used two cohorts of TIA patients: the University of Texas at Houston Stroke Center (UTH); and Tel-Aviv Sourasky Medical Center in Israel (TASMC) for external validation. We retrospectively reviewed medical records and imaging data. We defined positive yield (PY) of the hospital admission as identification of stroke etiologies that profoundly changes clinical management. RESULTS The UTH cohort included 178 patients. 24.7% had PY. In the multivariate analysis, the following were associated with PY: coronary disease (CAD); age; and acute infarct on DWI. We then derived a composite score termed the PY score to predict PY. One point is scored for: age>60, CAD, and acute infarct on DWI. The proportion of PY by PY score was as follows: 0-6%; 1-22%; 2-47%; 3-67% (p<0.001). In the validation cohort PY score was highly predictive of PY and performed in a very similar manner. CONCLUSIONS Our data suggest, the PY score may enable physicians to make better admission decisions and result in better, safer and more economical care for TIA patients.