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Magnetic Resonance Imaging in Acute Stroke

Article Last Updated: Mar 13, 2007 AUTHOR AND EDITOR INFORMATION
Section 1 of 8 Authors and Editors Introduction Differentials Workup Follow-up Miscellaneous Multimedia References
Author: Souvik Sen, MD, MS, FAHA, Associate Professor of Neurology, Founding Director of UNC Hospital Stroke Center, Department of Neurology, University of North Carolina at Chapel Hill Souvik Sen is a member of the following medical societies: American Academy of Neurology, American Heart Association, and Association for Patient Oriented Research Editors: Draga Jichici, HBSc, MD, FRCP(C), FAHA, Assistant Professor, Department of Medicine, Division of Critical Care Medicine, McMaster University Medical School, Canada; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center Author and Editor Disclosure Synonyms and related keywords: cerebrovascular accident, CVA, acute ischemic stroke, cerebrovascular disease, T1-weighted imaging, T2-weighted imaging, spin densityweighted imaging, gradient echo imaging, diffusion-weighted imaging,
perfusion-weighted imaging, MRI, MRI in acute stroke
INTRODUCTION
Background
MRI is a new and promising tool that is being increasingly used in the diagnosis and management of acute ischemic stroke. The aim of this article is to provide simple and up-to-date information about the use of MRI in acute ischemic stroke. MRI is a fastgrowing technology that is sensitive and relatively specific in detecting changes that occur after such strokes. It has some limitations, such as high cost, long scanning duration, and decreased sensitivity in the detection of subarachnoid hemorrhages; these constitute exciting challenges in the future of this technology. Recent advances in MRI, including higher strength of magnetic field (1.5-3.0 T field strength) yielding better resolution of images, newer sequences of images, and the advent of the open MRI for patients who are claustrophobic or overweight, have lead to widespread use of this technology in diagnosis and management of acute stroke.
Pathophysiology
Some nuclei in the human body become excited when positioned in a strong magnetic field; they absorb the radiofrequency energy of the magnetic field and then release it until they relax completely. The energy is released from the excited tissue over a short period of time according to 2 relaxation constants known as T1 and T2, and the emitted energy signals are converted into images. The contrasts in the images result from
different intensities of these emitted signals, which in turn result from different concentrations of the nuclei in different tissues in the body. Hydrogen (ie, protons) is the most common magnetic resonance (MR)observable nucleus in the human body and has the advantage of being present in many different tissues in different concentrations. Other organic particles have been tried but demonstrated less spatial resolution than hydrogen. Other biochemical compounds, lactate and N-acetyl aspartate, are under trial to increase understanding of the significance of the different concentrations of these compounds in different pathologic conditions (ie, MR spectroscopy). Commonly used MR imaging techniques are the following:

T1-weighted imaging (T1-WI) in which cerebrospinal fluid (CSF) has a low signal intensity in relation to brain tissue T2-weighted imaging (T2-WI) in which CSF has a high signal intensity in relation to brain tissue Spin densityweighted imaging in which CSF has a density similar to brain tissue Gradient echo imaging, which has the highest sensitivity in detecting early hemorrhagic changes Diffusion-weighted imaging (DWI) in which the images reflect microscopic random motion of water molecules Perfusion-weighted imaging (PWI) in which hemodynamically weighted MR sequences are based on passage of MR contrast through brain tissue
Pathogenesis of imaging findings Regardless of the cause, neuronal ischemia rapidly depletes intracellular adenosine triphosphate (ATP), which leads to failure of the membrane-bound ATP-dependent ionic channels responsible for both neuron resting membrane potentials as well as generation of action potentials. This metabolic aberration results in accumulation of intracellular ions (including calcium ions), creating an intracellular gradient responsible for intracellular accumulation of water (ie, cytotoxic edema). Cerebral endothelial cells are more resistant to ischemia than are neurons and neuroglial cells. About 3-4 hours after the onset of ischemia, the integrity of the bloodbrain barrier becomes compromised, and plasma proteins are able to pass into the extracellular space. The intravascular water follows when reperfusion occurs (vasogenic edema); this process begins 6 hours after the onset of stroke and reaches a maximum 2-4 days after the onset of stroke. Reperfusion can also be accompanied by hemorrhagic transformation of the infarct, which is usually related to the volume and site of the infarct, being more common in large cortical infarcts. Changes in MR images due to ischemic stroke follow the vascular territory of the occluded blood vessel, which is characteristic of cerebrovascular disease and helps in
differentiating it from other disease entities.
DIFFERENTIALS
Acute Stroke Management WORKUP

Imaging Studies
Radiography - A regular radiograph may be indicated if any possibility exists of a metallic implant or foreign body, pacemaker, aneurysm clip, or recently implanted prosthetic heart valve. MRI techniques - Diffusion-weighted imaging
o
DWI is sensitive to the microscopic random motion of the water molecule protons, a value known as the apparent diffusion coefficient (ADC), which is measured and captured by this type of imaging. The water molecules move in the direction of the magnetic field gradient; they accumulate a
phase shift in their transverse magnetization relative to that of a stationary one, and this phase shift is directly related to the signal attenuation of the image. Numerous studies have shown that ADCs in ischemic areas are lower by 50% or more than those of normal brain areas, and they appear as bright areas (ie, hyperintensities) on the DWI (see Image 1). Studies have demonstrated that changes in the ADC occur as early as 10 minutes following onset of ischemia. Cytotoxic edema appears following sodium/potassium pump failure, which results from energy metabolism failure due to ischemic insult; this occurs within minutes of the onset of ischemia and produces an increase in brain tissue water of up to 3-5%. Reduction in intracellular and extracellular water molecule movement is the presumed explanation for the drop in ADC values. The diffusion of water molecules is guarded by biologic barriers in the brain tissue (eg, cell membranes and cellular organelles). The behavior of water molecules is not symmetric and may show uneven distribution of the ADC when measured in one direction; this uneven distribution may give a false impression of a lesion. ADC values are measured in several directions (3, 6, or more), and ADC maps are created to produce a direction-insensitive measurement of the diffusion. When ADC is measured in 6 or more directions, the diffusion motion of all the water molecules (ie, ADC tensor matrix) can be calculated to create what is called full diffusion tensor mapping, which can also be used to visualize white matter tracts. Reduction in the ADC also occurs in other conditions such as global ischemia, hypoglycemia, and status epilepticus; it should always be evaluated in relation to the clinical condition of the patient. Human studies demonstrated that damage in the areas showing decreased ADC levels is very rarely reversible (in contrast to that in animal models), although a few studies have indicated that intra-arterial thrombolysis may occasionally result in disappearance of the diffusion defect. The technique most commonly used to acquire the DWI is an ultrafast one, echo-planar imaging (EPI); this technique decreases scanning time significantly and eliminates movement artifacts. The acute drop in ADC is gradually normalized to baseline at 5-10 days after ischemia (pseudonormalization); it even exceeds normal levels as time passes, helping in some cases to differentiate between acute, subacute, and chronic lesions. DWI is very sensitive and relatively specific in detecting acute ischemic stroke. DWI findings have shown high levels of diagnostic accuracy; however, recent studies demonstrated that small brainstem lacunar infarctions may escape detection. Normal DWI in patients with strokelike symptoms should trigger further investigation for a nonischemic cause of the symptoms. DWI has been shown to reveal diffusion abnormalities in almost 50% of patients with clinically defined transient ischemic attacks
(TIAs); it tends to be of higher yield at increasing time intervals from the onset of stroke symptoms. From the clinical experience at the Stroke Center at JFK Medical Center of Seton Hall University, the following differential for areas of hyperintensity on DWI was generated:
o
Subacute ischemic stroke - Usually takes 7-14 days for hyperintensity to subside Hemorrhagic stroke - Usually bright on T1-WI Multiple sclerosis plaque - Also bright on FLAIR and T2-WI Traumatic brain injury - History of trauma Brain abscess - Ring enhancement on contrast MRI Choroid plexus - Usually intraventricular in location, may be bilateral Epidermoid - Usually extra-axial in location Air-bone interface - Commonly bilateral, in the temporal bone MRI techniques - Perfusion-weighted imaging
o
With this technique, information about the perfusion status of the brain is available. The most commonly used technique is bolus-contrast tracking (other techniques include blood oxygen level and arterial spin tagging). The imaging is based on the monitoring of a nondiffusible contrast material (gadolinium) passing through brain tissue. The signal intensity declines as contrast material passes through the infarcted area and returns to normal as it exits this area. A curve is derived from this tracing data (ie, signal washout curve), which represents and estimates the cerebral blood volume (CBV). An arterial input function can be derived by measuring an artery in lower brain slices or by measuring gadolinium concentration that is proportional to the changes in T2 when gadolinium is used at low doses (<3 mg/kg). Based on this arterial input function, quantitative maps of cerebral blood flow (CBF), CBV, mean transit time (MTT), time to peak (TTP), and various other hemodynamic parameters can be obtained. Considerable debate surrounds the choice of which PWI parameter should be used. Most centers in the United States use time domain parameters such as MTT or TTP. DWI and PWI together have been shown to be superior to conventional MRI both in early phases and also up to 48 hours after the onset of stroke. Using both DWI and PWI is very important because together they provide information about location and extent of infarction within minutes of onset; when performed in series, they can provide information about the pattern of evolution of the ischemic lesion. This information may be of great importance in choosing the appropriate treatment modality as well as in predicting outcome and prognosis. Several recent randomized clinical trials are selecting patients with diffusion-perfusion mismatch to test thrombolytic treatment alternatives beyond the standard 3-hour time
window used for IV TPA. These studies have been reviewed by Davis et al (Davis, 2005). o The lesion usually enlarges on serial DWIs over a period of several days. It has been suggested that this enlargement can be halted if reperfusion (ie, resolution of original PWI lesion) occurs early enough. Lesions that are not large on initial PWI do not show this enlargement. o The diffusion-perfusion mismatch (see Image 3), ie, the difference in size between lesions captured by DWI and PWI, usually represents the ischemic penumbra (see Image 3), which is the region of incomplete ischemia that lies next to the core of the infarction. The ischemic penumbra is regarded as an area that is viable but under ischemic threat; it can be saved if appropriate intervention is promptly instituted. The viability of this region could extend up to 48 hours after the onset of stroke. Determining the volume of the ischemic penumbra may be very useful in identifying patients who would benefit from thrombolytic therapy and perhaps even conventional treatments such as carotid endarterectomy or blood pressure elevation. It could also aid in evaluating the risk/benefit ratio of using such treatments in stroke patients. o One limitation of these techniques is in detection of acute intracerebral hemorrhages; early studies demonstrated that susceptibility imaging could be sensitive in the detection of acute intracerebral hemorrhage. Gradientrecalled echo (GRE) imaging sequences demonstrated the most favorable sensitivity in detecting susceptibility dephasing associated with chronic intracerebral hemorrhages. o MRI still has some limitations in its application, namely, in patients with metal implants and acutely ill patients requiring close monitoring. o These new techniques, DWI and PWI, together represent the most exciting areas in MRI for their potential ability to detect early changes (ie, within minutes of the stroke). They are currently used in the evaluation of thrombolytic and neuroprotective therapy in acute stroke clinical trials. MRI techniques Blood oxygen level-dependent (BOLD) MRI Oxygen extraction fraction (OEF) measured by positron emission tomography (PET) imaging is considered the criterion standard for imaging the ischemic penumbra in acute ischemic stroke. Until now, MR diffusion-perfusion imaging has been the only MR technique that measures this reversibly damaged brain area. o BOLD is a new technique that can be used to detect deoxyhemoglobin in the cerebral capillaries and veins as an MRI indicator of brain OEF. Recent evidence suggests that BOLD MRI might provide a better estimation of the ischemic penumbra in acute ischemic stroke compared with MR diffusion-perfusion mismatch. o Further validation of the technique is required to confirm its clinical value in imaging of acute ischemic stroke. MRI techniques - Echo-planar imaging
o
EPI is a recent technique that can be used to visualize physiologic parameters in addition to measuring diffusion coefficients of the ischemic brain. Changes in brain oxygenation can be monitored by using gradient echo and EPI, in which deoxygenated blood acts as a susceptibility contrast agent. o EPI can be used in conjunction with bolus injection of intravenous paramagnetic agents to assess cerebral perfusion and functional changes in CBV. o In this technique, hypoperfused areas appear as hyperintense signals after injection of the contrast material. This technique is considered a way of reducing the traditionally long scanning time of MRI. MRI techniques - Magnetic resonance spectroscopy
o
Magnetic resonance spectroscopy (MRS) is one of the recent advances in MR technology; it evaluates metabolic activity and concentration of certain metabolites in specified areas of the brain. Proton and phosphorus spectroscopic studies have been performed. o In proton spectroscopy, depression of N-acetyl aspartate, which is considered to be a marker of neurons, is the most consistent finding in acute stroke. This depression may occur within hours after the onset of stroke and continues through the subacute and chronic phases of the stroke, presumably because of loss of neurons. o Increase in levels of lactate is another important finding and has been attributed to anaerobic metabolism in ischemic tissue. Initial studies of other metabolites, such as choline and creatine, demonstrated decreases in their levels in acute stroke. o Phosphorus spectroscopy provides information about energy metabolism and pH, depletion of ATP, decrease of tissue pH, and increase of the ratio of inorganic phosphate to phosphocreatine, which has been reported in both human and animal studies. o Long acquisition times, weak signal, and low spatial resolution of this technique have limited enthusiasm for its use in the clinical management of cerebral ischemia; however, some studies have suggested that MRS results can have prognostic value in stroke. MRI techniques - Magnetic resonance angiography
o
Magnetic resonance angiography (MRA) is very sensitive to flow and is based on the difference in signal between moving blood and stationary brain tissue; angiographiclike images of the cervicocranial vasculature are produced. MRA images are a useful tool in identifying dissections, in that both the true and false lumen of the involved artery can be observed on the source images. Following is a brief description of the 2 basic techniques. The three-dimensional (3D) time-of-flight (TOF) technique is based on flow-related enhancement; it is the preferred MRA technique. However, it has some limitations, especially flow signal dropout secondary to turbulent
flow in the tortuous and stenotic vascular segments, which makes interpretation of stenosis in these areas difficult. These are common predilection sites for atherosclerosis. Also, in slow-flow regions, the spin saturation of the scan causes overestimation of stenosis. In contrastenhanced studies, it provides more information than standard angiography, especially in detecting critical stenosis of extracranial vessels, but it is less reliable in intracranial critical stenosis. Always keep in mind that MRA is a flow-dependent technology; absence of flow signal does not mean literally a complete occlusion but rather that flow is below a critical value. o Two-dimensional (2D) TOF MRA also depends on the relative contrast between flowing blood and stationary tissue; it provides better images than 3D TOF in slow-flow regions. 2D TOF images correlate well with carotid angiography images in depicting cervical bifurcation disease. Its disadvantages, however, are the significant artifacts (eg, stepladder) that often occur, which may obscure vessel details, and the longer scanning time. o The modified TOF MRA technique, which uses multiple overlapping thin slab acquisitions (MOTSA), combines the advantages of 2D and 3D TOF techniques. It is very helpful in demonstrating severe stenosis, although the degree of stenosis might be slightly overestimated. o Two-dimensional phase-contrast (PC) MRA is a technique that is helpful specifically in differentiating slow and absent flow from normal flow; it captures only truly patent vessels. Other imaging sequences (eg, spinecho sequence or gradient-echo sequence) should be used with PC-MRA to avoid missing lesions such as paravascular hematomas, which are not captured by PC-MRA. PC-MRA also has the disadvantage of signal loss due to turbulent flow in tortuous vessels. Types of infarction
o
Thromboembolic infarction: This is the most common form of infarction. Typically, it is observed on MRI as a wedge-shaped infarct in the particular vascular distribution. Recent data support the hypothesis that a single infarct in a vascular territory is more likely to be thrombotic than multiple infarcts, which are more likely to be embolic. Watershed infarction: This type of infarction occurs at the distal margins of specific arterial territories. It can occur both superficially and deep in the brain parenchyma. Common etiologies for this lesion include hypotension, cardiac and respiratory arrest, and proximal arterial stenosis or occlusion. MRI findings follow the pattern of incomplete thromboembolic ischemic infarction in T1 and T2 morphologic and signal changes, with early parenchymal enhancement suggesting early reperfusion. Recent studies show that this type of infarction could be more readily detected by using DWI. Lacunar infarction: These are small deep cerebral infarctions believed to be caused by intrinsic small-vessel disease secondary to lipohyalinosis
and fibrinoid necrosis; they are most frequently observed in patients with hypertension or diabetes mellitus. Common sites for these lesions include basal ganglia, internal capsule, thalamus, brain stem, and cerebellum. MRI findings in these lesions follow the same pattern observed in thromboembolic infarction. Venous thrombosis and infarction: Occlusion of cerebral veins and venous sinuses is usually caused by systemic conditions, such as pregnancy, collagen vascular diseases, inflammatory bowel diseases, and hypercoagulable states, as well as local conditions such as infection, neoplasia, and trauma. Occlusion of the venous structure causes outflow obstruction and vascular congestion that results in parenchymal infarctions and hemorrhages.
o
Patients usually present in the late acute phase or in the subacute phase, which makes the diagnosis difficult because diagnosis at these stages depends on imaging studies. MRI findings in these lesions include loss of venous flow void signal, absence of normal venous enhancement, and visualization of isointense to hyperintense signals within the venous channels on both T1 and T2 images. These variable patterns of enhancement are due to mixed blood products, which are present in the lesion. These patterns are usually bilateral, do not respect arterial vascular territories, and have associated hemorrhage. Three-dimensional phase contrast magnetic resonance venography (MRV) is the preferred technique in the evaluation of venous thrombosis. MRI findings in acute stroke - Hyperacute phase (0-24 h) o DWI is able to detect ischemic changes within minutes of onset (see Image 1). Reduced proton motion is detected as a decreased ADC. o Early in the process of cerebral ischemia, PWI, using first-pass contrast bolus injection or spin tagging the protons in the water in blood, reveals reductions of CBF and CBV and an increased MTT of blood through the brain (see Image 2). o Matched diffusion- and perfusion-weighted abnormalities correlate with the region of infarction and are indicative of permanent neuronal death. Mismatched diffusion and perfusion abnormalities with the perfusion abnormality larger than the diffusion abnormality may be indicative of a region of reversible ischemic penumbra (see Image 3). o A few hours after stroke onset, a loss of arterial void signal is sometimes observed (30-40% of patients); it is best observed on T2-WI. o At 2-4 hours, T1-WI shows subtle effacement of the sulci due to cytotoxic edema. o At 8 hours, T2-WI shows hyperintense signal due to both cytotoxic and vasogenic edema. o At 16-24 hours, T1-WI shows hypointense signal due to both cytotoxic and vasogenic edema.
Contrast-enhanced images show arterial enhancement followed by parenchymal enhancement. The arterial enhancement can be very early (in more than 50% of patients) and is due to slow blood flow; it typically disappears after 1 week. Parenchymal enhancement differs in complete and incomplete infarctions. In complete infarction, it starts 5-7 days after the stroke and persists for several months. In incomplete infarctions, it can be observed within 2-4 hours and usually is more intense than in complete infarction. Although conventional MRI sequences most often do not show evidence of stroke in the acute phase, conventional MRI may show signs of intravascular thrombus such as absence of flow void on T2-WI, vascular hyperintensity on FLAIR, and hypointense vascular sign on GRE sequence.
MRI findings in acute ischemic changes Time 2-3 min 2-3 min 0-2 h 0-2 h 2-4 h 2-4 h 8h 16-24 h 5-7 d
MRI Finding DWI - Reduced ADC PWI - Reduced CBF, CBV, MTT T1-WI - Arterial enhancement T1-WI - Subtle sulcal effacement T1-WI - Parenchymal enhancement T2-WI - Hyperintense signal T1-WI - Hypointense signal Parenchymal enhancement
Etiology Decreased motion of protons Decreased CBF
T2-WI - Absent flow void signal Slow flow or occlusion Slow flow Cytotoxic edema Incomplete infarction Vasogenic and cytotoxic edema Vasogenic and cytotoxic edema Complete infarction
MRI findings in acute stroke - Acute phase (1-7 d)

o
In this phase, edema increases (edema maximizes at 48-72 h), and MRI signals become more prominent and well demarcated. The ischemic area continues to appear as an area of hypointensity on T1-WI and as a hyperintense area on T2-WI. Also, the mass effect can be appreciated in this phase. In contrast-enhanced images, the arterial enhancement usually persists
throughout the acute phase, while the parenchymal enhancement is usually appreciated at the end of this phase in complete infarction. In incomplete infarction, the parenchymal enhancement is usually earlier. o During this period, reperfusion occurs and both petechial and frank hemorrhage can be observed, typically 24-48 hours after the onset of the stroke. Usually, petechial hemorrhages cause the "fogging" phenomenon, due to hemoglobin degradation products, that masks the infarction on both T1-WI and T2-WI. MRI findings in acute stroke - Subacute phase (7-21 d) In this phase, the edema resolves and the mass effect becomes less appreciated; however, the infarcted areas still appear as a hypointensity on T1-WI and as a hyperintensity on T2-WI. o In contrast-enhanced images, the arterial enhancement is usually resolved by this time, and the parenchymal enhancement typically persists throughout this phase. The cortical parenchymal enhancement is usually in a gyriform pattern, while the subcortical enhancement is usually a homogenous central pattern. MRI findings in acute stroke - Chronic phase (>21 d) In this phase, the edema completely resolves, and the infarcted area still appears as a hypointensity on T1-WI and as a hyperintensity on T2-WI. Because of tissue loss in the infarcted area by this time, ex-vacuo ventricular enlargement and widening of the cortical gyri and fissures take place. o In contrast-enhanced images, parenchymal enhancement typically persists throughout this phase also; it usually disappears by 3-4 months. MRI findings in TIA A third to a half of the patients presenting with a TIA have lesions on DWI. A significant proportion of these patients may not reveal a corresponding lesion on T2-WI. PWI may be more sensitive but has not been adequately tested in patients with TIA. DWI-positive TIA lesions do necessarily show as infarction on follow-up MRI. o Although TIAs have been traditionally defined as transient (<24h) neurologic deficit of vascular origin, the advent of MRI has lead to reconsideration of the definition. Whether DWI-positive TIAs are to be regarded as stroke or TIA is unclear. MRI in hemorrhagic stroke
o o o o
GRE and EPI sequences have the ability to detect microbleeds that are clinically silent and not visualized by CT scanning or routine MR sequences. These microbleeds are visualized in a fifth to a quarter of patients with ischemic stroke and 5% of elderly asymptomatic individuals. The microbleeds depict hemosiderin deposit and have been histopathologically correlated with prior extravasations of blood. These
microbleeds may represent bleeding-prone angiopathy and a higher rate of hemorrhagic transformation from anticoagulation, antithrombotic, and thrombolytic therapy. GRE, EPI, and DWI (B0) are sensitive to detecting intraparenchymal hemorrhage (primary intracerebral hemorrhage and hemorrhagic transformation) in the hyperacute stages (first few hours), whereas the conventional T1-WI and T2-WI are sensitive in detecting subacute and chronic bleeding. FLAIR sequences may have a role in detecting extraaxial collections of blood (subdural hemorrhages). Having stated the above, the current guidelines do not advocate the use of MR in place of CT scanning to screen patients for thrombolysis.
FOLLOW-UP
Further Inpatient Care
Inpatients may often continue to be monitored and receive treatment while undergoing MRI because MRI-compatible ECG monitors, intravenous infusion pumps, and ventilators are available.
In/Out Patient Meds
A mild sedative may be ordered for patients with a history of claustrophobia. As an alternative, an open MRI may be ordered at the cost of lesser quality MR images.
Complications
Patients with metallic implants may have a variety of potential complications, such as heating and pacemaker malfunction and its consequences. For patients
with a metallic implant, checking with the manufacturer regarding its MR compatibility is advisable if such information is not available elsewhere. Claustrophobic patients may be unable to complete the sequence of MRI. In selected patients, mild sedation or imaging in an open MR system may be attempted. However, most open MR scanners provide lesser quality images. Rarely, patients may be allergic to the contrast agent (eg, gadolinium) used in MRI.
Patient Education
For excellent patient education resources, visit eMedicine's Imaging Center and Stroke Center. Also, see eMedicine's patient education articles Magnetic Resonance Imaging (MRI) and Stroke.
MISCELLANEOUS
Section 6 of 8 Authors and Editors Introduction Differentials Workup Follow-up Miscellaneous Multimedia
References
Patients who have received recent thrombolysis or are critically ill from stroke are probably not well suited for MRI because they cannot be monitored by clinical examinations during the period of imaging. If MRI is essential, it should be performed with the bare minimum of sequences required to make the diagnosis, such as T1, T2, DWI or PWI, and MRA. Many institutions have established acute stroke protocols to minimize scanning time. Patients with acute stroke who are considered for MRI should be evaluated for contraindications to MRI such as claustrophobia, metallic implants, pacemakers, and MR-incompatible prosthetic heart valves.
MULTIMEDIA
Media file 1: Magnetic resonance imaging in acute stroke. Left: Diffusionweighted MRI in acute ischemic stroke performed 35 minutes after symptom onset. Right: Apparent diffusion coefficient (ADC) map obtained from the same patient at the same time. View Full Size Image
Media type: MRI Media file 2: Magnetic resonance imaging in acute stroke. Left: Perfusion-
weighted MRI of a patient who presented 1 hour after onset of stroke symptoms. Right: Mean transfer time (MTT) map of the same patient. View Full Size Image
Media type: MRI Media file 3: Magnetic resonance imaging in acute stroke. Diffusion-perfusion mismatch in acute ischemic stroke. The perfusion abnormality (right) is larger than the diffusion abnormality (left), indicating the ischemic penumbra, which is at risk of infarction. View Full Size Image
Media type: MRI Media file 4: The diffusion-weighted MRI reveals a region of hypointensity in the distribution of the right middle cerebral artery. Flanking the anterior and posterior regions of this abnormality are regions of hyperintensities, which represent regions of new infarct. The contiguity of these regions suggests that they are extensions of the old infarct. View Full Size Image
Media type: MRI
REFERENCES
Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab. Jun 1998;18(6):583-609. [Medline]. Blatter DD, Parker DL, Ahn SS, et al. Cerebral MR angiography with multiple overlapping thin slab acquisition. Part II. Early clinical experience. Radiology. May 1992;183(2):379-89. [Medline]. Chalela JA, Haymore JB, Ezzeddine MA, et al. The hypointense MCA sign. Neurology. May 28 2002;58(10):1470. [Medline]. Davis SM, Donnan GA, Butcher KS, Parsons M. Selection of thrombolytic therapy beyond 3 h using magnetic resonance imaging. Curr Opin Neurol. Feb 2005;18(1):47-52. [Medline]. Duong TQ, Fisher M. Applications of diffusion/perfusion magnetic resonance imaging in experimental and clinical aspects of stroke. Curr Atheroscler Rep. Jul 2004;6(4):267-73. [Medline]. Fisher M, Albers GW. Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology. Jun 10 1999;52(9):17506. [Medline]. Geisler BS, Brandhoff F, Fiehler J, et al. Blood-oxygen-level-dependent MRI allows metabolic description of tissue at risk in acute stroke patients. Stroke. Jul 2006;37(7):1778-84. [Medline]. Kidwell CS, Alger JR, Di Salle F, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke. Jun 1999;30(6):1174-80. [Medline]. Kidwell CS, Saver JL, Villablanca JP, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: an emerging application. Stroke. Jan 2002;33(1):95-8. [Medline]. Medlock MD, Olivero WC, Hanigan WC, et al. Children with cerebral venous thrombosis diagnosed with magnetic resonance imaging and magnetic resonance angiography. Neurosurgery. Nov 1992;31(5):870-6; discussion 876. [Medline]. Mok V, Chang C, Wong A, et al. Neuroimaging determinants of cognitive performances in stroke associated with small vessel disease. J Neuroimaging. Apr 2005;15(2):129-37. [Medline]. Moseley ME, Cohen Y, Mintorovitch J, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and
spectroscopy. Magn Reson Med. May 1990;14(2):330-46. [Medline]. Moseley ME, Kucharczyk J, Mintorovitch J, et al. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibilityenhanced MR imaging in cats. AJNR Am J Neuroradiol. May 1990;11(3):4239. [Medline]. Rincon F. Anticoagulation and thrombolysis for acute ischemic stroke and the role of diagnostic magnetic resonance imaging. Arch Neurol. May 2004;61(5):801-2; author reply 802. [Medline]. Runge VM, Kirsch JE, Wells JW, Woolfolk CE. Assessment of cerebral perfusion by first-pass, dynamic, contrast-enhanced, steady-state free-precession MR imaging: an animal study. AJR Am J Roentgenol. Mar 1993;160(3):593600. [Medline]. Schlaug G, Benfield A, Baird AE, et al. The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology. Oct 22 1999;53(7):152837. [Medline]. Thurnher MM, Castillo M. Imaging in acute stroke. Eur Radiol. Mar 2005;15(3):408-15. [Medline]. Yuh WT, Crain MR, Loes DJ, et al. MR imaging of cerebral ischemia: findings in the first 24 hours. AJNR Am J Neuroradiol. Jul-Aug 1991;12(4):621-9. [Medline].
Magnetic Resonance Imaging in Acute Stroke excerpt
Article Last Updated: Mar 13, 2007
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Metabolic Disease & Stroke: Hyperglycemia/Hypoglycemia

Article Last Updated: Apr 4, 2006 AUTHOR AND EDITOR INFORMATION
Section 1 of 10 Authors and Editors Introduction Clinical Workup Treatment Medication Follow-up Miscellaneous Acknowledgments References
Author: Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center Pitchaiah Mandava is a member of the following medical societies: American Academy of Neurology, Sigma Xi, and Stroke Council of the American Heart Association Coauthor(s): Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center Editors: Richard M Zweifler, MD, Professor, Director of Stroke Center, Director of Neurosonology Lab, Director of Vascular Neurology Fellowship, Director of Medical Student Education, Department of Neurology, University of South Alabama; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center Author and Editor Disclosure Synonyms and related keywords: hyperglycemia, hypoglycemia, acute stroke, diabetes, diabetes mellitus, thrombolytic therapy, anticoagulation therapy, transient ischemic attack, TIA, recombinant tissue-type plasminogen activator, rtPA, metabolic disease and stroke
INTRODUCTION
Background
This article primarily addresses effects of hyperglycemia and hypoglycemia in the setting of acute stroke. Preexisting hyperglycemia is found commonly in patients presenting with acute stroke, and hypoglycemia may present with focal symptoms mimicking acute stroke. The reader is referred to more definitive discourses about the general management of diabetes and other manifestations of hyperglycemia and hypoglycemia in the general neurologic and endocrinologic literature. Hyperglycemia: Although confounded by other factors, such as severity of the infarct, hyperglycemia in the face of acute stroke worsens clinical outcome. Nondiabetic hyperglycemic ischemic stroke patients have a 3-fold higher 30-day mortality and diabetic patients have a 2-fold 30-day mortality (Capes, 2001). In several trials involving thrombolytic and anticoagulation therapy in patients with stroke, hyperglycemia appears to be an independent risk factor for worsened outcome. Hyperglycemia has been suggested as an independent risk factor in hemorrhagic conversion of the stroke after administration of thrombolytic therapy. Hypoglycemia: Several case reports describe hypoglycemia mimicking acute stroke or symptoms of transient ischemic attack (TIA). Misdiagnosis and improper treatment could worsen the outcomes. Therefore, evaluation of glucose levels is recommended in
patients presenting with symptoms suggestive of acute stroke, particularly prior to administration of recombinant tissue-type plasminogen activator (rtPA). Symptoms caused by hypoglycemia can occur suddenly and fluctuate, suggesting a vascular etiology.
Pathophysiology
Hyperglycemia Diabetes mellitus is an independent risk factor for stroke and may be one of the factors causing strokes at younger ages in groups such as Hispanic Americans that have a relatively high incidence of diabetes. The mechanism is believed to be accelerated atherosclerosis, which can affect vessels in many distributions, including small and large vessels. Cardiac involvement may predispose to embolic strokes as well. In addition, patients with diabetes may have any of several lipid abnormalities. Elevated levels of triglycerides, low-density lipoproteins (LDL), and very low-density lipoproteins (VLDL), along with lower than normal levels of high-density lipoprotein (HDL), are common findings in the lipid profiles of patients with diabetes. The combined effect of these factors results in promotion of atherosclerosis and thrombosis. The specific mechanism(s) by which hyperglycemia leads to poorer clinical outcome in patients receiving anticoagulants or thrombolytics is not known, although several have been proposed, including the following:
In some vascular beds, hyperglycemia causes glycosylation and thereby interferes with protein and enzyme function, including those functions that regulate production of substances that cause vasodilation and cellular adhesion within the vasculature. Hyperglycemia results in the formation of advanced glycation end products that are toxic to endothelial cells, and production of free radicals from various sources may result in further vascular injury.
Hyperglycemia worsens outcome and increases rate of mortality from stroke. Two mechanisms have been postulated to explain the negative influence of hyperglycemia on outcome following stroke:

Poorer reperfusion due to vascular injury Increased acidosis, perhaps from lactic acid, leading to further tissue injury
Both mechanisms have been supported by experimental data. Parsons et al (2002) used MRI and MR spectroscopy in patients with hyperglycemic stroke and report that the detrimental effect of hyperglycemia may be due to metabolic acidosis in the infracted brain parenchyma. However, earlier animal studies suggested that hyperglycemia has a detrimental effect on cerebral vascular tree (Kawai, 1997; Quast, 1997). In some studies, hyperglycemia appears to be associated with a reduced incidence of
primary intracerebral hemorrhage. However, risk of hemorrhagic conversion of strokes appears to increase after rtPA administration in patients with diabetes. This risk may be present even at moderate elevations of serum glucose level. Notably, moderate hyperglycemia is presently not an exclusion criterion for administration of rtPA in patients with acute stroke; the range of blood glucose for which rtPA treatment of patients with acute stroke is acceptable is 50-400 mg/dL. Hypoglycemia Low levels of glucose can result from the following:

Overuse of oral hypoglycemic agents or insulin Overproduction of endogenous insulin, which may be a result of an insulinoma Medical illnesses such as sepsis, renal failure, and hepatic failure
Two different mechanisms have been suggested as the causes of hypoglycemia-related strokelike episodes, as follows:
The brain uses glucose predominantly for oxidative metabolism. Different brain regions have different metabolic demands. The need for glucose is highest in the cerebral cortex and basal ganglia. The cerebellum and the subcortical white matter have less demand for this substrate. Focal deficits may be a result of asymmetric distribution of glucose transporters. Gold and Marshall suggest that coagulation defects may be the cause of strokelike episodes.
Frequency
International
Hyperglycemia: Hyperglycemia is reported to be present in 20-50% of patients incurring acute stroke. In many trials of thrombolytic agents, hyperglycemia occurred in about 2030% of subjects. Hypoglycemia: The Diabetes Control and Complications Trial (DCCT) found a 3-fold higher rate of severe hypoglycemia in the group that received intensive treatment for diabetes than in those who received conventional therapy. Patients in the group receiving intensive therapy required medical attention for hypoglycemia at an incidence of 62 episodes per 100 patient-years. Berkovic et al reported that hypoglycemia was the cause of symptoms mimicking acute stroke in 3 of a total of 1460 patients admitted to their stroke unit over a 5-year period.
CLINICAL
History
Hyperglycemia and acute stroke Patients may come to the attention of physicians because of preexisting diabetes mellitus. o Diabetes may be seen with other risk factors for stroke such as hypertension and hypercholesterolemia. o Hyperglycemia also may be seen in the setting of an acute stroke without a history of diabetes, presumably due to a sympathetic response to the infarct. Hypoglycemia and strokelike symptoms
o o o o
Diabetes mellitus may have been diagnosed earlier, and recent changes in the doses of hypoglycemic agents and insulin may have been instituted. Aggressively tight control, either patient driven or physician directed, may give rise to chronic hypoglycemia or recurrent episodes of hypoglycemia. If factitious hypoglycemia is suspected, such behavior may have manifested earlier by similar episodes or other factitious behaviors.
Physical

Signs and symptoms of acute stroke are covered in other articles (Stroke, Hemorrhagic; Stroke, Ischemic). Retinopathy, neuropathy, and peripheral vascular disease may be found in patients with long-standing diabetes. In the literature, signs of an acute stroke, such as hemiplegia, aphasia, and cortical blindness, have been reported with hypoglycemia.
WORKUP
Lab Studies
In the setting of acute stroke, obtaining serum glucose levels along with a broader panel of complete blood count, electrolyte values, prothrombin time (PT), and activated partial thromboplastin time (aPTT) is routine practice.
Imaging Studies
Obtain CT scan of the head when stroke is suspected. More recently, MRI with diffusion/perfusion sequences has been used for assessment of acute stroke. The mechanism by which these tests specifically affect the diagnosis or treatment of patients with stroke and hyperglycemia is not clear. o However, that hyperglycemia may accelerate the ischemic process has been postulated, so that features characteristic of acute stroke, such as hypodensity on CT scan, may be seen earlier than in patients without hyperglycemia. If strokelike symptoms are a result of hypoglycemia, abnormal findings on imaging studies are dependent on the degree and duration of insult to the brain.
o o o
Initially, results on CT scan of the head may be normal. Later, in patients with severe hypoglycemia that is prolonged and complicated by anoxic brain injury and coma, CT scan of the brain may show cortical atrophy reflecting laminar necrosis. The regions that are most prone to injury are cortical gray matter, followed by basal ganglia and cerebellar cortex. If hypoglycemia is transitory and the clinical status of the patient returns to normal, follow-up CT scan findings also may be normal.
TREATMENT
Section 5 of 10
Authors and Editors Introduction Clinical Workup Treatment Medication Follow-up Miscellaneous Acknowledgments References
Medical Care
Hyperglycemia In terms of primary prevention, treatment of diabetes appears to reduce the incidence of atherosclerotic complications. Intensive approaches to multiple risk factors in stroke have been suggested, including reduction of LDL (to below 100 mg/dL in diabetics), increase of HDL (with fibrates if tolerated, an effect especially beneficial in patients with insulin resistance [Robins, 2001]), tight glucose control, and hypertensive management. o Intensive insulin treatment for hyperglycemia has been studied in the surgical intensive care unit setting and has been proven to reduce incidence of critical care neuropathy (Van den Berghe, 2001). A subgroup analysis of patients with traumatic brain injury suggested that long-term clinical outcome was better in the group that was treated with intensive insulin (Van den Berghe, 2005). o Morbidity was reduced in patients treated with intensive insulin who were admitted to the medical intensive care unit, but overall mortality was unchanged (Van den Berghe, 2006). Mortality was reduced in the subset of patients who had ICU stays of at least 3 days. o Studies indicate that treatment of hypertension in diabetic patients reduces stroke risk by over 40%. Guidelines published by Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommend lower, more strict hypertension targets in diabetics of 130/80 (Chobanian, 2003). o The benefit of treatment of hyperglycemia with insulin in the setting of acute stroke has not been confirmed in randomized controlled clinical trials, and there is not yet sufficient evidence to recommend changing current recommendations to maintain glucose levels below 180 mg/dL. The risk of inducing hypoglycemia as part of an aggressive correction of serum glucose is as yet unknown in the acute stroke setting. Hypoglycemia
o o
Frequent monitoring of glucose levels may be necessary to prevent hypoglycemia, especially when changes in doses of medications have been
made. Other metabolic abnormalities, such as hepatic or renal failure, also may carry a risk of hypoglycemia. When hypoglycemia is discovered, the glucose level must be brought expeditiously to a normal level. Intravenous fluids, such as dextrose 25% in water (D25W) or dextrose 50% in water (D50W), may be necessary. Note that dextrose 5% in water (D5W) is not an appropriate fluid because excess of free water may exacerbate cerebral edema, and because hyperglycemia may be induced, with harmful effects as above. Also, serum glucose levels should be monitored at frequent intervals. Neurologists typically do not treat patients with glucose-containing fluids without coadministration of thiamine in order to avoid the possibility of precipitating acute Wernicke encephalopathy or chronic Korsakoff psychosis. A patient who is hypoglycemic because of systemic illness or malnutrition may be particularly vulnerable to vitamin deficiency.
Consultations
Diabetes is managed in a primary care setting. However, certain patients whose diabetes is difficult to control or patients who may be experiencing the myriad of complications of diabetes may benefit from consultation with an endocrinologist.
Diet
Advise patients with new-onset diabetes to consult a dietitian for dietary advice.
MEDICATION
Regarding the general management of diabetes, refer to appropriate sections of articles that deal with treatment of diabetes (Diabetes Mellitus, Type 1 - A Review; Diabetes Mellitus, Type 2 - A Review; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2). Typically, hyperglycemia in the setting of acute stroke is treated with subcutaneous insulin in a sliding scale. Refractory hyperglycemia may require the use of intravenous (IV) insulin; however, IV insulin increases the risk of hypoglycemia. Safety and efficacy of IV insulin in treatment of hyperglycemia in patients with acute stroke are being determined by ongoing/planned clinical trials.
Drug Category: Antihyperglycemic agents
These agents increase glucose metabolism.

Drug Name Insulin (Humulin, Novolin, Lente) Stimulates proper utilization of glucose by cells and reduces blood sugar levels. Use sliding scale. Sliding scales for insulin vary widely and must be tailored to individual needs of patient; an example using regular insulin is given below but local practices may mandate a tighter glucose control: Blood glucose 150-200 mg/dL: 2 units SC Blood glucose 201-250 mg/dL: 4 units SC Blood glucose 251-300 mg/dL: 6 units SC
Description
Adult Dose
Blood glucose 301-350 mg/dL: 8 units SC Blood glucose 351-400 mg/dL: 10 units SC Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; hypoglycemia Acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid hormone, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin may decrease hypoglycemia effects Calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone may increase hypoglycemic effects B - Usually safe but benefits must outweigh the risks. Closely monitor blood glucose levels when using sliding scale insulin in order to avoid hypoglycemia, especially when used in combination with oral hypoglycemic agents, because they may not reach maximum efficacy until several hours after administration and may have prolonged duration of action
Interactions
Pregnancy
Precautions
Drug Category: Vitamins
These are essential for normal DNA synthesis.

Drug Name Thiamine; vitamin B-1 (Thiamilate)
Description
For thiamine deficiency including Wernicke encephalopathy syndrome. Initial: 100 mg IV/IM qd; can be given PO, but for initial treatment parenteral routes preferable owing to poor oral absorption; occasionally, higher doses (eg, 300 mg) have been given as initial treatment Not established
Adult Dose
Pediatric Dose
Contraindications Documented hypersensitivity Interactions Pregnancy None reported A - Safe in pregnancy Sensitivity reactions can occur (intradermal testdose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke encephalopathy, following glucose, may occur in thiaminedeficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency
Precautions
FOLLOW-UP
Patient Education
For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.
MISCELLANEOUS
Medical/Legal Pitfalls

The usual medicolegal risks of delayed diagnosis or misdiagnosis of stroke as well as medication adverse effects are pertinent to this chapter. Hypoglycemia also is associated with complications, especially in the setting of stroke and possible ongoing cerebral ischemia. These complications were defined earlier in this article.
ACKNOWLEDGMENTS
Section 9 of 10 Authors and Editors Introduction Clinical Workup Treatment Medication
Follow-up Miscellaneous Acknowledgments References
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Sharyl Martini, MD to the development and writing of this article.
REFERENCES
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the JNC 7 report. JAMA. May 21 2003;289(19):2560-72. [Medline]. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline]. Demchuk AM, Morgenstern LB, Krieger DW. Serum glucose level and diabetes predict tissue plasminogen activator- related intracerebral hemorrhage in acute ischemic stroke. Stroke. Jan 1999;30(1):34-9. [Medline]. Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke. Jan 2006;37(1):267-73. [Medline]. Gold AE, Marshall SM. Cortical blindness and cerebral infarction associated with severe hypoglycemia. Diabetes Care. Sep 1996;19(9):1001-3. [Medline]. Gorelick PB, Sacco RL, Smith DB. Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA. Mar 24-31 1999;281(12):1112-20. [Medline]. Kawai N, Keep RF, Betz AL. Hyperglycemia and the vascular effects of cerebral ischemia. Stroke. Jan 1997;28(1):149-54. [Medline]. Lawson ML, Gerstein HC, Tsui E. Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes. A systematic review and metaanalysis. Diabetes Care. Mar 1999;22 Suppl 2:B35-9. [Medline]. Lukovits TG, Mazzone TM, Gorelick TM. Diabetes mellitus and cerebrovascular disease. Neuroepidemiology. 1999;18(1):1-14. [Medline]. Parsons MW, Barber PA, Desmond PM, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. Jul 2002;52(1):20-8. [Medline]. Quast MJ, Wei J, Huang NC, et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J Cereb Blood Flow Metab. May 1997;17(5):553-9. [Medline]. Richardson ML, Kinard RE, Gray MB. CT of generalized gray matter infarction due to hypoglycemia. AJNR Am J Neuroradiol. Jul-Aug 1981;2(4):366-7. [Medline]. Robins SJ, Collins D, Wittes JT, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. Mar 28 2001;285(12):1585-91. [Medline]. Shotliff K, Prasad A, Millard P. Hypoglycaemia masquerading as a stroke [letter]. Postgrad Med J. Oct 1992;68(804):843. [Medline]. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline]. The NINDS t-PA stroke study group. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. Nov 1997;28(11):211925. [Medline]. Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology. Apr 26 2005;64(8):1348-53. [Medline]. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. Feb 2 2006;354(5):449-61. [Medline]. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. Nov 8 2001;345(19):1359-67. [Medline]. Wallis WE, Donaldson I, Scott RS. Hypoglycemia masquerading as cerebrovascular
disease (hypoglycemic hemiplegia). Ann Neurol. Oct 1985;18(4):510-2. [Medline]. Young GB, Roper AH, Bolton CF. Metabolic encephalopathies. Coma and impaired consciousness: a clinical perspective. 1998;Chapter 13:333-8. Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96:380-5. [Medline].
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Cardioembolic Stroke
Article Last Updated: Feb 13, 2008 AUTHOR AND EDITOR INFORMATION
Section 1 of 11 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Multimedia References
Author: Michael J Schneck, MD, Associate Professor, Department of Neurology and Neurosurgery, Loyola University Chicago, Stritch School of Medicine Coauthor(s): Lei Xu, MD, PhD, Resident Physician, Department of Neurology, Loyola University Chicago, Stritch School of Medicine; Santiago Palacio, MD, Neurology Fellow, Department of Medicine (Division of Neurology) Editors: Edward Hogan, MD, Professor, Department of Neurology, Medical College of Georgia; Emeritus Professor and Chair, Department of Neurology, Medical University of South Carolina; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Author and Editor Disclosure Synonyms and related keywords: cardiogenic embolism, cardiac embolism, cardioembolic stroke, atrial fibrillation, atrial flutter, heart attack, transient ischemic attack, TIA, coronary artery disease, CAD, congestive heart failure, CHF, myocardial infarction, MI
INTRODUCTION
Background
The heart was established as an important source for the development of emboli when Gowers, in 1875, described a case of left middle cerebral artery and retinal artery emboli. Cardiogenic embolism accounts for approximately 20% of ischemic strokes each year. New diagnostic techniques (transesophageal echocardiography, cardiac magnetic resonance) have allowed clinicians to better characterize well-established sources of embolism and to discover other potential etiologies of cardioembolic stroke. Cardioembolic stroke is largely preventable, warranting efforts at primary prevention for major-risk cardioembolic sources. Once stroke due to cardiac embolism has occurred, the likelihood of recurrence is relatively high for most cardioembolic sources, and
consequently, secondary prevention is also important.
Pathophysiology
The underlying mechanism of cardioembolic stroke is occlusion of cerebral vessels with debris from a cardiac source. An embolus may consist of platelet aggregates, thrombus, platelet-thrombi, cholesterol, calcium, bacteria, etc. Most embolic debris contains platelet aggregates. However, no single mechanism is responsible for the development of cardiac emboli. The specific underlying cardiac disease determines the pathophysiology and natural history, and hence each cardioembolic source must be considered individually. Emboli secondary to chamber abnormalities (eg, atrial fibrillation, acute myocardial infarction) are induced mainly by stasis, while those secondary to valve involvement are the result of endothelial abnormalities with attachment of material (eg, platelets, bacteria) to their free borders. The nature of the embolus differs depending on the source (eg, calcified particles from calcific valves, neoplastic cells from myxomas). This must be considered when choosing specific therapies; no single treatment covers the wide variety of heart disease that can cause embolism to the brain. Emboli from the heart are distributed evenly throughout the body according to cardiac output, but more than 80% of symptomatic or clinically recognized emboli involve the brain. Of emboli to the brain, approximately 80% involve the anterior circulation (ie, carotid artery territory) while 20% involve the vertebrobasilar distribution, proportional to the distribution of cerebral blood flow. Once emboli have reached the cerebral circulation, they obstruct brain-supplying arteries, causing ischemia to the neurons and to the blood vessels within the area of ischemia. In contrast to thrombi, emboli are attached loosely to the vascular walls and thus commonly migrate distally. When this occurs, reperfusion of the damaged capillaries and arterioles allows blood to leak into the surrounding infarcted tissue. This explains the more frequent association of hemorrhagic infarction with cardiogenic embolism than with other causes of ischemic stroke. In the great majority of patients with hemorrhagic infarcts, the hemorrhagic transformation does not cause clinical worsening because the bleeding involves necrotic tissue. In short, cardioembolic stroke is not one disease with a single natural history. Many different types of cardiac disorders lead to cardioembolic stroke, each with unique clinical features, risks of initial and recurrent stroke, and optimal therapy.
Frequency
United States
Approximately 20% of ischemic strokes are considered cardioembolic. The annual
incidence is estimated at approximately 146,000 cases.

International
Estimated frequency varies from 12-31% of ischemic strokes depending on criteria applied for definition, extent of evaluation, and study design (see Table 1). Consistent geographic variation is not evident, and the frequency is likely similar throughout the world if adjusted for mean population age. The risk of a cardioembolic event rises with age. The older the cohort, the higher the estimated frequency of cardioembolic stroke because of the rapidly increasing prevalence of atrial fibrillation in elderly persons. Table 1. Frequency of Cardioembolic Stroke/All Ischemic Stroke
Frequency of Cardioembolic Stroke* Study N Patient Age (Mean) 73 Presumed Cardioembolic, %
Oxfordshire, UK (1989) Melbourne, Australia (1989) Lausanne, Switzerland (1991) Klosterneuburg, Austria (1992) Umea, Sweden (1992) Barcelona, Spain (1993)
224
20
353
--
19
1311
65
18
365
68
19
953
72
31
736
71
17
Guayaquil,
313
61
14
Ecuador (1993) Giessen, Germany (1994) Lund, Sweden (1994) Maastricht, Holland (1994) Paris, France (1995) Warsaw, Poland (1995) Barcelona, Spain (1997) Taipei, Taiwan (1997) Riyadh, Saudi Arabia (1999) Athens, Greece (2000) Bensaon, France (2000) Santiago, Chile (2007) 250 -17
166
73
28
813
71
22
250
--
29
297
69
22
1267
--
18
676
65
20
756
--
19
885
70
38
1776
69
31
239
66
9.3
Mashhad, Iran (2007) Aggregate
1392
--
12
13022
69
22
*Frequency of presumed cardioembolic stroke is a percentage of consecutive ischemic strokes, using each author's criteria. Criteria, design, and extent of evaluation varied substantially among studies. 20% had a major embolic source. This study included transient ischemic attacks (TIAs).
Mortality/Morbidity
In general, cardioembolic strokes have a worse prognosis and produce larger and more disabling strokes than other ischemic stroke subtypes. This general observation is derived from emboli originating in cardiac chambers, which are on average of large size (eg, atrial appendage, ventricular thrombi).
Race
Blacks and Hispanics reportedly have a lower frequency of cardioembolic strokes than whites, possibly reflecting a lower prevalence of atrial fibrillation in these racial groups, who tend to experience stroke at younger mean ages.
Sex
The female-to-male ratio of cardioembolic stroke increases with age, reflecting the increased prevalence of atrial fibrillation among elderly women.
Age
The relative frequency of cardioembolic stroke as a proportion of all strokes is bimodal, higher in young (<50 y) and very old (>75 y) individuals. The incidence steadily increases with age because of the escalating frequency of atrial fibrillation.
CLINICAL
History
Although not sufficiently sensitive or specific to establish the diagnosis, several clinical features help to distinguish cardiogenic embolism from other mechanisms of cerebral ischemia and are useful to consider in patient management.
Clinical features of cardioembolic stroke include the following: Decreased level of consciousness at onset of stroke Neurologic symptoms of abrupt onset with maximal severity at onset Rapid recovery from major hemispheric deficits ("spectacular shrinking deficit") due to reperfusion of brain with early lysis of the embolus o Onset of symptoms after a Valsalva-provoking activity (enhancing right-to-left shunting in patients with a patent foramen ovale [PFO]) o Symptoms reflecting involvement of different vascular territories of the brain Neither seizures nor headache at the onset is a useful predictor of cardiogenic embolism. Cardiogenic emboli (especially from chamber sources) do not often affect the deep penetrating arteries or manifest as a lacunar syndrome. Small cardiogenic emboli from valvular sources (eg, calcific aortic stenosis, infective endocarditis) can obstruct the small penetrating arteries, causing subcortical lacunar infarcts.
o o o
Physical

Evidence of cardiac atrial dysrhythmias (eg, atrial fibrillation, sick sinus syndrome) Presence of cardiac murmurs (eg, mitral stenosis, calcific aortic stenosis) Signs of congestive heart failure (eg, after acute myocardial infarction, nonischemic cardiomyopathies) Recent myocardial infarction (highest cerebral embolism in the first 4 weeks of acute myocardial infarction) Concomitant diseases (eg, systemic lupus erythematosus and Libman-Sacks
endocarditis, neoplasia, marantic endocarditis) Concomitant signs of systemic embolism

o o
The probability of finding such signs in patients with suspected cardioembolic stroke is low (approximately 1%) for most cardioembolic sources. The diagnosis of cardioembolic stroke is based on the triad of (1) identification of a potential cardioembolic source, (2) absence of other likely causes of stroke, and (3) supportive clinical features described above.
Causes
More than 20 specific cardiac disorders have been implicated in leading to brain embolism. Dividing cardiac sources of emboli into major- and minor-risk categories is clinically useful (see below). Major-risk sources carry a relatively high risk of initial and recurrent stroke convincingly linked to a cardioembolic mechanism. When a major-risk cardioembolic source is present, efforts at primary prevention of stroke usually are indicated; stroke in patients with any of these causes is most often cardioembolic. Minor-risk sources are frequent in the general population, and the associated risk of initial and recurrent stroke with any of these conditions is either low or uncertain. When a minor-risk cardioembolic source is present in a patient with cerebral ischemia, the etiologic role must be viewed with skepticism and considered in the context of other diagnostic information. Sources of cardioembolic embolism include the following: Asterisk (*) indicates a majorrisk source; dagger () indicates emboli originating in the venous circulation or right heart that cause ischemic stroke via abnormal cardiac or pulmonary shunting around the pulmonary capillary bed.
Valvular diseases Rheumatic mitral stenosis* Prosthetic valves* Infective endocarditis* Nonbacterial thrombotic (marantic) endocarditis* associated with malignancies and prothrombic states o Calcific aortic stenosis o Bicuspid aortic valves o Mitral annulus calcification o Myxomatous mitral valvulopathy with prolapse o Inflammatory valvulitis (ie, Libman-Sacks endocarditis, Behet disease, syphilis) o Lambl excrescences and/or strands Left ventricular thrombi
o o o o o o o o
Ischemic heart disease* Acute myocardial infarction* Left ventricular akinesis or aneurysm* Nonischemic cardiomyopathies* (eg, idiopathic dilating, viral myocarditis associated, echinococcal, peripartum, amyloid-associated, hypereosinophilia
syndromeassociated, rheumatic myocarditisassociated, sarcoidosis-related, neuromuscular disorderassociated, alcoholism-related, catecholamine-induced, Chagas diseaseassociated, doxorubicin-induced, mitoxantrone-related, crack cocainerelated, cardiac oxalosisassociated) o Idiopathic hypertrophic subaortic stenosis o Trauma (myocardial contusion o Ventricular noncompaction Left ventricular thrombi associated with prothrombotic states* Antiphospholipid antibodies Diffuse intravascular coagulation Essential thrombocythemia and myeloproliferative diseases Left atrial thrombi Atrial fibrillation* Atrial flutter* Sick sinus syndrome/atrial asystole Arrhythmias Atrial septal aneurysms Chiari network Cardiac tumors Atrial myxoma* Cardiac sarcoma Endocardial fibroelastoma Metastatic disease Paradoxical emboli Atrial septal defects Patent foramen ovale (PFO) Ventricular septal defects Pulmonary arteriovenous fistulas Miscellaneous
o o o o o o o o o o o o o o o o o
Postcardiac catheterization Postvalvuloplasty Esophageal-atrial fistula
Major-risk sources
Atrial fibrillation: The leading cause of cardioembolic stroke (see Media file 1), especially in elderly individuals. Atrial fibrillation is present in approximately 1% of the US population and in approximately 5% of those older than 70 years.
o
Formerly associated with rheumatic valvular disease, it now is related most frequently to hypertension and ischemic heart disease (ie, nonvalvular atrial fibrillation). Atrial fibrillation is found in up to 50% of all cardioembolic strokes. Both paroxysmal and chronic atrial fibrillation are associated with increased risk of stroke.
o o
o o
Stasis secondary to decreased contractility of the left atrium leading to thrombus formation in its appendage is the postulated mechanism (see Media file 2). Transesophageal echocardiography is more sensitive than transthoracic echocardiography for the visualization of the left atrium and its appendage (see Media file 3). Not all atrial fibrillationassociated strokes are cardioembolic; in individual cases, excluding other potential causes of stroke such as intrinsic cerebrovascular disease or aortic atheroma is important. The annual rate of stroke in atrial fibrillation varies widely from 0.5-12% per year depending on prevalence and combination of risk factors; thus, risk stratification is the first necessary step in choosing the best preventive therapy. Several clinical risk stratification schemes have been proposed to identify atrial fibrillation at high, moderate, or low risk; this is crucial for selecting which patients would benefit most and least from anticoagulation. The CHADS2 (ie, CHF, hypertension, age >75 y, diabetes, stroke or TIA) classification scheme (see Table 2 below) is the most validated and accurately stratifies stroke risk.1, 2, 3 Two randomized controlled trials have demonstrated that a strategy aimed at restoring (and maintaining) sinus rhythm neither improves the survival rate nor reduces the risk of stroke. In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study4, 4060 patients aged 65 years or older whose atrial fibrillation was likely to be recurrent and who were at risk for stroke were randomized to a strategy of rhythm control (cardioversion to sinus rhythm, plus a drug[s] to maintain sinus rhythm) versus a strategy of rate control (in which no attempt was made to restore or maintain normal sinus rhythm). No evidence suggested that the rhythm control strategy protected patients from stroke. The AFFIRM study (and similar findings from the smaller Rate Control Versus Electrical Cardioversion [RACE] trial5) has led to the development of consensus guidelines advocating a rate-control strategy for most patients with atrial fibrillation. Adjusted-dose warfarin (international normalized ratio [INR] 2-3) is associated with a 60% reduction in stroke incidence, while the efficacy of aspirin is modest (20%). Low-dose warfarin (INR <1.5), either alone or combined with aspirin, is not effective, highlighting the marginal benefit of warfarin when anticoagulation is not carefully regulated. Incidence of intracerebral hemorrhage, the most dreaded complication of warfarin therapy, is estimated to be 0.5% per year among elderly patients with atrial fibrillation and is sensitive to blood pressure control. When warfarin is given to elderly patients with atrial fibrillation, hypertension must be managed aggressively.6 Recommendations for primary and secondary prevention based on risk factor stratification are presented in Table 3 below. In the setting of acute stroke secondary to atrial fibrillation, anticoagulation with heparin has not demonstrated more benefit than early treatment with aspirin. Initiate aspirin early, followed by warfarin as soon as the patient is medically stable; discontinue aspirin after therapeutic anticoagulation is achieved.7 In short, warfarin has demonstrated high efficacy in stroke prevention in patients with this common arrhythmia. Disadvantages include the increased risk of hemorrhagic complications and the need for close INR monitoring in these patients; thus, consider patient preferences along with risk stratification and absolute risk reduction offered by this therapy. Alternative approaches (eg, surgical ablation of atrial appendage) are the subjects of ongoing clinical
investigation. Ximelagatran, an oral thrombin inhibitor, is comparable to adjusted-dose warfarin for stroke prevention in patients with atrial fibrillation. The Stroke Prevention Using an Oral Direct Thrombin Inhibitor in Patients with Atrial Fibrillation (SPORTIF) III and V clinical trials recently demonstrated that treatment of atrial fibrillation with ximelagatran twice daily is equivalent to adjusted-dose warfarin when considering stroke and major hemorrhage, but INR monitoring and dosage adjustments are unnecessary.8 However, potential liver toxicity led to disapproval by the US Food and Drug Administration (FDA) in late 2004. Table 2. CHADS2 Stratification Schemes for Prevention of Stroke in Nonvalvular Atrial Fibrillation3* Stroke Rates by CHADS2 Score* CHADS2 Score 0 1 2 3 >3 Risk Low Low Moderate High Very high Stroke Rate Per Year 1.9% 2.8% 4% 5.9% >8.5%
Table 3. Risk-Based Approach to Antithrombotic Therapy in Patients With Atrial Fibrillation9 Patient Features Antithrombotic Therapy Aspirin (81-325 mg/d) or no therapy Aspirin (81-325 mg/d) Class of Recommendation I
Age <60 y, no heart disease (lone AF) Age <60 y, heart disease but no risk factors*
Age 60-74 y, no risk factors* Age 65-74 y with diabetes mellitus or CAD Age 75 y, women
Aspirin (81-325 mg/d)
Oral anticoagulation (INR 2.0-3.0) Oral anticoagulation (INR 2.0-3.0) Oral anticoagulation (INR 2.0-3.0) or aspirin (81-325 mg/d) Oral anticoagulation (INR 2.0-3.0) Oral anticoagulation (INR 2.0-3.0)
Age 75 y, men, no other risk factors
Age 65, heart failure
LV EF <35% or fractional shortening <25%, and hypertension Rheumatic heart disease (mitral stenosis) Prosthetic heart valves
Oral anticoagulation (INR 2.0-3.0) Oral anticoagulation (INR 2.0-3.0 or higher) Oral anticoagulation (INR 2.0-3.0 or higher) Oral anticoagulation (INR 2.0-3.0 or higher)
Prior thromboembolism
Persistent atrial thrombus on TEE
IIA
*Risk factors for thromboembolism include heart failure (HF), left ventricular (LV) ejection fraction less than 35%, and history of hypertension. AF=atrial fibrillation; CAD=coronary artery disease; INR=international normalized ratio; TEE=transesophageal echocardiography; EF=ejection
fraction.
Rheumatic mitral stenosis: The incidence of this valvulopathy has decreased dramatically in recent decades in the United States, but it remains an important problem in developing countries. Few estimates of absolute stroke rates or randomized comparison of different therapies are available, but because it generally is associated closely with atrial fibrillation, anticoagulation with warfarin (INR 2-3) usually is recommended. Sick sinus syndrome: Also known as brady-tachy syndrome, this arrhythmia usually occurs in elderly (>70 y) individuals. Annual risk of stroke is 5-10%. Atrial and dual chamber pacing may reduce the stroke rate somewhat, but anticoagulation (INR 2-3) is still recommended for select patients, such as those with associated atrial fibrillation; a lower target INR (eg, 1.6-2.5) may be tolerated better in these elderly patients. Atrial flutter (sustained): This is an uncommon arrhythmia. Because of the close association of atrial fibrillation with appendage stasis, anticoagulation (INR 2-3) is advocated. Prosthetic valves: Mechanical prosthetic valves carry an annual risk of stroke of 2-4% even in patients receiving anticoagulation. Permanent anticoagulation (INR 2.5-3.5) is mandatory. Bioprosthetic valves carry a lower annual risk rate (0.2-2.9%), and aspirin usually is recommended unless the patient has atrial fibrillation or evidence of atrial stasis. Infective endocarditis: Of patients with infective endocarditis, 20% experience an embolic stroke but accounted for less than 1% of all causes of cerebral embolism in the Cerebral Embolism Stroke Registry10. Staphylococcus aureus is the agent producing the highest stroke rate. Mitral valve endocarditis is the most common source of emboli. Antibiotic therapy reduces the embolic potential when administrated in the acute phase. Anticoagulation is contraindicated because of unacceptable rates of hemorrhagic stroke due to either mycotic aneurysm rupture or septic arteritis. In patients with prosthetic valve endocarditis, the risk of thromboembolism is greater than the risk of intracranial hemorrhage, thus anticoagulation usually is recommended if no evidence of hemorrhage is found on CT scanning 24-48 hours after the stroke. Consensus is to start anticoagulation 7 days after the stroke. The role of antiplatelet therapy has not been established. Nonbacterial thrombotic endocarditis: Associated with a variety of malignancies, nonbacterial thrombotic endocarditis also has been reported in patients with severe diseases such as septicemia and extensive burns. Mitral and aortic valves are affected most commonly, and embolic stroke is frequent. A prothrombotic state has been postulated as the precursor of emboli development. Treatment is directed toward control of the underlying disease, and heparin (intravenous in the acute stage, subcutaneous in the outpatient setting) is advocated for stroke prevention. Warfarin failed to show any benefit. Atrial myxomas: This is the most common cardiac tumor, and it usually is located on the fossa ovalis. It is believed to cause 1% of strokes in young individuals. Surgical excision is the treatment of choice. Most can be detected by transthoracic echocardiography; rarely, they are detected only by transesophageal echocardiography. Acute myocardial infarction: The incidence of stroke after acute myocardial infarction is approximately 2% in the first 3 months. Anterior myocardial infarctions with mural thrombus on transthoracic echocardiography have been recognized as predictive of stroke. Anticoagulation (INR 2-3) is recommended in these patients in the first 3 months, while antiplatelet therapy is advocated long term. The presence of congestive heart failure after myocardial infarction usually dictates treatment with warfarin indefinitely,
although randomized comparisons with other therapies are ongoing. Low-output cardiac failure (ejection fraction <30%) also is considered a high-risk situation, as is the presence of a large ventricular aneurysm on echocardiography.
Minor-risk sources
Patent foramen ovale: Persistent connection between the right and left atrium has a prevalence of about 20% in the general population (see Media file 4). Screening for PFOs can be done reliably with contrast precordial echocardiography, which detects interatrial shunting, but transesophageal echocardiography is required to document the PFO and more accurately determine its size, associated atrial septal aneurysm, and amount of shunting. While case-control studies have documented a higher frequency of PFO in young adults with cryptogenic ischemic stroke, it is present by chance association in patients with stroke in at least 50% of cases. The rate of stroke recurrence is 12% per year. Larger size, spontaneous right-to-left shunting, and associated atrial septal aneurysm are postulated to identify subgroups at high risk for recurrence. o PFO is not associated with increased risk of subsequent stroke or death among medically treated patients with cryptogenic stroke. However, both PFO and ASA possibly increase the risk of subsequent stroke (but not death) in medically treated patients younger than 55 years. In patients with a cryptogenic stroke and an atrial septal abnormality, the evidence is insufficient to determine if warfarin or aspirin is superior in preventing recurrent stroke or death, but minor bleeding is more frequent with warfarin. Evidence evaluating the efficacy of surgical or endovascular closure is insufficient.11 o Elucidation of the role of other therapeutic approaches such as surgical closure (eg, transthoracic, percutaneous) awaits the results of clinical trials and better characterization of the natural history. At present, PFO should not be considered the cause of stroke until other etiologies have been excluded thoroughly. Atrial septal aneurysms: These aneurysms are areas of redundant atrial septal tissue that bulge alternatively into the right or left atrium. They have a high degree of association with other sources of embolism (mainly atrial fibrillation and PFO). Insufficient data are available at present to consider atrial septal aneurysm as an independent risk factor for stroke. When atrial septal aneurysms coexist with a PFO or other sources of embolism, anticoagulation usually is recommended (Mas, 2002), but there are no randomized trials supporting this policy. Mitral valve prolapse: Mitral valve prolapse is the most common valve disease in adults. The role of mitral valve prolapse as an independent risk factor for stroke is a controversial and evolving issue. The estimated prevalence is not greater in patients who have had a stroke than in the general population in recent population-based studies. Long-term aspirin therapy is recommended, although its value has not been confirmed by randomized trials. Anticoagulation is reserved for failure of antiplatelet therapy. Calcific aortic stenosis and bicuspid aortic valves: Systemic embolism is uncommon in isolated aortic valve disease. Calcific microemboli can be detected in the retinal artery in
o
asymptomatic patients, possibly reflecting the fact that most cerebral emboli are asymptomatic. Clinical embolism often follows invasive cardiac procedures (ie, catheterization). Because of the calcific nature of the emboli, anticoagulation is not recommended, and antiplatelet therapy remains an empiric approach. Fibroelastomas and Lambl excrescences: Fibroelastomas are rare benign tumors located on the valves. Antiplatelet therapy is indicated, and surgical repair is reserved for patients who have stroke recurrence. Lambl excrescences are filiform outgrowths from the free borders of the cardiac valves and have been implicated as sources of embolism when they attain large size. Antiplatelet therapy is initiated followed by surgery if aspirin fails. Mitral annular calcification: This is associated with advancing age, hypertension, and atherosclerosis, and it is rarely an embolic source.
DIFFERENTIALS
Seizures and Epilepsy: Overview and Classification
Other Problems to be Considered

No quantitatively valid clinical criterion standards exist for diagnosis of cardioembolic stroke. Clinical diagnosis is based on demonstration of a potential cardiac source of embolism, exclusion of other potential sources of cerebral ischemia, and consideration of neurologic features. Differential diagnoses include the conditions listed above.
WORKUP
Lab Studies

If fever or leukocytosis is present, blood cultures for infective endocarditis are warranted. Before initiating antithrombotic therapy, a CBC, platelet count, prothrombin time or INR and activated partial thromboplastin time (aPTT), erythrocyte sedimentation rate, serum glucose, electrolytes, lipids, urinalysis, and plain radiograph are recommended. In patients with PFO, determination of protein C antigen and activity, protein S antigen and activity, antithrombin III antigen and activity, factor V Leiden, activated protein C resistance, and prothrombin gene mutation are often recommended, particularly in patients with a history of venous thrombosis or a family history of unusual thrombosis. Several of these are acute phase reactants and can be artificially abnormal if obtained in the weeks following acute stroke. Protein C and S levels are suppressed by warfarin; antithrombin III levels and activity are suppressed by heparin.
Imaging Studies
Echocardiography
o
Transthoracic echocardiography (TTE) is usually the initial cardiac imaging modality and reliably detects left ventricular wall motion abnormalities, left ventricular thrombi, and (with contrast) interatrial shunts. The following is a list of sources detected by transthoracic echocardiography: Left ventricular thrombus Myxomatous mitral valvulopathy with prolapse Mitral annulus calcification Mitral stenosis Aortic valve vegetations Left ventricular wall motion abnormality (possible predictor of intracardiac thrombosis but not an embolic source per se) Transesophageal echocardiography (TEE) provides more information about the atria than TTE. In 40% of patients with normal TTE results, a cardiac source of
o
embolism was detected by TEE, independent of age. More than 1 in 8 patients of any age with normal TTE results had a major cardiac risk factor revealed on TEE, in whom anticoagulation is warranted. (Sebastiaan, 2006) The following is a list of sources better detected on TEE: Atrial septal aneurysm Atrial septal defect PFO Atrial myxoma Atrial thrombus Atrial appendage thrombus Aortic arch atheroma/thrombi Mitral valve vegetations - Infective endocarditis, nonbacterial thrombotic endocarditis Cardiac magnetic resonance (CMR): Current indications include the following: Patients with a TTE result that is questionable for the presence of LV thrombus Further evaluation of a cardiac mass seen on a TTE Patients who cannot tolerate TEE and/or cannot undergo TEE secondary to medical reasons o Patients with inconclusive TEE results o Suspected false-negative TEE results, where CMR can adequately image potentially missed sources of embolus such as LV thrombus, cardiac masses, aortic plaque, or LAA thrombus Radiologic studies: Several radiologic findings, when associated with clinical features, are suggestive of cardioembolic stroke, including the following:
o o o o o o o
Hemorrhagic infarct on CT scanning or MRI Multiple arterial infarcts on CT scanning or MRI (not lacunar) Embolus "in transit" on angiography
Other Tests

ECG - Atrial arrhythmias, myocardial infarction Ambulatory ECG - Indicated for elderly patients in whom paroxysmal atrial fibrillation is suspected (eg, history of palpitations, enlarged left atrium on echocardiography). In elderly patients with cryptogenic hemorrhagic cortical infarctions or other cardioembolic features, many clinicians obtain ambulatory ECG monitoring seeking occult atrial fibrillation that would necessitate anticoagulation.
TREATMENT
Section 6 of 11 Authors and Editors Introduction Clinical
Differentials Workup Treatment Medication Follow-up Miscellaneous Multimedia References
Medical Care
Antiplatelet and anticoagulant therapies are mainstays in the prevention of cardioembolic stroke. Consider the absolute rate of stroke associated with each source, the risk-benefit relationship of each therapy, and each patient's preferences. Warfarin is first-line anticoagulant treatment of most causes of cardioembolic stoke. Among antiplatelet agents, aspirin has been proved in clinical trials to reduce risk of cardioembolic stroke. Clopidogrel plus aspirin did not show efficacy compared to warfarin in patients with atrial fibrillation (ACTIVE W trial). A meta-analysis of several randomized trials indicates that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and increased intracranial bleeding. Early aspirin followed by vitamin K antagonists for longterm secondary prevention is reasonable.12 Randomized trials have demonstrated that the efficacy of warfarin anticoagulation is related directly to how carefully it is used. Inadequate anticoagulation produces minimal or no protection, while supratherapeutic anticoagulation may increase the risk of serious hemorrhagic complications. To optimize the level of anticoagulation, interactions with concomitant medications known to potentiate or inhibit the anticoagulant effect should be considered. Monitor INRs weekly initially, then at least monthly. Ximelagatran, a new oral thrombin inhibitor, has been tested in large clinical trials and appears to be an attractive alternative to adjusted-dose warfarin, but it was not approved by the US FDA because of potential hepatic toxicity.
Consultations

Cardiologist - To evaluate the management of arrhythmias and structural abnormalities of the heart Hematologist - When the possibility of a prothrombotic state is suspected, typically in patients with PFO who have a history of venous thromboembolism or family history of thrombosis Anticoagulation clinic personnel - Management of anticoagulation at a specialized clinic (if available) recommended in several studies
Diet
Provide patients treated with warfarin with a list of vitamin Kcontaining foods (eg, broccoli, avocado, other green vegetables) that inhibit its anticoagulant effects. Most physicians severely limit or proscribe consumption of alcoholic beverages in patients taking warfarin.
Activity
Review limitations on physical activities (eg, contact sports, skiing) in patients on warfarin.
MEDICATION
The goals of pharmacotherapy are to reduce morbidity and prevent complications. At present, warfarin and related coumarins remain the mainstay of oral anticoagulation. Several new oral anticoagulant medications are being tested in clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment is significant.
Drug Category: Anticoagulants
These agents prevent initial and recurrent cardiogenic embolism to the brain for many major-risk cardioembolic sources (eg, atrial fibrillation, left ventricular thrombi).
Drug Name Warfarin (Coumadin) Inhibits synthesis of 6 vitamin Kdependent proteins involved in coagulation system (factors II, VII, IX, X; proteins C, S). Many other coumarin derivatives are used worldwide. Initial dose: 5 mg/d PO for 2-4 d (lower in very elderly patients) Subsequent doses determined by INR achieved and source of embolism (INR 2-3 for most cardiac sources) Not established
Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; active bleeding; Contraindications heparin-induced thrombocytopenia; severe renal or hepatic disease; open wounds; gastric ulcer Extensive literature documents interactions with other drugs, with variable levels of evidence; drugs that increase anticoagulant effects include co-trimoxazole, erythromycin, fluconazole, isoniazid, amiodarone, aspirin, simvastatin, sulfinpyrazone, phenylbutazone, alcohol, cimetidine, and omeprazole; drugs that inhibit anticoagulant effect include rifampin, nafcillin, cholestyramine, barbiturates, carbamazepine,
Interactions
sucralfate, and azathioprine; OTC NSAIDs (eg, Naprosyn, ibuprofen) and aspirin are associated with increased risk of upper GI bleeding when used with warfarin; high doses of acetaminophen can prolong INR Pregnancy X - Contraindicated; benefit does not outweigh risk Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis
Precautions
Drug Category: Antiplatelet agents
Aspirin inhibits the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator.
Drug Name Aspirin (Bayer Aspirin, Anacin, Ascriptin) Inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). 1-2 mg/kg/d PO; dosages of 50-325 mg/d are FDA-approved for stroke prevention; typically, 81 mg/d (baby aspirin) or 325 mg/d (adult aspirin) are used, with no compelling evidence favoring either dosage Not established
Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; Contraindications bleeding disorders; asthma; administration in children ( <16 y) with flu because of association with Reye syndrome
Interactions
Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Chronic renal disease; severe anemia; blood dyscrasias
Pregnancy
Precautions
FOLLOW-UP
Patient Education
For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.
MISCELLANEOUS
Medical/Legal Pitfalls
Recently, the underuse of warfarin in patients with atrial fibrillation has been a highprofile issue and the source of many lawsuits. Health Care Financing Administration quality control monitoring now includes the use of warfarin at the time of discharge in patients with atrial fibrillation. When atrial fibrillation is identified, anticoagulation should be carefully considered, and if not prescribed (and perhaps half or more of outpatients with atrial fibrillation do not benefit sufficiently to warrant it), the reason should be recorded in the medical record (eg, estimated low risk for stroke based on CHADS2, warfarin too risky because of high bleeding risk, no access to reliable anticoagulation monitoring, patient declined after explanation of risks and benefits) in case of subsequent stroke. As discussed above, the CHADS2 (2001) scheme for estimation of risk stratification is the best validated. It is the authors' view that risk stratification to estimate stroke risk should be an integral part of the decision to begin anticoagulation treatment in these patients.
MULTIMEDIA
Section 10 of 11 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Multimedia
References
Media file 1: Sources of cardioembolic stroke.
View Full Size Image
Media type: Graph Media file 2: Cardioembolic stroke. Photo of left atrial thrombus.
Media type: Photo Media file 3: Cardioembolic stroke. Streaming video: Mobile left atrial thrombus on echocardiography. Notice periodic bulging of the thrombus in the left atrium. ECG on this patient indicated atrial fibrillation.
Media type: Video Media file 4: Cardioembolic stroke. Streaming video: Patent foramen ovale. Notice the diversion of contrast from the right to the left atrium due to abnormal communication between the 2 chambers.
Media type: Video
REFERENCES
1. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. Oct 19 2004;110(16):2287-92. [Medline]. 2. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?. JAMA. Nov 26 2003;290(20):2685-92. [Medline]. 3. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. Jun 13 2001;285(22):2864-70. [Medline]. 4. Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. Apr 7 2004;43(7):1201-8. [Medline].
5. Hagens VE, Ranchor AV, Van Sonderen E, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol. Jan 21 2004;43(2):2417. [Medline]. 6. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke. Jul 2005;36(7):158893. [Medline]. 7. Hart RG, Halperin JL, Pearce LA, et al. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med. May 20 2003;138(10):831-8. [Medline]. 8. Olsson SB. Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled. Lancet. Nov 22 2003;362(9397):1691-8. [Medline]. 9. Fuster V, Rydn LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. Aug 15 2006;114(7):e257354. [Medline]. 10. Ghandehari K, Izadi-Mood Z. Khorasan stroke registry: analysis of 1392 stroke patients. Arch Iran Med. Jul 2007;10(3):327-34. [Medline]. 11. Mess SR, Silverman IE, Kizer JR, et al. Practice parameter: recurrent stroke with patent foramen ovale and atrial septal aneurysm: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Apr 13 2004;62(7):1042-50. [Medline]. 12. Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke. Feb 2007;38(2):423-30. [Medline]. 13. Adams HP. Patent foramen ovale: paradoxical embolism and paradoxical data. Mayo Clin Proc. Jan 2004;79(1):15-20. [Medline]. 14. Bell C, Kapral M. Use of ambulatory electrocardiography for the detection of paroxysmal atrial fibrillation in patients with stroke. Canadian Task Force on Preventive Health Care. Can J Neurol Sci. Feb 2000;27(1):25-31. [Medline]. 15. Berge E, Abdelnoor M, Nakstad PH, et al. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. HAEST Study Group. Heparin in Acute Embolic Stroke Trial. Lancet. Apr 8 2000;355(9211):1205-10. [Medline]. 16. Corboy JR. Patent foramen ovale, atrial septal aneurysm, and recurrent stroke. N Engl J Med. Apr 25 2002;346(17):1331-2; author reply 1331-2. [Medline]. 17. de Bruijn SF, Agema WR, Lammers GJ, van der Wall EE, Wolterbeek R, Holman ER. Transesophageal echocardiography is superior to transthoracic echocardiography in management of patients of any age with transient ischemic attack or stroke. Stroke. Oct 2006;37(10):2531-4. [Medline]. 18. Hart RG, Albers G, Koudstaal P. Cardioembolic stroke. In: Ginsberg M, Bogousslavsly J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis and Management. Blackwell Science; 1998:1392-429. 19. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. Oct
5 1999;131(7):492-501. [Medline]. 20. Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. Mar 2001;32(3):803-8. [Medline]. 21. Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy: analysis of randomized clinical trials. Stroke. Nov 2002;33(11):27227. [Medline]. 22. Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med. Oct 9 2000;160(18):2781-7. [Medline]. 23. Homma S, Di Tullio MR, Sacco RL, et al. Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke. Dec 1997;28(12):2376-81. [Medline]. 24. Kapral MK, Silver FL. Preventive health care, 1999 update: 2. Echocardiography for the detection of a cardiac source of embolus in patients with stroke. Canadian Task Force on Preventive Health Care. CMAJ. Oct 19 1999;161(8):989-96. [Medline]. 25. Lavados PM, Sacks C, Prina L, Escobar A, Tossi C, Araya F. Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study. Lancet Neurol. Feb 2007;6(2):140-8. [Medline]. 26. Lavados PM, Sacks C, Prina L, Escobar A, Tossi C, Araya F. Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study. Lancet Neurol. Feb 2007;6(2):140-8. [Medline]. 27. Lavados PM, Sacks C, Prina L, et al. Incidence, case-fatality rate, and prognosis of ischaemic stroke subtypes in a predominantly Hispanic-Mestizo population in Iquique, Chile (PISCIS project): a community-based incidence study. Lancet Neurol. 02/2007;6:140-8. [Medline]. [Full Text]. 28. Mattioli AV, Aquilina M, Oldani A, et al. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and normal carotid arteries. A multicentre study. Eur Heart J. Feb 2001;22(3):261-8. [Medline]. 29. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc. Sep 1999;74(9):862-9. [Medline]. 30. Mooe T, Eriksson P, Stegmayr B. Ischemic stroke after acute myocardial infarction. A population-based study. Stroke. Apr 1997;28(4):762-7. [Medline]. 31. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. Sep 2004;126(3 Suppl):429S-456S. [Medline].
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Article Last Updated: Feb 13, 2008

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Article Last Updated: Feb 23, 2007 AUTHOR AND EDITOR INFORMATION
Section 1 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Multimedia References
Author: Salvador Cruz-Flores, MD, Associate Program Director, Director of Souers Stroke Institute, Associate Professor, Department of Neurology, Saint Louis University School of Medicine
Salvador Cruz-Flores is a member of the following medical societies: American Academy of Neurology, American College of Physicians, American Heart Association, American Medical Association, American Society of Neuroimaging, American Stroke Association, National Stroke Association, and Society of Critical Care Medicine Coauthor(s): Sombat Muengtaweepongsa, MD, Fellow in Stroke and Critical Care, Department of Neurology, St Louis University Editors: Draga Jichici, HBSc, MD, FRCP(C), FAHA, Assistant Professor, Department of Medicine, Division of Critical Care Medicine, McMaster University Medical School, Canada; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center Author and Editor Disclosure Synonyms and related keywords: basilar artery occlusion, anterior inferior cerebellar artery, AICA, posterior cerebral artery, PCA, atherothrombosis, embolism, arterial dissection, atherosclerotic occlusion, vertebrobasilar insufficiency, VBI, stroke, hypertension, partial basilar artery occlusion, intravenous thrombolysis, atherosclerotic basilar artery stenosis, occlusion of the distal basilar artery, pontine ischemia, locked-in syndrome, top-of-the-basilar syndrome, diabetes mellitus, coronary artery disease, peripheral vascular disease, cigarette smoking, hyperlipidemia, stroke, neck injury, chiropractic manipulation, atrial fibrillation
INTRODUCTION
Section 2 of 10
Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Multimedia References
Background
Basilar artery occlusion is associated with a poor prognosis. However, the advent of high-quality, reliable, and noninvasive technology (eg, MRI) has made its diagnosis possible early in the course of the condition, which has illustrated that some patients with partial occlusion have limited ischemic injury and, therefore, a better prognosis. Although outcomes continue to be poor, advances in pharmacological and mechanical thrombolysis and in endovascular therapy may increase the survival rate and limit the disability rate.
Pathophysiology
The basilar artery is the most important artery in the posterior circulation. It is formed at the pontomedullary junction by the confluence of both vertebral arteries. It lies on the ventral surface of the pons and, throughout its course, gives off its median, paramedian, short, and long circumferential branches. The branch of the basilar artery with the larger circumference is the anterior inferior cerebellar artery. It normally arises at the junction of the proximal and middle thirds of the basilar artery and supplies the lateral pontine tegmentum, brachium pontis or middle cerebellar peduncle, flocculus, and a small part of the anterior cerebellum. The internal auditory artery usually arises from the anterior inferior cerebellar artery; however, it may also arise as a direct branch of the basilar artery. The terminal branch of the basilar artery is the posterior cerebral artery (PCA); it supplies the midbrain, the thalamus, and the medial aspect of the temporal and occipital lobes. Proximal to its bifurcation into the terminal branches (ie, PCA), the basilar artery gives off the superior cerebellar arteries that supply the lateral aspect of the pons and midbrain and the superior surface of the cerebellum. Given the anatomy of the posterior circulation and the circle of Willis, the clinical
manifestations depend on the location of the occlusion, the extent of thrombus, and the collateral flow. Normally, the blood flows in an anterograde fashion from the vertebral arteries to the basilar artery up to its terminal branches. This pattern of flow may vary. If the proximal segment of the basilar artery is occluded and the occlusion resulted from a slowly progressive stenosis, collateralization occurs within the cerebellum into the circumferential branches of the basilar artery. Additionally, flow can be reversed from the PCAs into the distal basilar artery. The mechanism of basilar artery occlusion is different depending on the segment of the vessel that is occluded. On one hand, most cases of distal (top of the basilar) or proximal (vertebrobasilar junction) occlusions are due to embolism either from a cardiac or an arterial source. On the other hand, midbasilar artery occlusion is typically the result of atherothrombosis. Arterial dissections are very rare and usually involve the vertebral artery and occasionally extend to the basilar artery.
Frequency
United States
The actual frequency, incidence, and prevalence of basilar artery occlusion are not known; basilar artery occlusion was reported in 2 cases per 1000 autopsy cases. However, in stroke registries, basilar artery thrombosis may explain as many as 27% of ischemic strokes occurring in the posterior circulation.
Mortality/Morbidity
The prognosis of basilar artery occlusion is generally poor, although this is dependent on several factors. Those factors associated with poor outcome include decreased level of consciousness, dysarthria, pupillary abnormalities, bulbar symptoms, diplopia, bilateral cerebellar lesions, tetraplegia, and a cardiac cause of embolism. Up to 90% of patients with no such factors have a good functional outcome, while all patients with such factors either died or had severe disability in one study. The mortality rate is consistently reported at greater than 70%. Recanalization may decrease the mortality rate by 50%. However, the outcome in a recent series of patients with basilar artery thrombosis treated with antithrombotics was similar to the reported outcome in the available series of patients treated with thrombolytic therapy. Recanalization is an important requisite for a good functional outcome. Reportedly, a Barthel index of 85 can be achieved in as many as 58% of patients with vessel recanalization.
Race
Atherosclerotic basilar artery stenosis, like stenosis of any other intracranial artery, is more frequent in the African American and Asian populations than in white populations.
Sex
The male-to-female ratio is 2:1.
Age

Basilar artery occlusion secondary to atherosclerosis is most prevalent in the sixth and seventh decades of life. Occlusion of the distal basilar artery is usually secondary to embolism and is most frequent in the fourth decade. Women with basilar artery occlusion are typically older than men.
CLINICAL
History
A stuttering and progressive course of symptoms or transient ischemic attacks in the vertebrobasilar territory is seen in patients with atherosclerotic occlusion.

As many as 50% of patients experience transient ischemic attacks or a waxing and waning course for several days to weeks prior to the occlusion. The most common heralding symptoms include the following: Motor deficits such as hemiparesis or tetraparesis and facial paresis - 40-67% of cases o Dysarthria and speech impairment - 30-63% of cases o Vertigo, nausea, and vomiting - 54-73% of cases o Headache - 40-42% of cases o Visual disturbances - 21-33% of cases o Altered consciousness - 17-33% of cases In a few cases, convulsivelike movements along with hemiparesis (herald hemiparesis)
o
may be the only diagnostic clues. Occasionally, patients may present with isolated vertigo or dizziness with no other neurological symptoms, but this situation is very rare. The presence of vascular risk factors, headache, and the inability to walk may suggest the diagnosis of vertebrobasilar insufficiency. Any associated neurological signs of brainstem dysfunction also support the diagnosis of vertebrobasilar insufficiency. Based on the temporal profile of the symptoms, basilar artery thrombosis may manifest in at least these 3 different ways, as follows:
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Sudden onset of severe motor and bulbar symptoms with reduced consciousness Gradual or stuttering course of posterior circulation symptoms that finally (1) become progressively disabling motor and bulbar symptoms and (2) reduce consciousness Prodromal symptoms, including double vision, dysarthria, vertigo, and paresthesias: These symptoms precede monophasic basilar artery thrombosis symptoms by several days or even months.
Physical

An abnormal level of consciousness and motor signs, such as hemiparesis or quadriparesis (usually asymmetric), are seen in more than 70% of patients. Bulbar and pseudobulbar signs are the most common findings in one series, reportedly affecting 74% of patients. Pupillary abnormalities, oculomotor signs, and pseudobulbar manifestations (ie, facial weakness, dysphonia, dysarthria, dysphagia) are seen in more than 40% of patients. The signs described can be present in different combinations. The recognized syndromes more commonly associated with basilar artery occlusion are as follows: Locked-in syndrome: It is caused by infarction of the basis pontis secondary to occlusive disease of the proximal and middle segments of the basilar artery, which leads to quadriplegia. Because the tegmentum of the pons is spared, the patient has a spared level of consciousness, preserved vertical eye movements, and blinking. Coma associated with oculomotor abnormalities and quadriplegia also indicates proximal basilar and midbasilar occlusive disease with pontine ischemia. o Top-of-the-basilar syndrome: This is the manifestation of upper brainstem and diencephalic ischemia caused by occlusion of the rostral basilar artery, usually by an embolus. Patients present with changes in the level of consciousness. They may experience visual symptoms such as hallucinations and/or blindness. Third nerve palsy and pupillary abnormalities are also frequent. Motor abnormalities include abnormal movements or posturing. Oculomotor signs are common and can be associated with the syndromes described above. They usually reflect involvement of the vertical gaze center in the midbrain and/or the abducens nucleus, the horizontal gaze center located in the paramedian reticular formation contiguous to the abducens nucleus, and/or the medial longitudinal fasciculus. Lesions to these structures result in the following: o Ipsilateral abducens palsy o Ipsilateral conjugate gaze palsy
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Internuclear ophthalmoplegia One-and-a-half syndrome caused by a lesion simultaneously affecting the paramedian reticular formation and the medial longitudinal fasciculus, resulting in ipsilateral conjugate gaze palsy and internuclear ophthalmoplegia o Ocular bobbing, which localizes the lesion to the pons: This is characterized by a brisk downward movement of the eyeball with a subsequent return to the primary position. o Skew deviation Other reported signs of pontine ischemia include limb shaking, ataxia (usually associated with mild hemiparesis), facial weakness, dysarthria, dysphagia, and hearing loss.
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Causes
The risk factors are those seen in patients with stroke. The most common risk factor is hypertension, which is seen in as many as 70% of cases. It is followed by diabetes mellitus, coronary artery disease, peripheral vascular disease, cigarette smoking, and hyperlipidemia. The mechanism of stroke in basilar artery occlusion differs depending on the segment of the vessel involved.
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Atherosclerotic occlusive disease predominantly affects the mid segment of the basilar artery, followed by the vertebrobasilar junction. Embolism, either from a cardiac or arterial source, is much more frequent in the distal third of the basilar artery and the vertebrobasilar junction. Arterial dissection is much more common in the extracranial vertebral artery. It is often associated with a previous neck injury or chiropractic manipulation. Intracranial dissections are very uncommon.
DIFFERENTIALS
Central Pontine Myelinolysis Cerebellar Hemorrhage
Intracranial Hemorrhage Metastatic Disease to the Brain Subarachnoid Hemorrhage

Basilar meningitis Basilar migraine Cerebellar hemorrhage with brainstem compression Cerebellar infarct with edema and brainstem compression Pontine hemorrhage Space-occupying lesions in the posterior fossa Supratentorial hemispheric mass lesions with mass effect, herniation, and brainstem compression
WORKUP
Lab Studies
The laboratory workup should include a complete blood cell count, electrolyte values, BUN and creatinine determination, international normalized ratio (INR), prothrombin time and activated partial thromboplastin time, and lipid profile. Young patients (<45 y) or patients with no evidence of atherosclerosis should be investigated for the presence of procoagulant conditions, such as the following:
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Protein C, protein S, and antithrombin III deficiencies, especially if the patients has evidence of paradoxical embolism because these disorders have a stronger association with venous rather than arterial thrombosis Lupus anticoagulant and anticardiolipin antibodies
Creatine kinase levels, cardiac isoenzyme values, and troponin levels should be tested in the following:
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All symptomatic patients (eg, those with chest pain) Patients with ECG evidence of ischemic changes, because of the high incidence of concomitant coronary artery disease in patients with cerebrovascular disease
Imaging Studies
CT scanning of the head CT scanning is usually the first imaging study performed. It has a sensitivity of greater than 95% for identifying hemorrhage within the first 24 hours of onset and helps to exclude intra- or extra-axial hemorrhage. o It has a low sensitivity for early ischemia and usually has the disadvantage of significant artifacts caused by the bony structures surrounding the brain stem and cerebellum. o Helpful findings include infarcts in the thalamus and/or occipital lobe or lobes, which indicate involvement of the rostral basilar artery; hyperdense basilar artery (see Media file 5), which indicates probable occlusion; and dilated vertebral and/or basilar artery, which indicates a dolichoectatic vessel. o Spiral CT angiography is helpful in identifying occluded and dolichoectatic vessels. MRI and magnetic resonance angiography (MRA) MRI and MRA are more sensitive than CT scanning for identifying ischemia and vascular occlusion. o Gradient echo technique, with its higher sensitivity for identifying blood, and diffusion/perfusion-weighted images, with a higher sensitivity for identifying ischemia and hypoperfusion, make MRI a more powerful tool in the treatment of these patients (see Media file 1). o Helpful findings include lesions that suggest microbleeds, tumors, vertebral/basilar dolichoectasia, and vertebral/basilar dissections. o MRA can identify vertebral/basilar occlusion with sensitivity as high as 97% and a specificity of 98% (see Media file 2). o MRA has limitations because it frequently overestimates the degree of stenosis. Severe stenosis may resemble vascular occlusion. This occurs because the image of the vessel with MRA is a flow-related phenomenon; therefore, severe stenosis with significant flow compromise may result in poor visualization of the vessel. Transcranial Doppler
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Transcranial Doppler (TCD) is a useful tool for evaluating cerebrovascular disease; however, it is often inaccurate. In patients with basilar artery disease, the reported sensitivity is 72% and the specificity is 94%. TCD is helpful for purposes of follow-up once an initial evaluation has demonstrated the lesion. The flow direction detected by TCD, in combination with CT angiography, might
be useful before performing invasive angiography for helping predict the area of stenosis or occlusion.
Other Tests
Electrocardiography ECG should be performed in all patients during the initial evaluation because it can reveal paroxysmal arrhythmias such as atrial fibrillation. Additionally, the prevalence of coronary disease is high in patients with cerebrovascular disease. o Ischemic changes seen with ECG should be investigated further with serum creatine kinase measurements, cardiac isoenzyme profiles, and/or troponin levels for the following reasons: Of patients with acute stroke, 5-20% have an arrhythmia. Additionally, 2-3% have a myocardial infarction. The presence of arrhythmias (eg, atrial fibrillation) has an impact on the long-term management plan for stroke prevention. Echocardiography:
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This should be considered in all patients because cardioembolism is frequent enough in this population. Moreover, even those patients with documented atherothrombosis may have a concomitant cardiac source of embolism.
Procedures
Catheter angiography With the availability of noninvasive imaging modalities such as MRI, MRA, and TCD, the role of angiography has changed; however, it still is considered the criterion standard (see Media files 3-4). Angiography is performed (1) when MRA cannot be performed because the patient has an absolute contraindication such as a pacemaker or (2) when the quality of noninvasive studies is not satisfactory or the results of other tests do not explain clinical findings. o Angiography should be pursued as a first-line diagnostic test after CT scanning and once the decision is made that recanalization should be performed. The primary goals of the workup are to (1) establish the type of vascular lesion and the mechanism of the stroke and, if early enough, (2) establish if acute intervention is needed to achieve recanalization.
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TREATMENT
Section 6 of 10 Authors and Editors Introduction
Clinical Differentials Workup Treatment Medication Follow-up Multimedia References
Medical Care
All patients should be admitted to a stroke unit. Patients with unstable or fluctuating neurological symptoms, decreased level of consciousness, active cardiac or respiratory comorbid conditions, hemodynamic instability, or a need for interventional therapies (eg, thrombolysis) must be admitted to a neurological intensive care unit.
General care Care is required for all indwelling catheters, including monitoring for infection. Control body temperature because evidence suggests that fever worsens the outcome in patients with stroke. o Glucose levels should be monitored to avoid hypoglycemia and hyperglycemia. o Aggressive pulmonary toilet is instituted to avoid pneumonia. Hemodynamic management: The goal is to minimize ischemic injury.
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Cerebral ischemia results in impaired autoregulation. Therefore, under ischemic conditions, cerebral blood flow becomes dependent on blood pressure. In patients with severe cerebral vascular occlusive disease, mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) become critical in maintaining cerebral blood flow (CPP = MAP - intracranial pressure). No evidence from randomized trials indicates that treating hypertension is better than not treating it. Currently available guidelines for the management of acute stroke recommend the use of antihypertensives to lower blood pressure to less than a systolic value of 185 mm Hg or a diastolic value of less than 110 mm Hg only if thrombolysis is being considered. Additionally, some evidence suggests that induced hypertension in selected cases may be beneficial for limiting ischemic injury.
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If the neurological condition is fluctuating and blood pressure requires close monitoring, an arterial catheter should be placed. Hypertension should not be treated unless the patient has evidence of acute end organ damage such as hypertensive encephalopathy, unstable angina or acute myocardial infarction, heart failure, or acute renal failure. In the absence of any of these circumstances, treatment is indicated only when the diastolic blood pressure is greater than 120 mm Hg or systolic blood pressure is greater than 220 mm Hg.
Blood pressure treatment should be considered when thrombolytic therapy is to be administered, aiming to keep the diastolic blood pressure at less than 110 mm Hg and the systolic blood pressure at less than 185 mm Hg when thrombolysis will be used. The preferred antihypertensive agents are nicardipine and labetalol. When diastolic blood pressure is greater than 140 mm Hg and not responsive to nicardipine and labetalol, then nitroprusside should be used. Overzealous treatment of hypertension should be avoided because it can exacerbate the ongoing ischemia.
Patients with hypotension should be treated to normalize the MAP and therefore to improve blood pressuredependent cerebral blood flow.
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Every effort should be made to maintain a normal intravascular volume by administering isotonic solutions. If the MAP continues to be low despite fluid management, vasopressors such as dopamine, dobutamine, or phenylephrine should be used. Dopamine can cause significant tachycardia; therefore, phenylephrine (Neo-Synephrine) and norepinephrine (Levophed) are the vasopressors of choice after dopamine. Dobutamine should be used with caution and with close monitoring of the cardiac index because it can often cause vasodilatation and hypotension. Dobutamine is the pressor of choice in patients with congestive heart failure. o In patients whose intravascular volume status is unknown or who have comorbid conditions such as congestive heart failure or pulmonary edema, a pulmonary artery catheter should be placed to monitor the central venous pressure and the pulmonary capillary wedge pressure. This allows better management and optimization of the intravascular volume to avoid volume overload. Respiratory management: Early assessment and management of the airway is vital, given the frequent involvement of lower cranial nerves and impairment of consciousness in patients with brainstem ischemia. Other important aspects include assessment of the respiratory drive, the gag reflex, and the ability to handle secretions by a forceful cough.
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Generally, endotracheal intubation should be considered in patients with a decreased level of consciousness and Glasgow Coma Scale score of less than 8. Endotracheal intubation is recommended in most patients to keep their airway clear while maintaining normal ventilation. Of the mechanical ventilation modes, pressure support ventilation (PSV) and synchronized intermittent mandatory ventilation are used most often. For patients with good respiratory drive, the most comfortable mode is PSV. In this mode, the ventilator does not deliver a set of breaths but provides enough pressure support to maintain the desired tidal volume. The usual goal is to maintain a tidal volume of 5-8 mL/kg. Most patients with no comorbid pulmonary condition reach this goal with a PSV of 5-10. For patients with poor respiratory drive, synchronized intermittent mandatory ventilation may be a better mode. This form of ventilation delivers a set number of breaths with a set tidal volume, which is synchronized with the patient's
inspiratory effort while allowing the patient to take extra breaths. Adding PSV during the extra breaths can minimize the patient's respiratory effort during the extra breaths. o Sedation and paralysis should be avoided because they interfere with the neurologic assessment. Certain circumstances, such as neurogenic hyperventilation, may require the use of sedation and paralysis to avoid hypocarbia, which can worsen the ischemic process. However, sedation alone can and should be used to maintain comfort. Thrombolysis: Tissue plasminogen activator (tPA) is the only pharmaceutical agent approved by the US Food and Drug Administration (FDA) for the treatment of acute ischemic stroke within the first 3 hours of onset. Its approval was based on data from the trial by the National Institute for Neurological Disorders and Stroke. However, the trial did not include patients in stupor or coma and, thus, probably excluded patients who experienced a basilar artery occlusion. Moreover, the trial did not systematically study vascular anatomy in all patients. Intra-arterial thrombolysis: This has emerged as a therapeutic strategy despite the absence of data from randomized clinical trials.
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Several case series have been published. The average time to treatment has ranged from 8-48 hours. Overall mortality rates have decreased from 46-75% to 26-60%. The rate of hemorrhagic transformation is approximately 8%, which a little higher than that of intravenous thrombolysis in anterior circulation, confirmed by another study in animal models. The patient's condition at presentation is, apparently, the major prognostic factor; patients with quadriplegia and/or coma have worse outcomes than other patients. Despite these efforts, intra-arterial thrombolysis for vertebrobasilar occlusion has not been studied systematically in randomized controlled trials. Thrombolytic agents include urokinase, pro-urokinase, streptokinase, and tPA. Urokinase is not on the market in the United States because of concerns with its production. Streptokinase has not been used for stroke since multicenter European, Italian, and Australian trials were stopped because of greater mortality rates in treated patients than in untreated patients. Pro-urokinase was tested in a prospective randomized fashion. The trial involved only patients with occlusion of the middle cerebral artery stem. Results showed a better outcome in treated patients. However, prourokinase was not approved for use in acute stroke; therefore, the only option in the United States is tPA. This drug has been studied prospectively in trials involving combined intravenous and intra-arterial thrombolysis; the dosage used is 0.3 mg/kg, up to a maximum of 10-20 mg intra-arterially. An ongoing phase 3 trial is combining intravenous and intra-arterial thrombolysis with the addition of intravascular ultrasound or with the Merci Retriever, although the intervention is not focused only on basilar artery occlusion. Because the rate of reocclusion is approximately 30%, some investigators have reported limited experience with the use of glycoprotein IIb/IIIa inhibitors such as abciximab to block platelet function and rethrombosis. A recent systematic analysis demonstrated that the morbidity and mortality of
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patients treated with intra-arterial thrombolysis is not all that different from the effect of intravenous thrombolysis, although recanalization was achieved more frequently with intra-arterial thrombolysis. Ideally, patients with basilar artery occlusion should be treated within the context of a randomized trial. In the absence of this option, many stroke experts would advocate the use of intra-arterial thrombolysis. This decision, however, should be made with knowledge of the background information just described and with recognition of the absence of evidence from randomized trials. Some general guidelines should be followed when treating a patient with intravenous or intra-arterial thrombolysis, as follows:
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Patients with a stuttering course of longer than 3 hours and up to 12 hours should be considered for intra-arterial thrombolysis, provided that ischemic changes are not present on the CT scan. However, the care team should recognize that under these circumstances, the therapy is offered in a compassionate fashion, given the poor prognosis of basilar artery occlusion. Despite reports of the successful use of anticoagulation immediately following thrombolysis, avoiding systemic anticoagulation is recommended for the first 24 hours after thrombolysis, given the risk of hemorrhagic complications. Although treatment as late as 24-48 hours after symptom onset has been reported, the authors recommend caution because of the high risk of hemorrhagic complications. Systemic anticoagulation may be an alternative for patients with contraindications for thrombolysis, although no evidence clearly indicates any beneficial effect. With rare exceptions, patients should not be treated with thrombolysis if more than 12 hours have elapsed since the onset of more major symptoms or if they have marked ischemic changes on the CT scan, regardless of the time course. The benefits of intra-arterial thrombolysis in selected groups of patients with basilar artery thrombosis, such as patients with minor deficit or old patients with extensive brain stem infarcts, is even less clear. Other therapies
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Anticoagulation with heparin or low molecular weight heparinoids has been used, but no evidence shows that this has an impact on outcome. The role of other antiplatelets, such as clopidogrel and the combination of aspirin and dipyridamole, in the treatment of acute basilar artery occlusion is not known. Angioplasty with or without stent placement has been performed to treat patients with atherosclerotic stenosis or to mechanically dislodge thrombi. The advantage of angioplasty is the excellent and quick anatomical recanalization, but the success rate is still low. Angioplasty has been performed in patients with acute vertebrobasilar occlusion and in patients selected electively. The morbidity rates cited in the published case series range from 0-50%. The mortality rate is as high as 33%. The role of angioplasty in the therapy for this disorder is not known. Only one case report has described successful endovascular embolectomy in basilar artery thrombosis. Thrombus retrieval has been more recently added to the armamentarium by way of the Merci Retriever device. The FDA approved its use for blood vessel
recanalization, although its impact in improving neurological outcome is not known. o For patients with atherosclerotic stenosis who survive basilar artery occlusion, the estimated annual risk of recurrent stroke is 20%. Antiplatelet agents such as aspirin, clopidogrel, and the combination aspirin/dipyridamole (Aggrenox) could be used for stroke prophylaxis. No trials have been reported that directly compare clopidogrel with aspirin/dipyridamole. The most recent secondary prevention trials showed that these agents are marginally better than aspirin alone, and, therefore, they may be the drugs of choice. Long-term anticoagulation with warfarin was advocated as the treatment of choice, but the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Study Group demonstrated that warfarin is no better than aspirin in preventing strokes in patients with intracranial artery stenosis and is associated with bleeding complications. Conclusion
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Recanalization of the basilar artery is key to the successful treatment of basilar artery thrombosis and for improving its prognosis. Some unresolved issues need further clarification, such as the best method of recanalization (intra-arterial thrombolysis, mechanical thrombolysis, or combination), the time window for the treatment, and patient selection. In the absence of clear evidence, treating these patients in the context of a clinical trial seems most reasonable. If such an alternative is not available and given the limited time window, then intravenous thrombolysis within 3 hours seems to be a reasonable alternative. In institutions with the service available, intra-arterial pharmacological or mechanical thrombolysis can be considered.
Consultations
Physical therapy and occupational therapy should be started soon after admission depending on the condition of the patient. Once the symptoms have stabilized, the patient should be mobilized out of bed and allowed full physical and occupational therapy activities. Speech therapy should address the concerns of aspiration in patients with profound dysarthria and depressed cough reflex.
Diet
The patient should be restricted to taking nothing by mouth until the swallowing mechanism has been assessed and cleared and the airway has been protected. If the patient has a high risk of aspiration, a nasogastric or nasoduodenal tube should be placed. If the swallowing abnormalities are so severe that recovery is expected to take weeks or months, a gastrostomy tube should be placed either surgically or percutaneously.
Activity
Some patients have fluctuating symptoms and signs, and these are often position
related. Because of this, bed rest is advised until the symptoms have stabilized. In some patients, the severity of the deficits is such that free ambulation is not possible; however, patients should be mobilized out of bed and be actively involved with physical and occupational therapy.
MEDICATION
The medications used in the treatment of patients with basilar artery thrombosis include thrombolytic agents, anticoagulants, antihypertensive agents, and antiplatelet agents.
Some patients, particularly those with severe and active comorbid conditions, such as an acute myocardial infarction, require inotropic agents and vasopressors. Several new oral anticoagulant medications are in the final stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment is significant.
Drug Category: Antihypertensive Agents
Control severe hypertension. Recommended for patients considered candidates for thrombolytic therapy who have a systolic blood pressure >185 mm Hg and/or a diastolic blood pressure >110 mm Hg.
Drug Name Nicardipine (Cardene) Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery and reduces myocardial oxygen consumption. IV continuous drip: Start drip at 5 mg/h and titrate by 2.5 mg/h to target blood pressure q15min, not to exceed 15 mg/h; once target blood pressure reached, consider decreasing rate to 3 mg/h Not established
Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; advanced aortic stenosis (reduction of diastolic pressure in these Contraindications patients may worsen rather than improve myocardial oxygen balance) Fentanyl and alcohol may increase hypotensive effects; calcium channel blocker may increase cyclosporine levels; H2 blockers (cimetidine), erythromycin, nafcillin, and azole antifungals may increase toxicity (avoid combination or monitor closely); carbamazepine may reduce bioavailability (avoid this combination); rifampin may decrease levels (monitor and adjust dose of calcium channel blocker)
Interactions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Because nicardipine decreases peripheral resistance, monitoring of blood pressure during administration required; may occasionally produce symptomatic hypotension; caution advised to avoid systemic hypotension when administering drug to patients who have sustained acute cerebral infarction or hemorrhage Adjust dose in renal/hepatic impairment; may cause lower extremity edema; allergic hepatitis has occurred but is rare At high IV doses (5 mg/20 min), reported to increase hepatic venous pressure gradient by 4 mm Hg in cirrhotic patients (use with caution in patients with portal hypertension) Careful dose titration advised when treating renally impaired patients Labetalol (Normodyne, Trandate) Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing blood pressure. Initial dose: 5-10 mg IV bolus over 2 min; repeated doses can be given in escalating fashion from 20-80 mg IV push at 10-min intervals until desired blood pressure achieved or total of 300 mg has been administered Alternatively, may give drip at rate of 2 mg/min Not established
Precautions
Drug Name Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; heart failure; chronic obstructive pulmonary disease; bronchial Contraindications asthma; second- or third-degree heart block; cardiogenic shock; severe bradycardia; hepatic failure
Interactions
Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia that results from nitroglycerin use without interfering with hypotensive effects; cimetidine may increase blood levels; glutethimide may decrease effects by inducing microsomal enzymes C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Caution in impaired hepatic function; discontinue therapy upon signs of liver dysfunction; in elderly patients, response rate may be lower and incidence of toxicity may be higher than in other patients Nitroprusside sodium (Nitropress) Produces vasodilation and increases inotropic activity of heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate. 0.5-10 mcg/kg/min IV until blood pressure controlled Not established
Pregnancy
Precautions
Drug Name
Description
Adult Dose Pediatric Dose
Documented hypersensitivity; compensatory hypertension; aortic coarctation; heart failure; Contraindications congenital optic atrophy; tobacco-induced amblyopia Interactions None reported C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Caution in increased intracranial pressure, hepatic failure, severe renal impairment, and
Pregnancy
Precautions
hypothyroidism; in renal or hepatic insufficiency, levels may increase and can cause cyanide toxicity; sodium nitroprusside has ability to lower blood pressure and, thus, should be used only in patients with MAP >70 mm Hg Drug Name Enalapril (Vasotec) Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion. 0.650-1.25 mg IV q6h Not established
Description
Contraindications Documented hypersensitivity NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; diuretics may increase hypotensive effects C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Caution in renal impairment, valvular stenosis, or severe congestive heart failure
Interactions
Pregnancy
Precautions
Drug Category: Thrombolytic Agents
Potential benefits of thrombolytic therapy for the treatment of thrombosis include fast dissolution of physiologically compromising pulmonary emboli, faster recovery, prevention of recurrent thrombus formation, and rapid restoration of hemodynamic disturbances.
Drug Name Description Alteplase (Activase) This is a tPA. Safety and efficacy with concomitant heparin or aspirin during first 24 h
after symptom onset have not been investigated. Only drug approved for use in patients within 3 h of onset of acute ischemic stroke. IV: 0.9 mg/kg; not to exceed 90 mg; 10% of dose to be administered over 2-3 min and the rest over 1 h Intra-arterial: 0.3 mg/kg; not to exceed 10-20 mg Not established
Adult Dose
Pediatric Dose
Documented hypersensitivity; active systemic or intracranial bleeding; intracranial neoplasm; AVM; concurrent heparin with aPTT >1.5 times Contraindications control or concurrent warfarin with INR >1.6; coagulopathies; recent major surgery; head injury or stroke in previous 3 mo; history of ICH Drugs that alter platelet function (eg, aspirin, dipyridamole, abciximab) may increase risk of bleeding prior to, during, or after therapy; current guidelines prohibit use of any anticoagulant or antiplatelet agents for 24 h after IV tPA; interventionalists who use intra-arterial tPA empirically give heparin afterward to reduce risk of rethrombosis; either heparin or alteplase may cause bleeding complications C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Monitor for bleeding, especially at arterial puncture sites, with coadministration of vitamin K antagonists; control and monitor blood pressure frequently during and following administration (when managing acute ischemic stroke); do not use >0.9 mg/kg to manage acute ischemic stroke (doses >0.9 mg/kg may cause ICH)
Interactions
Pregnancy
Precautions
Drug Category: Anticoagulant agents
Rationale for use of these agents is to prevent recurrent embolism or extension of the thrombosis.
Drug Name Heparin Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. Although no nomogram exists for its use, authors do not regularly administer IV bolus; usually start IV drip at 1000 U/h; aPTT checked at 4 h, and infusion adjusted accordingly until aPTT of 1.5-2 times control achieved; drip also can be started at dose of 18 U/kg/h Prophylaxis of deep vein thrombosis: 5000 U q12h SC Not established
Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; active systemic or intracranial bleeding; severe thrombocytopenia Contraindications or blood dyscrasias; hypersensitivity during or after eye, brain, or spinal cord surgery Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus In neonates, preservative-free heparin recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as a preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary
Interactions
Pregnancy
Precautions
permeability, and with IM injections Drug Name Warfarin (Coumadin) Interferes with hepatic synthesis of vitamin K dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor dose to maintain INR in range of 2-3. Used for long-term stroke prophylaxis. Adjust PO dose to maintain INR between 2-3 for most indications and 2.5-3.5 for patients with prosthetic heart valves Not established Documented hypersensitivity; severe liver or kidney disease; open wounds; GI ulcers Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate Medications that may increase anticoagulant effects include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac X - Contraindicated; benefit does not outweigh risk Do not switch brands after achieving therapeutic response; caution in active tuberculosis or
Description
Adult Dose
Pediatric Dose Contraindications
Interactions
Pregnancy
Precautions
diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis
Inhibit cyclooxygenase system, decreasing the level of thromboxane A2, a potent platelet activator.
Drug Name Aspirin (Bayer Aspirin, Ascriptin, Anacin) Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low doses to inhibit platelet aggregation and improve complications of venous stasis and thrombosis. Used for longterm stroke prophylaxis. 81-1300 mg PO qd Not established
Description
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; Contraindications bleeding disorders; asthma Because of association with Reye syndrome, do not use in children (<16 y) with flu Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus May cause transient decrease in renal function and aggravate chronic kidney disease; avoid in
Interactions
Pregnancy
Precautions
patients with severe anemia, with history of blood coagulation defects, or who are taking anticoagulants Drug Name Clopidogrel (Plavix) Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. 75 mg PO qd Not established
Description
Documented hypersensitivity; active pathological Contraindications bleeding, such as peptic ulcer or intracranial hemorrhage Naproxen associated with increased occult GI blood loss; prolongs bleeding time; warfarin safety not established C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions (eg, ulcers) with propensity to bleed Aspirin 25 mg/dipyridamole 200 mg (Aggrenox) Drug combination with antithrombotic action. Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low doses to inhibit platelet aggregation and to improve complications of venous stasis and thrombosis. Dipyridamole is a platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself
Interactions
Pregnancy
Precautions
Drug Name
Description
an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cAMP within platelets and formation of potent platelet activator thromboxane A2. Adult Dose Pediatric Dose 1 tab PO bid Not established
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; Contraindications bleeding disorders; asthma Because of association with Reye syndrome, do not use in children ( <16 y) with flu Theophylline may decrease hypotensive effects of dipyridamole; antiplatelet activity of dipyridamole may increase heparin toxicity; antacids and urinary alkalinizers may decrease aspirin effects; corticosteroids decrease salicylate serum levels; anticoagulants may increase additive hypoprothrombinemic effects and bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs C - Fetal risk revealed in studies in animals but not established or not studies in humans; may use if benefits outweigh risk to fetus Aspirin may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or who are taking anticoagulants; caution in hypotension; dipyridamole has peripheral vasodilating effects
Interactions
Pregnancy
Precautions
FOLLOW-UP
Rehabilitation: Patients with brainstem, cerebellar, diencephalic, or occipital infarcts secondary to basilar artery occlusion have a significant degree of disability because of weakness, ataxia, swallowing difficulties, other cranial neuropathies, or a combination of all.
o o
Patients need training on balance and gait. Patients with dysphagia are at a significant risk for aspiration and pneumonia. Evaluation of these patients should be thorough and should include videofluoroscopy with modified barium swallow to assess for silent aspiration. Interventions for prevention of aspiration include compensatory strategies that include oromotor exercises; postural changes while swallowing; and facilitative strategies that include modification of bolus consistency, volume, and delivery. Using a patch on one eye or prisms can help diplopia.
Further Outpatient Care
These patients need strict risk factor control to decrease the risk of stroke recurrence.
Deterrence/Prevention
The prevention strategy depends on the cause of the basilar artery occlusion.
o o o
Patients with a definite cardioembolic source, such as atrial fibrillation, should be treated with warfarin to maintain an INR between 2 and 3. The treatment of patients with basilar artery and vertebral artery atherosclerosis includes antiplatelet agents and risk factor control. No definite indication currently exists for long-term anticoagulation in patients with noncardioembolic stroke.
Complications
Aspiration pneumonia Myocardial infarction Deep vein thrombosis and pulmonary embolism
Prognosis

Patients with acute basilar artery occlusion have a mortality rate greater than 85%, although the mortality rate may be as low as 40% in patients with recanalization. Good functional outcomes can be expected in as many as 24-35% of patients treated with intravenous or intra-arterial thrombolysis, respectively. For symptomatic patients who survive, the risk of recurrent stroke is 10-15%.
Patient Education
For excellent patient education resources, visit eMedicine's Cholesterol Center. In addition, see eMedicine's patient education articles High Cholesterol and Cholesterol FAQs.
MULTIMEDIA
Media file 1: Diffusion-weighted MRI images showing a right occipital infarct.
Media type: MRI Media file 2: Magnetic resonance angiography demonstrating the absence of flow in the vertebrobasilar system.
Media type: MRI Media file 3: Right vertebral artery angiography showing an occlusion with no flow in the basilar artery.
Media type: X-RAY Media file 4: Angiography performed after intra-arterial thrombolysis and angioplasty showing recanalization and perfusion of the basilar artery and its branches.
Media type: X-RAY Media file 5: Hyperdense basilar artery (arrow).
View Full Size Image Media type: X-RAY
REFERENCES
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Article Last Updated: Jan 3, 2006 AUTHOR AND EDITOR INFORMATION
Section 1 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up
Multimedia References
Author: Alison Baird, MD, PhD, National Institute of Neurological Disorders and Stroke, Chief, Stroke Neuroscience Unit, National Institutes of Health Alison Baird is a member of the following medical societies: American Academy of Neurology and American Heart Association Editors: Draga Jichici, HBSc, MD, FRCP(C), FAHA, Assistant Professor, Department of Medicine, Division of Critical Care Medicine, McMaster University Medical School, Canada; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center Author and Editor Disclosure Synonyms and related keywords: carotid artery territory ischemic stroke, major hemispheric syndrome, middle cerebral artery stroke, MCA stroke, MCA syndrome, anterior cerebral artery stroke, ACA stroke, lacunar stroke, reperfusion, anterior circulation stroke
INTRODUCTION
Section 2 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment
Medication Follow-up Multimedia References
Background
The anterior circulation of the brain describes the areas of the brain supplied by the right and left internal carotid arteries and their branches. The internal carotid arteries supply the majority of both cerebral hemispheres, except the occipital and medial temporal lobes, which are supplied from the posterior circulation (see Image 1). Ischemic strokes occurring in the anterior circulation are the most common of all ischemic strokes, accounting for approximately 70% of all cases. The internal carotid artery originates at the bifurcation of the common carotid artery at the level of the thyroid cartilage in the neck. The extracranial portion of the artery passes into the carotid canal of the temporal bone without giving off any branches. The intracranial portion of the artery consists of the petrosal, cavernous (ie, S-shaped carotid syphon), and supraclinoid portions. The major intracranial branches arise from the supraclinoid portion, the first being the ophthalmic artery that enters the orbit through the optic foramen to supply the retina and optic nerve. Next, the posterior communicating artery arises just distal to the ophthalmic artery and joins the posterior cerebral artery. The anterior choroidal artery arises prior to the terminal bifurcation of the internal carotid artery into the middle cerebral and anterior cerebral arteries. The middle cerebral artery (MCA) is the direct continuation of the artery, while the anterior cerebral artery (ACA) branches medially at the level of the anterior clinoid process. The circle of Willis consists of a vascular communication of blood vessels at the base of the brain connecting the anterior and posterior circulations. The vessels of the anterior circulation are connected via the posterior communicating arteries to the posterior circulation. A high degree of variation exists in the normal vascular anatomy. For example, in as many as 20% of patients, the posterior cerebral arteries (ie, fetal) arise from the internal carotid artery as normal vascular variants. Therefore, some variation exists in the exact parts of the brain supplied by the anterior circulation. For additional resources, visit Stroke/Cerebrovascular Disease.
Pathophysiology
Ischemic strokes in the anterior circulation are caused most commonly by occlusion of one of the major intracranial arteries or of the small single perforator (penetrator)
arteries. The most common causes of arterial occlusion involving the major cerebral arteries are (1) emboli, most commonly arising from atherosclerotic arterial narrowing at the bifurcation of the common carotid artery, from cardiac sources, or from atheroma in the aortic arch and (2) a combination of atherosclerotic stenosis and superimposed thrombosis. Lacunar strokes are believed to be caused by lipohyalinotic intrinsic disease of the small penetrating vessels. The most common sites of occlusion of the internal carotid artery are the proximal 2 cm of the origin of the artery and, intracranially, the carotid siphon. Factors that modify the extent of infarction include the speed of occlusion and systemic blood pressure. Occlusion of the internal carotid artery is not infrequently silent, because external orbital-internal carotid and willisian collaterals can open up if the occlusion has occurred gradually over a period of time. Mechanisms of ischemia resulting from internal carotid artery occlusion are, most commonly, artery-to-artery embolism or propagating thrombus and perfusion failure from distal insufficiency. The MCA is the largest of the intracerebral vessels and supplies through its pial branches almost the entire convex surface of the brain, including the lateral frontal, parietal, and temporal lobes; insula; claustrum; and extreme capsule. The lenticulostriate branches of the MCA supply the basal ganglia, including the caput nuclei caudati, the putamen, the lateral parts of the internal and external capsules, and sometimes the extreme capsule. Occlusion of the MCA commonly occurs in either the main stem (M1) or in one of the terminal superior and inferior divisions (M2). Occlusion of the M1 segment of the MCA prior to the origin of the lenticulostriate arteries in the presence of a good collateral circulation can give rise to the large striatocapsular infarct. Occlusion of the MCA or its branches is the most common type of anterior circulation infarct, accounting for approximately 90% of infarcts and two thirds of all first strokes. Of MCA territory infarcts, 33% involve the deep MCA territory, 10% involve superficial and deep MCA territories, and over 50% involve the superficial MCA territory. The ACA supplies the whole of the medial surfaces of the frontal and parietal lobes, the anterior four fifths of the corpus callosum, the frontobasal cerebral cortex, the anterior diencephalon, and the deep structures. Occlusion of the ACA is uncommon, occurring in only 2% of cases, often through atheromatous deposits in the proximal segment of the ACA. The anterior choroidal artery supplies the lateral thalamus and posterior limb of the internal capsule. Occlusion of the anterior choroidal artery occurs in fewer than 1% of anterior circulation strokes. Often, ischemia in the distribution of the ophthalmic artery is transient in the setting of symptomatic internal carotid artery occlusion (ie, transient monocular blindness, occurring in approximately 25% of patients), but central retinal artery ischemia is relatively uncommon, presumably because of the efficient collateral supply. Occlusion of single penetrating branches of the middle and anterior cerebral arteries
that supply the deep white and gray matter produce the lacunar type of stroke. These occlusions account for as many as 20% of ischemic strokes. The acute ischemic process varies markedly from patient to patient. Patients with similar clinical syndromes may have markedly different pathophysiological profiles. Many new pathophysiological insights have been obtained from studies using functional brain imaging (eg, magnetic resonance imaging [MRI], positron emission tomography [PET], single-photon emission computed tomography [SPECT]). Several pathophysiological ischemic stroke syndromes can be identified on the basis of imaging parameters of perfusion and tissue injury that could be used to target stroke treatment. Using new MRI methods, the following 3 patterns have been identified:
Perfusion-diffusion mismatch, which may represent a situation of viable but ischemic tissue that could be salvaged by timely reperfusion. In this pattern, a larger area of hypoperfusion surrounds a zone of ischemic injury on diffusion-weighted imaging. This pattern occurs in approximately 70% of patients in the first 24 hours. Complete ischemia, in which the perfusion and diffusion lesions are of equivalent size, likely representing a complete infarct. This pattern has been identified in approximately 10-20% of patients in the first 24 hours. Reperfusion pattern, in which a perfusion deficit no longer exists. This pattern occurs in approximately 10-15% of patients in the first 24 hours.
Efforts are now underway to incorporate MR angiography findings as well. Reperfusion is an important part of the ischemic process, and by 24 hours, 20-40% of arterial occlusions have begun to clear, with recanalization rates of 70% by 1 week and 90% by 3 weeks. Early reperfusion (<24 h) may have significant prognostic benefits and is associated with improved outcome and smaller infarct size, but later reperfusion may not alter outcome significantly and may be associated with hemorrhagic conversion of the infarct and edema formation.
Frequency
United States
In a recent study, Broderick et al estimated that approximately 731,000 new and recurrent cases of stroke occur each year in the United States. Approximately 80% of these are ischemic strokes. Anterior circulation ischemic stroke accounts for approximately 70% of all ischemic strokes. Approximately 409,360 new cases of anterior circulation ischemic stroke per year are reported in the United States.
International
The risk of stroke is highest in Eastern Europe, followed by Western Europe, Asia, the rest of Europe, and North America.
Mortality/Morbidity
Stroke is the third leading cause of death in the United States and the leading cause of adult disability. High rates of morbidity and mortality are associated with all types of ischemic strokes, but the prognosis varies among subtypes. For example, the lacunar syndromes (ie, caused by occlusion of a single small penetrating artery) quite often are associated with a good prognosis and have a better prognosis than MCA syndromes. Overall, at 6 months after a stroke, as many as 30% of patients have died, 20-30% are moderately to severely disabled, 20-30% have mild to moderate disability, and 20-30% are without deficits. Stroke recurs in as many as 10% of stroke survivors in the first 12 months after stroke, with an incidence of 4% per year thereafter. After transient ischemic attack, the risk of stroke is 10.5% over the next 3 months, with the highest risk in the 2 days following TIA.
Race
The patterns of arterial occlusion are different in African Americans and Asians than in Caucasians.
Asians and African Americans have higher rates of intracranial arterial occlusive disease than Caucasians. The intracranial arterial occlusive disease in these populations typically involves the main stem of the MCA or the ACA. In Caucasians, the arterial occlusive disease typically involves the extracranial carotid arteries, and lesions in the middle and anterior cerebral arteries are usually of embolic origin.
Sex
Strokes at all ages are more likely to occur in men, but overall more strokes occur in women. This is because strokes occur more commonly at older ages and females have a longer life span than males (the native protective effect of estrogen is lost at menopause). This disparity may become greater in the future with the aging of the population.
Age
The incidence of stroke rises exponentially with age, particularly in individuals older than 55 years.

However, 25% of all strokes occur in individuals younger than 65 years of age; so stroke is not just a condition of the elderly. Strokes can occur at any age.
CLINICAL
History
Patients typically present with sudden onset of focal neurological symptoms. Specific features of the time course and evolution, focal neurological symptoms, and global symptoms are listed below.
Time course and evolution Sudden or rapid onset Reaches maximal intensity within 24 hours Gradual or stepwise worsening in as many as 30% of patients Focal neurological symptoms Cognitive impairment - Difficulty with speech Weakness or incoordination - Unilateral Numbness or loss of sensation, typically unilateral Dysarthria Visual loss, either in one eye or in one visual field Global symptoms
o o o o o o o o o o o o o
Headache Altered mental status Syncope Seizure Coma
Physical
Left hemisphere (ie, dominant)

o o
Right hemiparesis, variable involvement of face and upper and lower extremity Right-sided sensory loss, in a similar pattern to the motor deficit; usually involves
all modalities, decreased stereognosis, graphesthesia Right homonymous hemianopia Dysarthria Aphasia, fluent and nonfluent Alexia Agraphia Acalculia Apraxia Right hemisphere (ie, nondominant)
o o o o o o o o o o o o o o o o
Left hemiparesis (same pattern as on right) Left-sided sensory loss (similar pattern as the motor deficit) Left homonymous hemianopia (same pattern as on right) Dysarthria Neglect of the left side of environment Anosognosia Asomatognosia Loss of prosody of speech Flat affect Cortical and subcortical: Findings consistent with both cortical and subcortical localization can be seen in this clinical scenario. ACA territory Crural paresis > arm paresis Frontal signs (eg, abulia) Anterior choroidal artery territory Hemiparesis Hemianesthesia Homonymous hemianopia Lacunar syndromes
o o o o o o
Pure motor hemiparesis Contralateral, usually affecting the face and upper and lower extremities equally Also associated with dysarthria No sensory or visual loss or cognitive impairment Pure sensory stroke Contralateral loss of all sensory modalities, equally affecting the face and upper and lower extremities No motor signs, dysarthria, visual loss, or cognitive impairment Dysarthria-clumsy hand syndrome - Dysarthria, dysphagia, contralateral tongue and facial weakness and paresis, and clumsiness of the contralateral arm and hand Homolateral ataxia and crural paresis - Paresis of the contralateral leg and side of the face, prominent ataxia of the contralateral leg and armalso called "ataxic hemiparesis," meaning ataxia and weakness on the same side. Isolated motor/sensory stroke Paralysis and sensory loss of the contralateral leg, arm, and face No visual loss or cognitive impairment
Causes
Risk factors include epidemiologic risk factors (ie, not modifiable) and potentially modifiable risk factors.
Epidemiologic risk factors Age (risk rises exponentially with age) Sex (more common in males at all ages) Race (African American > Asian > Caucasian) Geographic (Eastern Europe > Western Europe > Asia > rest of Europe or North America) o Genetic risk factors (stroke or heart disease in individuals younger than 60 y; some familial syndromes, eg, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) Potentially modifiable risk factors
o o o o o o o o o o o o o o
Hypertension (diastolic or isolated systolic) Diabetes mellitus type 1 or 2 Atrial fibrillation Smoking Coronary artery disease Hypercholesterolemia Alcohol abuse Drug abuse (eg, cocaine) Oral contraceptive use Pregnancy
DIFFERENTIALS
Cardioembolic Stroke Cavernous Sinus Syndromes
Cerebral Aneurysms Glioblastoma Multiforme Head Injury Herpes Simplex Encephalitis Intracranial Hemorrhage Low-Grade Astrocytoma Meningioma Metastatic Disease to the Brain Migraine Variants Primary CNS Lymphoma Seizures and Epilepsy: Overview and Classification Subarachnoid Hemorrhage Subdural Hematoma Transient Global Amnesia Viral Encephalitis

Brain tumor Hypoglycemia Brain abscess Carotid disease and stroke
WORKUP
Lab Studies
The following laboratory tests are indicated in the patient with stroke both to assist in their acute care and to uncover any underlying medical conditions that could complicate the clinical course.
o o o o o o
Coagulation profile Glucose level Electrolytes levels Liver function tests Erythrocyte sedimentation rate (ESR) Complete blood count (CBC)
Imaging Studies
Brain CT scan
o
Noncontrast CT scan of the brain is required emergently to rule out cerebral hemorrhage, subdural hematoma, and other intracerebral pathology prior to the administration of thrombolytic therapy. Early signs of infarction that can be detected with CT scan include loss of graywhite matter differentiation and cortical sulcal effacement. The hyperdense MCA sign is indicative of thrombus in the MCA. The Alberta Stroke Programme Early CT Score (ASPECTS) score may have prognostic utility (a favorable score is >7/10) but did not show utility in clinical decision-making for recombinant tissue plasminogen activator (rt-PA) therapy in a recent study. Other advances in CT scan include the advent of CT angiography and CT perfusion imaging.
MRI New MR sequences such as diffusion-weighted imaging (DWI) allow detection of ischemic lesions within minutes of stroke onset. Lesions appear as hyperintense and are easily distinguishable from the surrounding brain. o Even very small lesions can be detected, and old lesions may be distinguished from new ones by measuring the apparent diffusion coefficient. o In combination with MR angiography (MRA) and MR perfusion imaging, this modality allows multiple aspects of the ischemic process to be identified in a scanning session of approximately 25 minutes. This is available in many tertiary referral centers. Contrast-enhanced MRA using a neurovascular array permits rapid imaging of the vasculature from the aortic arch to the circle of Willis in as short as 2 minutes. This method seems sensitive for the detection of extracranial vascular disease, including vertebral and internal carotid artery dissections. Transcranial Doppler ultrasonography Transcranial Doppler ultrasonography is used for rapid and noninvasive identification of the site of major arterial occlusion in the MCA, internal carotid artery, and ACA. o It also is used to identify embolic load with emboli detection. Chest radiography - This is used to determine heart size and pulmonary status.
o o
Other Tests
Cardiac echocardiography Cardiac echocardiography helps in ruling out a cardiac source of cerebral embolism and in identifying aortic arch atheroma. o Transesophageal echocardiography is the investigation of choice, as it has higher detection rates for lesions in the left atrium (eg, thrombus) and the aortic arch. Imaging of the neck vessels Imaging of the neck vessels helps in ruling out a significant carotid artery stenosis as a cause of stroke that may require surgical intervention. o Perform imaging with ultrasound, MRA, or conventional digital subtraction angiography. Hypercoagulability screen - For patients with cryptogenic stroke and a possibility of a hypercoagulable etiology ECG
o o
Procedures

Intravenous thrombolysis is recommended for patients with ischemic stroke presenting within the first 3 hours. Intravenous thrombolysis beyond the first 3 hours is under investigation. Patients are eligible for trials if a perfusion-diffusion mismatch pattern can be identified (believed to be indicative of the presence of potentially viable tissue). Mechanical clot disruption using the MERCI clot retrieval device for acute ischemic stroke treated within 8 hours of symptom onset received clearance from the Food and Drug Administration (FDA) in 2004. A second-generation device and use of the device in patients with persistent clots after intravenous thrombolysis are still under investigation.
TREATMENT
Medical Care
The aim is to prevent acute, subacute, or chronic medical and neurological complications.

Check vital signs and perform neurological assessments. Check oxygen saturation; administer supplemental oxygen if hypoxic. Monitor cardiac function. Administer anticoagulants or advise compression stockings to bedridden patients to avoid deep venous thrombosis. Avoid indwelling bladder catheter if possible. Control blood pressure optimally.
Surgical Care
Emergency decompression with craniotomy is performed in some centers for patients with malignant MCA syndrome. It is performed most commonly for right hemisphere infarctions because of better potential for functional recovery than left hemisphere infarctions.
Consultations
The following consultations are made depending on the individual patient's needs. In some centers, specialists work as an integrated stroke team.

Physical therapy - For assessment of difficulty in sitting, standing, or walking and the need for assistive devices to aid walking Speech therapy - For assessment of swallowing, language impairments, or dysarthria Occupational therapy - For patients with decreased cognitive or upper extremity function and need for adaptive equipment Social services - For discharge planning Rehabilitation physician - For assessment of rehabilitation needs Psychiatry - For assessment of psychiatric status
Diet
Generally, patients are allowed nothing by mouth for the first 24 hours, except for patients with very mild or rapidly resolving deficits. Intravenous fluids should avoid dextrose and preferably involve isotonic saline. Perform bedside or fluoroscopic swallowing assessment. Adjust diet depending on results; if necessary to meet nutritional needs, commence nasogastric feeding. Assess for future need of enteral feeding (typically via percutaneous gastrostomy tube).
Activity
Advise bed rest for the first 24 hours with the head of the bed below 30 degrees to avoid
exacerbation of cerebral hypoperfusion in evolving infarcts, which sometimes can lead to neurological worsening. The focally ischemic brain has impaired autoregulatory capacity and so may not compensate for changes in blood pressure that are tolerated under nonischemic conditions. Intravenous normal saline is also administered. If the patient's condition is stable after 24 hours, graded ambulation with assistance may commence, depending on functional status.
MEDICATION
Intravenous recombinant tissue plasminogen activator (rt-PA) administered within 3
hours of stroke onset is the only FDA-approved pharmaceutical therapy for the acute treatment of ischemic stroke. Other medical management of anterior circulation ischemic stroke consists of optimal blood pressure control and administration of therapies aimed at secondary stroke prevention, usually antiplatelet agents or anticoagulants, depending on the etiology of the stroke.
Drug Category: Thrombolytic agents
These agents lyse thromboemboli lodged in cerebral blood vessels and restore blood flow, salvage the ischemic brain tissue, and improve clinical outcome. They must be administered within 3 hours of onset of stroke symptoms; beyond this time, the risk of intracerebral hemorrhage outweighs treatment benefits.
Drug Name Alteplase (Activase) Recombinant plasminogen activator that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, has been shown effective in achieving TIMI 2 or 3 patency at 90 min. Heparin and aspirin are not given for 24 h after tPA. Must be given within 3 h of stroke onset. Exclude hemorrhage by CT scan. If hypertensive, lower BP with labetalol, 10 mg IV. 0.9 mg/kg IV; not to exceed 90 mg Give bolus of 10% of total dose to be administered, infuse remainder over next 60 min Not established
Description
Adult Dose
Pediatric Dose
Beyond 3 h after stroke onset; cerebral hemorrhage; recent stroke (within 3 mo); serious Contraindications bleeding disorder or history of GI hemorrhage; BP >200/110 mm Hg; recent surgery Anticoagulants and antiplatelets may increase risk of bleeding (do not administer aspirin, heparin, or other anticoagulants for 24 h after infusion) C - Safety for use during pregnancy has not
Interactions
Pregnancy
been established. Precautions Caution in cardiovascular arrhythmias, hypotension, and perfusion arrhythmias
Drug Category: Anticoagulants
Emergent heparin therapy may be given for specific indications, such as internal carotid artery dissection or cerebral venous thrombosis. Heparin therapy also may be commenced in conjunction with warfarin therapy for secondary prevention of high-risk cardioembolic stroke; it may be started either on admission (if not receiving rt-PA) or 3-5 days after stroke onset. Early use of IV heparin has not, however, been proven to be of benefit in clinical trials. For patients confined to bed who do not have excessive risk of hemorrhagic transformation, administer subcutaneous heparin to prevent deep venous thrombosis.
Drug Name Heparin sodium In addition to heparin sodium, low-molecularweight heparins may be associated with lower rate of hemorrhagic complications. 100,000 U IV over 24 h 5000 U SC bid Not established
Description
Documented hypersensitivity; subacute bacterial Contraindications endocarditis; active bleeding; history of heparininduced thrombocytopenia Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity C - Safety for use during pregnancy has not been established. In neonates, preservative-free heparin recommended to avoid possible toxicity (ie, gasping syndrome) by benzyl alcohol, which is
Interactions
Pregnancy
Precautions
used as preservative; caution in severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when giving IM injections Drug Name Warfarin (Coumadin) Inhibits synthesis of 6 vitamin K-dependent proteins involved in anticoagulation system (factors II, VII, IX, X; proteins C, S). Many other coumarin derivatives are used worldwide. Initial dose: 5 mg/d PO for 2-4 d (lower in very elderly patients) Subsequent doses determined by INR achieved and source of embolism (INR 2-3 for most cardiac sources) Not established
Description
Adult Dose
Pediatric Dose
Documented hypersensitivity; active bleeding; Contraindications heparin-induced thrombocytopenia; severe renal or hepatic disease; open wounds; gastric ulcer Extensive literature available regarding warfarindrug interactions, with variable level of evidence; drugs that increase anticoagulant effects include co-trimoxazole, erythromycin, fluconazole, isoniazid, amiodarone, aspirin, simvastatin, sulfinpyrazone, phenylbutazone, alcohol, cimetidine, and omeprazole; drugs that inhibit anticoagulant effect include rifampin, nafcillin, cholestyramine, barbiturates, carbamazepine, sucralfate, and azathioprine; OTC NSAIDs (eg, Naprosyn, ibuprofen) and aspirin are associated with increased risk of upper GI bleeding when used with warfarin; high doses of acetaminophen can prolong INR X - Contraindicated in pregnancy
Interactions
Pregnancy
Precautions
Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis
These agents are used for secondary prevention of ischemic stroke caused by atherosclerotic disease of small or large arteries. Data also support aspirin use within 48 h of an acute stroke.
Drug Name Aspirin (Anacin, Bayer Aspirin, Ascriptin, Bayer Buffered Aspirin) Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. 75-325 mg/d PO Not established
Description
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; Contraindications bleeding disorders; asthma Because of association with Reye syndrome, do not use in children ( <16 y) with flu Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease salicylate serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs D - Unsafe in pregnancy
Interactions
Pregnancy
Precautions
May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants Aspirin plus slow-release dipyridamole (Aggrenox) Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Dipyridamole is platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of potent platelet activator thromboxane A2. European Stroke Prevention Trial 2 demonstrated that combination therapy was better than aspirin alone for prevention of recurrent stroke or transient ischemic attack. 25 mg aspirin + 200 mg dipyridamole SR PO bid (1 tab bid) Not established
Drug Name
Description
Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; Contraindications bleeding disorders; asthma Because of association with Reye syndrome, do not use in children ( <16 y) with flu Aspirin: Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease salicylate serum levels; anticoagulants may cause additive hypoprothrombinemic effects and increase bleeding time; may antagonize uricosuric effects of probenecid and increase
Interactions
toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs Dipyridamole: Theophylline may decrease hypotensive effects; antiplatelet activity may increase heparin toxicity Pregnancy D - Unsafe in pregnancy Aspirin may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants Caution in hypotension when using dipyridamole; dipyridamole has peripheral vasodilating effects Clopidogrel (Plavix) Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. 75 mg/d PO qd Not established
Precautions
Drug Name
Description
Documented hypersensitivity; active pathological Contraindications bleeding, such as peptic ulcer; intracranial hemorrhage Naproxen associated with increased occult GI blood loss; safety of coadministration with warfarin not established C - Safety for use during pregnancy has not been established. Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions (eg, ulcers) with propensity to bleed; prolongs
Interactions
Pregnancy
Precautions
bleeding time Drug Name Ticlopidine (Ticlid) Reported to be 15% more effective than aspirin. However, is associated with risks of neutropenia and thrombocytopenia and requires regular blood testing; therefore, use in patients who do not respond to aspirin or are allergic to aspirin. 250 mg PO bid Not established
Description
Documented hypersensitivity; neutropenia or Contraindications thrombocytopenia; liver damage; active bleeding disorders Corticosteroids and antacids may decrease effects; theophylline, cimetidine, aspirin, and NSAIDS increase toxicity B - Usually safe but benefits must outweigh the risks. Discontinue if absolute neutrophil count decreases to <1200/mm3 or if platelet count falls to <80,000/mm3
Interactions
Pregnancy
Precautions
FOLLOW-UP
Section 8 of 10 Authors and Editors Introduction Clinical Differentials Workup Treatment Medication Follow-up Multimedia
References

Treatment and monitoring of comorbid diseases such as diabetes, heart disease, hypertension, and arthritis Symptomatic treatment of confusion, agitation, headache, pain, nausea, and vomiting Referral for chest physiotherapy, if required
Complications
Neurological complications include cerebral edema, hemorrhagic transformation of cerebral infarction, seizures, hydrocephalus, increased intracranial pressure, and depression. Respiratory complications include aspiration, pneumonia, airway obstruction, hypoventilation, and atelectasis. Urinary complications include incontinence and urinary tract infections. Cardiovascular complications include myocardial infarction, congestive heart failure, hypertension, orthostatic hypotension, deep venous thrombosis, and pulmonary embolism. Nutritional, metabolic, and gastrointestinal complications include stress ulcers, gastrointestinal bleeding, constipation, dehydration, electrolyte disturbances, malnutrition, and hyperglycemia. Orthopedic and dermatologic complications include pressure sores, contractures, adhesive capsulitis of the shoulder, and falls with fractures.
Prognosis
At 6 months after a stroke, approximately 20-30% of patients have died, 20-30% are moderately to severely disabled, 20-30% have mild to moderate disability, and 20-30% are without deficit. Despite treatment for secondary prevention, stroke recurrence rate is significant. A significant percentage of patients (ie, as many as 50% in some studies) suffer from depression after stroke. Also, a significant rate of stress and depression exists among caregivers of patients disabled by stroke.
Patient Education

Educate patients and their families regarding stroke, its treatment, its complications, and plans for future care. Refer to stroke support groups. Provide educational material from organizations such as the American Stroke Association and the National Stroke Association. For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education articles Stroke and Transient Ischemic Attack (Mini-
stroke).
MULTIMEDIA
Media file 1: Anterior circulation stroke. Vascular territories.
Media type: Image
REFERENCES
Section 10 of 10 Authors and Editors Introduction Clinical Differentials
Workup Treatment Medication Follow-up Multimedia References
Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab. Jun 1998;18(6):583-609. [Medline]. Bogousslavsky J. Topographic patterns of cerebral infarcts. Correlation with etiology. Cerebrovasc Dis. 1991;1 (suppl 1):61-68. Broderick J, Brott T, Kothari R. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. Feb 1998;29(2):415-21. [Medline]. Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic computed tomography changes using ASPECTS in NINDSrtPA Stroke Study. Stroke. Oct 2005;36(10):2110-5. [Medline]. Fisher CM. Lacunar infarcts. A review. Cerebrovasc Dis. 1991;1:311-320. Furlan A, Higashida R, Wechsler L. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. Dec 1 1999;282(21):2003-11. [Medline]. Greshem GE. Rehabilitation of the stroke survivor. In: Barnett H, et al, eds. Stroke: Pathophysiology, Diagnosis and Management. 2nd ed. New York: Churchill Livingstone; 1992:1189-201. Helgason CM. A new view of anterior choroidal artery territory infarction. J Neurol. Sep 1988;235(7):387-91. [Medline]. Johnston SC, Gress DR, Browner WS. Short-term prognosis after emergency department diagnosis of TIA. JAMA. Dec 13 2000;284(22):2901-6. [Medline]. Koga M, Saku Y, Toyoda K. Reappraisal of early CT signs to predict the arterial occlusion site in acute embolic stroke. J Neurol Neurosurg Psychiatry. May 2003;74(5):649-53. [Medline]. Libman RB, Kwiatkowski TG, Hansen MD. Differences between Anterior and Posterior Circulation Stroke in TOAST. Cerebrovasc Dis. 2001;11(4):311-6. [Medline]. Mohr JP, Gautier JC, Pessin MS. Internal carotid artery disease. In: Barnett H, et al, eds. Stroke: Pathophysiology, Diagnosis and Management. 2nd ed. New York: Churchill Livingstone; 1992:285-335. Rajamani K, Gorman M. Trancranial Doppler in stroke. Biomed Pharmacother. Jun 2001;55(5):247-57. [Medline]. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: resultsof the MERCI trial. Stroke. Jul 2005;36(7):14328. [Medline]. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study G. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline]. Wright VL, Olan W, Dick B, et al. Assessment of CE-MRA for the rapid detection of supra-aortic vascular disease. Neurology. Jul 12 2005;65(1):27-32. [Medline].
Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96(4):3805. [Medline].
Anterior Circulation Stroke excerpt
Article Last Updated: Jan 3, 2006
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Quick Find Authors & Editors Introduction Discontinued Study: Angiojet System Discontinued Study: Latis Laser Device Discontinued Study: Endovascular Photo Acoustic Recanalization Laser Ongoing Studies: EKOS Ultrasound Device, Penumbra System Approved Device: Mechanical Embolus Removal in Cerebral Ischemia System Devices Not Evaluated in AcuteStroke Trials Conclusions and Future
Considerations Multimedia References
Patient Education
Mechanical Thrombolysis in Acute Stroke

Article Last Updated: Nov 2, 2006 AUTHOR AND EDITOR INFORMATION
Section 1 of 11 Authors and Editors Introduction Discontinued Study: Angiojet System Discontinued Study: Latis Laser Device Discontinued Study: Endovascular Photo Acoustic Recanalization Laser Ongoing Studies: EKOS Ultrasound Device, Penumbra System Approved Device: Mechanical Embolus Removal in Cerebral Ischemia System Devices Not Evaluated in Acute-Stroke Trials Conclusions and Future Considerations Multimedia References
Author: Helmi L Lutsep, MD, Associate Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep is a member of the following medical societies: American Academy of Neurology and American Stroke Association Editors: Richard M Zweifler, MD, Professor, Director of Stroke Center, Director of Neurosonology Lab, Director of Vascular Neurology Fellowship, Director of Medical Student Education, Department of Neurology, University of South Alabama; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants Author and Editor Disclosure Synonyms and related keywords: mechanical thrombectomy, endovascular thrombectomy, intraarterial treatment of acute stroke, intra-arterial treatment of acute stroke, IA treatment of acute stroke, intraarterial thrombolysis, intra-arterial thrombolysis, IA thrombolysis, tissue-type plasminogen activator, tissue plasminogen activator, tPA, t-PA, mechanical thrombolysis in acute stroke
INTRODUCTION
At present, intravenous (IV) tissue-type plasminogen activator (tPA) is the only medical therapy approved for treatment of acute stroke in the United States. Almost 50% of patients treated with tPA in the trial by the National Institutes of Neurologic Disorders and Stroke (NINDS) achieved essentially full recovery. However, subgroup analyses of the NINDS data showed that patients with severe strokes have only an 8% likelihood of achieving clinically significant improvement with tPA. The poor outcome in these patients has inspired the search for acute-stroke treatments that are more effective than tPA. One treatment involves the use of catheters to directly deliver a clot-disrupting or retrieval device to a thromboembolus that is occluding a cerebral artery. Mechanical thrombolytic devices can remove a clot in a matter of minutes, whereas pharmaceutical thrombolytics, even those delivered intra-arterially (IA), take as long as 2 hours to dissolve a thrombus. This timesaving feature has encouraged the use of long treatment windows in trials of acute-stroke treatments. In addition, IA delivered devices were anticipated to lower rates of intracranial hemorrhage (ICH) compared with IA pharmaceutical lytics. A number of mechanical thrombolysis devices have entered clinical trials for treatment of acute stroke. These devices have used suction-creating saline jets, laser energy, ultrasound, and a corkscrew apparatus to treat strokes. Other mechanical approaches have not been assessed in clinical trials. One such method takes advantage of the suction created by pulling back on a syringe, and another uses a snare to retrieve a clot. Most devices are used in cerebral vessels that 2-5 mm, and mechanical clot thrombolysis should be performed at an institution where angiography is available because catheters are used to deliver the device to the clot during angiography. This article reviews these devices and the known clinical safety data. For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.
DISCONTINUED STUDY: ANGIOJET SYSTEM

Section 3 of 11 Authors and Editors Introduction Discontinued Study: Angiojet System Discontinued Study: Latis Laser Device Discontinued Study: Endovascular Photo Acoustic Recanalization Laser
Ongoing Studies: EKOS Ultrasound Device, Penumbra System Approved Device: Mechanical Embolus Removal in Cerebral Ischemia System Devices Not Evaluated in Acute-Stroke Trials Conclusions and Future Considerations Multimedia References
The AngioJet system (Possis Medical, Inc, Minneapolis, MN) uses saline jets that are directed back into the catheter to create a low-pressure zone around the catheter tip, inducing suction (see Images 1-2). The clot is pulled into the exhaust lumen and removed from the vessel. Although US Food and Drug Administration (FDA) has approved this device for use in arteriovenous dialysis grafts and fistulae and for the treatment of coronary arteries, saphenous vein grafts, and peripheral vessels, clinical trials for the treatment of acute stroke are no longer in progress. The randomized Vein Graft AngioJet Study (VeGAS 2) trial was conducted to compare treatment with the AngioJet system with urokinase followed by percutaneous treatment to revascularize both native coronary arteries and saphenous vein bypass grafts in 349 patients. Patients receiving AngioJet treatment had in-hospital outcomes significantly better than those of the other patients, though 30-day event rates were similar in the 2 groups. However, the primary endpoints comprised a large number of events: stroke, death, myocardial infarction, target lesion revascularization, creatine kinase MB release, Thrombolysis in Myocardial Infarction (TIMI) blood-flow grade less than 3, and stenosis less than 50% of vascular diameter. For the treatment of thromboemboli causing stroke, a device was developed to fit the size of the internal carotid artery (ICA). Two centers reported their experiences using the AngioJet system to treat ICA occlusion. In 3 patients, the device was used to debulk extensive ICA clots to allow for access to intracranial vessels. The thrombectomy was technically feasible, and clot burden was reduced in all patients. However, despite angiographic successes, clinical outcomes were poor. The authors postulated that these outcomes likely represented poor collateral flow in these patients. Possis Medical, Inc, designed a small device to allow treatment of thromboemboli in vessels other than the ICA. Safety and efficacy trials were in progress to investigate its use in occlusions of the M1 or M2 segment of the middle cerebral artery (MCA), carotid terminus, vertebral arteries, and basilar arteries within 6 hours of symptom onset. Between April 2000 and July 2003, 22 patients were enrolled in the Thrombectomy in Middle Cerebral Artery Embolism (TIME) trial. Two, and possibly 3, vessel perforations occurred, with subarachnoid hemorrhage. The company has stopped the trials.
DISCONTINUED STUDY: LATIS LASER DEVICE

The Latis laser device (Latis, Inc, Coon Rapids, MN) used laser energy to ablate clots. The device was evaluated in a safety and feasibility trial at 2 centers in the United States. Arteries 2-5 mm in diameter could be treated, including the ICA, M1 or M2 branch of the MCA, A1 branch of the anterior cerebral artery (ACA), basilar artery, posterior cerebral artery (PCA), and vertebral artery. Patients could receive treatment as late as 8 hours after symptom onset in the anterior circulation and within 24 hours in the posterior circulation. A preliminary account of the first 5 patients enrolled in the trial reported that the device could not be delivered to the clot in 2. Enrollment stopped at 12 patients. Although the catheter design was changed, an efficacy trial was not pursued.
DISCONTINUED STUDY: ENDOVASCULAR PHOTO ACOUSTIC RECANALIZATION LASER

The first mechanical thrombolysis device for which safety and feasibility results in patients with stroke were reported was the Endovascular Photo Acoustic Recanalization (EPAR) laser system (EndoVasix, Inc, Belmont, CA). A laser power source generated energy for the system. The energy was delivered by means of fiberoptics to the tip of the catheter at the treatment site. Absorption of laser light by darkly pigmented materials (ie, the clot) occurred inside the 1-mm catheter tip, and the system was designed to minimize scattering of laser light. Absorption converted photo energy to acoustic energy, which then emulsified the clot inside the catheter tip (see Images 3-5). Initial safety results for the EPAR system in the IA treatment of acute stroke were reported in February 2001, and final results were published in 2004. The trial was performed at 6 centers in the United States and in Germany. Patients received treatment for occlusions in the ICA, vertebral artery, basilar artery, ACA, MCA, and PCA. They were treated within 6 hours of stroke onset if they had a lesion in the anterior circulation and within 12 hours if they had a lesion in the posterior circulation. The median baseline National Institutes of Health Stroke Scale (NIHSS) score was 19 (range, 6-39). In patients in whom the device was deployed, recanalization occurred in 12 (44%) of 27 who received EPAR treatment plus adjuvant therapy but only 4 (15%) treated with the device alone. ICH occurred in 2 (7%) patients: 1 (10%) of 10 treated with the device alone and in 1 (6%) of 17 who received an adjuvant in addition to the device. About 38% of patients died. The EPAR laser system showed acceptable safety, causing no complications during active lasering. However, 1 vessel ruptured during manual injection with a 1-mL syringe (instead of the recommended 3-mL syringe), causing the distal catheter to balloon and fatal vascular rupture. Although an international efficacy trial was approved to evaluate this device in treatment of acute stroke, loss of funding stopped further clinical testing.
ONGOING STUDIES: EKOS ULTRASOUND DEVICE, PENUMBRA SYSTEM

Section 6 of 11 Authors and Editors Introduction Discontinued Study: Angiojet System Discontinued Study: Latis Laser Device Discontinued Study: Endovascular Photo Acoustic Recanalization Laser Ongoing Studies: EKOS Ultrasound Device, Penumbra System Approved Device: Mechanical Embolus Removal in Cerebral Ischemia System Devices Not Evaluated in Acute-Stroke Trials Conclusions and Future Considerations
EKOS ultrasound As its name suggests, the Ultrasound Thrombolytic Infusion Catheter (EKOS Corporation, Bothell, WA) combines the use of a distal ultrasound transducer with infusion of a thrombolytic agent through the microcatheter (see Images 6-8). Ultrasound changes the structure of the clot to temporarily increase its permeability while providing an acoustic pressure gradient to move the drug into the clot to speed its dissolution. In a preclinical study investigating the efficacy of the device in peripheral vascular occlusion, thrombi were induced in the bilateral superficial femoral arteries of 9 dogs. Although urokinase 5000 IU/kg was delivered to the vessels on both sides, the ultrasound transducer of the catheter was activated on only 1 side. After treatment, angiography showed good flow (ie, TIMI grade 2 or 3) in 9 (100%) of the ultrasoundtreated segments and in 6 (67%) of the controls not treated (P = .058). Angioscopy and histopathology revealed more thrombi in the vessels that did not receive treatment than in those that did. In human studies, results from the first 14 patients with acute stroke were reported in April 2000. In a safety and feasibility study, ultrasound was used with IA tPA infusion. The EKOS catheter was placed in the proximal portion of the clot. After a 2-mg bolus of tPA was injected through the catheter, the patient received a continuous infusion of IA tPA 0.3 mg/min to a maximum of 20 mg and simultaneous ultrasound transmission for as long as 60 minutes. One patient was treated with a total of 4 units of recombinant reteplase (Retavase) hand-injected over 60 minutes. Five patients with MCA thrombi and in 5 patients with carotid-T occlusions were treated within 6 hours of symptom onset, and 4 patients with posterior-circulation strokes were treated within 24 hours. The median NIHSS score was 19.5 (range, 9-27). TIMI grade 23 flow was attained in 8 (57%) of 14 patients in the first hour. The average time to recanalization was 46 minutes. No adverse events attributable to the catheter occurred. After briefly considering a safety and feasibility trial using IA prourokinase in conjunction with the device, the EKOS Corporation pursued another trial with tPA. In this trial, called the Interventional Management of Stroke (IMS) II trial, patients were first treated with IV tPA at a dose of 0.6 mg/kg within 3 hours. Those with persistent clots received IA tPA in conjunction with ultrasound therapy. Indirect comparisons of the IMS II trial results with those in the NINDS tPA trial that included only those patients with an NIHSS of at least 10 and age 80 years or less suggested that outcomes were at least as favorable at 3 months in the IMS II study. IMS III will compare IV tPA treatment alone to lower-dose IV tPA plus one of a few intra-arterial treatments in patients in whom treatment is initiated
within 3 hours. Penumbra system The Penumbra system (Penumbra, Inc.) provides a dual approach to clot extraction, using aspiration followed by clot retrieval with a "ring" device, if needed. An initial safety trial has been completed in Europe, and a study assessing the safety and efficacy of the system for recanalization of vessels is now in progress primarily in the United States. Patients are included up to 8 hours after symptom onset.
APPROVED DEVICE: MECHANICAL EMBOLUS REMOVAL IN CEREBRAL ISCHEMIA SYSTEM

The FDA has approved the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retrieval system, a corkscrew-like apparatus, "to remove blood clots from the brain in patients experiencing an ischemic stroke" (Concentric Medical, Inc, Mountain View, CA) (see Images 9-10). The corkscrew itself resides in the catheter tip, which shields it from the wall of the vessel until it is ready to be burrowed into the clot. Once lodged in the clot, the device and clot are withdrawn from the vessel. MERCI 1 study Results for the first 28 patients treated within an 8-hour window as part of this multicenter safety trial, were published in 2004. Occlusions of the ICA, proximal segments of the MCA, basilar artery, or vertebral arteries were included. Successful recanalization (TIMI grades 2 or 3) occurred in 12 patients (43%) with the retriever alone and in 18 (64%) with additional IA tPA. No symptomatic ICH occurred.
MERCI study Results of the full MERCI trial, in which the device was deployed in 141 of 151 patients, were published in 2005. The mean NIHSS score was 20.1 (standard deviation [SD] 6.6). Recanalization with the device occurred in 68 patients (48%), which was significantly better than the rate in the placebo arm of the Prolyse in Acute Cerebral Thromboembolism (PROACT) II trial of patients with MCA occlusions (P <.0001). Additional adjuvant therapy led to recanalization in 85 (60%) subjects. Symptomatic ICH occurred in 7 (8%) of 90 patients who were treated with the device alone and in 11 (8%) of 141 who received adjuvant treatment. Mortality rates in the 141 patients in whom the device was deployed was 44% (60 of 136), and the percentage with a modified Rankin score of 2 or less at 90 days was 28% (36 of 130). Multi-MERCI study The Multi-MERCI study included patients who had persistent clots after IV tPA treatment, as well as other patients with acute stroke who presented within 8 hours of symptom onset, like those in MERCI. Twenty-seven percent of patients received IV tPA and treatment with the MERCI Retriever. Results for 111 patients showed a recanalization rate of 54% (60 of 111) with the device alone and 69% (77 of 111) with the device plus adjuvant treatment. Symptomatic ICH occurred in 10% (8 of 81) of patients treated with the device alone and in 7% (2 of 30) of those treated with device plus IV tPA. The Retriever has approval for use in patients with persistent vessel occlusion after IV tPA. NINDS has funded a randomized trial of the MERCI Retriever compared with medical therapy as long as 8 hours after symptom onset, called Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE). The effects of therapy will be stratified by the presence of a penumbra on MRI at randomization.
DEVICES NOT EVALUATED IN ACUTE-STROKE TRIALS

Snarelike devices In anecdotal reports, interventionists used retrieval devices to remove thrombi from cerebral vessels. Snares, such as the Neuronet snare (Guidant Endovascular, Santa Clara, CA), have been developed specifically for use in the treatment of strokes. These devices are simple in design and do not require the clot to be amenable to emulsification. X-Sizer device Yet another approach to mechanical clot disruption involves a device with small, moving blades at the catheter tip. This device, the X-Sizer device (EndiCor Medical, San Clemente, CA), can be used to excise the thrombus and aspirate it. The device was being evaluated in randomized studies of coronary vessels and in a registry of patients with acute myocardial infarction. Although the manufacturer had modified the device for use in cerebral vessels, a safety and feasibility study was indefinitely suspended after only 1 patient was treated with the device in Europe. Suction thrombectomy This method of mechanical thrombolysis is one of the simplest. In this readily available technique, suction is applied with a syringe to remove thrombus in the ICA. It requires no other devices. The use of suction thrombectomy in 2 patients with angiographically visualized ICA thrombus with TIMI grade 0 or 1 flow was reported in 1999. Patient 1 (NIHSS score, 12) was treated 17 hours after the onset of progressive right hemispheric symptoms, and patient 2 (NIHSS score, 23) was treated 5 hours after an abrupt onset of a severe neurologic deficit. A catheter with a large inner diameter (Brite Tip; Cordis Corporation, Miami, FL) was placed in the symptomatic vessel and navigated over a guidewire into the thrombus. A 60-mL syringe was used to aspirate the thrombus. Each patient required angioplasty and stenting of carotid bifurcation stenosis and received daily aspirin and ticlopidine after the procedure. No complications occurred. Both patients had excellent angiographic results, which showed minimal residual ICA stenosis and improved distal flow. Patient 1 had full functional recovery and a 3-month NIHSS score of 2, but patient 2 had a 3-month NIHSS score of 22.
CONCLUSIONS AND FUTURE CONSIDERATIONS

Clinical trials have shown that thrombectomy with mechanical thrombolysis devices is indeed feasible in the treatment of acute stroke. Although a number of such devices have been discontinued, some because of financial considerations, one, the Concentric MERCI Retriever, has received FDA clearance. The EKOS ultrasound device and the Penumbra System continue to be evaluated in trials and other approaches are being considered. Because few patients with stroke arrive at the hospital quickly enough to receive IV tPA, mechanical thrombolysis potentially extends the treatment window because they act promptly at the site of the thrombus. The devices can retrieve large clots that
pharmaceutical agents may not successfully lyse. Patients treated with IV tPA may be considered for treatment of residual clot with some of these devices. The MERCI Retriever has shown success in recanalizing vessels, though its overall effect on clinical outcomes of the patients with severe stroke in its studies is somewhat unclear. Although researchers had also hoped that the MERCI Retriever and other IA delivered devices would lower ICH rates compared with pharmaceutical thrombolytics delivered in the same manner, study results to date have not borne this out. ICH rates have been similar to the 10% reported from a randomized trial in which patients with MCA strokes received IA prourokinase within 6 hours of symptom onset. However, hemorrhages occurring with the use of mechanical devices have included subarachnoid and intraparenchymal hemorrhages. Because relatively few patients with stroke and angiographically visualized clots present soon after symptom onset, trials have been designed to enhance the likelihood of their completion. Study designs have included the primary use of angiographic outcomes and clots in more than 1 vascular distribution, as well as the use of historical controls. The high morbidity rate of this patient population and the cost of the procedure have led to the use of historical controls instead of a traditional control group, especially one randomized to receive placebo. However, this approach to facilitate the approval of devices compared with medical therapies has been controversial. Comparisons with medical treatments must still be done to assess clinical outcomes and the financial impact of these devices. The MR RESCUE trial is the first study to begin addressing this need. In the end, clots may best be treated with a combined approach by using various devices, lytics, and antithrombotics. In the future, referring patients with acute stroke to designated stroke centers that are equipped to offer these treatments must be considered.
MULTIMEDIA
Media file 1: AngioJet catheter, shown with its saline jets activated. Courtesy of Possis Medical, Inc, Minneapolis, MN. View Full Size Image
Media type: Photo Media file 2: Possis Neuro Catheter. Courtesy of Possis Medical, Inc, Minneapolis, MN. View Full Size Image Media type: Photo Media file 3: Endovascular Photo Acoustic Recanalization (EPAR) system. Image shows the laser energy source and catheter. Courtesy of EndoVasix, Inc, Belmont, CA. View Full Size Image
Media type: Photo Media file 4: Endovascular Photo Acoustic Recanalization (EPAR) catheter tip. Courtesy of EndoVasix, Inc, Belmont, CA. View Full Size Image
Media type: Photo Media file 5: Image of a cerebral vessel shows the Endovascular Photo Acoustic Recanalization (EPAR) catheter tip at the treatment site, in the thrombus. Courtesy of EndoVasix, Inc, Belmont, CA. View Full Size Image
Media type: Image Media file 6: EKOS Micro Infusion Catheter. The catheter has a central lumen, an end-hole infusion port, and a 1.7-MHz ultrasound element. Courtesy of EKOS Corporation, Bothell, WA. View Full Size Image
Media type: Photo Media file 7: EKOS catheter tip. Courtesy of EKOS Corporation, Bothell, WA. View Full Size Image
Media type: Photo Media file 8: Schlieren photograph of EKOS device in operation. Courtesy of EKOS Corporation, Bothell, WA.
Media type: Photo Media file 9: Concentric MERCI Retriever embedded in a clot. Courtesy of Concentric Medical, Inc, Mountain View, CA. View Full Size Image
Media type: Image Media file 10: Clot retrieved from the basilar artery by using the MERCI Retriever. Courtesy of Concentric Medical, Inc, Mountain View, CA, and Yu et al, 2003. View Full Size Image
Media type: Photo
REFERENCES
Section 11 of 11 Authors and Editors Introduction Discontinued Study: Angiojet System Discontinued Study: Latis Laser Device Discontinued Study: Endovascular Photo Acoustic Recanalization Laser Ongoing Studies: EKOS Ultrasound Device, Penumbra System Approved Device: Mechanical Embolus Removal in Cerebral Ischemia System Devices Not Evaluated in Acute-Stroke Trials Conclusions and Future Considerations
Atar S, Luo H, Nagai T, et al. Arterial thrombus dissolution in vivo using a transducer-tipped, high- frequency ultrasound catheter and local low-dose urokinase delivery. J Endovasc Ther. Jun 2001;8(3):282-90. [Medline]. Becker KJ, Brott TG. Approval of the MERCI clot retriever: a critical view. Stroke. Feb 2005;36(2):400-3. [Medline]. Berlis A, Lutsep H, Barnwell S, et al. Mechanical thrombolysis in acute ischemic stroke with endovascular photoacoustic recanalization. Stroke. May 2004;35(5):1112-6. [Medline]. Clark WM, Buckley LA, Nesbit GM. Intraarterial laser thrombolysis therapy for clinical stroke: A feasibility study. Stroke. 2000;31:307. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. Dec 1 1999;282(21):200311. [Medline]. Furlan AJ, Fisher M. Devices, drugs, and the Food and Drug Administration: increasing implications for ischemic stroke. Stroke. Feb 2005;36(2):3989. [Medline]. Greenberg RK, Ouriel K, Srivastava S, et al. Mechanical versus chemical thrombolysis: an in vitro differentiation of thrombolytic mechanisms. J Vasc Interv Radiol. Feb 2000;11(2 Pt 1):199-205. [Medline]. Gruberg L. New coronary devices. Medscape conference coverage. Presented at: 50th Annual Scientific Sessions of the American College of Cardiology. March 19, 2001; Orlando, FL. Available at: www.medscape.com. Lutsep HL, Campbell M, Clark WM. EPAR therapy system for treatment of acute stroke: Safety study results. Stroke. 2001;32:319b. Lutsep HL, Clark WM, Nesbit GM, et al. Intraarterial suction thrombectomy in acute stroke. AJNR Am J Neuroradiol. May 2002;23(5):783-6. [Medline]. Mahon BR, Nesbit GM, Barnwell SL. The North American clinical experience with the EKOS ultrasound thrombolytic drug infusion catheter for treatment of embolic stroke. Presented at: Annual Meeting of the American Society of Neuroradiology. April 26, 2001; Boston, MA. NINDS t-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. N Engl J Med. Dec 14 1995;333(24):1581-7. [Medline]. NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. Nov 1997;28(11):2119-25. [Medline]. Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. Jul 2005;36(7):1432-8. [Medline].
Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol. Jun-Jul 2006;27(6):1177-82. [Medline]. Whisenant BK, Baim DS, Kuntz RE, et al. Rheolytic thrombectomy with the Possis AngioJet: technical considerations and initial clinical experience. J Invasive Cardiol. Jul 1999;11(7):421-6. [Medline]. Wikholm G. Mechanical intracranial embolectomy: A report of two cases. Interventional Neuroradiol. 1998;4:159-64. Yu W, Binder D, Foster-Barber A, et al. Endovascular embolectomy of acute basilar artery occlusion. Neurology. Nov 25 2003;61(10):1421-3. [Medline]. Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96(4):3805. [Medline].
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