WO2003096898A1

WO2003096898A1 - Method of assessing ischemia in a patient

Info

Publication number: WO2003096898A1
Application number: PCT/US2003/015368
Authority: WO
Inventors: Steven Warach; Lawrence L. Latour
Original assignee: Steven Warach; Latour Lawrence L
Priority date: 2002-05-17
Filing date: 2003-05-16
Publication date: 2003-11-27
Also published as: AU2003234605A1

Abstract

The invention provides a method of assessing ischemia, stroke or reperfusion injury in a patient that includes administering a contrast agent to a patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to assess the ischemia, stroke, or reperfusion injury of the patient. The invention also provides a method of determining the effectiveness of a therapeutic protocol for the treatment or prevention of reperfusion injury in a patient that has previously suffered an ischemic event that includes beginning the therapeutic protocol, administering a contrast agent to the patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to determine the effectiveness of the therapeutic protocol for the treatment or prevention of reperfusion injury.

Description

METHOD OF ASSESSING ISCHEMIA IN A PATIENT

This application is being filed as a PCT international patent application in the names of Steven Warach and Lawrence L. Latour, both U.S. citizens and residents, on 16 May 2003, designating all countries.

Field of the Invention

The invention relates to methods of diagnosing and treating patients suspected of having ischemia to the brain and/or other organs. More specifically, the invention relates to methods of diagnosing and treating patients who may be more susceptible to reperfusion injury to the brain and/or other organs.

Background of the Invention

Stroke is a condition characterized by a sudden loss of blood circulation to an area of the brain, which results in a corresponding loss of neurological function. Strokes can be hemorrhagic or ischemic. Hemorrhagic strokes occur when a blood vessel in the brain bursts, spilling blood into the spaces surrounding the brain cells. Ischemic strokes, which account for about 80% of all strokes, are caused by an abrupt blockage of arteries leading to the brain, often due to formation of a blood clot. Blood clots can either block the artery where they are formed (thrombosis), or can dislodge and become trapped in distal arteries (embolism). Another type of ischemia is not due to blood clots, but instead due to decreases in cerebral blood flow (hypoperfusion) from diagnostic (e.g., balloon test occlusion of the internal carotid artery) or therapeutic procedures (e.g., carotid endarterectomy, arterial stent placement, coronary artery bypass grafting, other surgery of the heart or blood vessels) or hypotension is the setting of stenotic cerebral or pre-cerebral arteries.

Stroke is diagnosed by utilizing one or a combination of a number of different diagnostic tools, including but not limited to, obtaining a medical history, a thorough physical examination, computerized tomography (CT) scan, and various types of magnetic resonance imaging (MRI) scans. The goal of stroke diagnosis is to verify that a stroke has occurred, identify the type of stroke, find the locus of the occlusion, and/or delineate the extent of the injury. Because the mechanisms of injury are different, the treatment for the different types of stroke are also different. For ischemic stroke, the most obvious therapy is to restore blood flow to the affected area of the brain as soon as possible after the event, resulting in the reperfusion of the ischemic brain tissue. Currently, the only approved pharmacological intervention is tissue plasminogen activator (t-PA), a thrombolytic ("clot-buster"), which must be given very early after the onset of neurological deficit.

Although reperfusion is the most widely accepted treatment of ischemic strokes, it is not without risk. Studies have demonstrated that rapid restoration of blood flow may paradoxically exacerbate cerebral injury through a cascade of events termed "reperfusion injury". Reperfusion injury is not restricted to the brain or to the occurrence of stroke. Reperfusion injury has important deleterious clinical effects on the endothelium of the blood vessel wall, the heart, lungs, kidneys, liver, skeletal muscle, intestines, and other viscera. The mechanism of reperfusion injury is currently unknown, however there is thought to be a strong association to an inflammatory response. There is currently no known therapy for treating reperfusion injury in humans once it has occurred but it is an important area of ongoing research.

Therefore, there remains a need for methods that may be capable of detecting patients in which additional injury may occur upon reperfusion and for methods of monitoring the effects of therapeutic intervention in order to help minimize reperfusion injury.

Summary of the Invention

One embodiment of the invention provides a method of assessing ischemia in a patient that includes administering a contrast agent to a patient, acquiring a fluid-attenuated inversion-recovery (FLAIR) image, and observing the presence or absence of hyperintense acute reperfusion marker (HARM) on the acquired image to assess the ischemia of the patient.

Another embodiment of the invention provides a method of assessing stroke in a patient that includes administering a contrast agent to a patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to assess the stroke of the patient. Yet another embodiment of the invention includes a method of assessing reperfusion injury in a stroke patient that includes administering a contrast agent to the patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to assess reperfusion injury of the patient. Even another embodiment of the invention includes a method of assessing the integrity of the blood brain barrier in a patient that includes administering a contrast agent to the patient, acquiring a FLAER image, and observing the presence or absence of HARM on the acquired image to assess the integrity of the blood brain barrier. A further embodiment of the invention includes a method of determining the effectiveness of a therapeutic protocol for the treatment or prevention of reperfusion injury in a patient that has previously suffered an ischemic event that includes beginning the therapeutic protocol, administering a contrast agent to the patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to determine the effectiveness of the therapeutic protocol for the treatment or prevention of reperfusion injury.

Brief Description of the Drawings

Figure 1 depicts an image of a patient exhibiting hyperintense acute reperfusion marker (HARM) acquired using FLAIR-DWI. Figure 2 depicts DWI, FLAIR, and GRE images of a patient at one, four, and twenty-eight hours past the onset of stroke.

Detailed Description of the Preferred Embodiment

One embodiment of the invention includes methods of using fluid-attenuated inversion-recovery (FLAIR) magnetic resonance imaging (MRI) and/or other sequences providing similar image contrast to assess ischemia, stroke or reperfusion injury, in a patient.

The phrase, "assess ischemia" as used herein means determining if an ischemic event has occurred in an organ of the body, determining the location of a blockage, determining the severity of the damage to an organ from the ischemia, determining the integrity of an organ barrier, determining the likelihood that a patient who has previously suffered from an ischemic event will or has already suffered from reperfusion injury, or any combination thereof.

The phrase "assess stroke" as used herein means determining if a stroke has occurred in a patient, determining the type of stroke, determining the location of the blockage, determining the severity of the damage to the brain from the stroke, determining the integrity of the blood brain barrier (BBB), determining the likelihood that a stroke patient will suffer from reperfusion injury, or any combination thereof.

The phrase "assess reperfusion injury" means determining if reperfusion injury has occurred, determining the extent of reperfusion injury, determining if reperfusion injury is likely to occur, or any combination thereof.

The phrase "determine the effectiveness of a therapeutic protocol" means determining if a therapeutic protocol is more or less likely to result in the occurrence of reperfusion injury in a stroke patient, determining if a therapeutic protocol is effectively diminishing the damage or the prevalence of reperfusion injury, or combinations thereof.

A "patient" as used herein means any human being. An "experimental stroke model" as used herein means any animal used to model stroke in humans including but not limited to, rodents, feline, canine, and non-human primates. In some embodiments of the invention, the patient is thought to have suffered a stroke, or may have some injury, which is the result of a stroke.

Assessing ischemia or stroke in a patient or an experimental model can utilize a number of different techniques, including but not limited to, MRI techniques referred to as FLAIR techniques. FLAIR techniques are MRI techniques that function to image the brain parenchyma while suppressing the signal from cerebral spinal fluid (CSF). They are often used in place of conventional T₂- weighted imaging of stroke patents, primarily to identify sub-acute lesions that appear hyperintense on T -weighted images without the confounding intensity from the CSF. FLAIR techniques exploit the marked difference in Tj relaxation time constant between parenchyma and CSF. By performing a magnetic resonance (MR) technique known as inversion recovery as a preparation to a T₂-weighted imaging sequence, it is possible to select an operator chosen parameter, inversion time (TI), such that the image is collected at the exact instance that the signal from the CSF is passing through a "null" point, or essentially zero signal intensity. Success of the CSF suppression relies on properly selecting TI in relation to the Ti of the CSF. While in practice the TI value is generally optimized interactively, once it is determined for a given set of imaging parameters, it can be kept fixed for all patients and still obtain satisfactory suppression. For example, for conventional T₂ spin-echo FLAIR sequences with long repetition times, TI ranges from about 1.2 to 3.0 seconds. In one embodiment TI equals about 2.2 seconds.

Numerous incarnations of the FLAIR technique exists, including standard spin-echo (SE) FLAIR, fast spin-echo (FSE) FLAIR, echo planar imaging (EPI) FLAIR, and FLAIR diffusion weighted imaging (FLAIR-DWI). These techniques and the steps for acquiring such images are well known to those of skill in the art having read this specficiation. A FLAIR technique, as defined above, is a MRI technique that is capable of suppressing the signal from CSF. The differences in the various FLAIR techniques differ in terms of acquisition time, resolution, signal-to- noise ratio of the image, and susceptibility to patient motion and other artifacts. Suppression of CSF in all versions depends on properly setting TI according to the Ti of the CSF, a technique which is well known to those of skill in the art having read this specification. Many MRI techniques, as well as FLAIR techniques used in methods of the invention, utilize contrast agents. A contrast agent is a compound that functions to make at least one portion of the area to be imaged appear differently on a MRI than does at least one other portion of the area to be imaged. A number of different types of contrast agents can but need not be utilized in methods of the invention. An example of a contrast agent utilized in one embodiment of the invention is a chelate of a paramagnetic ion.

In one embodiment of the invention, any chelate of a paramagnetic ion can be utilized. Paramagnetic gadolinium ions are one example of a paramagnetic ion that is suitable as a contrast agent in methods of the invention. Often the gadolinium ions alone can be potentially toxic when injected intravenously (IN) at or near doses needed for clinical imaging. Chelation of these ions is needed to reduce the acute toxicity and increases the elimination rate thereby reducing the chance of long term toxicity. One such chelate is gadolinium diethylenetriaminepentaacetic acid (Gd- DTPA). Gd-DTPA was the first IN MR contrast agent to be approved for human use. Gadolinium has a large magnetic moment, exceeded only by Dysprosium(III) and Holmium(III), which leads to its paramagnetic properties at low concentrations. This large magnetic moment is related to its seven unpaired orbital electrons. Gd- DTPA is distributed in the intravascular space but does not cross an intact blood- brain-barrier (BBB) and is normally excreted rapidly by glomerular filtration. The chemical structure of Gd-DTPA is seen below.

In one embodiment of a method of the invention, Gd-DTPA is utilized as a contrast agent. Other contrast agents that can be used include, but are not limited to, paramagnetic and superparamagnetic contrast agents; contrast agents containing gadolinium, dysprosium, holmium, iron, iron oxide; magnetic nanoparticle based MR contrast agents; superparamagnetic nanoparticles; ultrasmall superparamagnetic iron oxides; ferumoxides; ferumoxtran-10; Gd(DTPA)2-; Gd(DOTA)-; and

Gd(DTPA-BMA); Gadomer-17; gadobutrol; gadoteridol; gadobenate dimeglumine; gadophrin-2; gadophrin-3; MIOΝ-47; amino-CLIO; Tat-CLIO; superparamagnetic iron oxide agent FeO-BP A; gadolinium polymer WIN 22181 ; very small superparamagnetic iron oxide particles; SH U 555 A; magnetodendrimers; magnetically labeled stem and progenitor cells; MION-46L iron oxide nanoparticles; dendrimer-encapsulated particles, and MD-100.

Methods of the invention can include administration of a contrast agent. In one embodiment of the invention, the contrast agent is a paramagnetic contrast agent. In methods of the invention for the assessment of stroke, if the blood brain barrier (BBB) is modified, a contrast agent may leave the vasculature and enter the peri vascular space and the brain parenchyma. In one embodiment of the invention, the contrast agent, such as Gd-DTPA can be administered, intravenously for example, by injection at a dose of about 0.1 mM/kg to about 0.3 mM/kg. In one embodiment, the amount of Gd-DTPA that is administered is about 0.2 mM/kg. The amount of a different contrast agent that is used would depend on the specific contrast agent. However, generally, an increased dosage of any paramagnetic contrast agent will likely be related to an increased probability of seeing hyperintense acute reperfusion marker (HARM).

Generally, the rate at which the contrast agent is administered depends at least in part on the specific contrast agent that is utilized. Determination of an applicable administration rate would be well within one of skill in the art. In an embodiment of the invention wherein Gd-DTPA is administered to the patient, the rate of IN injection can be about 0.1 ml/sec to about 10 ml/sec. In another embodiment, the rate of administration is about 5 ml/sec.

After administration of the contrast agent, imaging is performed some time later. Generally, the imaging is performed from about 10 minutes to about 7 days after administration of the contrast agent. In one embodiment of the invention, the FLAIR imaging is performed about 5 minutes after the administration of the contrast agent.

In the case of assessing ischemia, of which stroke assessment is an example, uptake of the contrast agent by the tissue in the brain allows the assessment of the stroke by enhancing the suspect tissue in the MR image and is referred to as post- contrast enhancement. Post-contrast enhancement of parenchyma can also occur during the later stages of stroke when the parenchyma and endothelial wall become damaged. However, by the time such enhancement occurs during stroke, it is generally thought to be too late for acute therapeutic intervention. Contrast agent is also routinely administered during acute stroke to help diagnose cerebral perfusion abnormalities by a method known as dynamic contrast enhancement or perfusion weighted imaging (PWI). In such studies, a contrast agent such as Gd-DTPA, for example, is administered intravenously by rapid injection (about 5 ml/sec) of about 0.2 ml/kg. Simultaneously, rapid MR images are acquired in a time series. As the contrast agent traverses the vasculature, the regions of no or low cerebral blood flow can be visualized by the lack of contrast agent in the perfused vascular territory. One method of visualizing the area of a perfusion abnormality is by creating an image of the mean transit time (MTT) of the contrast agent traversing the perfused tissue. MTT images can be used to evaluate a perfusion deficit, or the reperfusion of a vascular territory after therapeutic intervention, such as with thrombolytic t-PA

In one embodiment of a method of the invention, assessing ischemia in a patient is concerned with the effects of reperfusion. Reperfusion of some stroke patients causes a hyperintense acute reperfusion marker (referred to herein as HARM) in the CSF space on FLAIR images. It is thought, but not relied upon that the HARM is most likely caused by an abrupt BBB disruption that is the result of reperfusion. Similar to the contrast enhanced technique aforementioned, it is thought that Gd-DTPA crosses the BBB and enters the perivascular space and CSF. However in contrast, parenchymal enhancement is not necessary in order to observe this phenomena. In one embodiment of a method of the invention, the accumulation of contrast agent in the CSF alters the TI relaxation time constant of the CSF, thereby resulting in poor suppression of CSF in the FLAIR imaging technique. Because FLAIR techniques depend on a constant TI value for the CSF in order to obtain adequate signal suppression, they are sensitive to changes in TI of CSF caused by a contrast agent. In another embodiment of the invention, direct mapping of TI relaxation time constants allows the effect of contrast agent on CSF to be directly probed and may be a quantitative indicator of BBB permeability. Such direct mapping methods would be known to those of skill in the art having read this specification.

On FLAIR images of patients exhibiting HARM, the subarachnoid space and leptomeninges appear hyperintense relative to both the pre-contrast FLAIR and to homologous, unaffected regions in the contralateral hemisphere. In the most dramatic cases, CSF spaces appear far brighter than adjacent gyri. An example of an image acquired of a patient exhibiting HARM is seen in Figure 1. The images were acquired using a FLAIR-DWI sequence (at b=0). Both images are of the same location, separated by approximately 3 hrs in time. Marked hyperintensity of the leptomeninges in the left hemisphere (right side of the images) is observable in the post-GD-DTPA image.

Enhancement of the subarachnoid space generally begins in the hemisphere containing the primary ischemic stroke, but is not necessarily limited to the same vascular territory. HARM has been both observed to first appear as a bilateral leptomeninges enhancement as well as to progress bilaterally in patients where it first appears as a unilateral leptomeningial enhancement. HARM can also be seen as a hyperintensity of the CSF, relative to pre-contrast images, of the ventricles. Ventricular enhancement has been observed on initial post-contrast image as well as progressing to such a state in patients that first exhibited unilateral or bilateral enhancement of the leptomeninges. HARM also can be seen as a hyperintensity, relative to pre-contrast images, of the vitreous humor of the orbits. HARM has been observed as early as 3.5 hours after the onset of the ischemic stroke, and enhancement has remained as late as 5 days. HARM has been found to resolve in all patients with follow-up examination at 30 or 90 days.

In one embodiment of the invention, the presence or absence of HARM in a FLAIR acquired image can be utilized to assess ischemia. In such an embodiment, a contrast agent is administered to a patient, a FLAIR image is acquired, and the presence or absence of HARM is observed on the acquired image. In another embodiment, the contrast agent is a paramagnetic contrast agent. In yet another embodiment, the FLAIR image is acquired at least about 10 minutes after the contrast agent is administered to a patient.

In another embodiment of a method of the invention, stroke is assessed in a patient or a stroke model by administering a contrast agent to a patient, acquiring a FLAIR image, and observing the presence or absence of HARM on the acquired image to assess stroke in the patient or the stroke model.

In another embodiment, the presence or absence of HARM in a FLAIR acquired image can be utilized to assess reperfusion injury in a patient who has had a stroke. In such an embodiment, a contrast agent is administered to a patient, a FLAIR image is acquired, and the presence or absence of HARM on the acquired image is observed, wherein HARM, if present indicates that that patient may be more likely to have already suffered from or may suffer from reperfusion injury in the future.

In yet another embodiment of the invention, the presence or absence of HARM in a FLAIR acquired image can be utilized to assess the integrity of the

BBB. In such an embodiment, a contrast agent is administered to a patient, a FLAIR image is acquired, and the presence or absence of HARM is observed, wherein the presence of HARM indicates that the integrity of the BBB has been compromised. In a further embodiment of the invention, the presence or absence of HARM in a FLAIR acquired image can be utilized to determine the effectiveness of a therapeutic treatment. In such an embodiment, a contrast agent is administered to a patient, a FLAIR image is acquired, and the presence, absence, or severity of HARM is observed, wherein the presence, absence or severity of HARM is an indicator of the efficacy of a therapeutic treatment that is being administered to the patient.

Working Examples

EXAMPLE 1: Study of 150 stroke patients 150 patients presenting with acute stroke symptoms were screened using a standardized imaging protocol. Imaging was performed on acute patients as part of the standard care pathway using a 1.5 Tesla clinical MR system (GE Medical Systems, Milwaukee, WI) and follow-up scans were performed under informed consent (NIH protocol number Ol-N-0007). The protocol included, EPI-FLAIR, conventional and FLAIR DWI (b= {0, 1000} ), FSE-FLAIR, gradient recalled echo (GRE), and bolus-tracking perfusion weighted imaging (PWI), all having the following relevant parameters: 24 cm field of view, 7 mm thick axial-oblique slices aligned with the AC-PC, 20 slices contiguous, interleaved, and co-localized. Images were acquired using DWI with, TR/TE= 6000/95ms, an acquisition matrix of 128x128, and with both b=0 and b=1000 isofropically weighted, using PWI with an acquisition matrix of 64x64, Δt=2 s, 25 time points, 0.2 ml/kg Gd-DTPA contrast agent injected at a rate of 5 ml/sec, using FLAIR T2 weighted imaging with an FSE sequence having TR/TE=9000/85 ms, TI=1750 ms and a 256x128 matrix, and using GRE T2* imaging with TR/TE = 800/20 ms and a 256x192 matrix. Maps of mean transit time (MTT), an indicator of vascular perfusion, and EPI-FLAIR images from all patients having two or more PWI studies were reviewed by an observer blinded to the clinical history, for patients exhibiting HARM and for evidence of reperfusion.

Of the 150 patients with a diagnosis of acute stroke and two or more PWI, no patients had HARM on their initial scan, which was always prior to administration of contrast agent. Overall, 42 (28%) patients had images on which HARM appeared. HARM was observed as early as 3.5 hours post-ictus, and remained as late as 5 days. In the 24 patients that had follow up exams, HARM was found to resolve in all. In 12 of the 42 patients, HARM was observed predominately as a focal enhancement of the sulci in the vascular territory of the DWI lesion, then progressed bilaterally and diffusely over subsequent studies to include the ventricles and the vitreous humor of the orbits. In the remaining 30, it first appeared bilaterally. The maximum decrease in TI of CSF was estimated to be about 60%.

In 35 of 42 patients with HARM, and 61 of 108 without HARM, there were perfusion deficits on the initial MTT scan (p = 0.002 for association with initial perfusion deficit). As shown in Table 1, in 29 of 35 (83%) with HARM, an improvement in MTT from baseline to repeat scan was found, providing evidence that reperfusion has occurred. However, in only 27 of 61 (44%) patients without HARM there was evidence of reperfusion by MTT. The association of HARM with evidence of reperfusion was statistically significant (p=0.0002). The association between reperfusion and HARM and its imaging appearance suggests that it is related to reperfusion.

TABLE 1

Patient did not Patient did have have Reperfusion reperfusion Totals

HARM was not

27 34 61 present on FLAIR image HARM was present

6 on FLAIR image 29 35

Totals 33 63 96

EXAMPLE 2: Patient with ischemic stroke undergoing hemorrhagic transformation: A 77 yr old male patient who woke up normal at 6:30 am had sudden onset of slurred speech, weakness, and right visual field cut, was witnessed to fall down at approximately 7:00 am and was brought to the emergency room for triage at 7:30 am. Neurological examination upon arrival indicated patient had a decreased level of consciousness, left gaze deviation, visual field cut, facial weakness, hemiparesis, and was unable to follow commands and was mute. The NIH stroke scale score (NΓHSS) of the patient was 26. MRI began at 8:10 am and revealed a large area of hyperintensity on DWI of the left side (see Figure 2), corresponding to an occlusion of the left anterior circulation as demonstrated by magnetic resonance angiography and a large perfusion deficit on MTT maps (not shown). FLAIR indicated that there was no sub-acute lesion and HARM and GRE images indicated no hemorrhage.

Patient was treated with t-PA at 9:05 and re-imaged 2 hrs later. Patient was noted to improve, NIHSS=21, with a notable reduction of the lesion volume on DWI. Partial reperfusion was noted on both the MTT and MRA. HARM was present in the subarachnoid space in the same vascular territory as the lesion. No hemorrhage was noted on GRE at this time point.

A third MRI scan was acquired 28 hours post onset. The lesion had expanded on DWI. Further improvement in perfusion was noted on MTT and MRA showed obvious vessels. Hyperintensity of the parenchyma was seen on the FLAIR images with noted mass indicating vasogenic edema and hydrocephalus. Hypointensity was evident on the GRE indicating hemorrhagic transformation. Patients conditioned slightly worsened, but stroke scale score remained at NIHSS=22.

In this patient, treatment with TV t-PA resulted in recanalization of the occluded vessel and the appearance of HARM in the imaging set acquired 4 hours after stroke onset. It is thought that the appearance of HARM in this patient indicated an acute disruption of the blood brain barrier and was a herald for a severe form of reperfusion injury, hemorrhagic transformation, demonstrated on MRI at 28 hrs.

The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended.

Claims

WE CLAIM:

1. A method of assessing ischemia in a patient comprising the steps of: a) administering a contrast agent to a patient; b) acquiring a fluid-attenuated inversion-recovery image; and c) observing the presence or absence of hyperintense acute reperfusion marker on the acquired image to assess the ischemia of the patient.

2. The method of claim 1, wherein said contrast agent is administered intravenously.

3. The method of claim 1, wherein said contrast agent comprises a paramagnetic contrast agent.

4. The method of claim 3, wherein said paramagnetic contrast agent comprises a gadolinium containing contrast agent.

5. The method of claim 4, wherein said contrast agent comprises Gd- DTP A.

6. The method of claim 5, wherein said Gd-DTPA is administered at a dosage of from about 0.1 mM/kg to about 0.3 mM/kg.

7. The method of claim 5, wherein said Gd-DTPA is administered at a rate of about 0.1 ml/sec to about 10 ml/sec.

8. The method of claim 1, wherein said fluid-attenuated inversion- recovery image is acquired from about 10 minutes to about 7 days after administration of said contrast agent.

9. The method of claim 1, wherein said assessment of the ischemia is utilized to determine the likelihood that the patient will or has already suffered from reperfusion injury.

10. A method of assessing stroke in a patient comprising the steps: a) administering a contrast agent to a patient; b) acquiring a fluid-attenuated inversion-recovery image; and c) observing the presence or absence of hyperintense acute reperfusion marker on the acquired image to assess the stroke of the patient.

11. The method of claim 10, wherein said contrast agent is administered intravenously.

12. The method of claim 10, wherein said contrast agent comprises a paramagnetic contrast agent.

13. The method of claim 12, wherein said paramagnetic contrast agent comprises a gadolinium containing contrast agent.

14. The method of claim 13, wherein said contrast agent comprises Gd- DTPA.

15. The method of claim 14, wherein said Gd-DTPA is administered at a dosage of from about 0.1 mM/kg to about 0.3 mM/kg.

16. The method of claim 15, wherein said Gd-DTPA is administered at a rate of about 0.1 ml/sec to about 10 ml/sec.

17. The method of claim 10, wherein fluid-attenuated inversion-recovery image is acquired from about 10 minutes to about 7 days after administration of said contrast agent.

18. The method of claim 10, wherein said assessment of the stroke is utilized to determine the likelihood that the patient will or has already suffered from reperfusion injury.

19. A method of assessing reperfusion injury in a stroke patient comprising the steps: a) administering a contrast agent to the patient; b) acquiring a fluid-attenuated inversion-recovery image; and c) observing the presence or absence of hyperintense acute reperfusion marker on the acquired image to assess the reperfusion injury of the patient.

20. The method of claim 19, wherein said contrast agent is administered intravenously.

21. The method of claim 19, wherein said contrast agent comprises a paramagnetic contrast agent.

22. The method of claim 19, wherein said paramagnetic contrast agent comprises a gadolinium containing contrast agent.

23. The method of claim 22, wherein said contrast agent comprises Gd- DTPA.

24. The method of claim 23, wherein said Gd-DTPA is administered at a dosage of from about 0.1 mM/kg to about 0.3 mM/kg.

25. The method of claim 24, wherein said Gd-DTPA is administered at a rate of about 0.1 ml/sec to about 10 ml/sec.

26. The method of claim 25, wherein said fluid-attenuated inversion- recovery image is acquired from about 10 minutes to about 7 days after administration of said contrast agent.

27. The method of claim 19, wherein said assessment of the reperfusion injury is used to determine the likelihood that a stroke patient will suffer from reperfusion injury.

28. A method of assessing the integrity of the blood brain barrier in a patient comprising the steps: a) administering a contrast agent to the patient; b) acquiring a fluid-attenuated inversion-recovery image; and c) observing the presence or absence of hyperintense acute reperfusion marker on the acquired image to assess the integrity of the blood brain barrier.

29. The method of claim 28, wherein said contrast agent is administered intravenously.

30. The method of claim 28, wherein said contrast agent comprises a paramagnetic contrast agent.

31. The method of claim 28, wherein said paramagnetic contrast agent comprises a gadolinium containing contrast agent.

32. The method of claim 31, wherein said contrast agent comprises Gd- DTPA.

33. The method of claim 32, wherein said Gd-DTPA is administered at a dosage of from about 0.1 mM/kg to about 0.3 mM/kg.

34. The method of claim 33, wherein said Gd-DTPA is administered at a rate of about 0.1 ml/sec to about 10 ml/sec.

35. The method of claim 34, wherein said fluid-attenuated inversion- recovery image is acquired from about 10 minutes to about 7 days after administration of said contrast agent.

36. The method of claim 28, wherein the presence of hyperintense acute reversion marker, if present indicates that the integrity of the blood brain barrier has been compromised.

37. A method of determining the effectiveness of a therapeutic protocol for the treatment or prevention of reperfusion injury in a patient that has previously suffered an ischemic event comprising the steps: a) beginning the therapeutic protocol; b) administering a contrast agent to the patient; c) acquiring a fluid-attenuated inversion-recovery image; and d) observing the presence or absence of hyperintense acute reperfusion marker on the acquired image to determine the effectiveness of the therapeutic protocol for the treatment or prevention of reperfusion injury.

38. The method of claim 37, wherein said contrast agent is administered intravenously.

39. The method of claim 37, wherein said contrast agent comprises a paramagnetic contrast agent.

40. The method of claim 37, wherein said paramagnetic contrast agent comprises a gadolinium containing contrast agent.

41. The method of claim 40, wherein said contrast agent comprises Gd- DTPA.

42. The method of claim 41, wherein said Gd-DTPA is administered at a dosage of from about 0.1 mM kg to about 0.3 mM/kg.

43. The method of claim 42, wherein said Gd-DTPA is administered at a rate of about 0.1 ml/sec to about 10 ml/sec.

44. The method of claim 43, wherein said fluid-attenuated inversion- recovery image is acquired from about 10 minutes to about 7 days after administration of said contrast agent.