Diagnostic Imaging
November 2002

Special Section -- Cardiovascular MR

Perfusion, diffusion MR assess cerebral infarct

Use in clinical workup of stroke patients helps detect brain tissue at risk

By: Mark E. Mullins, M.D., PH.D., Pamela W. Schaefer, M.D., R. Gilberto Gonzalez, M.D., PH.D.

The accurate and timely diagnosis of ischemic stroke remains a challenge.1,2 And the advent of thrombolytic and other therapies for stroke has heightened the need for effective neuroradiology methodologies.3-6 Diffusion-weighted imaging is the diagnostic tool most frequently used for stroke, while perfusion-weighted imaging is one of the most promising diagnostic techniques for defining brain tissue at risk for infarction.

Diffusion-weighted imaging is an MR scan sequence that provides contrast based on water molecular movement.7,8 The primary application of DWI has been to diagnose acute ischemic stroke, which is in the differential diagnosis of most acute neurologic deficits.9

Diffusion is defined as the distance that molecules move in relation to random collisions.8,10 The diffusion coefficient "D" measures the diffusivity of a particle.8 The DWI sequence was first described by Stejskal and Tanner in 1965 using a spin-echo T2-weighted sequence with two additional gradient pulses. The magnitude of the gradient pulses was equal but opposite in direction along an axis,8,11 and the strength increased as distance increased. If no net movement occurred, the gradients canceled and signal intensity was equal to spin-echo T2. If net movement did occur, protons experienced the first gradient pulse at one location and the second gradient pulse at a different location. The difference in gradient pulse magnitude was proportional to the net displacement.8

In practice, molecular motion due to concentration gradients cannot be differentiated from other etiologies or corrected for available volume fraction or tortuosity.8 Therefore, only the apparent diffusion coefficient (ADC), not the true coefficient, is calculated. The environment in which water diffuses in brain is inhomogeneous, or anisotropic.10 To avoid potential pitfalls, we measure D in at least three different directions. Most commercial DWI sequences create an image by multiplying three images with a diffusion gradient applied in three orthogonal directions.8

DWI AND CLINICAL PRACTICE

For clinical studies, we routinely interpret the following sequences for potential acute infarct: DWI, exponential image (Exp), ADC map, and echo-planar spin-echo T2-weighted images. The signal intensity on DWI is linearly T2 weighted and exponentially diffusion weighted. T2 contrast may be removed by dividing the DWI by the T2-weighted image, to give an exponential image. The signal intensity on ADC maps is linearly diffusion weighted and has no T2 component.

On DWI, regions with decreased diffusion are hyperintense. Regions with elevated diffusion may be hypointense, isointense, or hyperintense, depending on both the diffusion and T2 components.8 On Exp, regions with decreased diffusion are hyperintense, and regions with elevated diffusion are hypointense. On ADC maps, regions with decreased diffusion are hypointense, while regions with elevated diffusion are hyperintense. Because DWI has both diffusion and T2 components, it offers superior conspicuity for lesions with decreased diffusion.8 Since hyperintense signal abnormality on DWI could result from the T2 component, however, review of the ADC maps or Exp is important.8

After ischemia, ADC of affected brain decreases rapidly.12-15 This mechanism is complex and not well understood.8 Cytotoxic edema develops, and the Na+/K+-ATPase and other ionic pumps fail.8,15-17 Loss of ionic gradients occurs, with a net translocation of water from the extracellular to the intracellular compartment.8 Water movement is relatively restricted in the intracellular compared with the extracellular compartment,8 and cell swelling leads to decreased size and increased tortuosity of the extracellular space. Increased intracellular viscosity, increased tortuosity of the intracellular space, and reduced cytoplasmic mobility due to breakdown of microtubules and other cellular components may also contribute to the decreased diffusion associated with acute stroke.

This decreased diffusion in ischemic human brain may be observed as early as 30 min postictally.8,18-21 ADC continues to decrease, reaching maximal reduction at one to four days and returning to baseline at one to two weeks (pseudonormalization).8 ADC is elevated thereafter. Copen and colleagues demonstrated that the course may be affected by infarct type and patient age.22 Early reperfusion following the administration of intravenous tissue plasminogen activator (tPA) may result in pseudonormalization at one to two days.23 Most authorities agree that, in the absence of thrombolysis, initial reduction in ADC nearly always progresses to neuropathologic infarction.8

Accurate and timely diagnosis of ischemic stroke is important to guide the course of treatment for each individual patient. Paramount in this decision-making process is the identification of patients with hyperacute stroke who may be candidates for thrombolysis. Conventional CT and MR scans do not reliably detect infarction in the early hours following stroke onset.24 In patients with early stroke, CT has a reported sensitivity of 38% to 45% and specificity of 71% to 100%, and conventional MR imaging has a reported sensitivity of 18% to 78% and specificity of 86% to 100%.24,25 By contrast, DWI is highly sensitive and specific in the detection of hyperacute and acute infarctions, with reported sensitivity of 82% to 100% and specificity of 86% to 100%.24,26-31

False-negative DWI occurs with brain stem or deep gray nuclei lacunar infarctions.8 It also occurs in ischemic but viable tissue (DWI normal, perfusion abnormal) that progresses to infarction. Follow-up DWI within several hours in patients with normal initial DWI but persistent strokelike deficits is useful to identify these infarctions and treat them appropriately.8

False-positive DWI may be seen as a result of T2-weighed effects rather than restricted diffusion.8 This potential error can be avoided by comparing the DWI results to the appropriate ADC map or Exp.8,32-34

PERFUSION MR

By definition, "perfusion" means capillary-level, or tissue, blood flow. The measurement of absolute perfusion is not yet widely available with MRI, but the modality is capable of measuring relative cerebral hemodynamics. Perfusion MR involves two primary types: dynamic susceptibility contrast imaging and spin tagging (arterial spin labeling).35 The former uses intravenous contrast material, has better signal to noise, and is most commonly used. The latter has the advantage of being a noncontrast technique.35

When a paramagnetic gadolinium-based contrast material is injected intravenously, it induces adjacent signal perturbations. The contrast material is relatively concentrated, and T2 and T2* effects outweigh T1 effects.35 Loss of signal related to the T2*-weighted (susceptibility) effects may be imaged and measured. We find that review of the 40 to 50 individual images per slice thus obtained is impractical. Our postprocessing technique computes the log of the signal change in each time point, which effectively converts the map of signal change to a map of 1/T2* versus time. Integrating this curve produces a map of relative cerebral blood volume (rCBV).

Deconvolution of the tissue signal versus time curve from an arterial input function, most frequently the ipsilateral middle cerebral artery, yields relative cerebral blood flow (rCBF). We then calculate maps of mean transit time (MTT) from the central volume theorem MTT = CBV/CBF. Additional methods used are beyond the scope of this review.

Potential pitfalls concerning the formulation of perfusion-weighted images include abnormalities in the vessel chosen for arterial input function, cardiac output variations such as arrhythmias, and extra- and intracranial vasculature flow variations in time and pathway.35 Evaluation of conventional images and the clinical scenario typically help reduce the potential for error.

Noncontrast PWI methodologies are analogous to MR angiography. Both create contrast by marking moving proton spins and saturating stationary tissue. Very low or absent blood flow may result in erroneous results.35 Unfortunately, a low-blood-flow state is precisely the condition in which an accurate measurement may be most critical.35 Currently, noncontrast perfusion remains more theoretical and experimental than dynamic susceptibility contrast methodologies.

Reported sensitivities for PWI in the diagnosis of acute ischemic stroke range from 74% to 84% (data provided for CBV, CBF, and MTT).35 These values are less sensitive than DWI's 90% to 99% in comparable studies and cohorts. Potential interpretive pitfalls include very small lesions, in which DWI has better spatial resolution, and early reperfusion. Reported PWI specificities range from 96% to 100 %.35,36

NEUROIMAGING OF ACUTE STROKE

Patients with clinical diagnosis of acute and hyperacute ischemic stroke undergo conventional brain MR imaging with DWI and gadolinium-enhanced PWI. The abnormal tissue seen on DWI is thought to represent the infarct core. The tissue characterized by decreased perfusion but normal diffusion is thought to represent the ischemic penumbra. This perfusion-diffusion mismatch may represent tissue at risk for infarction and potentially salvageable brain.21,26,29,35,37-40

Most infarcts increase in DWI volume with a peak at two to three days postictus.35 Compared with initial DWI abnormal signal volume, most infarcts will grow by an average of 20%.29,35,41 In our experience, the initial CBV abnormal signal volume is usually similar to the DWI lesion volume and also grows on average about 20%.35 In the instance of a rare DWI-CBV mismatch, the DWI abnormality grows into the mismatch, and DWI abnormal signal growth is then approximately 60%.35 CBF and MTT, however, usually overestimate final infarct volume.35 DWI-CBF or DWI-MTT mismatches demonstrate tissue with altered perfusion that may or may not progress to infarction depending on factors such as timing of reperfusion, collateral blood supply, and blood pressure.42,43

Perfusion ratios can better define the complex interactions of the PWI variables and their prognostic implications.35 Typically, three types of tissue are defined: infarcted core, hypoperfused penumbra that progresses to infarction, and hypoperfused penumbra that does not progress to infarction.35 Many authors have designated rCBF as the most accurate and useful PWI parameter in differentiating these regions.36,44-46 Low rCBV ratios are prognostic of infarction, but elevated rCBV ratios are not prognostic of tissue viability. Some authors have found MTT to be useful in differentiating these regions, while others have found no significant differences in MTT ratios in the three regions.36,44-47

Investigators are beginning to combine diffusion and perfusion maps to determine tissue outcome. Wu and colleagues performed a voxel by voxel analysis of abnormal signal by applying thresholding and generalized linear model algorithms with a combination of six maps: conventional T2-weighted imaging, ADC, DWI, CBV, CBF, and MTT.43 They reported that combining DWI and PWI yielded 66% sensitivity and 83% to 84% specificity for tissue voxels that proceeded to infarct.43

Dr. Mullins is a clinical assistant and co-chief fellow, Dr. Shaefer is associate director of neuroradiology and clinical director of MRI, and Dr. Gonzalez is director of neuroradiology, all at Massachusetts General Hospital, Harvard Medical School, in Boston.

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