Mild Acute Ischemic Stroke With Large Vessel Occlusion (MISTWAVE)

Patients who present with mild stroke symptoms (mAIS), and are also found to have an intracranial large vessel occlusion (LVO) pose an exceptionally difficult therapeutic dilemma. The need for any acute treatment is often debated since these patients "only" have mild deficits, and any therapy has associated risks. However, it has been shown that acute ischemic stroke (AIS) can lead to considerable morbidity and mortality even in patients presenting with mild symptoms (mAIS) in the presence of LVO. Despite reports that such patients have less favorable outcomes, these patients are often excluded from acute stroke therapy. Recent studies demonstrated that, despite mild and rapidly improving symptoms, many patients end up with unfavorable outcome. While the most recent AHA/ASA guidelines no longer recommend excluding patients with milder improving symptoms from intravenous tissue plasminogen activator administration, the role of endovascular intervention has not been clarified for these patients.

Prior data has shown high morbidity and mortality in mAIS patients (without specified large vessel status), who did not receive IV tPA, demonstrating that as high as 32% of patients was dependent during discharge or died in one study. A common reason for foregoing treatment in this patient group was that mild symptoms or rapid improvement were a contraindication to IV-tPA administration according to previous ASA/AHA guidelines. Higher morbidity was specifically noted in patients with concurrent large vessel occlusion as a cause of the symptom in another study. Mokin et al showed that for LVO patients excluded from thrombolysis, only 2/3rd could walk independently at discharge.

When assessing predictors of poor outcome, LVO seems to correlate with poor outcome despite mild symptoms. Nedeltchev et al published a study with 162 patients with either mild stroke symptoms (NIHSS of 3 or less) or rapidly improving symptoms (NIHSS improvement of 4 points or more), in which 25% of the patients had an unfavorable outcome. NIHSS of 10 or more and proximal vessel occlusion were independent predictors of poor outcome. LVO in patients with rapidly improving /mild symptoms conferred an 18-fold increased risk of early neurological deficit with infarct expansion. Patients with LVO were also more likely to have increased modified ranking scale (mRS), and LVO was an independent predictor of decline in functional status and a borderline significant predictor of poor outcome when adjusting for age, gender and presenting NIHSS.

NIH Stroke Scale Score Threshold The ideal NIHSS cutoff value for "mild" stroke remains unclear, and varies across studies. The investigators specifically chose the NIHSS 5 cut-off value for the cohort after careful consideration of the results of several earlier reports, which were available at the initiation of our research project. These studies, albeit with limited sensitivity and specificity, have concluded that an NIHSS cut-off of 7-10 and higher might be a reliable predictor of LVO. Since the investigators were trying to capture a controversial stroke population that was unlikely to have LVO because of mild symptoms, the investigators decided to include patients with NIHSS 5 or less.

Currently approved treatment and limitations At present, the American Heart Association and American Stroke Association guidelines recommend that eligible ischemic strokes be treated with IV tissue plasminogen activator (tPA) and/or mechanical thrombectomy. Severity of the stroke is based on the National institute of health stroke scale (NIHSS), and the guidelines do not specify any thrombolysis treatment for mild strokes.

Mechanical thrombectomy using stent retrievers for LVO stroke has become the standard of care; however, current guidelines exclude patients with mild or improving symptoms. These recommendations were made based on the 2015 randomized control trials, most of which did not include patients with NIHSS <6.

Despite the MR-CLEAN trial's inclusion of patients with NIHSS as low as 2, which showed efficacy of IAT for LVO, it is unclear what proportion of successfully treated patients were actually in the mAIS category. The PRISMS study investigated the efficacy IV-tPA in mAIS patients, although establishment of large vessel status was not specifically required (NCT02072226). The TEMPO -1 trial showed safety and feasibility of tenecteplase in patients with LVO and mAIS, and the TEMPO - 2 trial (NCT02398656) comparing tenecteplase to standard therapy is currently ongoing.

The recently completed DAWN trial is an international multi-center randomized trial study of patients with acute ischemic anterior stroke due to large vessel occlusions between 6 -24 hours of stroke with endovascular therapy. The results from 206 patients enrolled in the trial demonstrated treatment with use of stentriver significantly decreased post-stroke disability and improved functional independence at 90 days when compared to medical management alone (48.6% vs 13.1%, p<0.001), a relative reduction in disability of 73% percent. The study showed that one in 2.8 patients treated with the stentriever within 24 hours of a stroke is saved from severe disability. Another large trial, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 3 (DEFUSE 3), was halted after the DAWN trial results were presented. This study enrolled patients with large vessel occlusion presenting within 6 and 16 hours of stroke onset based on advanced imaging criteria. Patients who underwent endovascular therapy had 2.77 times greater odds of regaining functional independence at 90 days, versus medical management alone (45% vs 17%, p<0.001), showing benefit for the endovascular group.

Acute vertebrobasilar occlusion The efficacy of mechanical thrombectomy in the anterior circulation raised the question of its potential applicability in the posterior circulation. Acute basilar occlusion accounts for approximately 1% of all acute ischemic strokes, and is disproportionately associated with a mortality rate of approximately 70%. Given these statistics, procedural risks in acute basilar occlusion syndromes have long been regarded much lower than the risk of unfavorable outcome without intervention. Therefore these patients have largely been omitted from clinical trials resulting in a paucity of clinical evidence, in contrast with anterior circulation strokes. Patients with mild-to-moderate posterior circulation AIS pose a unique challenge, as retrospective data correlate the patients' clinical outcome with severity at presentation, giving them up to 67% chance of achieving a favorable outcome.