DIFFUSION MR IMAGING OFACUTE ISCHEMIC STROKE

Javier M. Romero, MD, Pamela W. Schaefer, MD,P. Ellen Grant, MD, Lino Becerra, PhD,

and R. Gilberto González, MD, PhD

Diffusion MR imaging is now a routine com-ponent of the brain MR imaging examinationand is critical in the evaluation of the stroke pa-tient. The use of diffusion MR imaging residesin the ability to detect and provide image con-trast dependent on the translational motion ofwater through brain tissue. The method wasintroduced into clinical practice in the mid-1990s, but because of its demanding MR engi-neering requirements and primarily high-performance magnetic-field gradients, it hasonly recently undergone widespread dissem-ination. Its primary application has been main-ly in brain imaging because of its exquisite sen-sitivity to ischemic stroke—a common con-dition that appears in the differential diagnosisin virtually all patients who present with a neu-rologic complaint. Added use is found in dis-tinguishing irreversible ischemic lesions frompotentially reversible lesions characterized byvasogenic edema and providing valuable in-formation for further treatment strategies.

THE BIOPHYSIC BASIS FORDIFFUSION

How Diffusion Is Measured

Diffusion is the translation that particles ormolecules experience because of randomcollisions. It should not be mistaken by flow, in

which particles or molecules are displaced inbulk.13 Diffusion depends on several factorsincluding the type of particle or molecule un-der study, the temperature, and the environ-ment in which diffusion takes place. Diffusionis characterized by a diffusion coefficient D,which measures the diffusivity of a particle ormolecule in a certain medium. For instance, itis possible to measure D for a molecule ofwater diffusing in water or for a molecule ofethanol diffusing in water.

It is possible to measure diffusion coeffi-cients using MR techniques. Stejskal and Tan-ner70 first described the diffusion-weighted se-quence in 1965. The pulse sequence they usedwas a spin-echo (SE) T2-weighted sequencewith two extra gradient pulses that were equaland opposite in direction. This sequence en-ables the measurement of net water protonmovement in one direction at a time. To mea-sure the rate of movement along one direction(e.g., the x-direction), the magnitude of thesetwo extra gradients are equal but opposite indirection for all points at the same x location.The strength of these two balanced gradients,however, increases along the x-direction. There-fore, if a region of tissue contained water pro-tons that had no net movement in the x-direction, the extra gradients would cancel,and the signal intensity (SI) of that region of

From the Neuroradiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts

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tissue on the diffusion-weighted image (DWI)would equal its T2 SI. If a region of tissuecontained water protons that had a net move-ment in the x-direction, the water protonswould experience the first gradient pulse atone x location and the second gradient pulse ata different x location. As a result, the twogradients would no longer be equal in magni-tude and would no longer cancel. The differ-ence in magnitude would be proportional tothe velocity of the water protons in the x-direction with faster moving protons receivinga larger net dephasing pulse. The relationshipbetween the SI of a voxel and the rate ofdiffusion can generally be expressed as:

S � S0 � exp [�b � D] Equation 1

in which S0 is the SI of the T2-weighted or b�0image and b��2G�2(� � �/3), and D is thediffusion coefficient. � is the gyromagnetic ratio.G is the magnitude of, � is the width of, and �is the time between the two balanced diffusiongradient pulses. By repeating the experimentvarying b, D can be determined.

Fick’s law determines that true diffusion isthe net movement of molecules caused by aconcentration gradient. With MR imaging, mo-lecular motion caused by concentration gradi-ents cannot be differentiated from molecularmotion caused by pressure gradients, thermalgradients, or ionic interactions. Also, with MRimaging, correction is not made for the vol-ume fraction available or the increases in dis-tance traveled caused by tortuous pathways.Therefore, when measuring molecular motionwith DWI, the rate of molecular motion isinfluenced by many factors and only the ap-parent diffusion coefficient (ADC) (not the truediffusion coefficient) can be calculated. The SIof a DWI is therefore more accurately ex-pressed as:

S � S0 � exp [�b � ADC].Equation 2

With the development of high performancegradients, the original SE T2-weighted se-quence has been replaced by an echo-planar(EP) SE T2-weighted sequence. This substitu-tion has resulted in a significant decrease inimaging time and the motion artifacts, result-ing in a diffusion-weighted sequence that isclinically feasible to perform. Although not

currently available clinically, some pulse se-quences, such as line scan diffusion, spiraldiffusion, or fast SE diffusion allow DWI to beperformed on 1.5T or lower system withoutEP capabilities. These sequences have somedrawbacks such as increased imaging timecompared with EP studies, but often there areadditional benefits such as decreased suscep-tibility artifacts.

The ADC is not the same in all directions(not isotropic) in the brain. In the brain theapparent diffusion varies in different direc-tions (anisotropic), primarily because of theunderlying anatomic structure of the tissue.9

Directional physiologic processes, such as ax-olemmelic flow and capillary blood flow, alsomay play a role in determining the anisotropiccharacter of the apparent diffusion, althoughthe magnitude of these contributions isunknown. The anisotropic nature of diffusionin the brain can be appreciated by comparingimages obtained with diffusion gradients ap-plied in three different orthogonal directions(Fig. 1). In each of these images, the SI is equalto the EP T2 SI decreased by an amount relatedto the rate of diffusion in the direction of theapplied gradients. This directional informa-tion is useful when evaluating the underlyingstructure of the brain, but when looking forabsolute changes in the magnitude of the dif-fusion, directional information can beconfusing. The ADC actually is a tensor quan-tity or matrix:

ADC �

ADCxx ADCxy ADCxz

ADCyx ADCyy ADCyz

ADCzx ADCzy ADCzz

Equation 3

The diagonal elements of this matrix can becombined to give information about the mag-nitude of the apparent diffusion:

Magnitude of ADC � 1/3 (ADCxx �

ADCyy � ADCzz), Equation 4

whereas the off diagonal elements provideinformation about the interactions betweenthe x, y, and z directions. For example, ADCyx

gives information about the probability thatmolecules initially moving in the x-directionend up moving in the y-direction because ofthe forces driving apparent diffusion.35 Images

36 ROMERO et al

displaying the magnitude of the ADC are usedin clinical practice.

Diffusion-gradient pulses are applied in onedirection at a time. The resulting image hasinformation about the direction and the mag-nitude of the ADC (Fig. 1). To create an imagethat is related to only the magnitude of theADC, at least three of these images must becombined. The simplest way to do this is tomultiply the three images created with thediffusion-gradient pulses applied in three dif-ferent but orthogonal directions. The cube rootof this product is the DWI (Fig. 2). It is impor-tant to understand that the DWI has T2 con-trast and contrast caused by differences inADC. To remove the T2 contrast, the DWI canbe divided by the EP SE T2 image (or b�0image), to give an exponential image (Fig. 3).Alternatively, an ADC map, which is an imagein which SI is equal to the magnitude of theADC, can be created.

Most commercial diffusion-weighted se-quences create a DWI by combining three im-ages with a diffusion gradient applied in threeorthogonal directions, and with each of thethree images acquired using a single acquisi-tion (1 NEX [number of excitations]). Instead ofobtaining images with b�0 s/cm2 and b�1000s/cm2 and solving for ADC using Equation 2,

the ADC usually is determined graphically.This is done by obtaining two image sets, onewith a very low but nonzero b-value and onewith b�1000 s/cm2. By plotting ln (S) versus bfor these two b-values, the ADC can be deter-mined from the slope of this line.

For the authors’ clinical studies, the DWI,exponential image, ADC map, and EP T2images are routinely available for review.Because the ADC values of gray and whitematter are similar, typically there is nocontrast between gray and white matter onthe exponential image or the ADC map. Thecontrast between gray and white matter seenon the DWI is caused by T2 contrast. Thisresidual T2 component that is present on theDWI deems it important to view either theexponential image or ADC map in conjunc-tion with the DWI. In lesions such as acutestrokes, the T2 and diffusion effects causeincreased signal on the DWI. Therefore, theauthors find that they identify regions ofdecreased diffusion best on DWI. The expo-nential image and ADC maps are used toexclude “T2 shine through” as the cause ofthe increased signal on DWI. The exponentialimage and ADC map are useful for detectingareas of increased diffusion that may bemasked by T2 effects on the DWI.

Figure 1. Anisotropic nature of diffusion in the brain. Axial diffusion-weighted images (b � value of 1000s/mm2, effective gradient of 14 mT/m; TR/TE 7500/minutes; matrix 128 � 128; field of view (FOV) 200� 200 mm, slice thickness 6 mm with 1-mm gap) with the diffusion gradients applied in three orthogonaldirections: the x (A), y (B), and z (C) axes demonstrate anisotropy. The signal intensity decreases whenthe white-matter tracts run in the same direction as the diffusion gradient because water protons movepreferentially in this direction. Note that the corpus callosum (black arrow) is hypointense when thegradient is applied in the x (right–left) direction, the frontal and posterior white matter (arrowhead) arehypointense when the gradient is applied in the y (anterior–posterior) direction, and the corticospinaltracts (white arrows) are hypointense when the gradient is applied in the z (superior–inferior) direction.(From Schaefer PW, Grant PE, Gonzalez RG: Diffusion-weighted MR imaging of the brain. Radiology217: 331–345, 2000; with permission.)

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 37

The power of DWI is related to its ability toprovide information about the physiologicstate of brain tissue in vivo. This ability ispossible because DWI is very sensitive to themicroscopic motion of water protons, whichin turn, is influenced by the underlyingmicroscopic structure of the tissue. Factorsrelated to the microscopic tissue structurethat can potentially influence DWI includethe relative size of the intracellular versusextracellular space, intracellular versus extra-cellular rates of diffusion, tortuosity of thespace through which the water moleculediffuse, membrane permeability, capillaryflow, and temperature. Under disease states,and in particular ischemic stroke, there aremarked alterations in the tissue microstruc-

ture, which give rise to marked changes inthe DWI SI. These factors are examined andtheir implications for the observed ADC arediscussed in the following text.

Cell Structure

Many of the previously mentioned mecha-nisms can have a valid contribution to theobserved change in ADC, however, there is afactor that has not been discussed much in theliterature. Most of the models assume that theintracellular properties remain the same dur-ing an ischemic insult. The collapse of theadenosine triphospate (ATP)-producing cyclesnot only affects ion pumps, however, it alsoaffects the continuous production of neurofila-

Figure 2. Calculating the signal intensity of the isotropic diffusion-weighted image (DWI) (b � value of1000 s/mm2; effective gradient of 14 mT/m; TR/TE 7500/min; matrix 128 � 128; FOV 400 � 200 mm,slice thickness 6 mm with 1-mm gap). The signal intensities of the three axial images, each with adiffusion gradient applied in one of three orthogonal directions, are multiplied together. Here the diffusiongradients were applied along the x, y, and z axes. The signal intensity of the isotropic DWI essentiallyis the cube root of the signal intensities of these three images multiplied together. Note that both T2contrast and the rate of diffusion contribute to the signal intensity of the isotropic DWI. (From SchaeferPW, Grant PE, Gonzalez, RG. Diffusion-weighted MR imaging of the brain. Radiology 217: 331–345,2000; with permission.)

38 ROMERO et al

ments and neurotubules, both structures nec-essary to maintain the cytostructure, the trans-port of vesicles and organelles, and the removalof debris. The cytoskeleton conforms to a tightstructure in neurons and their processes andfills a significant fraction of the cytoplasm. Itsalignment in the neuron processes explains theanisotropy observed in water in white matter.Furthermore, vesicle and organelle transportby neurotubules might impart an added mo-bility to water molecules. The cessation ofproduction of ATP disrupts this transport ef-fectively, and reduces the mobility of water.

Neurofilaments and neurotubules are theresult of the polymerization of actin and tu-bulin, they require the hydrolysis of adenosinediphosphate (ADP) (guanosine diphosphate

[GDP]) to ATP (guanosine triphosphate [GTP]to be able to polymerize. The absence of ATP(GTP) will result in an increase of monomericactin and tubulin and the reduction of thecorresponding filaments and tubules.

MR experiments performed on cancer cellshave shown that the increase in diffusion con-stants might be caused by the collapse of thefilaments and tubules happening during celldivision.12 Further MR experiments have mea-sured ADC of several metabolites in animalbrains under ischemic conditions, and it wasfound that they also experience a reduction intheir mobility. Hence, these results seem topoint out that a significant viscosity changetakes place in the cytoplasm that affects themobility of water and metabolites.

Figure 3. To remove the T2 contrast in the isotropic axial DWI (b � value of 1000 s/mm2; effectivegradient of 14 mT/m; TR/TE 7500/min; matrix 128 � 128; FOV 200 � 200 mm, slice thickness 6 mmwith 1-mm gap), the axial DWI is divided by the axial echo planar (EP) T2. The resulting image is calledthe exponential image because its signal intensity is exponentially related to the apparent diffusioncoefficient (ADC). SE � spin echo. (From Schaefer PW, Grant PE, Gonzalez RG. Diffusion-weightedMR imaging of the brain. Radiology 217: 331–345, 2000; with permission.)

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 39

Tortuosity

If there are no barriers to water protonmovement as in a glass of water, the tortu-osity is low, and the apparent diffusion isequal to the free diffusion of water. In thenormal brain, there are cellular structures thatrestrict the movement of water. As a result,molecules cannot move in a straight path andmust follow tortuous routes to cover thesame total distance. This results in a reduc-tion in the measured ADC to a value less thanthe free diffusion of water. At the onset ofcytotoxic edema, fluid shifts from the extra-cellular to the intracellular space. This resultsin a decrease in the size and an increase intortuosity of the extracellular space. Becausethe measured ADC is inversely proportionalto the square of the tortuosity factor, �,increases in tortuosity of the extracellularspace that occur with ischemia have a signifi-cant effect on ADC.

Temperature

The temperature of the medium affects dif-fusion of molecules; the higher the tempera-ture, the more collisions a molecule experi-ences and farther away it can move. The ADCappears higher in hotter areas and lower incolder areas. Hence, a reasonable theory is thatunder ischemic conditions, the underperfusedtissue might lose temperature, and the diffu-sion constant in water will diminishcorrespondingly. To test that hypothesis, a se-ries of careful experiments were performed innormal animals in which the diffusion con-stant of the parenchyma was followed as thebody temperature was changed. There was agood correlation between normal ADC andtemperature. Given this relationship, it is pos-sible to estimate the required change in tem-perature necessary to accommodate the ob-served change in ADC under ischemicconditions. It was found that the reduction ofADC could be explained with a drop in tem-perature of 12°C. Further experiments by thisgroup found that the ischemic area experi-ences a drop in temperature of the order of1.5°C when the temperature of the animal isregulated. Furthermore, Minamisawa et al43

have performed experiments in which the body

temperature was not regulated under ischemicconditions and observed a change of up to 5°Cin 15 minutes.

Experiments by Davis et al15 found that thesignificant change in ADC takes place after thefirst 3 to 4 minutes of ischemic conditions.

All of these results indicate that the ob-served decrease in ADC cannot be explainedby a temperature effect because it requires adrop in temperature larger than the ones ob-served, and the time required for this drop totake place is much shorter than the time mea-sured.

Macroscopic Motion

MR has the ability to distinguish if mol-ecules have been moving in a medium; unfor-tunately, diffusion measurements are not ableto distinguish random motion from flow or“macroscopic” motion originated in blood orcerebrospinal fluid (CSF) pulsation. The ob-served ADC might be a combination of truediffusion with blood/CSF pulsation. If a majorcomponent of ADC is caused by macroscopicmotion, then a sudden cessation of it (like theone in ischemic conditions) should produce asignificant change in ADC. Careful experi-ments performed by Davis et al,15 in whichADC values were measured every 10 secondsin an occlusion model (rats) and cardiac arrest(cats), have shown that for the occlusion modelthe ADC of the affected area remained essen-tially the same for 3 to 4 minutes before asignificant drop was observed. For the cardiacmodel, the time delay was of the order of 2minutes. In both cases, a sudden cessation ofblood/CSF pulsation did not produce an im-mediate change in ADC as expected, but wasdelayed for 2 to 4 minutes. Hence, blood/CSFpulsation might not contribute significantly tothe observed drop in ADC.

Cell Swelling

The energy reserves held in the brain arevery limited. The lack of oxygen and glucosequickly results in the failure of the cells toproduce ATP and maintain ion pumps as wellas other energy-related processes working inthe cell. There is a significant release ofglutamate to the extracellular space.73,76

40 ROMERO et al

Furthermore, the mechanisms that regulatecell volume (volume-regulated anion chan-nels) are ATP driven, and the lack of it resultsin their inability to remove excess water, re-sulting in a net gain of water intracellularly. Tomeasure water displacement, investigators haverelied on impedance measurements.53 Basi-cally, electrical current is run through the pa-renchyma, and because of the electrical prop-erties of the membrane, any electricalmeasurement corresponds to electrical currenttraveling through the extracellular water. Achange in the electrical current will indicate achange in the extracellular water. Impedancemeasurement under ischemic conditions indi-cates a shift of water from the extracellularspace to the intracellular one. This result showsthat there is a cytotoxic edema taking placeduring an ischemic process. In the same model,after reperfusion was established, a net in-crease in the water content of the brain wasobserved (vasogenic edema), probably result-ing from the breakdown of the blood–brainbarrier and a net influx of an ultrafiltrate intothe parenchyma.

Based on these results, it was theorized thatthe observed ADC changes arise because ofthe shift of extracellular water to the intracel-lular space.52

This concept is further supported by thefact that the cytoplasm is full of organellesand other organic structures such as thecytoskeleton and vesicles, which might sig-nificantly reduce the diffusion coefficient ofwater. Hence, if the observed ADC can bethought of as arising from the contribution ofextracellular and intracellular water, the over-all observed ADC could have the followingrelationship:

ADC � fintra ADCintra � fextraADCextra.

Equation 5

This equation assumes that there is rapidwater exchange between both compartments.fintra (fextra) represents the relative fraction ofintra- (extra-) cellular water.

Under ischemic conditions, fintra increases andthe observed ADC should become smaller.With reported estimates of ADCintra andADCextra, however, it is not possible to explainthe observed 40% reduction in ADC even if all

of the extracellular water is absorbed intra-cellularly.

Membrane Permeability

An assumption made in the previous equa-tion is that the permeability of the membraneis not affected and the membrane remainshighly permeable to water. The first few mod-els of diffusion including membrane perme-ability were based on parallel membranes withknown permeability. These models were ableto explain the observed reduction in ADC ifthe permeability changed. Recently, however,models based on a three-dimensional array ofcells indicate that the permeability does notplay a major role in the diffusion constant. Thisis especially valid for the time scale of mostdiffusion measurements (20 to 200milliseconds).

Diffusion MR Imaging of theIschemic Stroke

Reliability of Diffusion-weighted Imagingin Acute Stroke

Early detection of stroke has gained impor-tance with the recent advent of thrombolytictherapies. The detection of hypoattenuationon CT scan and hyperintensity on T2-weighted MR images requires a substantialincrease in tissue water. Therefore, CT and MRimaging cannot reliably detect infarction at theearliest time points. For infarctions imagedwithin 6 hours after stroke onset, reportedsensitivities are 38% to 45% for CT scan and18% to 46% for MR imaging.22,46 For infarctionsimaged within 24 hours, one study reported asensitivity of 58% for CT scan and 82% for MRimaging11 (Fig. 4).

Because DWIs are sensitive to the moleculardiffusion of water and because they have muchhigher contrast to noise ratio, however, theyare highly sensitive and specific in the detec-tion of hyperacute and acute infarctions.Reported sensitivities range from 88% to100% and specificities range from 86% to100%.5,22,38,41,57,61,68 Lesions with decreased diffu-sion strongly correlate with irreversibleinfarction. Acute neurologic deficits suggest-

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 41

ing stroke but without restricted diffusion aretypically caused by transient ischemic attacks,peripheral vertigo, migraines, seizures, intra-cerebral hemorrhages, dementia, functional dis-orders, amyloid angiopathy, and metabolicdisorders.

After 24 hours, however, infarctions usuallycan be detected as hypoattenuated lesions onCT scans and hyperintense lesions on T2- andfluid-attenuated inversion-recovery (FLAIR)-weighted images. Diffusion imaging also isuseful in this setting. Older patients com-monly have T2 hyperintense abnormalities thatmay be indistinguishable from acute lesionson T2- and FLAIR- weighted images. The acuteinfarctions are hyperintense on DWI and hy-pointense on ADC maps, however, whereasthe chronic foci usually are isointense on DWIand hyperintense on ADC maps because ofelevated diffusion. In one study in which therewere indistinguishable acute and chronic white-matter lesions on T2-weighted images in 69%of patients (Fig. 5), the sensitivity and speci-ficity of DWI for detecting the acute subcorti-cal infarction were 94.9% and 94.1%,respectively.68

False-negative DWI lesions have been re-ported for lacunar brainstem or deep graynuclei infarctions.3,22,38 Some of these lesionswere seen on follow-up DWI (Fig. 6). Otherswere presumed on the basis of clinical deficits.False-negative DWI images also occur in pa-tients with regions of decreased perfusion (i.e.,decreased cerebral blood volume, decreased

cerebral blood flow, or increased mean transittime), which are abnormal on follow-up DWI.This is consistent with ischemic but viabletissue, which progresses to infarction. There-fore, early follow-up imaging should be ob-tained in patients with normal DWI and per-sistent stroke-like deficits so that infarctions orareas at risk for infarction are identified andtreated as early as possible.

Cerebral abscess (with restricted diffusionon the basis of viscosity) and tumor (withrestricted diffusion on the basis of dense cellpacking) show similarities to acute ischemicstroke on DWI and have been reported asproducing false-positive DWI. When these le-sions are viewed in combination with otherroutine T1- and T2-weighted MR images, theyusually can be differentiated from acuteinfarctions.

Evolution of Acute Stroke onDiffusion-weighted Imaging

Animal studies show that restricted diffu-sion associated with acute ischemia has beendetected as early as 10 minutes to 2 hours aftervascular occlusion.32,33,42,45,47–49 The ADCs mea-sured at these time points are approximately16% to 68% below those of normal tissue. Inanimals, diffusion coefficients pseudonormal-ize (the ADCs are similar to those of normalbrain tissue; however, the tissue is infarcted) atapproximately 48 hours and are elevated

Figure 4. The sensitivity of DWI for hyperacute stroke is demonstrated in a 57-year-old patient withless than 6 hours of right-sided numbness. Unremarkable CT scan and T2 MR sequence. The DWIdemonstrates hyperintense signal in the left postcentral gyrus.

42 ROMERO et al

thereafter. In adult humans, the time course ismore prolonged.39,65,66,75 The authors have ob-served restricted diffusion associated with acuteischemia 30 minutes after a witnessed ictus.The peak signal reduction of ADC is at 8 to 32hours, remaining significantly reduced for 3 to5 days. This decreased diffusion is markedlyhyperintense on DWI (a combination of T2and diffusion weighting) and hypointense onADC images. The ADC returns to baseline at 1to 4 weeks. This most likely reflects persis-

tence of cytotoxic edema (associated with de-creased diffusion) and development of va-sogenic edema and cell membrane disruptionleading to increased extracellular water (asso-ciated with increased diffusion). At this point,a stroke usually is mildly hyperintense be-cause of the T2 component on the DWI andisointense on the ADC images. Thereafter, theADC is elevated secondary to the accumula-tion of extracellular water, tissue cavitation,and gliosis. There is slight hypointensity, isoin-

Figure 5. Patient with acute onset of right-sided weakness with nonspecificsmall vessel ischemic changes. The axial DWI images (b � value of 1000s/mm2; effective gradient of 14 mT/m; TR/TE 6000/108; matrix 256 � 128;FOV 400 � 200 mm, slice thickness 6 mm with 1-mm gap) clearly demon-strate the acute infarction in the left internal capsule and corona radiata.Fluid-attenuated inversion-recovery (FLAIR) images (TR/TE 10000/141, Tl2200 milliseconds, echo train length (ETL) 8, matrix 256 � 192; FOV 240 �240 mm, slice thickness 5 mm with 1-mm gap, 1 NEX [number of excita-tions]) demonstrate multiple white-matter lesions in which acute and chroniclesions (white arrow) cannot be differentiated.

Figure 6. False-negative DWI images. Patient with acute onset of left-sided weakness. CT, T2, and DWIimages obtained at 4 hours are unremarkable. Follow-up T2 images demonstrate a right medullaryinfarction (white arrow). F/U � follow-up.

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 43

tensity, or hyperintensity on the DWI (de-pending on the strength of the T2 anddiffusion components), and increased SI onADC maps.

This time course pattern is not alwaysfollowed. Early reperfusion may cause pseudo-normalization (i.e., return to baseline of theADC reduction associated with acute ischemicstroke) at a much earlier time point: as early as1 to 2 days in humans who received intrave-nous recombinant tissue plasminogen activa-tor (rtPA) administered within 3 hours afterstroke onset.40 Other studies have demon-strated different ADCs (e.g., low, pseudonor-mal, and elevated) within one area of infarc-tion, suggesting different temporal stages oftissue evolution toward infarction.51 In spite ofthese variations, human studies demonstratethat initial reduction in the ADC nearly alwaysundergoes infarction.

Diffusion Combined with Perfusion MRImaging in Stroke Assessment

Diffusion MR combined with perfusion MRmay provide more information than eithertechnique alone in the evaluation of strokeevolution. Perfusion imaging involves the de-tection of a decrease in signal resulting fromthe susceptibility of T2* effects of gadoliniumduring the passage of a bolus of gadoliniumthroughout the intracranial vasculature.59,74 Thisdecrease of signal will be low in the setting ofan area with reduced perfusion in which thegadolinium concentration is low. A variety ofhemodynamic images may be constructed fromthese data, including relative cerebral bloodvolume (rCBV), relative cerebral blood flow(rCBF), mean transit time (MTT) and time topeak (TTP) maps.56,57,59,61

The role of perfusion MR imaging in con-junction with DWI is not understoodcompletely. The most important clinical im-pact may result from defining the ischemicpenumbra, a region that is ischemic, but stillviable and may infarct if not treated. Conse-quently, investigation is focused on strokeswith a diffusion-perfusion mismatch. Proxi-mal occlusions are far more likely to result ina diffusion-perfusion mismatch than distal orlacunar infarctions. Operationally, the diffu-sion abnormality is thought to represent theischemic core and the region characterized bynormal diffusion, but abnormal perfusion is

thought to represent the ischemic penumbra.Definition of the penumbra is complicated be-cause of the multiple hemodynamic param-eters that may be calculated from the perfu-sion MR imaging data.

With arterial occlusion, brain regions withdecreased diffusion and decreased perfusionare believed to represent nonviable tissue orthe core of an infarction.5,33,45,49,57,61,60,66 The ma-jority of infarcts increase in volume on DWIwith the peak volumetric measurementsachieved at 2 to 3 days post ictus. The initialDWI lesion volume correlates highly with thefinal infarct volume and with strokes, growingat an average of approximately 20%.5,58

The initial cerebral blood volume (CBV) le-sion volume usually is similar to the initialDWI lesion volume, and correlates highly withfinal infarct volume and with strokes, growingat an average of 20%. When there is a rareDWI-CBV mismatch, the DWI lesion volumestill correlates highly with final infarct vol-ume, but the predicted lesion growth is ap-proximately 60%. The CBV also correlateshighly with final infarct volume with no pre-dicted lesion growth. In other words, whenthere is a DWI-CBV mismatch, the DWI ab-normality grows into the size of the CBVabnormality.

Cerebral blood volume and MTT correlatepoorly with final infarct volume, but greatlyoverestimate final infarct volume on average.Many more strokes are characterized by aDWI-CBF or a DWI-MTT mismatch comparedwith a DWI-CBV mismatch. In the authors’experience, a DWI-CBF or DWI-MTT mis-match demonstrates regions with altered he-modynamics but is not predictive of increasedlesion growth. Others have reported that DWI-CBF and DWI-MTT mismatches do predictincreased lesion growth, however, and the sizeof the mismatch is predictive of amount oflesion growth43 (Fig. 7).

In small vessel infarctions (i.e., perforatorinfarctions and distal middle cerebral arteryinfarctions [MCA]), the initial perfusion anddiffusion lesion volumes usually are similar,and the diffusion lesion volume increases onlyslightly with time. A diffusion lesion largerthan the perfusion lesion or a diffusion lesionwithout a perfusion abnormality usually oc-curs with early reperfusion. In this situation,the diffusion lesion usually does not changesignificantly over time.

44 ROMERO et al

Figure 7. Diffusion-perfusion mismatch in a left MCA stroke. A, Axial DWI images (b � value of1000 s/mm2; effective gradient of 14 mT/m; TR/TE 6000/108; matrix 256 � 128; FOV 400 � 200mm, slice thickness 6 mm with 1-mm gap), demonstrate left middle cerebral artery infarct involvingthe basal ganglia, insular region, and the deep white matter. B, Axial cerebral blood volume (CBV)images (spin-echo planar technique; 0.2 mmol/kg gadopentetate dimeglumine (Magnevist, BerlexLaboratories, Wayne, NJ); 51 images per slice; TR/TE 1500/75; matrix 256 � 128; FOV 400 � 200mm; slice thickness 6 mm with 1-mm gap), demonstrate decreased dynamic CBV in the left middlecerebral artery (MCA) territory, which is larger than the abnormalities identified in the DWI images.C, Follow-up DWI images demonstrate that the infarct has extended into regions, which showedto be normal in the initial DWI, but demonstrated to be hypoperfused on the CBV maps.

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 45

In animals treated with neuroprotectiveagents following MCA occlusion, there is sta-bilization of the size of the early diffusion MRlesion; in other words, the expected growth ofthe early lesion is not present.69,63 The benefit ofthis therapy has not been convincingly dem-onstrated in humans’ trials.

Reversibility of Diffusion-weightedImaging of Stroke Lesions

In the absence of thrombolysis in humans,reversibility of DWI hyperintense lesions isvery rare. In a review of DWI reversible le-sions, Karonen et al28 could identify only 21 ofthousands of DWI hyperintense lesions (in theliterature and at their institution) that demon-strated reversibility. The etiologies were acutestroke or transient ischemic attack (TIA), (threepatients) (Fig. 8), transient global amnesia(seven patients), status epilepticus (four pa-tients), hemiplegic migraine (three patients),and venous sinus thrombosis with seizure (fourpatients). Gray matter ADC ratios were 0.64 to0.79. White-matter ADC ratios were 0.20 to0.87.

In the setting of intravenous and intra-arterial thrombolysis, decrease in lesion sizefrom the initial DWI abnormality to the finalinfarct or partial reversibility of the initial DWIabnormality is common (Fig. 9). Kidwell et al30

reported that of 7 patients treated with intra-venous thrombolysis, 5 lesions decreased insize from the initial DWI abnormality to thefinal infarct.

In another recent study of 24 patients whounderwent thrombolysis, 6 patients had par-tial reversibility of their initial DWI lesionswith average decrease in infarct size of ap-proximately 37%. In the reversible regions, themean ADC ratios obtained on a slice-by-slicebasis ranged from 0.8 to 1.1 with 90% above0.85. In the irreversible regions, ADC ratiosranged from 0.66 to 0.96 with 90% below 0.89.In the reversible regions, the mean DWI ratiosobtained on a slice-by-slice basis ranged from1.08 to 1.55 with 90% below 1.28. In the irre-versible regions, DWI ratios ranged from 1.19to 2.06 with 90% above 1.27.24,42

The ADC and DWI values are similar tothreshold values reported in animalexperiments.26,54 Both demonstrated a thresh-old ADC ratio of 0.77 for energy failure in ratssubject to temporary or permanent MCAocclusion. Furthermore, a separate experimentdemonstrated that there was good agreementbetween tissue with an initial ADC ratio of lessthan 0.80 and histologic infarction.25 In a ratmodel of cerebral ischemia, Minematsu et al44

reported a DWI ratio of 1.186 in tissue thatinitially had a DWI abnormality following MCAocclusion for 1 hour, but did not progress toinfarction and a DWI ratio of 1.397 in tissue,which did progress to infarction.

In animal models, a threshold time for re-versibility also has been established. In gen-eral, when the MCA is temporarily occludedfor 1 hour or less in animals, the diffusionlesion size significantly decreases or resolves,whereas when the MCA is occluded for 2

Figure 8. Patient with transient ischemic attack characterized by right-sided weakness, which resolvedwithin 24 hours. T2, FLAIR, and DWI sequences demonstrate hyperintensity, consistent with acuteinfarction, in the left caudate nucleus and left occipital lobe.

46 ROMERO et al

hours or more, the lesion size remains thesame or increases.23,32,45,44,50 A threshold time forreversibility has not been established inhumans.

Correlation of Diffusion MR Imagingwith Clinical Outcome

Recent studies have demonstrated that thecombination of DWI images with the NationalInstitutes of Health Stroke Scale Score (NIHSS)may predict clinical recovery of cortical in-farcts better than any factor alone.44 Previousstudies have demonstrated statistically signifi-cant correlations between the acute diffusionMR lesion volume and both acute and chronicneurologic assessment tests including theNIHSS, the Canadian Neurologic Scale, the

Barthel Index, and the Rankin Scale measure-ments.6,37,60,66,72 This correlation is stronger withcortical strokes and weaker with penetratingartery strokes.6,66 This presentation can be ex-plained by the anatomic location of the lesion;for example, an ischemic lesion in a majorwhite-matter tract can produce a more pro-found neurologic deficit than a cortical lesionof the same size. In addition, there is a sig-nificant correlation between the acute ADCratio (ADC of lesion/ADC of normal contralat-eral brain) and chronic neurologic assessmentscales.66,72 The assessment of acute and chronicstroke with perfusion MR also has been evalu-ated by several trials showing significantcorrelation.37,60 In one study, patients who hadPerfusion-weighted image (PWI) lesion vol-umes larger than diffusion MR lesion volumes

Figure 9. Partially reversible ischemic lesion. Patient with acute right-sided hemiparesis imaged at 2hours. The axial DWI (b � value of 1000 s/mm2; effective gradient of 14 mT/m; TR/TE 6000/108; matrix256 � 128; FOV 400 � 200 mm, slice thickness 6 mm with 1-mm gap) shows hyperintensity in the leftposterior frontal and anterior parietal lobes (arrow). The patient was treated with intra-arterial recom-binant tissue plasminogen activator (rtPA). Follow-up study performed 2 days later demonstrates thatthe final infarct is smaller than the initial DWI abnormality.

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 47

(perfusion, diffusion mismatches) had worseclinical outcomes with larger final infarctvolumes.7 In another study, patients with earlyreperfusion had smaller final infarct volumesand better clinical outcomes.66 The ability ofperfusion MR and diffusion MR to predictclinical outcome may be useful in the selectionof patients for further treatment with throm-bolytic or neuroprotective agents.

Transient Ischemic Attacks

Nearly 50% of patients with transient is-chemic attacks have lesions with restricteddiffusion, which usually is less than 15 milli-meters in maximal diameter.2,21 The compro-mised vascular territory detected on the dif-fusion images and the clinical symptomsusually correlate. In one study, 20% of thelesions were not seen in the follow-up study;the lesions could have been reversible or causedby atrophy no longer visible on conventionalMR images.2 Kidwell et al29 detected how in-formation obtained from diffusion MR imag-ing changed the suspected etiologic mecha-nism and the suspected localization of anischemic lesion in over one third of patients.Ay et al2 demonstrated that statistically signifi-cant independent predictors of identifying theselesions on diffusion MR imaging were previ-ous nonstereotypic TIA, cortical syndrome, or

an identified stroke mechanism, and the studysuggested an increased stroke risk in patientswith these lesions.

Other Stroke Mimics

Patients with acute neurologic deficits thatmimic acute stroke or TIA generally fall intotwo categories: (1) nonischemic lesions withno acute abnormality on routine or DWI; and(2) vasogenic edema syndromes that mimicacute infarctions on conventional imaging.Nonischemic syndromes with no acute abnor-mality identified on diffusion or conventionalMR imaging and reversible clinical deficitsinclude peripheral vertigo, migraines, sei-zures, dementia, functional disorders, amy-loid angiopathy, and metabolic disorders.22,38,41

When patients with these syndromes presentand their DWI are normal, it can be predictedthat they are not undergoing infarction; theyare spared unnecessary anticoagulation andfurther stroke evaluations.

Syndromes with potentially reversible va-sogenic edema include eclampsia, hyperten-sive encephalopathy (Fig. 10), cyclosporin tox-icity, other posterior leukoencephalopathies,venous thrombosis, HIV encephalopathy, andhyperperfusion syndrome following carotidendarterectomy. Patients with these syn-dromes frequently present with neurologic defi-

Figure 10. Patient with hypertension, lethargy, and confusion. DWI demonstrate mild periventricularhyperintensity secondary to T2 shine-through and are hyperintense on the apparent diffusion coefficient(ADC) maps. These findings are most likely secondary to vasogenic edema; the cause is hypertensiveencephalopathy.

48 ROMERO et al

cits, which raise the question of acute ischemicstroke, or with neurologic deficits such as head-ache or seizure, which suggest vasogenicedema. Ischemic stroke, however, still is astrong diagnostic consideration. Furthermore,conventional imaging cannot always differen-tiate cytotoxic from vasogenic edema. Bothtypes of edema produce T2 hyperintensity ingray or white matter. Consequently, posteriorleukoencephalopathies sometimes can mimicposterior cerebral artery infarctions. Hyperper-fusion syndrome following carotid endarter-ectomy can resemble MCA infarctions. HIVencephalopathy can produce lesions in a va-riety of distributions, some of which appearsimilar to arterial infarctions. Deep venousthrombosis can produce bilateral thalamic hy-perintensity, which is indistinguishable from“top of the basilar” syndrome arterialinfarctions.

Diffusion MR imaging, however, can reli-ably distinguish vasogenic from cytotoxicedema. Vasogenic edema is characterized byelevated diffusion caused by a relative in-crease in water in the extracellular compart-ment where water is more mobile and cyto-toxic edema is characterized by restricteddiffusion. Vasogenic edema is characterizedon the diffusion MR images by hypointenseto slightly hyperintense signal because theseimages have both T2 and diffusion contribu-tions. When vasogenic edema is hyperintenseon the diffusion MR images, it can mimichyperacute or subacute infarction. On ADCimages, cytotoxic edema caused by ischemiais always hypointense for 1 to 2 weeks andvasogenic edema always is hyperintense.Therefore, comparison of the ADC imageswith diffusion MR images is mandatory foraccurate diagnosis.

Differentiating vasogenic from cytotoxicedema affects patient management and out-come. The incorrect diagnosis of a vasogenicedema syndrome as acute ischemia couldlead to unnecessary and potentially danger-ous use of thrombolytics, antiplatelet agents,anticoagulants, and vasoactive agents. Fur-thermore, failure to correct relative hyperten-sion could result in increased cerebral edema,hemorrhage, seizures, or death. Misinterpre-tation of acute ischemic infarction as a va-sogenic edema syndrome would discourageanticoagulation, evaluation for an embolic

source, and liberal blood pressure control,which could increase the risk of recurrentbrain infarction.

Other Entities with Restricted Diffusion

There are a number of entities other thanacute ischemic stroke characterized by re-stricted diffusion. These entities are character-ized by hyperintensity on DWI and exponen-tial images and by hypointensity on ADCimages. It is important not to mistake theseentities for ischemic stroke.

Infections

Pyogenic infections, including abscess cavi-ties and empyemas, are characterized by re-stricted diffusion, which is believed to resultfrom the relatively high viscosity and cellular-ity of pus.17,31,64 Occasionally abscess cavitiesmay mimic acute infarction on T2-weightedimages. If there is any clinical reason to sus-pect infection, gadolinium-enhanced imagescan easily distinguish the two entities. Abscesscavities are rim enhancing, whereas acutestrokes usually do not enhance.

Herpes virus lesions are characterized byrestricted diffusion. This effect likely resultsfrom cytotoxic edema developing in tissueundergoing necrosis. Herpes frequently can bedifferentiated from acute ischemic stroke be-cause the lesions involve more than one vas-cular territory. These lesions, however, cansimulate stroke on conventional and diffusionMR images when they seem to be in a singlevascular territory. For example, medial tempo-ral lobe lesions can simulate posterior cerebralartery strokes. If there is clinical suspicion thata medial temporal lobe lesion could representherpes rather than an acute stroke, a poly-merase chain reaction test should be performed.

Diffusion MR images in patients withCreutzfeldt Jakob disease (CJD) have demon-strated lesions characterized by low ADCs incortex and basal ganglia.4,16,62 The restricted dif-fusion observed with CJD is consistent withspongiform change. If diffuse, the pattern ofrestricted diffusion can appear similar to thatseen with hypoxia. If more focal, the patterncan resemble that seen with acute infarct. CJDand ischemia, however, usually can be distin-guished easily because they have very differ-

DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 49

ent clinical presentations. Acute ischemic strokeis characterized by sudden onset of an acuteneurologic deficit, whereas CJD is classicallycharacterized by progressive dementia, myo-clonic jerks, and periodic sharp-wave electro-encephalography activity.

Diffuse Axonal InjuryIn humans, diffuse axonal injury (DAI) le-

sions may be characterized by restricted dif-fusion as long as 18 days after injury.36 Experi-mental head trauma studies have suggestedthat this effect may be secondary to ischemicor neurotoxic edema. Ito et al27 demonstratedno significant change in brain ADCs when ratswere subjected to impact acceleration traumaalone. When trauma was coupled with hy-poxia and hypotension, however, the ADCs inrat cortex and thalami decreased significantly.They concluded that ischemic cytotoxic edemacaused the reduced ADCs and neuronal injury.Using an impact acceleration model in rats toinduce severe closed head injury, Barzo et al8

demonstrated significantly reduced ADCs inthe caudate nuclei and cortex from 1 hour toseveral weeks following injury. They con-cluded that the mild reductions in cerebralblood flow in their model are not sufficient tocause ischemic edema and neurotoxic edemamost likely causes the reduced ADCs and neu-ronal injury.

When evaluating lesions with restricted dif-fusion in head trauma, it is important to assesslesion location. Both diffuse axonal injury le-

sions and strokes secondary to vascular injuryhave restricted diffusion. If lesions seem to bein a vascular distribution (e.g., the MCA ter-ritory) rather than in locations characteristic ofDAI (i.e., splenium of the corpus callosum,gray–white matter junctions, deep white mat-ter, deep gray nuclei, brainstem), then addi-tional imaging should be performed to assessfor vascular injury. Additional MR imagingsequences should include fat-saturated axialT1-weighted images (to look for the eccentricT1 hyperintensity characteristic of dissection)and MR angiography.

Demyelinative Lesions

Although most acute multiple sclerosisplaques demonstrate increased diffusion,14,34

acute multiple sclerosis plaques rarely haverestricted diffusion. This may result from cy-totoxic edema or increased inflammatory cel-lular infiltration with little extracellular edema.These plaques may demonstrate a ring-enhancing pattern, which differentiates themfrom acute infarctions. However, occasionallynonenhancing acute plaques may resembleacute infarctions. In a young patient with awhite-matter lesion characterized by restricteddiffusion, it is important to search for otherlesions. Associated deep white-matter lesionsmay suggest a demyelinating process, whereasassociated cortical lesions may suggest an is-chemic process.

Figure 11. A 79-year-old man with blurred vision, dizziness, apraxia, and motor dysphasia. CT scandemonstrates an area of hypodensity in the inferior parietal lobe and occipital lobe. The FLAIR imagesdemonstrate hyperintensity of the same area described. The DWI demonstrate no restriction in thediffusion. The patient diagnosis is metastatic disease.

50 ROMERO et al

Mass Lesions

Solid, central necrotic, and cystic portions ofmost intra-axial mass lesions have elevateddiffusion.1,18,55 Mass lesions such as lymphoma,however, rarely have restricted diffusion com-pared with normal brain tissue. The restricteddiffusion is believed to result from dense tu-mor cellularity. These lesions usually are eas-ily differentiated from acute infarct becausethey appear mass like, are T2 hypointense, andenhance with gadolinium. In addition, pa-tients with mass lesions usually have a moreindolent presentation than those with acuteischemic events. Occasionally small lesions areconfused with acute infarcts, however, when apatient presents with an acute neurologic defi-cit and gadolinium is not administered (Fig.11). In this case, follow-up imaging will dem-onstrate no change in lesion size or lesionenlargement rather than tissue loss and gliosis.

Hemorrhage

Oxyhemoglobin is characterized by re-stricted diffusion and is hyperintense to nor-mal brain tissue on DWI. This may indicate therelative restriction of water movement insidethe red blood cell.79 Oxyhemoglobin, with sig-nal characteristics similar to acute infarct onT1- and T2-weighted images (hypointense onT1 and hyperintense on T2), can mimic acutestroke in the early hyperacute period. Duringthis time period, CT can easily differentiatebetween hemorrhage and stroke. Hemorrhageis hyperattenuating, whereas stroke ishypoattenuating. Because of T2 prolongation,extracellular methemoglobin also is hyperin-tense on DWI. Extracellular methemoglobinmay have a higher ADC than normal braintissue, indicating the increased mobility of wa-ter in the extracellular space, and can be dif-ferentiated from infarct with ADC maps orexponential images. Also, unlike ischemic le-sions, extracellular methemoglobin is T1hyperintense.

SUMMARY

Diffusion MR imaging provides unique in-formation about the physiologic state of is-chemic tissue. It is highly sensitive and specific

in the detection of acute and hyperacute is-chemic stroke and has greatly improved thediagnosis and treatment of acute stroke. TheDWI abnormality provides information aboutclinical outcome and final infarct size. Diffu-sion combined with perfusion MR imagingprovides information about the operationalischemic penumbra and final infarct size. Dif-fusion MR imaging seems to be promising inthe evaluation of candidates for thrombolysis.

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DIFFUSION MR IMAGING OF ACUTE ISCHEMIC STROKE 53