Navdeep Sangha

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.

Endovascular therapy for acute ischemic stroke with occlusion of the middle cerebral artery M2 segment

Importance Randomized clinical trials have shown the superiority of endovascular therapy (EVT) compared with best medical management for acute ischemic strokes with large vessel occlusion (LVO) in the anterior circulation. However, of 1287 patients enrolled in 5 trials, 94 with isolated second (M2) segment occlusions were randomized and 51 of these received EVT, thereby limiting evidence for treating isolated M2 segment occlusions as reflected in American Heart Association guidelines. Objective To evaluate EVT safety and effectiveness in M2 occlusions in a cohort of patients with acute ischemic stroke. Design, Setting, and Participants This multicenter retrospective cohort study pooled patients with acute ischemic strokes and LVO isolated to M2 segments from 10 US centers. Patients with acute ischemic strokes and LVO in M2 segments presenting within 8 hours from their last known normal clinical status (LKN) from January 1, 2012, to April 30, 2015, were divided based on their treatment into EVT and medical management groups. Logistic regression was used to compare the 2 groups. Univariate and multivariate analyses evaluated associations with good outcome in the EVT group. Main Outcomes and Measures The primary outcome was the 90-day modified Rankin Scale score (range, 0-6; scores of 0-2 indicate a good outcome); the secondary outcome was symptomatic intracerebral hemorrhage. Results A total of 522 patients (256 men [49%]; 266 women [51%]; mean [SD] age, 68 [14.3] years) were identified, of whom 288 received EVT and 234 received best medical management. Patients in the medical management group were older (median [interquartile range] age, 73 [60-81] vs 68 [56-78] years) and had higher rates of intravenous tissue plasminogen activator treatment (174 [74.4%] vs 172 [59.7%]); otherwise the 2 groups were balanced. The rate of good outcomes was higher for EVT (181 [62.8%]) than for medical management (83 [35.4%]). The EVT group had 3 times the odds of a good outcome as the medical management group (odds ratio [OR], 3.1; 95% CI, 2.1-4.4; P < .001) even after adjustment for age, National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomographic Score (ASPECTS), intravenous tissue plasminogen activator treatment, and time from LKN to arrival in the emergency department (OR, 3.2; 95% CI, 2-5.2; P < .001). No statistical difference in symptomatic intracerebral hemorrhage was found (5.6% vs 2.1% for the EVT group vs the medical management group; P = .10). The treatment effect did not change after adjusting for center (OR, 3.3; 95% CI, 1.9-5.8; P < .001). Age, NIHSS score, ASPECTS, time from LKN to reperfusion, and successful reperfusion score of at least 2b (range, 0 [no perfusion] to 3 [full perfusion with filling of all distal branches]) were independently associated with good outcome of EVT. A linear association was found between good outcome and time from LKN to reperfusion. Conclusions and Relevance Although a randomized clinical trial is needed to confirm these findings, available data suggest that EVT is reasonable, safe, and effective for LVO of the M2 segment relative to best medical management.

Acute Ischemic Stroke Treated with Intravenous Tissue Plasminogen Activator in a Patient Taking Dabigatran with Radiographic Evidence of Recanalization

Dabigatran etexelate is a new oral direct thrombin inhibitor that has been approved by the US Food and Drug Administration to prevent stroke in patients with nonvalvular atrial fibrillation. A 51-year-old man with a history of atrial fibrillation who was taking dabigatran presented with an acute ischemic stroke. The patient had a normal international normalized ratio, activated partial thromboplastin time, and an elevated thrombin time of 26.4 seconds. Recanalization of the middle cerebral artery with intravenous tissue plasminogen activator was apparent on digital subtraction angiography, and there was no evidence of intracerebral hemorrhage on the repeat computed tomographic scan. This is the first report of a patient who was taking dabigatran etexilate and who had an ischemic stroke caused by a middle cerebral artery occlusion, with an elevated thrombin time and radiographic recanalization with intravenous tissue plasminogen activator without evidence of hemorrhagic transformation.

Treatment Targets in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) imparts a higher mortality and morbidity than ischemic stroke. The therapeutic interventions that are currently available focus mainly on supportive care and secondary prevention. There is a paucity of evidence to support any one acute intervention that improves functional outcome. This chapter highlights current treatment targets for ICH based on the pathophysiology of the disease.

Thromboelastography in patients with acute ischemic stroke.

Background Thromboelastography measures the dynamics of coagulation. There are limited data about thromboelastography in acute ischemic stroke other than a single study from 1974 suggesting that acute ischemic stroke patients are hypercoagulable. There have been no studies of thromboelastography in the thrombolytic era despite its potential usefulness as a measure of clot lysis. This study was designed to provide initial thromboelastography data in stroke patients before and after tissue plasminogen activator therapy and to provide the necessary preliminary data for further study of thromboelastographys ability to identify clot subtype and predict response to tissue plasminogen activator therapy. Methods All acute ischemic stroke patients presenting between 11/2009 and 2/2011 eligible for tissue plasminogen activator therapy were screened and 56 enrolled. Blood was drawn before (52 patients) and 10 mins after tissue plasminogen activator bolus (30 patients). Demographics, vitals, labs, 24 h National Institutes of Health Stroke Scale, and computed tomography scan results were collected. Patients were compared with normal controls. Results Acute ischemic stroke patients had shorter R (4·8 ± 1·5 vs. 6·0 ± 1·7 min, P = 0·0004), greater a Angle (65·0 ± 7·6 vs. 61·5 ± 5·9°, P = 0·01), and shorter K (1·7 ± 0·7 vs. 2·1 ± 0·7 min, P = 0·002) indicating faster clotting. Additionally, a subset formed clots with stronger platelet-fibrin matrices. Treatment with tissue plasminogen activator resulted in reduction in all indices of clot strength (LY30 = 0 (0–0·4) vs. 94·4 (15·2–95·3) P < 0·0001); however, there was considerable variability in response. Conclusions Thromboelastography demonstrates that many acute ischemic stroke patients are hypercoaguable. Thromboelastography values reflect variable clot subtype and response to tissue plasminogen activator. Further study based on these data will determine if thromboelastography is useful for measuring the dynamic aspects of clot formation and monitoring lytic therapy.

Thrombolysis for acute stroke in hemodialysis: international survey of expert opinion.

BACKGROUND AND OBJECTIVES Although data are absent, it has been stated that thrombolysis is probably not safe in the treatment of acute stroke in patients undergoing hemodialysis. The objective of this study was for stroke experts to define the range of management concerning thrombolytic treatment of acute stroke in hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Sixty-five stroke experts in thrombolytic therapy of acute ischemic stroke were queried regarding their personal experience in the use of thrombolysis in hemodialysis patients. Hypothetical case scenarios were presented. RESULTS Of the 65 stroke experts who were queried, 40 (62%) responded. One-third of the responders had previously treated hemodialysis patients with recombinant tissue-type plasminogen activator (rt-PA). Most favored use of intravenous rt-PA for hemodialysis patients with acute ischemic stroke. When presented with a case of a patient who had recently undergone dialysis with a mildly prolonged activated partial thromboplastin time (aPTT), 50% favored immediate intravenous thrombolysis. Seventy-eight percent of the experts would have considered an intra-arterial approach and would have preferred mechanical clot retrieval to thrombolysis. CONCLUSIONS Despite the acknowledged absence of data and prevalent concerns about bleeding risk, most surveyed experts favored its use. One-third reported treating hemodialysis patients with this therapy. Although these results do not substitute for data, they usefully define the range of current practice of stroke experts.

Clotting Factors to Treat Thrombolysis-related Symptomatic Intracranial Hemorrhage in Acute Ischemic Stroke

BACKGROUND Symptomatic intracranial hemorrhage (sICH) occurs uncommonly after ischemic stroke therapy with tissue plasminogen activator (tPA). Clotting factor administration may be a treatment option. OBJECTIVE To determine if treatment with clotting factors (fresh frozen plasma [FFP] or cryoprecipitate) was associated with improved outcomes in sICH. METHODS We conducted a retrospective cohort study within University of Texas at Houston Stroke registry involving consecutive patients from February 1, 2007, to June 30, 2011, with tPA-related sICH, including cases with subsequent intra-arterial therapy. Outcomes were Modified Rankin Scale (mRS) score at discharge, death, and hematoma expansion. RESULTS Of 921 patients treated with tPA, 48 (5.2%) had sICH and 45 met criteria for the study. Nineteen patients received clotting factors (42.2%; 18 received FFP and 7 received cryoprecipitate), whereas 26 (57.8%) patients received conservative management without clotting factors. None of the patients treated with clotting factors and only 2 of those who did not receive clotting factors had a good outcome, mRS score of 2 or less. All the patients treated with clotting factors and most of those not treated were left bedridden or dead (mRS score 4-6), 19 (100%) versus 22 (85%). Mortality was 9 (47.4%) versus 9 (34.6%), respectively. There was no difference in hematoma expansion between the 2 groups. CONCLUSIONS We found no evidence that treatment for sICH with clotting factors has a favorable effect on clinical or radiological outcomes. However, the sample was small because of the low frequency of sICH. New treatments are urgently needed for this uncommon yet serious condition.

Misdiagnosis of cerebellar infarctions.

BACKGROUND This retrospective study addresses for the first time the differences in clinical features and outcomes between those individuals with a cerebellar infarct who were correctly diagnosed on initial presentation compared to those who experienced delayed diagnosis. METHODS A retrospective review was conducted of our stroke registry from 09/2003 to 02/2011. Forty seven patients had an isolated cerebellar infarction confirmed by MRI. Misdiagnosis was defined as the diagnosis given by the first physician. RESULTS Among 47 patients identified, 59.6% had delayed diagnosis. Five patients in the correct diagnosis group received intravenous tissue plasminogen activator, compared to none in the delayed diagnosis group. Complaints of weakness were protective from delayed diagnosis (OR 0.087, 95% CI 0.019-0.393, p=0.001). Conclusion : Patients with an isolated cerebellar infarction need to be considered when patients present with acute non-specific symptoms. Critical components of the neurological examination are omitted which are imperative to diagnose cerebellar infarcts. A thorough neurological examination may increase clinical suspicion of an ischemic stroke.

Iodinated Contrast Does Not Alter Clotting Dynamics in Acute Ischemic Stroke as Measured by Thromboelastography

Background and Purpose— Iodinated contrast agents used for computed tomography angiography (CTA) may alter fibrin fiber characteristics and decrease fibrinolysis by tissue plasminogen activator (tPA). Thromboelastography (TEG) measures the dynamics of coagulation and correlates with thrombolysis in acute ischemic stroke patients. We hypothesized that receiving CTA before tPA will not impair thrombolysis as measured by TEG. Methods— Acute ischemic stroke patients receiving 0.9 mg/kg tPA <4.5 hours of symptom onset were prospectively enrolled. For CTA, 350 mg/dL of iohexol or 320 mg/dL of iodixanol at a dose of 2.2 mL/kg was administered. TEG was measured before tPA and 10 minutes after tPA bolus. CTA timing was left to the discretion of the treating physician. Results— Of 136 acute ischemic stroke patients who received tPA, 47 had CTA before tPA bolus, and 42 had either CTA after tPA and post–tPA TEG draw or no CTA (noncontrast group). Median change in clot lysis (LY30) after tPA was 95.3% in the contrast group versus 95.0% in the noncontrast group (P=0.74). Thus, tPA-induced thrombolysis did not differ between contrast and noncontrast groups. Additionally, there was no effect of contrast on any pre–tPA TEG value. Conclusions— Our data do not support an effect of iodinated contrast agents on clot formation or tPA activity.

Limb-Shaking Syndrome with Light-Induced Amaurosis Fugax: A Rare Presentation of Near-Occlusive Carotid Disease

A 65-year-old woman with a history of carotid artery disease status post coronary artery bypass grafting and percutaneous coronary intervention, hypertension, hyperlipidemia, diabetes, and peripheral vascular disease complained of blurry vision, for which the neurology team was consulted. Her blurry vision involved only her left eye and was described as haziness over her entire left visual field. Blurry vision was induced by sunlight exposure and would resolve spontaneously over minutes. Each episode was associated with severe retro-orbital pain. Upon further interview, she reported having involuntary right arm shaking for the past 6 years. These shaking episodes occurred constantly at rest and worsened with voluntary movement. She also reported episodic, involuntary right leg shaking, which was worse at night. These shaking symptoms were attributed to possible Parkinson’s disease in the past. On examination, it was noted that she had significant right upper extremity rhythmic jerking movements at rest (Video 1) with a frequency from 3 to 4 Hz. The amplitude of tremor was increased with hyperextension of the upper extremity. The patient also had sustained clonus of her right patella precipitated by passive raising of right lower extremity. The rest of the neurological examination was normal. The carotid ultrasound revealed significant left internal carotid artery (ICA) stenosis (>70%) and moderate right ICA stenosis (range, 50–69%). Further work-up with carotid artery angiography revealed extensive calcification of the left proximal ICA with high-grade stenosis. She was then evaluated by vascular surgery for carotid endarterectomy. At the time, the vascular surgery service deemed that the patient had no emergency need for intervention. She was subsequently discharged and planned for outpatient follow-up. Six days later, the patient presented to the emergency department with transient aphasia and right upper extremity weakness and was then transferred back to our hospital for further management. According to the stroke neurologist’s evaluation, her presenting symptoms were concerning for transient ischemic attack with symptomatic left carotid near-occlusive disease. She was re-evaluated for vascular intervention by vascular surgery. Given the significant risk for carotid endarterectomy due to the patient’s cardiac history, she underwent cerebral angiography. Cerebral angiography demonstrated eccentric, calcified plaque with 95% stenosis in the left ICA. Subsequently, the patient underwent carotid artery stenting for revascularization. Poststenting, there was no residual stenosis, and she had improved intracranial flowy. After the procedure, she had complete resolution of her right arm tremor and right leg clonus.