Rafael H. Llinas

MRI Features of Intracerebral Hemorrhage Within 2 Hours From Symptom Onset

BACKGROUND AND PURPOSE MRI has been increasingly used in the evaluation of acute stroke patients. However, MRI must be able to detect early hemorrhage to be the only imaging screen used before treatment such as thrombolysis. Susceptibility-weighted imaging, an echo-planar T2* sequence, can show intracerebral hemorrhage (ICH) in patients imaged between 2.5 and 5 hours from symptom onset. It is unknown whether MRI can detect ICH earlier than 2.5 hours. We describe 5 patients with ICH who had MRI between 23 and 120 minutes from symptom onset and propose diagnostic patterns of evolution of hyperacute ICH on MRI. METHODS As part of our acute imaging protocol, all patients with acute stroke within 24 hours from symptom onset were imaged with a set of sequences that included susceptibility-weighted imaging, diffusion- and perfusion-weighted imaging, T1- and T2-weighted imaging, fluid-attenuated inversion recovery (FLAIR), and MR angiography using echo-planar techniques. Five patients with ICH had MRI between 23 and 120 minutes from the onset of symptoms. RESULTS ICH was identified in all patients. Distinctive patterns of hyperacute ICH and absence of signs of ischemic stroke were the hallmark features of this diagnosis. The hyperacute hematoma appears to be composed of 3 distinct areas: (1) center: isointense to hyperintense heterogeneous signal on susceptibility-weighted and T2-weighted imaging; (2) periphery: hypointense (susceptibility effect) on susceptibility-weighted and T2-weighted imaging; and (3) rim: hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, representing vasogenic edema encasing the hematoma. CONCLUSIONS MRI is able to detect hyperacute ICH and show a pattern of evolution of the hematoma within 2 hours from the onset of symptoms.

Clinical and Vascular Outcome in Internal Carotid Artery Versus Middle Cerebral Artery Occlusions After Intravenous Tissue Plasminogen Activator

Background and Purpose— Early reperfusion is a predictor of good outcome in acute ischemic stroke. We investigated whether middle cerebral artery (MCA) occlusions have a better clinical outcome and proportion of recanalization compared with internal carotid artery (ICA) occlusion after standard treatment with intravenous (IV) tissue plasminogen activator (tPA). Patients— In a retrospective analysis of our prospective stroke database between January 7, 1998, and January 30, 2002, we identified 36 consecutive patients who were treated with IV tPA within 3 hours after symptom onset of a stroke in the distribution of a documented ICA or MCA occlusion. The National Institutes of Health Stroke Scale (NIHSS) score was recorded before tPA, at 24 hours, 3 days, and 3 months after stroke. Three-month outcome was recorded by modified Rankin scale. Magnetic resonance angiography or computed tomographic angiography was obtained before tPA. The presence of recanalization was assessed by transcranial Doppler and/or magnetic resonance angiography within 3 days after stroke onset. Results— Nineteen patients had MCA occlusion, and 17 had ICA-plus-MCA occlusion before tPA. Although there was no difference in age and NIHSS at day 0 between the 2 groups, the MCA group had a lower day 3 NIHSS score compared with the ICA group (P =0.006) in an ANCOVA. In addition, patients who had a MCA occlusion had lower day 1 and 3 NIHSS scores compared with the ICA group (P =0.04 and P =0.03, respectively; Wilcoxon rank sum). Similarly, NIHSS was significantly lower in patients who recanalized on days 1 and 3 (P =0.004 and P =0.003 respectively, Wilcoxon rank sum). When we adjusted for NIHSS score at day 0 in an ANCOVA, the adjusted mean was lower in the group that recanalized compared with the group that did not recanalize (P <0.001). There was a significant difference between the proportion of recanalization in the MCA group (15 of 17 recanalized, 88%) at 3 days after tPA compared with that of the ICA group (5 of 16 recanalized, 31%;P =0.001, Fisher exact test). The 3-month modified Rankin scale was not different between the 2 groups. Conclusions— Despite comparable age and NIHSS scores before IV tPA, MCA occlusions have lower day 1 and 3 NIHSS scores and higher proportion of recanalization compared with ICA occlusions. A combined IV/intra-arterial or mechanical thrombolysis may be needed to achieve early recanalization in ICA occlusions.

Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke. Results of a Prematurely Terminated Randomized Clinical Trial

Background and Purpose— Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA. Methods— The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a “best” dose of tenecteplase to carry forward. Once a “best” dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III. Results— The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established. Conclusion— This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.

Differences in Stroke Subtypes Among Natives and Caucasians in Boston and Buenos Aires

Background and Purpose Several issues regarding ethnic-cultural factors, sex-related variation, and risk factors for stroke have been described in the literature. However, there have been no prospective studies comparing ethnic differences and stroke subtypes between populations from South America and North America. It has been suggested that natives from Buenos Aires, Argentina, may have higher frequency of hemorrhagic strokes and penetrating artery disease than North American subjects. The aim of this study was to validate this hypothesis. Methods We studied the database of all consecutive acute stroke patients admitted to the Ramos Mejia Hospital (RMH) in Buenos Aires and to the Beth Israel Deaconess Medical Center (BIMC) in Boston, Massachusetts, from July 1997 to March 1999. Stroke subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. All information on patients (demographic, clinical, and radiographic) was recorded prospective to the assessment of the stroke subtype. Results Three hundred sixty-one and 479 stroke patients were included at RMH and BIMC stroke data banks, respectively. Coronary artery disease was significantly more frequent in BIMC (P <0.001), whereas tobacco and alcohol intake were significantly more frequent in RMH (P <0.001). Intracerebral hemorrhage (P <0.001) and penetrating artery disease (P <0.001) were significantly more frequent in the RMH registry, whereas large-artery disease (P <0.02) and cardioembolism (P <0.001) were more common in the BIMC data bank. Conclusions Penetrating artery disease and intracerebral hemorrhage were the most frequent stroke subtypes in natives from Buenos Aires. Lacunar strokes and intracerebral hemorrhage were more frequent among Caucasians from Buenos Aires than Caucasians from Boston. Poor risk factor control and dietary habits could explain these differences.

Significance of early CT signs in acute stroke. A CT scan-diffusion MRI study.

Objective: To study the pathophysiology of early CT signs. Background: Early CT signs, due to an increase in tissue water content, are commonly attributed to cytotoxic edema and development of irreversible injury. This may have important implications for thrombolysis. Methods: In patients with acute ischemic stroke in the middle cerebral artery territory, the areas of early CT signs and diffusion weighted imaging (DWI) hypersignal were independently assessed and drawn on a standardized atlas. Then, patients were classified into three groups (early CT signs larger than, similar to or smaller than DWI hypersignal) and compared with perfusion weighted imaging (PWI). Results: Of 16 patients, CT scanning was performed with a median time of 3 h after onset and early CT scan signs were recorded in 10/16 patients (62.5%). DWI signal hyperintensity was present in 15/16 (94%) patients. In 7/16 (43%) patients, the area with early CT scan signs was larger than the DWI lesion (‘CT-larger group’). Only in 2/16 (12%) patients were the areas matching (‘matching group’). In 7/16 (43%) the DWI lesion was larger than the early CT scan signs area (‘DWI-larger group’). When compared with PWI, the areas of early CT signs were larger than DWI hypersignal and were matching with PWI abnormalities (rMTT) in 2 cases, suggesting that they may represent a reversible process. Conclusions: Early CT signs might have a potential dual fate: infarction or reversibility. Other techniques of recognizing reversible ischemic damage, such as DWI-PWI, are needed to improve acute stroke diagnosis and management.

Spongiform encephalopathy mimicking corticobasal degeneration

The presentation of subacute spongiform encephalopathies (SSE) is varied. The following case of SSE presented clinically similar to corticobasal degeneration. The SSE diagnosis was suspected because of magnetic resonance imaging (MRI) findings and confirmed pathologically.

Tremor as a Cause of Pseudo–Ventricular Tachycardia

Figure 1. An 84-year-old woman with a history of falling was found on the ground unable to get up. On admission to the hospital for evaluation of syncope, she had a normal pulse and blood pressure. Examination revealed a masklike face, bradykinesia, gait instability, and a pill-rolling tremor. An electrocardiogram showed the 4-to-6-Hz tremor associated with Parkinsons disease. The QRS complexes are indicated by the arrows. Postural instability associated with Parkinsons disease was the most likely cause of the patients falls.

Serum creatinine may indicate risk of symptomatic intracranial hemorrhage after intravenous tissue plasminogen activator (IV tPA).

AbstractSymptomatic intracranial hemorrhage (sICH) is a known complication following administration of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke. sICH results in high rates of death or long-term disability. Our ability to predict its occurrence is important in clinical decision making and when counseling families. The initial National Institute of Neurological Disorders and Stroke (NINDS) investigators developed a list of relative contraindications to IV tPA meant to decrease the risk of subsequent sICH. To date, the impact of renal impairment has not been well studied. In the current study we evaluate the potential association between renal impairment and post-tPA intracranial hemorrhage (ICH).Admission serum creatinine and estimated glomerular filtration rate (eGFR) were recorded in 224 patients presenting within 4.5 hours from symptom onset and treated with IV tPA based on NINDS criteria. Neuroimaging was obtained 1 day post-tPA and for any change in neurologic status to evaluate for ICH. Images were retrospectively evaluated for hemorrhage by a board-certified neuroradiologist and 2 reviewers blinded to the patient’s neurologic status. Medical records were reviewed retrospectively for evidence of neurologic decline indicating a “symptomatic” hemorrhage. sICH was defined as subjective clinical deterioration (documented by the primary neurology team) and hemorrhage on neuroimaging that was felt to be the most likely cause. Renal impairment was evaluated using both serum creatinine and eGFR in a number of ways: 1) continuous creatinine; 2) any renal impairment by creatinine (serum creatinine >1.0 mg/dL); 3) continuous eGFR; and 4) any renal impairment by eGFR (eGFR <60 mL/min per 1.73 m2). Student paired t tests, Fisher exact tests, and multivariable logistic regression (adjusted for demographics and vascular risk factors) were used to evaluate the relationship between renal impairment and ICH.Fifty-seven (25%) of the 224 patients had some evidence of hemorrhage on neuroimaging. The majority of patients were asymptomatic. Renal impairment (defined by serum creatinine >1.0 mg/dL) was not associated with combined symptomatic and asymptomatic intracranial bleeding (p = 0.359); however, there was an adjusted 5.5-fold increased odds of sICH when creatinine was >1.0 mg/dL (95% confidence interval, 1.08–28.39), and the frequency of sICH for patients with elevated serum creatinine was 10.6% (12/113), versus 1.8% (2/111) in those with normal renal function (p = 0.010).Our study suggests that renal impairment is associated with higher risk of sICH after administration of IV tPA. As IV tPA is an important and effective treatment for acute ischemic stroke, a multicenter study is needed to determine whether the observation that renal dysfunction is associated with sICH from this retrospective study holds true in a larger prospective trial.

Differentiation of Transverse Sinus Thrombosis From Congenitally Atretic Cerebral Transverse Sinus With CT

Background and Purpose— Transverse sinus thrombosis can have nonspecific clinical and radiographic signs. We hypothesized that the novel “sigmoid notch sign” (on head CT) can help differentiate transverse sinus thrombosis from a congenitally atretic sinus among individuals with absent signal in 1 transverse sinus by MR venography. Methods— We retrospectively evaluated 53 subjects with a unilaterally absent transverse sinus signal on MR venography. Eleven had true transverse sinus thrombosis and 42 had an atretic transverse sinus. Reviewers were trained in the sigmoid notch sign: “positive” if 1 of the sigmoid notches was asymmetrically smaller than the other, consistent with a congenitally absent transverse sinus on that side. This sign was scored on CT scans by 2 blinded reviewers to determine if signal dropout was clot or atretic sinus. A consensus rating was reached when the reviewers disagreed. Characteristics of the sigmoid notch sign as a diagnostic test were compared with a gold standard of full chart review by an independent reviewer. Results— Each reviewer had a sensitivity of 91% (detecting 10 of 11 clots based on a negative sigmoid notch sign) and specificity of 71% to 81%; consensus specificity increased to 86% (36 of 42 individuals with an atretic sinus had a positive notch sign, detecting atretic sinuses based on presence of the sign). Conclusion— Asymmetries of the sigmoid notches on noncontrast brain CT is a very sensitive and specific measure of differentiating transverse sinus thrombosis from an atretic transverse sinus when absence of transverse sinus flow is visualized on MR venography.

Predicting Symptomatic Intracerebral Hemorrhage Versus Lacunar Disease in Patients With Longstanding Hypertension

Background and Purpose— Hypertension results in a spectrum of subcortical cerebrovascular disease. It is unclear why some individuals develop ischemia and others develop hemorrhage. Risk factors may differ for each population. We identify factors that predispose an individual to subcortical symptomatic intracerebral hemorrhage (sICH) compared with ischemia. Methods— Demographic and laboratory data were prospectively collected for hypertensive patients presenting with ischemic stroke or sICH during an 8.5-year period. Neuroimaging was retrospectively reviewed for acute (subcortical lacunes [<2.0 cm] versus subcortical sICH) and chronic (periventricular white matter disease and cerebral microbleeds) findings. We evaluated the impact of age, race, sex, serum creatinine, erythrocyte sedimentation rate, low-density lipoprotein, presence of periventricular white matter disease or cerebral microbleeds, and other factors on the risk of sICH versus acute lacune using multivariate logistic regression. Results— Five hundred seventy-one patients had subcortical pathology. The presence of cerebral microbleeds (adjusted odds ratio [OR], 3.39; confidence interval [CI], 2.09–5.50) was a strong predictor of sICH, whereas severe periventricular white matter disease predicted ischemia (OR, 0.56 risk of sICH; CI, 0.32–0.98). This association was strengthened when the number of microbleeds was evaluated; subjects with >5 microbleeds had an increased risk of sICH (OR, 4.11; CI, 1.96–8.59). It remained significant when individuals with only cortical microbleeds were removed (OR, 1.77, CI, 1.13–2.76). An elevated erythrocyte sedimentation rate (OR, 1.19 per 10 mm/h increase; CI, 1.06–1.34) was significantly associated with sICH, whereas low-density lipoprotein was associated with ischemic infarct (OR, 0.93 risk of sICH per 10 mg/dL increase; CI, 0.86–0.99). Conclusions— Subclinical pathology is the strongest predictor of the nature of subsequent symptomatic event. Low-density lipoprotein and erythrocyte sedimentation rate may also have a role in risk stratification.