The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial.

BACKGROUND: Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography. STUDY DESIGN: SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography. RESULTS: SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained. CONCLUSIONS: Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.

Carotid endarterectomy--an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy combined with cardiac surgery, are also reviewed. METHODS: The authors selected nine important clinical questions. A systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from 2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from 2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. RESULTS: For several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at 5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5 years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing endarterectomy. CONCLUSIONS: Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis (Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not indicated for symptomatic patients with <50% stenosis (Level A). For asymptomatic patients with 60 to 99% stenosis, the benefit/risk ratio is smaller compared to symptomatic patients and individual decisions must be made. Endarterectomy can reduce the future stroke rate if the perioperative stroke/death rate is kept low (<3%) (Level A). Low dose aspirin (81 to 325 mg) is preferred for patients before and after carotid endarterectomy to reduce the rate of stroke, myocardial infarction, and death (Level A).

Optimization of the safety and efficacy of interferon beta 1b and azathioprine combination therapy in multiple sclerosis.

We conducted an open-label pilot clinical trial to evaluate the safety and efficacy of adding oral azathioprine to the treatment regimen of 15 multiple sclerosis patients breaking through monotherapy with interferon beta-1b. There were no serious adverse events. Gastrointestinal side effects and leukopenia were the most common adverse events and limited dose escalation. There was a 65% reduction in the number of gadolinium-enhanced magnetic resonance imaging (MRI) lesions on combination therapy compared to the baseline values (P =0.003). A total WBC count less than 4800/mm3 was the best predictor of MRI response.

[Delirium in a 73-year-old man after many years of unwise use of betahistine]. / Delirium bij een 73-jarige man na jarenlang ongewijzigd gebruik van betahistine.

A 73-year-old man was admitted because of delirium that had already persisted for 5 days. The physical examination and extensive tests did not reveal any somatic pathology. The only drug he used was betahistine, taken for several years because of supposed Ménière's disease. After withdrawal of betahistine and treatment with haloperidol the patient recovered completely within a few days. A new delirium was induced when, after discharge from the hospital, betahistine was restarted because of dizziness. There was again a complete remission after betahistine was stopped and haloperidol was restarted. Betahistine is not known to induce delirium, but an investigation in side-effects databases did reveal several cases in which delirium might have been present, even though the term was not actually used. In this case, delirium was possibly caused by the combination of an elevated betahistine plasma level and a damaged blood-brain barrier due to cerebral infarctions, which were revealed by CT and MRI.

Use of Ephedra-containing products and risk for hemorrhagic stroke.

This case-control study examined the association between Ephedra use and risk for hemorrhagic stroke. For use of Ephedra at any dose during the 3 days before the stroke, the adjusted OR was 1.00 (95% CI 0.32 to 3.11). For daily doses of < or =32 mg/day, the OR was 0.13 (95% CI 0.01 to 1.54), and for >32 mg/day, the OR was 3.59 (95% CI 0.70 to 18.35). Ephedra is not associated with increased risk for hemorrhagic stroke, except possibly at higher doses.

An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS.

An open-label study was performed to evaluate the safety and efficacy of combination therapy with weekly oral methotrexate (20 mg) and interferon beta-1a (IFN beta-1a) in 15 patients with MS who had experienced exacerbations while receiving IFN beta monotherapy. Nausea was the only major side effect. A 44% reduction in the number of gadolinium-enhanced lesions seen on MRI scan was observed during combination therapy (p = 0.02). There was a trend toward fewer exacerbations. This combination therapy appears to be safe and well tolerated, and should be studied in a controlled trial.

Effect of prior aspirin use on stroke severity in the trial of Org 10172 in acute stroke treatment (TOAST).

BACKGROUND AND PURPOSE: Although the efficacy of aspirin in reducing stroke incidence is clear, its role in reducing stroke severity is disputed. This study compares stroke severity between patients who did or did not take aspirin in the week before stroke and enrollment in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). METHODS: Of 1275 patients randomized, 509 reported aspirin use in the week before stroke; 766 did not. Clinical stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Supplementary Motor Examination (SME) at trial entry and at 3 months. Using these scales, we compared the categorization of stroke severity (mild, moderate, and severe) and mean scores between aspirin users and nonusers. RESULTS: The difference in distribution of baseline NIHSS scores was statistically significant between aspirin users and nonusers (P=0.006), with a greater percentage of milder strokes among aspirin users. The difference in mean baseline NIHSS scores was also significantly lower in aspirin users (8.2) and nonusers (9.3) (P=0.003). The distribution of baseline SME scores and mean SME scores also showed lower stroke severity in aspirin users than in nonusers (P=0.048 and P=0.004, respectively). At 3 months, differences in stroke severity measured by the SME but not the NIHSS remained statistically significant. Seven-day and 3-month mortality did not differ significantly. CONCLUSIONS: In this study aspirin use is associated with milder clinical deficits at stroke onset. These deficits may affect prognosis and influence response to treatment. Future clinical trials should ensure that prestroke aspirin use is comparable in study groups.

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Dipyridamole plus aspirin in cerebrovascular disease.

BACKGROUND: The second European Stroke Prevention Study (ESPS-2) recently reported a substantial benefit of dipyridamole combined with aspirin over aspirin alone in the prevention of stroke. This appears to be at odds with previous studies suggesting that dipyridamole adds nothing to aspirin alone. OBJECTIVES: To review and compare the results of ESPS-2 and previous studies of dipyridamole plus aspirin and aggregate them in a meta-analysis. METHODS: We combined the detailed data provided by the Antiplatelet Trialists' Collaboration on the previous studies of dipyridamole plus aspirin with the results from ESPS-2. The data on the previous trials were listed in the appendix of the 1994 publication of the Antiplatelet Trialists' Collaboration. RESULTS: The results of our meta-analysis demonstrate that for the outcome of nonfatal stroke, ESPS-2 overwhelms previous data, which, even in the aggregate, did not include enough patients or outcome events to exclude efficacy for the combination of dipyridamole and aspirin. Differences between ESPS-2 and previous studies, which may have contributed to different results, include the doses and preparations of aspirin and dipyridamole. CONCLUSIONS: The ESPS-2 showed that dipyridamole alone prevents stroke. More importantly, it showed a substantial benefit for dipyridamole combined with aspirin over aspirin alone. When the ESPS-2 data are aggregated with the 14 previous trials of dipyridamole combined with aspirin over aspirin alone, the combination reduces the risk of stroke by 23% over aspirin alone. Nevertheless, important questions remain unanswered. We conclude that another randomized clinical trial showing a significant benefit of the combination of dipyridamole plus aspirin over aspirin alone may be needed before the addition of dipyridamole to aspirin is widely accepted for prevention of stroke.

Cardiac evaluation of stroke patients.

There are two potential purposes for cardiac evaluation in patients with cerebrovascular disease: to identify possible cardioembolic pathophysiology for ischemic symptoms and to identify concomitant coronary artery disease. Both have important implications for patient prognosis and treatment, and testing therefore appears to be warranted. On the other hand, the cost conservation movement in medicine dictates that physicians limit unnecessary, costly, possibly risky testing when the diagnostic yield is low. For example, the overall yield of cardiac testing in "usual stroke patients" who have no suggestive history or findings on examination, chest X-ray, or electrocardiogram is less than 10% and may not be indicated routinely. Conversely, young patients with stroke of unknown cause are likely to benefit from aggressive cardiac testing. Many reported series and clinical trials have demonstrated that patients with cerebrovascular disease are more likely to die in follow-up from cardiovascular than from cerebrovascular causes. This risk is best defined and may be highest in patients with carotid disease, in whom the 5-year cardiac mortality rate may be as high as 40 to 50%. Studies have shown that such patients are also likely to have abnormal tests for cardiac ischemia, even when a history of cardiovascular events or symptoms or electrocardiographic abnormalities are lacking. These results, combined with further investigations into which cerebrovascular patients are at highest risk for cardiovascular disease and what testing best identifies underlying, treatable cardiovascular disease, are needed to direct the care and improve the cardiovascular prognosis of patients with cerebrovascular disease.

[The global eradication of polio by the year 2000]. / Polio de wereld uit, rond het jaar 2000.

The World Health Organization wants to attain global eradication of poliomyelitis in the year 2000. In all countries commissions are installed to document polio-free certification. Four activities are considered vital by the WHO to achieve this goal: (a) strict surveillance of all suspected cases of poliomyelitis, (b) close clinical and virological examination of all children younger than 15 years with acute flaccid paralysis (AFP), (c) laboratory surveillance of poliovirus isolates and (d) surveillance of sewage. The Netherlands has been selected as example country for the certification process. However, the AFP surveillance is not yet optimal, therefore all physicians are asked to join in the effort.

Transcranial Doppler ultrasound battery reliably identifies severe internal carotid artery stenosis.

BACKGROUND AND PURPOSE: There is a clinical imperative for noninvasive tests for carotid disease that have high sensitivity. Previous studies have shown that transcranial Doppler ultrasound (TCD) can identify intracranial collateral flow patterns and other hemodynamic consequences of carotid occlusion. We hypothesized that a battery of such TCD findings would have a greater sensitivity than any one TCD finding alone and would have clinical utility in identifying carotid disease. METHODS: We determined the prevalence of seven TCD findings in patients with various degrees of carotid stenosis as measured by a blinded observer on 138 cerebral angiograms. We further determined the sensitivity and specificity of any one finding or any single abnormality in the TCD battery (the combination of all seven findings) for identifying severe (> or = 70%) carotid stenosis by angiography. RESULTS: The following four individual TCD findings were associated (P < .001) with > or = 70% carotid stenosis on cerebral angiography: ophthalmic and anterior cerebral artery flow reversal and low middle cerebral artery flow acceleration and pulsatility. The presence of any single abnormality in the TCD battery had a similar association (P < .001) with > or = 70% carotid stenosis. The individual TCD findings had sensitivities of 3% to 83% and specificities of 60% to 100% for identifying > or = 70% carotid stenosis. The TCD battery had a sensitivity of 95% and specificity of 42% for identifying > or = 70% carotid stenosis. CONCLUSIONS: A battery of TCD findings that can be routinely measured reliably identified patients with > or = 70% angiographic internal carotid artery stenosis with high sensitivity.

Carotid stenosis. A neurologist's perspective.

The initial step performed by neurologists in the evaluation of patients with potential carotid disease is to establish whether patients have had carotid territory symptoms. Symptoms are most often believed to be caused by emboli passing onto the cerebral circulation. Despite some limitations, conventional angiography remains the gold standard test to evaluate the carotid bifurcation. Because of the costs and risks of angiography, some combination of carotid duplex ultrasonography and MR angiography is chosen to select patients for angiography. Future research will focus on markers other than percent stenosis to assess stroke risk and treatments, such as angioplasty and stenting, for carotid lesions.

The evaluation of symptomatic carotid artery disease. A survey of specialty practices in Rhode Island.

Severe, symptomatic carotid artery disease is most often diagnosed by conventional cerebral angiography. Noninvasive tests are commonly used to identify candidates for angiography and endarterectomy. The purpose of this study, a mail and telephone survey of academic and community neurologists, neurosurgeons, and vascular surgeons in Rhode Island in 1994, was to determine which noninvasive tests physicians used to evaluate these patients and how the test results were used to select patients for angiography. One hundred (86%) of a possible 116 responses were collected. Seventy-six percent of physicians chose carotid duplex ultrasound as the first diagnostic test, a percentage significantly higher than that for any other test (p < 0.0001). Fourteen percent chose angiography without a prior screening test; 3% chose magnetic resonance angiography (MRA) prior to angiography, 6% chose carotid duplex ultrasound plus MRA prior to angiography, and 1% chose MRA without angiography. The specific noninvasive test results required for angiography referral were surprisingly variable, both within and across the three physician specialties. Vascular surgeons and neurosurgeons were more likely to choose angiography without prior screening tests than were neurologists. In conclusion, the majority of specialty physicians in the state of Rhode Island chose carotid ultrasound as the screening test of choice for the evaluation of a potential endarterectomy candidate. Few responding physicians chose MRA in combination with carotid duplex ultrasound prior to angiography, or MRA prior to angiography or MRA alone. Awareness of the actual practice patterns of specialists may lead to programs of education for physicians to improve practice and patient outcome through more refined use of diagnostic tests prior to angiography or endarterectomy.

Performance of carotid ultrasound in evaluating candidates for carotid endarterectomy is optimized by an approach based on clinical outcome rather than accuracy.

BACKGROUND AND PURPOSE: The best method of selecting endarterectomy candidates for cerebral angiography is controversial. Carotid duplex ultrasound (CDUS) is widely used, but its performance varies across institutions. The clinical utility of CDUS could be improved with test criteria based on patient outcome rather than test accuracy. METHODS: In 155 carotid bifurcations studied by CDUS and cerebral angiography, the degree of angiographic stenosis was measured by a reader, blinded to CDUS, using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. We calculated accuracy, sensitivity, and specificity for predicting > or = 70% angiographic carotid stenosis of different peak systolic frequencies (PSF) measured by CDUS and generated a receiver operator characteristic (ROC) curve. We used NASCET outcome data and published data on angiographic complications to define relative "costs" of false-positive and false-negative CDUS, and we determined the point on the ROC curve representing the CDUS criterion with the highest clinical utility. We compared projected morbidity and mortality rates for 1000 hypothetical endarterectomy candidates resulting from the use of the most accurate CDUS criterion versus the CDUS criterion with the highest clinical utility by ROC analysis. RESULTS: While PSF > or = 8 kHz had the highest CDUS accuracy (93%), its projected stroke and death rate due to CDUS error was 10.4/1000. On the other hand, PSF > or = 7 kHz, defined by ROC analysis to have the highest clinical utility, had a lower morbidity and mortality rate of 6.8/1000. CONCLUSIONS: The use of ROC analysis and available outcome data can improve the performance of CDUS in selecting endarterectomy candidates for cerebral angiography.

An absent ophthalmic artery or carotid siphon signal on transcranial Doppler confirms the presence of severe ipsilateral internal carotid artery disease.

Transcranial Doppler ultrasound provides a useful adjunct to extracranial ultrasound in the diagnosis of carotid bifurcation disease. Previous studies have shown that collateral flow patterns and diminished flow velocities in the ipsilateral middle cerebral artery correlate with hemodynamically significant carotid disease. In a series of 7,054 carotid duplex and transcranial Doppler examinations, 12.5% (95% confidence interval [CI]: 8.7, 16.4) of 287 ophthalmic arteries ipsilateral to an apparent carotid occlusion had no detectable flow signal, compared with 0.5% (95% CI: 0.3, 0.7) of 6,767 ophthalmic arteries ipsilateral to a non-occluded carotid artery (p < 0.001). Carotid siphon signals were not detectable in 24.4% (95% CI: 19.4, 29.4) of arteries ipsilateral to the carotid occlusion, versus 1.0% (95% CI: 0.8, 1.3) ipsilateral to nonoccluded carotid arteries (p < 0.001). A significant number of absent ophthalmic artery and carotid siphon signals (5.7 and 8.7%, respectively) were also found in patients with 80 to 99% extracranial carotid stenosis. A subset of 216 studies with angiographic correlation confirmed the high association of these transcranial Doppler findings with severe stenosis or occlusion of the internal carotid artery. Primary ophthalmological disease or siphon occlusion did not explain these findings. An absent ophthalmic artery or carotid siphon signal on transcranial Doppler examination is believed to represent a failure to detect slow flow distal to severe carotid bifurcation lesions. As a sign of ipsilateral carotid occlusion, the sensitivities of absent ophthalmic artery and carotid siphon signals are quite low (12.5 and 24.4%, respectively). The high specificities of 99.5 and 99.0%, however, make these findings useful in confirming the diagnosis of presumptive carotid occlusion by carotid duplex ultrasound.