Jose G. Romano

Predictors of Ischemic Stroke in the Territory of a Symptomatic Intracranial Arterial Stenosis

Background— Antithrombotic therapy for intracranial arterial stenosis was recently evaluated in the Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial. A prespecified aim of WASID was to identify patients at highest risk for stroke in the territory of the stenotic artery who would be the target group for a subsequent trial comparing intracranial stenting with medical therapy. Methods and Results— WASID was a randomized, double-blinded, multicenter trial involving 569 patients with transient ischemic attack or ischemic stroke due to 50% to 99% stenosis of a major intracranial artery. Median time from qualifying event to randomization was 17 days, and mean follow-up was 1.8 years. Multivariable Cox proportional hazards models were used to identify factors associated with subsequent ischemic stroke in the territory of the stenotic artery. Subsequent ischemic stroke occurred in 106 patients (19.0%); 77 (73%) of these strokes were in the territory of the stenotic artery. Risk of stroke in the territory of the stenotic artery was highest with severe stenosis ≥70% (hazard ratio 2.03; 95% confidence interval 1.29 to 3.22; P=0.0025) and in patients enrolled early (≤17 days) after the qualifying event (hazard ratio 1.69; 95% confidence interval 1.06 to 2.72; P=0.028). Women were also at increased risk, although this was of borderline significance (hazard ratio 1.59; 95% confidence interval 1.00 to 2.55; P=0.051). Location of stenosis, type of qualifying event, and prior use of antithrombotic medications were not associated with increased risk. Conclusions— Among patients with symptomatic intracranial stenosis, the risk of subsequent stroke in the territory of the stenotic artery is greatest with stenosis ≥70%, after recent symptoms, and in women.

Warfarin vs aspirin for symptomatic intracranial stenosis: Subgroup analyses from WASID

The WASID trial showed no advantage of warfarin over aspirin for preventing the primary endpoint of ischemic stroke, brain hemorrhage, or vascular death. In analyses of selected subgroups, there was no definite benefit from warfarin. Warfarin reduced the risk of the primary endpoint among patients with basilar artery stenosis, but there was no reduction in stroke in the basilar artery territory or benefit for vertebral artery stenosis or posterior circulation disease in general.

Risk factor status and vascular events in patients with symptomatic intracranial stenosis

Background: There are limited data on the relationship between control of vascular risk factors and vascular events in patients with symptomatic intracranial arterial stenosis. Methods: We utilized the Warfarin Aspirin Symptomatic Intracranial Disease study database to analyze vascular and lifestyle risk factors at baseline and averaged over the course of the trial. Cutoff levels defining good control for each factor were prespecified based on national guidelines. Endpoints evaluated included 1) ischemic stroke, myocardial infarction, or vascular death or 2) ischemic stroke alone. Univariate associations were assessed using the log-rank test and multivariable analysis was done using Cox proportional hazards regression. Results: From baseline until year 2 follow-up, there was not a significant improvement in blood pressure control. During the same period, there were improvements in patients with total cholesterol <200 mg/dL (54.6% to 79.2%, p < 0.001) or low-density lipoprotein <100 mg/dL (28.7% to 55.9%, p < 0.001). Multivariable analysis showed that systolic blood pressure ≥140 mm Hg (HR = 1.79, p = 0.0009, 95% confidence limits 1.27 to 2.52), no alcohol consumption (HR 1.69, 1.21 to 2.39, p = 0.002), and cholesterol ≥200 mg/dL (HR 1.44, 1.004 to 2.07, p = 0.048) were associated with an increased risk of stroke, myocardial infarction, or vascular death. The same risk factors were predictors of ischemic stroke alone in multivariable analysis. Conclusions: Elevated blood pressure and cholesterol levels in symptomatic patients with intracranial stenosis are associated with an increased risk of stroke and other major vascular events.

Mechanisms of ischemic stroke in HIV-infected patients.

Objective: To evaluate the types and mechanisms of stroke in a large population of HIV-infected patients. Methods: We reviewed records of consecutive HIV-infected patients with acute stroke admitted to a large metropolitan hospital between 1996 and 2004. Stroke mechanism was defined by consensus between two cerebrovascular neurologists using TOAST classification. Results: A total of 82 patients were included, 77 with ischemic stroke and 5 with intracerebral hemorrhage. Mean age was 42 years and 89% were African American. Previous diagnosis of HIV infection was documented in 91% and AIDS diagnosis in 80%. Mean CD4 count was 113 cells/mm3 and 85% had CD4 count <200 cells/mm3. A total of 61% of patients had received combination antiretroviral treatment (CART). The mechanism of ischemic stroke was large artery atherosclerosis in 12%, cardiac embolism in 18%, small vessel occlusion in 18%, other determined etiology in 23%, and undetermined in 29% (including 19% with incomplete evaluation). Vasculitis was deemed responsible for the stroke in 10 patients (13%) and hypercoagulability in 7 (9%). Protein S deficiency was noted in 10/22 (45%) and anticardiolipin antibodies in 9/31 (29%) tested patients. When comparing patients with large or small vessel disease (atherothrombotic strokes) vs the rest of the population, there were no differences in exposure to CART or CD4 count, but patients with non-atherothrombotic strokes were younger (p = 0.04). Recent cocaine exposure was less common among patients with atherothrombotic strokes (p = 0.02). Strokes were fatal or severely disabling in 35% of cases. Conclusions: Stroke mechanisms are variable in HIV-infected patients, with a relatively high incidence of vasculitis and hypercoagulability. In our population of severely immunodepressed patients, exposure to combination antiretroviral treatment did not significantly influence the mechanism of stroke.

Design, Progress and Challenges of a Double-Blind Trial of Warfarin versus Aspirin for Symptomatic Intracranial Arterial Stenosis

Background and Relevance: Atherosclerotic stenosis of the major intracranial arteries is an important cause of transient ischemic attack (TIA) or stroke. Of the 900,000 patients who suffer a TIA or stroke each year in the USA, intracranial stenosis is responsible for approximately 10%, i.e. 90,000 patients. There have been no prospective trials evaluating antithrombotic therapies for preventing recurrent vascular events in these patients. The main objective of this trial is to compare warfarin [International Normalized Ratio (INR) 2–3] with aspirin (1,300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients presenting with TIA or stroke caused by stenosis of a major intracranial artery. Study Design: Prospective, randomized, double-blind, multicenter trial. The sample sizerequired will be 403 patients per group, based on stroke and vascular death rates of 33% per 3 years in the aspirin group vs. 22% per 3 years in the warfarin group, a p value of 0.05, power of 80%, a 24% rate of ‘withdrawal of therapy’, and a 1% rate of ‘lost to follow-up’. Conduct of Trial: Patients with TIA or nondisabling stroke caused by ≧50% stenosis of a major intracranial artery documented by catheter angiography are randomized to warfarin or aspirin. Patients are contacted monthly by phone and examined every 4 months until a common termination date. Mean follow-up in the study is expected to be 3 years. Conclusion: This study will determine whether warfarin or aspirin is superior for patients with symptomatic intracranial arterial stenosis. Furthermore, it will identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high to justify a subsequent trial comparing intracranial angioplasty/stenting with best medical therapy in this subset of patients.

Detection of microemboli by transcranial Doppler ultrasonography in aneurysmal subarachnoid hemorrhage

OBJECTIVE To determine the frequency and characteristics of microembolic signals (MES) in subarachnoid hemorrhage (SAH). METHODS Twenty-three patients with aneurysmal SAH were monitored with transcranial Doppler ultrasonography for the presence of MES and vasospasm. Each middle cerebral artery was monitored for 30 minutes three times each week. Patients were excluded if they had traumatic SAH or cardiac or arterial sources of emboli. Monitoring was initiated 6.3 days (1–16 d) after SAH and lasted 6.6 days (1–13 d). Eleven individuals without SAH or other cerebrovascular diseases who were treated in the same unit served as control subjects. Each patient underwent monitoring of both middle cerebral arteries a mean of three times; therefore, 46 vessels were studied (a total of 138 observations). Control subjects underwent assessment of each middle cerebral artery once, for a total of 22 control vessels. RESULTS MES were detected for 16 of 23 patients (70%) and 44 of 138 patient vessels (32%) monitored, compared with 2 of 11 control subjects (18%) and 2 of 22 control vessels (9%) (P < 0.05). MES were observed for 83% of patients with clinical vasospasm and 54% of those without clinical vasospasm. Ultrasonographic vasospasm was observed for 71 of 138 vessels monitored; MES were observed for 28% of vessels with vasospasm and 36% of those without vasospasm. Aneurysms proximal to the monitored artery were identified in 38 of 138 vessels, of which 34% exhibited MES, which is similar to the frequency for vessels without proximal aneurysms (31%). Coiled, clipped, and unsecured aneurysms exhibited similar frequencies of MES. CONCLUSION MES were common in SAH, occurring in 70% of cases of SAH and one-third of all vessels monitored. Although MES were more frequent among patients with clinical vasospasm, this difference did not reach statistical significance. We were unable to demonstrate a relationship between ultrasonographic vasospasm and MES, and the presence of a proximal secured or unsecured aneurysm did not alter the chance of detection of MES. Further studies are required to determine the origin and clinical relevance of MES in SAH.

Acetazolamide for the treatment of migraine with aura in CADASIL.

making it impossible to perform the intended task. She expressed anxiety and frustration with regard to these involuntary actions. She had left motor neglect, presenting with slowing and underutilizing the left hand voluntarily for tasks on intention and verbal command. Automatic gestures of the left hand were normal. She also presented left hand apraxia on imitation (she failed 10 items out of 24 with her left hand) and tactile anomia of the left hand (she failed 8 items out of 10 with the left hand; the right hand performed well on all items). There was no visuospatial neglect or extinction of the sensory modalities. Discussion. I propose the term “compulsive grasping hand syndrome” in my patient to refer to spontaneous, stereotyped, involuntary left hand grasp reaction to her right hand as a consequence of her right hand movements. This abnormal behavior fits partially with the definition of anarchic hand, but the behavioral type could be distinguished by the presence of compulsive contralateral hand grasping without groping, mirror movements, and utilization behavior.3,5 In patients with intermanual conflict alien hand,5,6 or diagonistic dyspraxia,7 there is a dissociative phenomenon in which one hand is acting at cross-purpose to the other following voluntary activities. In our patients, the involuntary left hand grasping related to all type of movements of the right hand suggests a motor grasp response phenomenon to the contralateral hand movements. Paradoxical motor behavior in my patient could be related to the involvement of pathways projecting to supplementary motor area via corpus callosum that drive intentional and volitional movements. Compulsive grasping hand movement could be interpreted as a release phenomenon of the learned praxis of the left hand due to damage to genu and body of the corpus callosum. Compulsive grasping hand and other anarchic hand movements are clinical signs of a defective internal response inhibition, and more generally, fragments of the spectrum of frontal hand syndromes.

Transcranial Doppler Detection of Fat Emboli

BACKGROUND AND PURPOSE The fat embolism syndrome (FES) is characterized by the simultaneous occurrence of pulmonary and neurological symptoms as well as skin and mucosal petechiae in the setting of long-bone fractures or their surgical repair. Its pathophysiology is poorly understood, and effective treatments are lacking. We present 5 patients with long-bone fractures in whom in vivo microembolism was detected by transcranial Doppler. METHODS Five patients with long-bone fractures were monitored with transcranial Doppler for microembolic signals (MESs) after trauma. Two patients also had intraoperative monitoring. A TC-2020 instrument equipped with MES detection software was used. Detected signals were saved for subsequent review. Selected signals satisfied criteria defined previously and were categorized as large or small. RESULTS Cerebral microembolism was detected in all 5 patients and was transient, resolving within 4 days of injury. Intraoperative monitoring revealed an increase in MESs during intramedullary nail insertion. The characteristics of MESs after injury varied among patients, with large signals being more frequent in the only patient with a patent foramen ovale. CONCLUSIONS Cerebral microembolism after long-bone fractures can be detected in vivo and monitored over time. These findings may have potential diagnostic and therapeutic implications.

Failure of antithrombotic therapy and risk of stroke in patients with Symptomatic Intracranial Stenosis

Background and Purpose— We sought to determine if patients with intracranial stenosis who have a transient ischemic attack or stroke on antithrombotic therapy are at particularly high risk for recurrent stroke. Methods— We compared baseline features and the rates of stroke or vascular death and stroke in the territory of the symptomatic artery between patients ON (n=299) versus OFF (n=269) antithrombotics at the time of their qualifying event for the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. Results— In univariate analyses, there was no difference in the rates of stroke or vascular death (21% versus 23%; hazard ratio [ON/OFF], 0.91; 95% CI, 0.64 to 1.29; P=0.59) or stroke in territory (13% versus 14%; hazard ratio [ON/OFF], 0.90; 95% CI, 0.57 to 1.39; P=0.61) between patients ON versus OFF antithrombotics at the time of their qualifying event. A multivariable analysis adjusted for the difference in risk factors between patients ON and OFF antithrombotic therapy also showed no significant differences in the combined end point of stroke or vascular death (hazard ratio [ON/OFF], 0.86; 95% CI, 0.55 to 1.34; P=0.51) or stroke in territory (hazard ratio [ON/OFF], 1.01; 95% CI, 0.58 to 1.77; P=0.97) between patients ON versus OFF antithrombotic therapy at the time of the qualifying event. Conclusions— Patients with intracranial stenosis who fail antithrombotic therapy are not at higher risk of stroke than those who do not fail antithrombotic therapy. Given our finding that patients ON and OFF antithrombotic therapy are both at high risk for stroke in the territory, intracranial stenting trials should not be limited to just those who fail antithrombotic therapy.

Cerebral Fat Microembolism and Cognitive Decline After Hip and Knee Replacement

Background and Purpose— Intra-operative cerebral microembolism may be a factor in the etiology of cognitive decline after orthopedic surgery. We here examine the impact of intra-operative microembolism on cognitive dysfunction after hip and knee replacement surgery. Methods— We enrolled 24 patients, at least 65 years old, requiring elective knee or hip replacement surgery. A transcranial Doppler shunt study was done to determine study eligibility so that the final study population consisted of 12 consecutive patients with and 12 consecutive patients without a venous-arterial shunt. A standard neuropsychological test battery was administered before surgery, at hospital discharge and 3 months after surgery. All patients were monitored intra-operatively for microemboli. Quality of life data were assessed at 1 year. Results— The mean age of patients was 74 years. All patients had intra-operative microemboli. The mean number of emboli was 9.9±18. Cognitive decline was present in 18/22 (75%) at discharge and in 10/22 (45%) at 3 months, despite improved quality of life measures. There was no correlation between cognitive decline and intra-operative microembolism. Conclusion— Cognitive decline was seen frequently after hip and knee surgery. Intra-operative microembolism occurred universally but did not significantly influence postoperative cognition. Quality of life and functional outcome demonstrated improvement in all cases in spite of cognitive dysfunction.