In-silico trial emulation to predict the cardiovascular protection of new lipid-lowering drugs: an illustration through the design of the SIRIUS programme.

INTRODUCTION: Inclisiran, an siRNA targeting hepatic PCSK9 mRNA, administered twice-yearly (after initial and 3-month doses), substantially and sustainably reduced LDL-cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) is not yet established. In-silico trials applying a disease computational model to virtual patients receiving new treatments allow to emulate large scale long term clinical trials. The SIRIUS in-silico trial programme aims to predict the efficacy of inclisiran on CV events in individuals with established atherosclerotic cardiovascular disease (ASCVD). METHODS: A knowledge-based mechanistic model of ASCVD was built, calibrated, and validated to conduct the SIRIUS programme (NCT05974345) aiming to predict the effect of inclisiran on CV outcomes.The SIRIUS Virtual Population included patients with established ASCVD (previous myocardial infarction (MI), previous ischemic stroke (IS), previous symptomatic lower limb peripheral arterial disease (PAD) defined as either intermittent claudication with ankle-brachial index <0.85, prior peripheral arterial revascularization procedure, or vascular amputation) and fasting LDL-C ≥ 70 mg/dL, despite stable (≥ 4 weeks) well-tolerated lipid lowering therapies.SIRIUS is an in-silico multi-arm trial programme. It follows an idealized crossover design where each virtual patient is its own control, comparing inclisiran to 1) placebo as adjunct to high-intensity statin therapy with or without ezetimibe, 2) ezetimibe as adjunct to high-intensity statin therapy, 3) evolocumab as adjunct to high-intensity statin therapy and ezetimibe.The co-primary efficacy outcomes are based on time to the first occurrence of any component of 3P-MACE (composite of CV death, nonfatal MI or nonfatal IS) and time to occurrence of CV death over 5 years. PERSPECTIVES/CONCLUSION: The SIRIUS in-silico trial programme will provide early insights regarding a potential effect of inclisiran on MACE in ASCVD patients, several years before the availability of the results from ongoing CV outcomes trials (ORION-4 and VICTORION-2-P).

The SIRIUS in-silico trial programme is a knowledge-based computer model built to simulate the biological and clinical long-term effects of inclisiran, an siRNA targeting hepatic PCSK9 mRNA, on virtual patients with cardiovascular disease. Key Findings: The model accurately replicates the biological processes of cardiovascular disease and the impact of lipid-lowering therapies, allowing for the prediction of randomized clinical trials.Simulating clinical trials with virtual patients can provide insights into the efficacy and safety of new treatments before the results of randomized clinical trials, potentially speeding up the drug development process.

The ASCOD phenotyping of ischemic stroke (Updated ASCO Phenotyping).

ASCO phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) assigns a degree of likelihood of causal relationship to every potential disease (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but the disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke describing all underlying diseases in every patient. In this new evolution of ASCO called ASCOD, we have added a 'D' for dissection, recognizing that dissection is a very frequent disease in young stroke patients. We have also simplified the system by leaving out the 'levels of diagnostic evidence', which has been integrated into grades 9 and 0. Moreover, we have also changed the cutoff for significant carotid or intracranial stenosis from 70% to more commonly used 50% luminal stenosis, and added a cardiogenic stroke pattern using neuroimaging. ASCOD captures and weights the overlap between all underlying diseases present in ischemic stroke patients.

Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Classification of stroke subtypes.

This article reviews published stroke subtype classification systems and offers rules and a basis for a new way to subtype stroke patients. Stroke subtyping can have different purposes, e.g. describing patients' characteristics in a clinical trial, grouping patients in an epidemiological study, careful phenotyping of patients in a genetic study, and classifying patients for therapeutic decision-making in daily practice. The classification should distinguish between ischemic and hemorrhagic stroke, subarachnoid hemorrhage, cerebral venous thrombosis, and spinal cord stroke. Regarding the 4 main categories of etiologies of ischemic stroke (i.e. atherothrombotic, small vessel disease, cardioembolic, and other causes), the classification should reflect the most likely etiology without neglecting the vascular conditions that are also found (e.g. evidence of small vessel disease in the presence of severe large vessel obstructions). Phenotypes of large cohorts can also be characterized by surrogate markers or intermediate phenotypes (e.g. presence of internal carotid artery plaque, intima-media thickness of the common carotid artery, leukoaraiosis, microbleeds, or multiple lacunae). Parallel classifications (i.e. surrogate markers) may serve as within-study abnormalities to support research findings.

New approach to stroke subtyping: the A-S-C-O (phenotypic) classification of stroke.

We now propose a new approach to stroke subtyping. The concept is to introduce a complete 'stroke phenotyping' classification (i.e. stroke etiology and the presence of all underlying diseases, divided by grade of severity) as distinguished from past classifications that subtype strokes by characterizing only the most likely cause(s) of stroke. In this phenotype-based classification, every patient is characterized by A-S-C-O: A for atherosclerosis, S for small vessel disease, C for cardiac source, O for other cause. Each of the 4 phenotypes is graded 1, 2, or 3. One for 'definitely a potential cause of the index stroke', 2 for 'causality uncertain', 3 for 'unlikely a direct cause of the index stroke (but disease is present)'. When the disease is completely absent, the grade is 0; when grading is not possible due to insufficient work-up, the grade is 9. For example, a patient with a 70% ipsilateral symptomatic stenosis, leukoaraiosis, atrial fibrillation, and platelet count of 700,000/mm(3) would be classified as A1-S3-C1-O3. The same patient with a 70% ipsilateral stenosis, no brain imaging, normal ECG, and normal cardiac imaging would be identified as A1-S9-C0-O3. By introducing the 'level of diagnostic evidence', this classification recognizes the completeness, the quality, and the timing of the evaluation to grade the underlying diseases. Diagnostic evidence is graded in levels A, B, or C: A for direct demonstration by gold-standard diagnostic tests or criteria, B for indirect evidence or less sensitive or specific tests or criteria, and C for weak evidence in the absence of specific tests or criteria. With this new way of classifying patients, no information is neglected when the diagnosis is made, treatment can be adapted to the observed phenotypes and the most likely etiology (e.g. grade 1 in 1 of the 4 A-S-C-O phenotypes), and analyses in clinical research can be based on 1 of the 4 phenotypes (e.g. for genetic analysis purpose), while clinical trials can focus on 1 or several of these 4 phenotypes (e.g. focus on patients A1-A2-A3).

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study: baseline characteristics of the population.

BACKGROUND: The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study is an international double-blind, randomized controlled trial designed to investigate the superiority of the specific TP receptor antagonist terutroban (30 mg/day) over aspirin (100 mg/day), in reducing cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack. Here we describe the baseline characteristics of the population. METHODS AND RESULTS: Parameters recorded at baseline included vital signs, risk factors, medical history, and concomitant treatments, as well as stroke subtype, stroke-associated disability on the modified Rankin scale, and scores on scales for cognitive function and dependency. Eight hundred and two centers in 46 countries recruited a total of 19,119 patients between February 2006 and April 2008. The population is evenly distributed and is not dominated by any one country or region. The mean +/- SD age was 67.2 +/- 7.9 years, 63% were male, and 83% Caucasian; 83% had hypertension, and about half the population smoked or had quit smoking. Ninety percent of the qualifying events were ischemic stroke, 67% of which were classified as atherothrombotic or likely atherothrombotic (pure or coexisting with another cause). Modified Rankin scale scores showed slight or no disability in 83% of the population, while the scores on the Mini-Mental State Examination, Isaacs' Set Test, Zazzo's Cancellation Test, and the instrumental activities of daily living scale showed a good level of cognitive function and autonomy. CONCLUSIONS: The PERFORM study population is homogeneous in terms of demographic and disease characteristics. With 19,119 patients, the PERFORM study is powered to test the superiority of terutroban over aspirin in the secondary prevention of cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack.

Chlamydia pneumoniae seropositivity in aetiological subtypes of brain infarction and carotid atherosclerosis: a case control study.

BACKGROUND AND OBJECTIVE: Many patients with brain infarction (BI) lack traditional risk factors, suggesting that other factors (including infectious agents) might contribute to stroke risk. We investigated Chlamydia pneumoniae infection in a large cohort of patients with BI according to aetiological subtypes and carotid atherosclerosis. METHODS: We measured serum IgG and IgA to C. pneumoniae by microimmunofluorescence in 483 BI cases and 483 controls matched for age, sex and centre. IgG > or = 1/32 and IgA > or = 1/24 were considered positive. Cases with BI proven by magnetic resonance imaging were consecutively recruited and were classified into aetiological subtypes. Carotid atherosclerosis (intima-media thickness, plaques, stenosis) was evaluated by duplex ultrasonography in all subjects following the same method and with central reading. RESULTS: C. pneumoniae IgG seropositivity was not associated with BI (adjusted odds ratio (OR) 1.10, 95% confidence interval (CI) 0.80-1.51) and did not increase the risk of any aetiological subtype. Overall, C. pneumoniae IgA was not associated with BI (adjusted OR 1.54, 95% CI 0.84-2.81), but there was a significant interaction with hypertension. IgA seropositivity increased the BI risk in patients without hypertension (adjusted OR 2.79, 95% CI 1.15 to 6.74). When stratifying BI into subtypes, IgA seropositivity increased the risk of BI of unknown cause, but without significant heterogeneity. There was neither association with atherothrombotic, lacunar and cardioembolic BI nor with carotid intima-media thickness, carotid plaques or stenosis. CONCLUSIONS: We found no evidence that C. pneumoniae seropositivity is associated with carotid atherosclerosis and BI, regardless of aetiological subtype; but it might be associated with an increased risk of BI in normotensive patients.

[Update on vascular dementias]. / Mise au point sur les démences vasculaires.

The concept of vascular dementia greatly evolved since Hachinski's description of multi-infarct dementia. Vascular dementias are reviewed with emphasis on current diagnostic criteria, elusive natural history, neuroradiological aspects, difficult epidemiological features and intriguing links with Alzheimer's disease. The recent proposed shift from vascular dementias to a broader definition of "vascular cognitive disorders", including non demented subjects with "vascular cognitive impairment", is described, followed by a brief review of current treatments.

[Feasibility of percutaneous exclusion of the left atrial appendage: results of 11 cases]. / Faisabilité de l'exclusion percutanée de l'auricule gauche. A propos de 11 cas.

Atrial fibrillation is associated with a risk of cerebral embolism, the only proven effective prevention of which is anticoagulant therapy. There is no known alternative in cases with contra-indications to this treatment. Percutaneous exclusion of the left atrial appendage by the implantation of a prosthesis (PLAATO System, ev3 Inc., Plymouth, Minnesota) is a new approach to the prevention of these complications. The authors report the results observed in a series of 11 consecutive patients (7 men, mean age 72 +/- 9 years) in whom this procedure was proposed. All patients had atrial fibrillation for over 3 months, were at high risk and had contra-indications to oral anticoagulants. The implantation of the prosthesis was performed after treatment with aspirin and clopidogrel, under general anaesthesia radioscopy and transoesophageal echocardiographic guidance with success in 9 cases (1 implantation refused in the catheter laboratory and 1 failure). The only complication observed was transient ST elevation treated by emergency angioplasty. The echographic and angiographic criteria of success of left atrial appendage exclusion were fulfilled in all implanted patients. The hospital course was uncomplicated. One recurrence of stroke was observed at the second month: transoesophageal echocardiography confirmed the absence of thrombosis, of migration of the prosthesis and its impermeability in all the patients. After 7 +/- 5 months' follow-up, no other adverse event was observed. This new procedure is technically feasible. Despite encouraging results, its long-term efficacy in the prevention of thromboembolic complications of atrial fibrillation remains to be demonstrated.

Diffusion weighted imaging of cerebellar lesions in Wernicke's encephalopathy.

We report unusual findings on MR imaging in a 62-year-old woman with Wernicke's encephalopathy (WE). Initial fluid-attenuated inversion recovery (FLAIR) and diffusion weighted MR imaging (DW-MRI) showed hyperintense lesions in the cerebellum and medial thalami, with a decreased apparent diffusion coefficient (ADC) in the cerebellum (reduced by 45%). After thiamine supplementation, the T2 and diffusion hyperintensities disappeared. However, clinical examination at three months showed persistent cerebellar impairment. The importance of the ADC values should be further investigated.

Common carotid artery intima-media thickness and brain infarction : the Etude du Profil Génétique de l'Infarctus Cérébral (GENIC) case-control study. The GENIC Investigators.

BACKGROUND-The use of intima-media thickness (IMT) as an outcome measure in observational studies and intervention trials relies on the view that it reflects early stages of atherosclerosis and cardiovascular risk. There is little knowledge concerning the relation between IMT and brain infarction (BI). METHODS AND RESULTS-We investigated the relation of IMT with BI and its subtypes in 470 cases and 463 controls. Cases with BI proven by MRI were consecutively recruited and classified into subtypes by cause of BI. Controls were recruited among individuals hospitalized at the same institutions and matched for age, sex, and center. IMT was measured at the far wall of both common carotid arteries (CCA) using an automatic detection system. Adventitia-to-adventitia diameters and CCA-IMT were measured on transverse views; lumen diameter was computed using these measures. Mean (+/-SEM) CCA-IMT was higher in cases (0.797+/-0.006 mm) than in controls (0.735+/-0.006 mm; P<0. 0001). This difference remained after adjustment for lumen diameter and when analyses were restricted to subjects free of previous cardiovascular or cerebrovascular history. The difference in CCA-IMT between cases and controls was significant in the main subtypes. The risk of BI increased continuously with increasing CCA-IMT. The odds ratio per SD increase (0.150 mm) was 1.82 (95% confidence interval, 1.54 to 2.15); adjustment for cardiovascular risk factors slightly attenuated this relation (odds ratio, 1.73; 95% confidence interval, 1.45 to 2.07). CONCLUSIONS-An increased CCA-IMT was associated with BI, both overall and in the main subtypes. An increased IMT may help select patients at high risk for BI.

Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases.

Cathepsin G (CTSG), a serine protease released from activated neutrophils, may cause platelet activation, leading to intravascular thrombosis, thus contributing to cardiovascular and cerebrovascular disease. Applying the candidate gene approach, we screened the 5'-flanking region and the entire coding region of the CTSG gene for genetic variation by using polymerase chain reaction/single-strand conformation polymorphism analysis from 96 patients at high risk for myocardial infarction (MI). We identified 4 polymorphisms in the 5'-flanking region (G-618C, G-315A, C-179T, and C-160T) and 1 polymorphism in the coding region (Asn125Ser) of the gene and genotyped the participants in the Etude Cas-Temoins sur l'Infarctus du Myocarde (ECTIM Study), a case-control study for MI, and in the Etude du Profil Génétique de l'Infarctus Cérébral (GENIC Study), a case-control study for brain infarction (BI), for all identified genetic variants. The potential in vitro functionality of the 4 variants in the 5'-flanking region was investigated with transient transfection analyses in U937 cells with different allelic promoter constructs by using a luciferase assay. Our in vitro analyses did not reveal any differences for the investigated allelic constructs with respect to promoter activity, and none of the polymorphisms in the 5'-flanking region was associated with the available phenotypes in either study. Allele and genotype distributions of all identified polymorphisms did not globally differ between cases and controls in the ECTIM Study. However, in patients from the ECTIM Study, the Ser125 allele was significantly associated with elevated plasma fibrinogen levels (P=0.006), but this effect was not seen in controls (case-control heterogeneity, P=0.04). There was a significant interaction between CTSG Asn125Ser and the beta-fibrinogen gene polymorphism G-455A on plasma fibrinogen levels (P=0.04). In the GENIC Study, the odds ratio for BI associated with CTSG Ser125 carrying was 1.82 (95% CI 1.16 to 2.84, P=0.008) in patients without a history of cardiovascular or cerebrovascular diseases. Our results indicate that the CTSG Ser125 allele is associated with plasma fibrinogen levels in MI patients from the ECTIM Study and with BI in the GENIC Study. Further studies should be carried out to define the underlying mechanisms.

Anterior inferior cerebellar artery territory infarcts. Mechanisms and clinical features.

Arterial lesions, mechanisms, territory, and clinical features of anterior inferior cerebellar artery (AICA) territory infarcts are only based on necropsy cases. To our knowledge, no large clinical series has been reported. We selected nine consecutive patients with AICA territory infarction confirmed by magnetic resonance imaging and angiography. Atherosclerosis was the only cause and all patients were hypertensive. Patients with pure AICA territory infarcts (n = 4) were diabetic and likely had basilar branch occlusion due to basilar artery plaques that extended into the AICA or microatheroma that blocked the AICA origin. These patients had no or had only recently had (1 day) prodromata. Patients with AICA plus infarct (n = 5) had basilar artery occlusion at the AICA and reconstitution of the distal basilar artery by collaterals through hemispheric anastomoses from the posterior inferior cerebellar arteries and posterior communicating arteries. All these patients except one had prodromata. In seven of nine patients, cranial nerve involvement indicated a lateral pontine lesion in the territory supplied by the AICA. Only two patients had the complete AICA syndrome, and none of the patients had isolated vertigo. The outcome was good in seven of nine patients. Isolated unilateral AICA infarcts should be regarded as most likely due to small artery atherosclerotic disease in diabetic patients. More widespread infarctions that include that AICA territory are due to basilar artery occlusive disease.

Hypercholesterolemia, lipid-lowering agents, and the risk for brain infarction.

Clinical trials in the 1990s using HMG-CoA reductase inhibitors (statins) showed that cholesterol-lowering treatment significantly reduces cardiovascular events including strokes in the primary and secondary prevention of myocardial infarction (MI). Paradoxically, the link between serum cholesterol level and the incidence of stroke remains to be fully established. This is largely due to conflicting evidence from a series of observational cohort studies and a suggestion that lowering serum cholesterol increased the risk for hemorrhagic stroke. These findings have tended to influence the treatment of stroke, despite alternative interpretations for the failure of these studies to find a clear association between cholesterol levels and stroke. The statin trials present a strong argument for a reappraisal of the link between cholesterol and stroke. Three meta-analyses have all shown a relative risk reduction in stroke of 12 to 48% in patients with coronary heart disease (CHD) after MI. There was no statistically significant increase in hemorrhagic stroke. Recently, gemfibrozil has also been shown to reduce the relative risk for stroke (25%), which contradicts the findings of previous fibrate trials. It is becoming clear that the clinical action of many cholesterol-lowering drugs is the result of pleiotropic/antiatherogenic effects rather than simply a reduction in cholesterol. There is also evidence that these agents exert direct effects that promote atherosclerotic plaque stability. After these observations, it is now generally accepted that lipid-lowering treatment should be considered in all stroke patients with a history of CHD/MI. However, for the remaining patients with ischemic stroke, there is no proven therapeutic approach, and several large randomized, placebo-controlled trials are under way or planned for this indication.

Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathologic study of 33 cases.

We reviewed the clinical and pathologic findings in 33 patients with infarcts in the territory of the superior cerebellar artery (SCA). The clinical manifestations included the rostral basilar artery syndrome (8); coma at onset, often with tetraplegia (11); cerebellar and vestibular signs (9, with delayed coma due to cerebellar swelling in 6); and, in only 1 patient, the "classic" syndrome of the SCA. Clinical features were overshadowed by an infarct in the territory of the middle cerebral artery in 3 other patients, and the diagnosis was made only at autopsy in a fourth. Pathologically, SCA infarcts occurred in isolation in 7 patients. The most striking finding was the high frequency of associated infarcts in the territory of the rostral part of the basilar artery (73%). One-third of patients also had an infarct in the territory of the posterior inferior cerebellar artery, sometimes associated with infarction of the anterior inferior cerebellar artery. Tonsillar herniation was observed in 15 patients, 8 of whom had no infarcts in other cerebellar territories. Occlusions occurred mainly in the distal basilar artery and distal vertebral artery. The infarcts were mostly caused by cardiac and artery-to-artery emboli.

Infarction in the anterior rostral cerebellum (the territory of the lateral branch of the superior cerebellar artery).

We report 9 patients with an isolated infarct of the anterior part of the rostral cerebellum, ie, the territory of the lateral branch of the superior cerebellar artery. Clinicoanatomic correlations are based on CT, MRI, or both in 8 patients and on pathologic data in the ninth. The main clinical features were ipsilateral dysmetria and axial lateropulsion, dysarthria, and unsteadiness. In 1 patient, the clinical presentation mimicked a lacunar stroke (dysarthria and clumsy hand syndrome). There were no edematous cerebellar infarcts with signs of brainstem compression, and all patients spontaneously improved without significant sequellae. Angiography in 2 patients and pathologic examination of arteries in 1 patient disclosed no occlusion in the vertebrobasilar system. Six patients had a cardiac source of emboli. In conclusion, infarcts of the anterior part of the rostral cerebellum can be regarded as a benign condition in which there is, frequently, a cardiac source of emboli.

Brain infarction following 5-fluorouracil and cisplatin therapy.

Five patients with oropharyngeal cancer treated with 5-fluorouracil and cisplatin had ischemic stroke within 2 to 5 days after the drug infusion. This occurred during the second course of chemotherapy in three patients, and during the third course in two patients. There may be a relation between treatment and brain infarction because 1) there was no other cause identified despite extensive tests, including postmortem examination in one patient; 2) there was a short delay between treatment infusion and stroke; and 3) there was a similar pattern of ischemic stroke after the second or third course of chemotherapy.

Peduncular 'rubral' tremor and dopaminergic denervation: a PET study.

Lesions causing so-called rubral tremors frequently involve the substantia nigra or the nigrostriatal fibers, suggesting dopaminergic denervation as possibly contributory. We examined this hypothesis using PET and [18F]-fluorodopa in six patients with a contralateral tremor following a peduncular lesion. The denervation revealed by PET was even more marked than in severe parkinsonian patients. All patients showed partial to complete improvement with levodopa therapy. PET evaluation of D2-receptors with [76Br]bromolisuride showed no asymmetry of the D2 binding despite the important asymmetry of 18F-fluorodopa uptake. Our results indicate an important involvement of the nigral dopaminergic system in peduncular tremors that appears to be independent of postsynaptic dopamine receptors.