Notch receptor expression in human brain arteriovenous malformations

The roles of the Notch pathway proteins in normal adult vascular physiology and the pathogenesis of brain arteriovenous malformations are not well-understood. Notch 1 and 4 have been detected in human and mutant mice vascular malformations respectively. Although mutations in the human Notch 3 gene caused a genetic form of vascular stroke and dementia, its role in arteriovenous malformations development has been unknown. In this study, we performed immunohistochemistry screening on tissue microarrays containing eight surgically resected human brain arteriovenous malformations and 10 control surgical epilepsy samples. The tissue microarrays were evaluated for Notch 1-4 expression. We have found that compared to normal brain vascular tissue Notch-3 was dramatically increased in brain arteriovenous malformations. Similarly, Notch 4 labelling was also increased in vascular malformations and was confirmed by western blot analysis. Notch 2 was not detectable in any of the human vessels analysed. Using both immunohistochemistry on microarrays and western blot analysis, we have found that Notch-1 expression was detectable in control vessels, and discovered a significant decrease of Notch 1 expression in vascular malformations. We have demonstrated that Notch 3 and 4, and not Notch 1, were highly increased in human arteriovenous malformations. Our findings suggested that Notch 4, and more importantly, Notch 3, may play a role in the development and pathobiology of human arteriovenous malformations

Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator

Background and Purpose—TIMI angiographic classification measures coronary residual flow and recanalization. We developed a Thrombolysis in Brain Ischemia (TIBI) classification by using transcranial Doppler (TCD) to noninvasively monitor intracranial vessel residual flow signals. We examined whether the emergent TCD TIBI classification correlated with stroke severity and outcome in patients treated with intravenously administered tPA (IV-tPA). Methods—TCD examination occurred acutely and on day 2. TIBI flows were determined at distal MCA and basilar artery depths, depending on occlusion site. TIBI waveforms were graded as follows: 0, absent; 1, minimal; 2, blunted; 3, dampened; 4, stenotic; and 5, normal. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours after administration of tPA. Results—One hundred nine IV tPA patients were studied. Mean±SD age was 68±16 years; median NIHSS score before administration of tPA (pre-tPA) was 17.5. The tPA bolus was administered 143±58 minutes and the TCD examination 141±57 minutes after symptom onset. Pre-tPA NIHSS scores were higher in patients with TIBI grade 0 than TIBI grade 4 or 5 flow. TIBI flow improvement to grade 4 or 5 occurred in 35% of patients (19/54) with an initial grade of 0 or 1 and in 52% (12/23) with initial grade 2 or 3. The 24-hour NIHSS scores were higher in follow-up in patients with TIBI grade 0 or 1 than those with TIBI grade 4 or 5 flow. TIBI flow recovery correlated with NIHSS score improvement. Lack of flow recovery predicted worsening or no improvement. In-hospital mortality was 71% (5/7) for patients with posterior circulation occlusions; it was 22% (11/51) for patients with pre-tPA TIBI 0 or 1 compared with 5% (1/19) for those with pre-tPA TIBI 2 or 3 anterior circulation occlusions. Conclusions—Emergent TCD TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in IV-tPA–treated stroke patients. A flow-grade improvement correlated with clinical improvement

Validity and Reliability of the Thrombolysis in Brain Infarction (TIBI) Flow Grades

Background: In patients eligible for thrombolytic therapy, the TIBI grading system defines residual transcranial Doppler (TCD) flow signals at the site of clot location. In addition, TIBI flow grades correlate with angiography and predict short-term improvement following TPA therapy. The aim of this study was to develop a valid and reliable instrument to assess how accurately health professionals determine TIBI flow grades. Methods: Two expert sonographers developed a 60 question computerized examination of the 6 TIBI flow grades. Gold standard interpretation was determined by a consensus interpretation by a pool of expert sonographers. All items were equally weighted and written in a standard format. A computerized TIBI grading tutorial and standard interpretation rules were available for all test-takers. To assess content validity and reliability, a blinded panel of 3 experts independently took the examination. Inter-rater agreement was determined among experienced sonographers, stroke neurologists, and other health professionals (N=11). Results: Expert assessment of each test item measured objective congruence at 1.0, overall test validity coefficient of 0.996 (95%CI 0.993–0.997), and an item/TIBI flow grade validity coefficient of 0.992 (95%CI 0.996–0.997). Overall test and individual item reliability had coefficients of 0.98(95%CI 0.97–0.99) and 0.97 (95%CI 0.95–0.98,