A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design.

RATIONALE: While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain. AIM: The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset. SAMPLE SIZE ESTIMATES: A total of 456 patients will provide ⩾90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level. METHODS AND DESIGN: TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion. STUDY OUTCOMES: The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate. DISCUSSION: Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5-24 h following symptom onset for patients with an ICA or MCA occlusion.

Novel GDF2 Gene Mutation Associated with Pulmonary Arteriovenous Malformation.

Pulmonary arteriovenous malformations (PAVMs) are pathologic low-resistance conduits between a pulmonary artery and vein. Over 80% PAVMs occur in patients with hereditary hemorrhagic telangiectasia (HHT) and result from mutations in the transforming growth factor-beta signaling pathway. Mutations in the Growth Differentiation Factor 2 (GDF2) gene have recently been described to result in a vascular-anomaly syndrome with phenotypic overlap with HHT. We report a 43-year-old woman with a PAVM related ischemic stroke who was subsequently found to have a novel GDF2 gene mutation. The patient underwent coil-embolization of the PAVM with stable clinical and radiographic follow-up. It is important to diagnose PAVMs as they are an important cause of stroke-in-young; and can be treated definitively, reducing risk of recurrent stroke and migraine.

Three Territory Sign: An MRI marker of malignancy-related ischemic stroke (Trousseau syndrome).

BACKGROUND: Multiple acute cerebral territory infarcts of undetermined origin are typically attributed to cardioembolism, most frequently atrial fibrillation. However, the importance of 3-territory involvement in association with malignancy is under-recognized. We sought to highlight the "Three Territory Sign" (TTS) (bilateral anterior and posterior circulation acute ischemic diffusion-weighted imaging [DWI] lesions), as a radiographic marker of stroke due to malignancy. METHODS: We conducted a single-center retrospective analysis of patients from January 2014 to January 2016, who suffered an acute ischemic stroke with MRI-DWI at our institution, yielding 64 patients with a known malignancy and 167 patients with atrial fibrillation, excluding patients with both to eliminate bias. All DWI images were reviewed for 3-, 2-, and 1-territory lesions. Chi-square test of proportion was used to test significance between the 2 groups. RESULTS: We found an association between the groups (malignancy vs atrial fibrillation) and the number of territory infarcts (p < 0.0001). Pairwise comparisons using the Holm p value adjustment showed no difference between 1- and 2-territory patterns (p = 0.465). However, the TTS was 6 times more likely observed within the malignancy cohort as compared to patients with atrial fibrillation (23.4% [n = 15] vs 3.5% [n = 6]) and was different from both 1-territory (p < 0.0001) and 2-territory patterns (p = 0.0032). CONCLUSION: The TTS is a highly specific marker and 6 times more frequently observed in malignancy-related ischemic stroke than atrial fibrillation-related ischemic stroke. Evaluation for underlying malignancy in patients with the TTS is reasonable in patients with undetermined etiology.

High Mortality among 30-Day Readmission after Stroke: Predictors and Etiologies of Readmission.

BACKGROUND: Although some risk factors for stroke readmission have been reported, the mortality risk is unclear. We sought to evaluate etiologies and predictors of 30-day readmissions and determine the associated mortality risk. METHODS: This is a retrospective case-control study evaluating 1,544 patients admitted for stroke (hemorrhagic, ischemic, or TIA) from January 2013 to December 2014. Of these, 134 patients readmitted within 30 days were identified as cases; 1,418 other patients, with no readmissions were identified as controls. Patients readmitted for hospice or elective surgery were excluded. An additional 248 patients deceased on index admission were included for only a comparison of mortality rates. Factors explored included socio-demographic characteristics, clinical comorbidities, stroke characteristics, and length of stay. Chi-square test of proportions and multivariable logistic regression were used to identify independent predictors of 30-day stroke readmissions. Mortality rates were compared for index admission and readmission and among readmission diagnoses. RESULTS: Among the 1,544 patients in the main analysis, 67% of index stroke admissions were ischemic, 22% hemorrhagic, and 11% TIA. The 30-day readmission rate was 8.7%. The most common etiologies for readmission were infection (30%), recurrent stroke and TIA (20%), and cardiac complications (14%). Significantly higher proportion of those readmitted for recurrent strokes and TIAs presented within the first week (p = 0.039) and had a shorter index admission length of stay (p = 0.027). Risk factors for 30-day readmission included age >75 (p = 0.02), living in a facility prior to index stroke (p = 0.01), history of prior stroke (p = 0.03), diabetes (p = 0.03), chronic heart failure (p ≤ 0.001), atrial fibrillation (p = 0.03), index admission to non-neurology service (p < 0.01), and discharge to other than home (p < 0.01). On multivariate analysis, index admission to a non-neurology service was an independent predictor of 30-day readmission (p ≤ 0.01). The mortality after a within 30-day readmission after stroke was higher than index admission (36.6 vs. 13.8% p ≤ 0.001) (OR 3.6 95% CI 2.5-5.3). Among those readmitted, mortality was significantly higher for those admitted for a recurrent stroke (p = 0.006). CONCLUSION: Approximately one-third of 30-day readmissions were infection related and one-fifth returned with recurrent stroke or TIA. Index admission to non-neurology service was an independent risk factor of 30-day readmissions. The mortality rate for 30-day readmission after stroke is more than 2.5 times greater than index admissions and highest among those readmitted for recurrent stroke. Identifying high-risk patients for readmission, ensuring appropriate level of service, and early outpatient follow-up may help reduce 30-day readmission and the high associated risk of mortality.

Rheumatoid Meningitis: Diagnostic and Therapeutic Observations.

A 75-year-old female with untreated rheumatoid arthritis presented with two weeks of behavioral changes and cognitive decline. A neurologic examination showed severe encephalopathy, brisk reflexes, and bilateral Babinski sign. A contrast-enhanced brain MRI demonstrated right meningeal enhancement and periventricular white matter disease. A computed tomographic angiogram (CTA) of the head and neck was negative for vasculitis. The cerebrospinal fluid (CSF) demonstrated lymphocytic pleocytosis. The patient's serum rheumatoid factor levels were elevated. A biopsy of the leptomeninges and cortex showed lymphocytic vasculitis of the cortical tissue and patchy lymphoplasmacytic infiltrates of dural small vessels consistent with rheumatoid meningitis. The patient received pulse-dose steroids followed by cyclophosphamide infusions. At her three month follow-up appointment, the patient's mental status had improved mildly. A follow-up brain MRI showed resolution of enhancement, but progression of subcortical bihemispheric white matter disease. Subsequently, the patient developed a respiratory infection and passed away. In rheumatoid arthritis, symptoms of encephalopathy, headaches, seizures, or focal neurologic deficits should raise suspicion for CNS involvement. This potentially treatable disease warrants prompt diagnosis.