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Show NEURO- OPHTHALMOLOGY AT LARGE The 27th International Stroke Conference San Antonio, Texas, February 7- 9, 2002 The 27th International Stroke Conference was held in San Antonio, Texas from February 7- 9,2002. The covered topics included epidemiology, prevention, acute treatment, outcomes, and rehabilitation, but the emphasis was on acute stroke intervention and neuroprotection. There were 18 special symposia, 15 sessions of platform presentations focused on various issues in stroke, and two poster sessions: one on basic research and one on clinical research. An anticipated special symposium on the results of the International Study of Unruptured Intracranial Aneurysms was canceled. Abstracts for the platform presentations and posters are published in Stroke ( 2002; 33: 342- 420). Abstracts of oral presentations are referenced by number and page number ( OA #, p #), and abstracts of posters are referenced by number and page number ( P #, p #). The symposia were not accompanied by published abstracts. Warfarin and Aspirin Prophylaxis of Stroke The most practical information included data from studies of warfarin and aspirin in preventing stroke. Patients with cerebrovascular stenoses are sometimes placed on warfarin after antiplatelet agents fail to prevent symptomatic episodes, although limited research exists to support such treatment. Others advocate warfarin to prevent stroke in patients with antiphospholipid antibody syndrome. The Warfarin- Aspirin Recurrent Stroke Study ( WARSS), the results of which were published in November 2001 ( 1), enrolled 2206 patients with ischemic stroke not attributable to cardioembolic events. Patients were treated with either 325 mg aspirin daily or with warfarin adjusted to maintain an international normalized ratio ( INR) of 1.4 to 2.8 in a randomized, double blind trial. Over a 2- year period, there was no significant difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage, although there was a trend toward increased major hemorrhages in the warfarin group ( 44 patients versus 30 in the aspirin group). In addition, there was a significantly increased frequency of minor hemorrhage in the warfarin group. The conclusion of the WARSS was that warfarin and aspirin are reasonable therapeutic alternatives in preventing recurrent noncardioembo-lic ischemic stroke, but that aspirin should still be the first-line agent because of its more favorable safety profile. At the Stroke Conference, the results were reviewed, and additional results of subgroup analysis were reported. None of the subgroup analyses found a more favorable outcome for either drug, although the study was not powered sufficiently to do so. This information leaves cardioembolic stroke as the sole setting in which warfarin is proven to be more effective than antiplatelet agents. This is the most definitive study to date, although it was not powered to evaluate efficacy in specific stroke subtypes, such as those due to vertebrobasilar intracranial stenosis. The Antiphospholipid Antibody Stroke Study ( APASS) examined the role of antiphospholipid antibodies ( aPL) in stroke ( 2,3). The initial studies demonstrated that anticardiolipin antibodies ( aCL) are an independent risk factor for stroke, but that the presence of aCL positivity at the time of an initial stroke did not confer a significantly increased risk for subsequent thromboocclusive events or death. WARSS and APASS researchers collaborated to determine whether there was a difference in the effect of aspirin and warfarin on recurrent stroke in patients with aPL. Of 2206 patients enrolled in WARSS, 1954 were eligible for APASS, and 1770 were enrolled in the second study. Patients were observed for the primary endpoints of recurrent ischemic stroke, death, transient ischemic attack, myocardial infarction, pulmonary embolism, deep venous thrombosis, peripheral arterial thrombosis, and systemic visceral arterial thrombosis. Forty- one percent of patients were aPL positive. There was no difference in event rates in aPL- positive versus aPL- negative groups, regardless of treatment with warfarin or aspirin. There was also no difference in time to recurrent event in any treatment or aPL group. Average INR among patients treated with warfarin was 1.9, which may not be sufficient to have an impact or recurrent stroke in patients with aPL. The APASS and WARSS groups collaborated to study subtypes of antiphospholipid antibodies in the cohort ( PI 53). The lupus anticoagulant ( LA) and aCL are currently used to diagnose patients with aPL. Stored serum samples from 200 randomly selected WARSS/ APASS patients were tested for LA and aCL and for two more recently available aPL antibodies, anti-( 3- 2- glycoprotein- l (( 32GP1) and an-tiphosphatidylserine antibodies ( aPS). They found that 29% of patients negative for LA/ aCL were positive for either ( 32GP1 or aPS, confirming the heterogeneous nature of „ JNeuro- OphthqlViol,, Vol. 22, Na.] 2,2002n,, r.„, . , DOI: 10.1097/ 01. WNO. 0Q00019699.15.867. IE , .129 , Copyright © Lip pincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JNeuro- Ophthalmol, Vol. 22, No. 2, 2002 NEURO- OPHTHALMOLOGY AT LARGE this autoantibody family and suggesting that conventional testing with LA and aCL is not sufficient to exclude the presence of aPL in a given patient. Endovascular Intervention in Cerebrovascular Disease Carotid angioplasty with stenting is a proposed alternative therapy to carotid endarterectomy ( CEA) to prevent stroke. Appropriate selection of patients for these procedures continues to be important. Two papers investigated the relationship between carotid plaque characteristics, symptoms, and complications of therapy. Degree of stenosis has been the variable used to determine need for intervention in clinical trials of CEA, without regard to plaque morphology. Authors interested in widening the safety margin of CEA argue that unstable plaques have a higher stroke risk. Aburahma et al. ( OA # 6, p 343) evaluated 2460 patients undergoing carotid ultrasonography over 1 year, reviewing plaque heterogeneity, severity of stenosis, and underlying symptoms. Increasing stenosis correlated with heterogeneous plaque characteristics ( Table 1). As the degree of stenosis increased, the percentage of heterogeneous plaques also increased. Furthermore, heterogeneous plaques were more often symptomatic at all degrees of stenosis ( Table 2). Carotid angioplasty and stenting remodel an atherosclerotic plaque instead of removing it. Plaque composition may play an even more important role in endovascular procedures than in CEA. Biasi reported the correlation of carotid plaque composition and complications in patients undergoing carotid stenting in the Imaging in Carotid Angioplasties and Risk Of Stroke ( ICAROS) study ( OA 5, p 342). Plaque composition was graded from 0 ( very soft, nonhomogeneous plaque) to 100 ( hard, homogeneous plaque). ICAROS studied 387 patients undergoing carotid stenting at 19 centers worldwide. There were 24 complications ( 6.2%): 12 transient ischemic attacks, 7 minor strokes, and 5 major strokes. Plaque characteristics correlated with complications. Nineteen of 24 complications occurred in patients with plaques graded 0 to 25, and the remaining 5 TABLE 1. The proportion of cases with heterogeneous plaques at increasing degrees of stenosis Degree of stenosis Heterogeneous plaques < 50% 16% 50 to < 60% 34% 60 to < 70% 62% 70% or more 81% Data adapted from OA # 6, p 343 Copyright © Lippincott Williams & Wilkins. Un TABLE 2. The proportion of heterogeneous versus homogeneous plaques degrees of stenosis Degree of stenosis < 50% 50 to < 60% 60 to < 70% 70% or more in patients with Symptomatic heterogeneous plaques 68% 76% 79% 86% symptoms at various Symptomatic homogeneous plaques 16% 21% 23% 31% Data adapted from OA # 6, p 343 complications occurred in cases with plaques graded 25 to 50. About half of the procedures used a debris capture device, and 70% of the complications, including 4 of 5 major strokes, occurred in association with procedures performed without a debris capture device. Cardiologists have taken the initiative in endovascular therapy for carotid stenosis at many institutions. Physicians who are not yet ready to accept this technology without demonstrated efficacy and safety from randomized clinical trials will be interested in a paper by Malisch et al., " When Is carotid stenting really necessary? Results of a conservative algorithm" ( OA 35, p 348). Among 39 patients evaluated prior to carotid stenting, 25 with atherosclerotic disease and 14 with dissections or fibromuscular dysplasia, endovascular intervention was thought to be indicated in only 12, seven of whom underwent stenting in addition to angioplasty. Five more had surgery, 20 were treated medically, and three required no therapy. During a mean follow- up of 19 months, there were no strokes in either treated or untreated groups. Two randomized trials examining the role of angioplasty and stenting in carotid stenosis are underway. Carotid stenting may be performed safely, but it is not clear that the procedure is safer than CEA in patients with carotid stenosis, including those for whom referral for stenting is made because of a perceived high surgical risk. Long-term efficacy compared with CEA remains unknown. One problem in undertaking controlled trials comparing endovascular therapy with CEA would seem to be the rapid evolution in the technology of endovascular therapy. Today's best technology is likely to be supplanted with better technology by the time a study has been approved. Special symposia on management of extracranial and intracranial stenosis concentrated on endovascular interventions. These invoked as sense of awe, as interventionalists demonstrated dramatic rescues from apparently irrevocable deterioration by intraarterial tPA and stenting procedures in patients with evolving stroke already treated with maxi- . © 2002 Lippincott Williams & Wilkins , orized reproduction of this article is prohibited. NEURO- OPHTHALMOLOGY AT LARGE JNeuro- Ophthalmol, Vol. 22, No. 2, 2002 mum systemic antithrombotic therapy. As with stenting and CEA, the benefit of this focused therapy compared with systemic thrombolysis in acute stroke remains unproven. A symposium on the management of heart ischemia showed why neurologists are still behind cardiologists in intervention for stroke or threatened stroke. Cardiologists are using third generation thrombolytics, whereas neurologists are still using tPA alone. However, many of the newer agents used for cardiac ischemia have failed preliminary safety studies for acute stroke, largely because of increased rates of intracranial hemorrhage. Adjunctive therapy with antifi-brinogen agents ( such as GPIIb/ IIIa- receptor antagonists) to prevent rethrombosis, and repeated arterial endovascular procedures based on a variety of clinical, electrocardiogram, and laboratory parameters are used in patients with coronary artery ischemia, while no similar parameters for moment- to- moment change are available for use in patients with acute cerebrovascular ischemia. Neuroprotection Myron Ginsberg, MD, PhD was honored as the Willis Lecturer and brought a life's work using animal models for basic research in acute stroke treatment to the podium in his discussion, " Brain Ischemia: Adventures in Pathophysiology." He focused his lecture on the utility and applicability of studying the pathophysiology of brain ischemia using small animal models of human disease, and the challenges of neuroprotective therapy. Animal models allow replica-bility, reproducibility, and genomic modulation- concepts often inaccessible in human subject research. Dr. Ginsberg's research has examined local cerebral blood flow in brain ischemia, particularly as it identifies the ischemic penumbra and its associated metabolic changes in animals, and how flow gradients in ischemia determine gene expression. He stated that his work in neuroprotection has been a natural outgrowth of his cerebral blood flow research. In addressing the question, " Why have neuroprotective agents in humans failed?" he commented that human studies have often been unable to replicate the conditions that are efficacious in the laboratory, including critical treatment variables such as timing and medication doses. In addition, he mentioned that a few human studies have been conducted using agents with only a modestly protective effect in animals. He ended the lecture by emphasizing the need for a multidisciplinary approach in cerebrovascular basic science and clinical research. Basic science posters and platform presentations also discussed the use of neuroprotective agents in animal models. Neuroprotection studies examined a variety of agents, from those commonly available in the home to viral vector gene transfers and factors influencing the success of these novel procedures. Ethanol plus caffeine (" Caffeinol") had a neuroprotective effect in rats at doses equivalent to 3 cups of coffee and 1- 2 cocktails in humans, but chronic use of alcohol reduced this benefit. A controlled clinical trial was suggested. Interferon- B and dexamethasone at a dose of 20 mg/ kg were beneficial to rats with stroke. Novel agents continue to have benefit in rat models and include IL10 gene transfer and other gene transfer models, SL327 ( MEK1 protein kinase inhibitor), and nitric oxide donors. Several neuroprotection human studies and metaanalyses were reported. A review of all trials of NMD A or AMPA receptor antagonists and glutamate antagonists indicates no benefit from these agents in acute stroke. Metaanalysis of choline precursors in humans indicated a beneficial and substantial treatment effect, with an absolute reduction of 10- 12% in long- term death and disability ( OA 64, p353). A small randomized, double blind pilot trial of erythropoietin treatment in 20 patients begun within 8 hours of symptom onset showed a better outcome on clinical and imaging parameters for the treated patients ( OA 71, p 354). However, expert commentary during the conference highlighted the idea that the results of neuroprotection studies in humans continue to be disappointing, compared with those achieved in animal models using the same agents. Reports of benefit using acute neuroprotective therapy in humans have been more closely associated with improvement in neuroimaging parameters than in clinical outcome. This discrepancy has included studies of citicholine and tirofiban ( a GPIIb/ IIIa- receptor antagonist). Neuroimaging Imaging of cerebrovasculature was discussed in abstracts and in a special symposium with magnetic resonance angiography ( MRA), computed tomography angiography, and ultrasonography each proposed to be the superior test. Presenters each advocated for a particular modality; attendees were left with the impression that all are helpful in the appropriate context, and that the most effective modality at any institution will be the one performed by the most technically proficient individuals. High field- strength MRI, utilizing up to 8 Tesla magnets ( Tesla Engineering Ltd., West Sussex, England), is being studied in humans. This MRI technique was reported to be useful in assessing vascular plaque characteristics, although it was not compared with ultrasonography, which is generally effective and considerably less expensive. The use of contrast- enhanced MRA was not significantly more helpful in examining the intracranial vasculature for aneurysms, according to one study from the Mayo Clinic ( Rochester, MN) ( P 12, p 364). The authors noted that 3.0 Tesla images were of superior quality, but both 3.0 Tesla MRA and 1.5 Tesla MRA imaged 100% of 27 aneu- Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JNeuro- Ophthalmol, Vol. 22, No. 2, 2002 NEURO- OPHTHALMOLOGY AT LARGE rysms while 3.0 Tesla contrast- enhanced MRA found only 94.7% of the aneurysms. Emergency Treatment In Stroke Clinical use of acute stroke therapies in community hospitals continues to lag behind academic medical centers with stroke research programs. Stroke neurologists would like all physicians to be more aggressive in their approach to acute stroke treatment, especially those neurologists who do not take an active role in the treatment of acute stroke patients in emergency room settings ( 4). Two trials currently underway examine the utilization of emergency room physicians to manage acute stroke without direct help from neurologists. Presentations entitled, " Emergency Physicians Can Learn Acute Stroke CT Interpretation" ( OA 42, p349) and " The Teleradiology Assessment of CT's Online Reliability Study" ( OA 43, p 349) each provide support for a system allowing for the initiation of acute stroke therapy without neurologists. Since " time is brain" in acute stroke management, treatment in the field by EMS technicians would be ideal if agents with more optimal safety margins were available. The use of intravenous magnesium sulfate is being studied in the Field Administration of Stroke Treatment- Magnesium Sulfate ( FAST-MAG) pilot trial ( OA 66, p 353). Diagnostic accuracy by paramedics in the field was excellent, and this pilot study demonstrates the feasibility of delivering neuroprotective therapy in the field. A larger, placebo- controlled trial is planned. Prothrombotic States and Stroke Transient monocular blindness ( TMB) was found to be frequent in patients with systemic lupus erythematosus ( SLE), with a calculated incidence of 422/ 100,000 compared with 14/ 100,000 in the normal population ( P 173, p 393). One hundred seventy- five unselected patients were studied. At onset, 10 patients had experienced TMB. During a mean follow- up of 5.7 years, an additional four of 165 patients developed TMB. During this follow- up period, 10% of patients with TMB at baseline experienced a major vascular event compared with 5.5% of patients without TMB ( OR 1.9, CI 0.2- 16.9). The authors concluded that patients with SLE and TMB did not have a significantly increased risk of major vascular complications compared with those without TMB, but the statistical power may have been inadequate to say this with confidence. Investigators in Perth, Australia examined inherited thrombophilias in ischemic stroke and their etiologic subtypes using 219 hospital cases of first- ever stroke versus case controls ( OA # 58, p352). Thrombophilia was present in 14.7% of stroke patients and 11.7% of controls. Thus, the association of thrombophilia with stroke may be coincidental. The investigators did not look at patients selected for age or for the presence of other factors suggesting a thrombophilia. This study confirms that physicians need to be selective in choosing tests for prothrombotic states in this clinical setting. Kemmeren et al. ( OA 16, p 344) reported a multi-center, case- control study of ischemic stroke in 203 women using oral contraceptive pills ( OCPs). Use of any OCP produces a stroke risk about 2.3 times greater than that among women who do not use these drugs. First- generation OCPs had a stroke odds ratio of 1.7 ( 95% CI 0.7- 4.4), second generation low- dose OCPs an odds ratio of 2.4 ( 97% CI 1.4- 4.1), and third generation OCP an odds ratio of 2.2 ( 05% CI 1.2- 3.9), showing unexpectedly that the newer, low- dose OCPs are not safer in regard to stroke. As expected, other risk factors for stroke added to the total risk for stroke in women using OCPs. Neuro- ophthalmology Several papers that dealt directly with neuro-ophthalmic issues did not present substantially new information. In one study ( P 67, p 3 74) of 280 patients referred to a stroke service, 23 had ocular bruits auscultated, only eight of whom also had cervical carotid bruits. Surprisingly, the most frequent association was in patients with contralateral extracranial carotid stenosis or occlusion ( 65%), followed by patients with ipsilateral intracranial carotid stenosis ( 21%), and patients with a generalized hyperdynamic state ( 9%). Blood flow in the ophthalmic artery was examined in a study using Power- M Mode Doppler, insonated at 50- 60 mm ( P 47, p 370). Reversed ophthalmic artery flow was reported to be specific for > 95% to 100% cervical carotid artery stenosis ( P 47, p 370). No reversal of flow was seen in any patient with less than 95% stenosis of the ipsilateral cervical carotid artery. These results would have to be compared with prior studies of orbital blood flow for correlation. Central retinal artery ( CRA) flow velocity was studied using Doppler flowmetry ( P 53, p 371). Five measures of flow velocity were determined and then compared with the MRI- detected number of lacunes in the studied patients ( P 53, p 371). There were correlations between numbers of lacunes in two of the five CRA velocity measurements. Interestingly, the number of lacunes was not correlated with the usual arteriosclerotic risk factors of hypertension, diabetes, age, hyperlipidemia, or smoking. Finally, low-contrast letter recognition using luminance- defined random dot letters was studied as a simple measure of postoperative cognitive function in patients after coronary artery bypass grafting ( CABG) ( P 73, p 375). The change in the lumi-nancegradient needed for recognition of low contrast letters correlated with the number of microemboli detected during CABG. _ 132 _ „ , . © 2002 Lippincott Williams & WUkins , Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. NEURO- OPHTHALMOLOGY AT LARGE JNeuro- Ophthalmol, Vol. 22, No. 2, 2002 John E. Carter, MD REFERENCES Departments of Medicine ( Neurology) and Ophthalmology i. Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of war- University of Texas Health Science Center farin and aspirin for the prevention of recurrent ischemic stroke. San Antonio Texas N Engl J Med 2001; 345: 1444- 51. ' 2. The Antiphosphohpid Antibodies in Stroke Study ( APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurol 1993; 43: 2069- 73. Renee D. Bailey, M D 3. The Antiphospholipid Antibodies And Stroke Study Group Department of Neuroloav ( APASS). Anticardiolipin antibodies and the risk of recurrent . . thrombo- occlusive events and death. Neurology 1997; 48: 91- 4. University of Texas Health Science Center 4 Horowitz SH. Thrombolytic therapy in acute stroke: neurologists, San Antonio, Texas get off your hands! Arch Neurol 1998; 55: 155- 7. 133 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited |