Definition: The type of MRI sequence used to identify areas of an organ, such
as the brain, which have recently been damaged or injured.
Introduction
Diffusion-weighted imaging
BASIC CONCEPTS OF DW MR
IMAGING
CLINICAL APPLICATIONS
Ischemic Stroke
Masses
Intracranial Infections
Trauma
Hemorrhage
Demyelination
CONCLUSION
The Physics and
Representation of Diffusion
Molecular Displacement,
Diffusion, and Flux
Diffusion Contrast
Encoding
Diffusion
Spectrum Imaging
Technique
Diffusion-weighted MR Imaging
ADC and Trace
Diffusion Tensor Imaging and Derived Scalars
Diffusion Tensor Imaging
and Diffusion Spectrum Imaging
Diffusion
MR Tractography
The MRI machine is set
to detect small restrictions in the movement of water molecules inside the
injured areas. These small changes, which are commonly referred to as
"areas of restricted diffusion," are detected by the MRI machine and
ultimately appear as bright spots inside the organ being investigated.
Introduction
Diffusion-weighted
magnetic resonance (MR) imaging, boosted by established successes in clinical
neurodiagnostics and powerful new applications for studying the anatomy of the
brain in vivo, has been an important area of research in the past decade.
Current clinical applications are based on many different types of contrast,
such as contrast in relaxation times for T1- or T2-weighted MR imaging, in time
of flight for MR angiography, in blood oxygen level dependency for functional
MR imaging, and in diffusion for apparent diffusion coefficient (ADC) imaging. Even
more advanced techniques than these are in use today for the study of neural
fiber tract anatomy and brain connectivity.
Over the
years, increasingly complex data acquisition schemes have been developed, while
the theoretical foundations of diffusion MR imaging have come to be better
understood. For the radiologist who wants to use these techniques in clinical
practice and research, it is important to understand a few key principles of
diffusion imaging so as to select the appropriate technique for answering a
specific question. The article therefore begins with an explanation of the
physics of water diffusion and the ways in which the great complexity of
diffusion in the brain, the main organ targeted for investigation with
diffusion MR imaging, can be described. Next, the basic principles that
underlie diffusion contrast encoding with MR imaging are described to enable
the reader to understand the relation between the MR imaging signal and
diffusion as well as the limitations of simple diffusion imaging techniques.
This discussion provides a context for the description of diffusion spectrum
imaging, the most complex diffusion MR imaging technique, which provides the
largest body of information and the greatest detail. With the general
principles of diffusion MR imaging in mind, the range of current diffusion MR
imaging techniques, from the simplest to the most sophisticated, is then
reviewed with an emphasis on the underlying assumptions and hypotheses,
advantages, and potential pitfalls of each. The technical requirements
(hardware capabilities, acquisition time) for each type of diffusion imaging
examination, and the types of data provided by each type, are compared.
Diffusion-weighted magnetic resonance (MR)
imaging provides image contrast that is different from that provided by
conventional MR techniques. It is particularly sensitive for detection of acute
ischemic stroke and differentiation of acute stroke from other processes that
manifest with sudden neurologic deficits. Diffusion-weighted MR imaging also
provides adjunctive information for other cerebral diseases including
neoplasms, intracranial infections, traumatic brain injury, and demyelinating
processes. Because stroke is common and in the differential diagnosis of most
acute neurologic events, diffusion-weighted MR imaging should be considered an
essential sequence, and its use in most brain MR studies is recommended.
Diffusion-weighted (DW) magnetic resonance (MR) imaging provides
potentially unique information on the viability of brain tissue. It provides
image contrast that is dependent on the molecular motion of water, which may be
substantially altered by disease. The method was introduced into clinical
practice in the middle 1990s, but because of its demanding MR engineering
requirements—primarily high-performance magnetic field gradients—it has only
recently undergone widespread dissemination. The primary application of DW MR
imaging has been in brain imaging, mainly because of its exquisite sensitivity
to ischemic stroke—a common condition that appears in the differential
diagnosis in virtually all patients who present with a neurologic complaint.
Because DW MR imaging uses fast (echo-planar) imaging technology,
it is highly resistant to patient motion, and imaging time ranges from a few
seconds to 2 minutes. As a consequence, DW MR imaging has assumed an essential
role in the detection of acute brain infarction and in the differentiation of
acute infarction from other disease processes. DW MR imaging is also assuming
an increasingly important role in the evaluation of many other intracranial
disease processes.
Diffusion-weighted magnetic resonance (MR)
imaging, boosted by established successes in clinical neurodiagnostics and
powerful new applications for studying the anatomy of the brain in vivo, has
been an important area of research in the past decade. Current clinical
applications are based on many different types of contrast, such as contrast in
relaxation times for T1- or T2-weighted MR imaging, in time of flight for MR
angiography, in blood oxygen level dependency for functional MR imaging, and in
diffusion for apparent diffusion coefficient (ADC) imaging. Even more advanced
techniques than these are in use today for the study of neural fiber tract
anatomy and brain connectivity.
Over the years, increasingly complex data
acquisition schemes have been developed, while the theoretical foundations of
diffusion MR imaging have come to be better understood. For the radiologist who
wants to use these techniques in clinical practice and research, it is
important to understand a few key principles of diffusion imaging so as to
select the appropriate technique for answering a specific question. The article
therefore begins with an explanation of the physics of water diffusion and the
ways in which the great complexity of diffusion in the brain, the main organ
targeted for investigation with diffusion MR imaging, can be described. Next,
the basic principles that underlie diffusion contrast encoding with MR imaging
are described to enable the reader to understand the relation between the MR
imaging signal and diffusion as well as the limitations of simple diffusion
imaging techniques. This discussion provides a context for the description of
diffusion spectrum imaging, the most complex diffusion MR imaging technique,
which provides the largest body of information and the greatest detail. With
the general principles of diffusion MR imaging in mind, the range of current
diffusion MR imaging techniques, from the simplest to the most sophisticated, is
then reviewed with an emphasis on the underlying assumptions and hypotheses,
advantages, and potential pitfalls of each. The technical requirements
(hardware capabilities, acquisition time) for each type of diffusion imaging
examination, and the types of data provided by each type, are compared.
Diffusion-weighted imaging
Diffusion-weighted
imaging is
an MRI method that produces in vivo magnetic
resonance images of biological tissues weighted with the local characteristics
of water diffusion.
DWI is a modification of
regular MRI techniques, and is an approach which utilizes the measurement
of Brownian motion of molecules. Regular MRI acquisition utilizes the
behaviour of protons in water to generate contrast between clinically relevant
features of a particular subject. The versatile nature of MRI is due to this
capability of producing contrast, called weighting. In a typical T1-weighted image, water
molecules in a sample are excited with the imposition of a strong magnetic
field. This causes many of the protons in water molecules to precess
simultaneously, producing signals in MRI. In T2-weighted images,
contrast is produced by measuring the loss of coherence or synchrony between
the water protons. When water is in an environment where it can freely tumble,
relaxation tends to take longer. In certain clinical situations, this can
generate contrast between an area of pathology and the surrounding healthy
tissue.
In diffusion-weighted
images, instead of a homogeneous magnetic field, the homogeneity is varied linearly
by a pulsed field gradient. Since precession is proportional to the magnet
strength, the protons begin to precess at different rates, resulting in
dispersion of the phase and signal loss. Another gradient pulse is applied in
the same direction but with opposite magnitude to refocus or rephase the spins.
The refocusing will not be perfect for protons that have moved during the time
interval between the pulses, and the signal measured by the MRI machine is
reduced. This reduction in signal due to the application of the pulse gradient
can be related to the amount of diffusion that is occurring through the
following equation:
where S0 is the signal
intensity without the diffusion weighting, S is the signal with the
gradient, γ is the gyromagnetic ratio, G is the strength of
the gradient pulse, δ is the duration of the pulse, Δ is the time
between the two pulses, and finally, D is the diffusion-coefficient.
By rearranging the
formula to isolate the diffusion-coefficient, it is possible to obtain an idea
of the properties of diffusion occurring within a
particular voxel (volume picture element). These values, called
apparent diffusion coefficients (ADC) can then be mapped as an image, usingdiffusion as
the contrast.
The first successful
clinical application of DWI was in imaging the brain following stroke in
adults. Areas which were injured during a stroke showed up "darker"
on an ADC map compared to healthy tissue. At about the same time as it became
evident to researchers that DWI could be used to assess the severity of injury
in adult stroke patients, they also noticed that ADC values varied depending on
which way the pulse gradient was applied. This orientation-dependent contrast
is generated by diffusion anisotropy, meaning that the diffusion in parts of
the brain has directionality. This may be useful for determining structures in
the brain which could restrict the flow of water in one direction, such as the
myelinated axons of nerve cells (which is affected by multiple sclerosis).
However, in imaging the brain following a stroke, it may actually prevent the
injury from being seen. To compensate for this, it is necessary to apply a
mathematical operator, called a tensor, to fully characterize the motion
of water in all directions.
Diffusion-weighted
images are very useful to diagnose vascular strokes in the brain. It is also
used more and more in the staging of non small cell lung cancer, where it is a
serious candidate to replace positron emission tomography as the 'gold
standard' for this type of disease. Diffusion tensor imaging is being developed
for studying the diseases of the white matter of the brain as well as
for studies of other body tissues (see below).
Diffusion tensor imaging
Diffusion tensor imaging (DTI) is
a magnetic resonance imaging (MRI) technique that enables the
measurement of the restricted diffusion of water in tissue in order to produce
neural tract images instead of using this data solely for the purpose of
assigning contrast or colors to pixels in a cross sectional image. It also
provides useful structural information about muscle—including heart muscle, as
well as other tissues such as the prostate.
In DTI, each voxel has
one or more pairs of parameters: a rate of diffusion and a preferred direction
of diffusion—described in terms of three dimensional space—for which that
parameter is valid. The properties of each voxel of a single DTI image is
usually calculated by vector or tensor math from six or more different
diffusion weighted acquisitions, each obtained with a different orientation of
the diffusion sensitizing gradients. In some methods, hundreds of
measurements—each making up a complete image—are made to generate a single
resulting calculated image data set. The higher information content of a DTI
voxel makes it extremely sensitive to subtle pathology in the brain. In
addition the directional information can be exploited at a higher level of
structure to select and follow neural tracts through the brain—a process
called tractography.
A more precise statement
of the image acquisition process is that the image-intensities at each position
are attenuated, depending on the strength (b-value) and direction of the
so-called magnetic diffusion gradient, as well as on the local microstructure
in which the water molecules diffuse. The more attenuated the image is at a
given position, the greater diffusion there is in the direction of the
diffusion gradient. In order to measure the tissue's complete diffusion
profile, one needs to repeat the MR scans, applying different directions (and
possibly strengths) of the diffusion gradient for each scan.
Diffusion-weighted
magnetic resonance (MR) imaging provides image contrast that is different from
that provided by conventional MR techniques. It is particularly sensitive for
detection of acute ischemic stroke and differentiation of acute stroke from
other processes that manifest with sudden neurologic deficits.
Diffusion-weighted MR imaging also provides adjunctive information for other
cerebral diseases including neoplasms, intracranial infections, traumatic brain
injury, and demyelinating processes. Because stroke is common and in the
differential diagnosis of most acute neurologic events, diffusion-weighted MR
imaging should be considered an essential sequence, and its use in most brain
MR studies is recommended.
Diffusion-weighted (DW) magnetic
resonance (MR) imaging provides potentially unique information on the viability
of brain tissue. It provides image contrast that is dependent on the molecular
motion of water, which may be substantially altered by disease. The method was
introduced into clinical practice in the middle 1990s, but because of its
demanding MR engineering requirements—primarily high-performance magnetic field
gradients—it has only recently undergone widespread dissemination. The primary
application of DW MR imaging has been in brain imaging, mainly because of its
exquisite sensitivity to ischemic stroke—a common condition that appears in the
differential diagnosis in virtually all patients who present with a neurologic
complaint.
Because DW MR imaging uses fast
(echo-planar) imaging technology, it is highly resistant to patient motion, and
imaging time ranges from a few seconds to 2 minutes. As a consequence, DW MR
imaging has assumed an essential role in the detection of acute brain
infarction and in the differentiation of acute infarction from other disease
processes. DW MR imaging is also assuming an increasingly important role in the
evaluation of many other intracranial disease processes.
BASIC CONCEPTS OF DW MR
IMAGING
In this section, the
basic concepts involved in DW MR imaging will be briefly reviewed. For more
detailed descriptions of the physics of DW imaging, a number of excellent
reviews (1–5) are available. Stejskal and Tanner (6) provided an early description of a DW sequence in
1965. They used a spin-echo T2-weighted pulse sequence with two extra gradient
pulses that were equal in magnitude and opposite in direction. This sequence
enabled the measurement of net water movement in one direction at a time. To
measure the rate of movement along one direction, for example the x direction,
these two extra gradients are equal in magnitude but opposite in direction for
all points at the same x location. However, the strength of these two balanced
gradients increases along the x direction. Therefore, if a voxel of tissue
contains water that has no net movement in the x direction, the two balanced
gradients cancel each other out. The resultant signal intensity of that voxel
is equal to its signal intensity on an image obtained with the same sequence
without the DW gradients. However, if water molecules have a net movement in
the x direction (eg, due to diffusion), they are subjected to the first
gradient pulse at one x location and the second pulse at a different x
location. The two gradients are no longer equal in magnitude and no longer
cancel. The difference in gradient pulse magnitude is proportional to the net
displacement in the x direction that occurs between the two gradient pulses,
and faster-moving water protons undergo a larger net dephasing. The resultant
signal intensity of a voxel of tissue containing moving protons is equal to its
signal intensity on a T2-weighted image decreased by an amount related to the
rate of diffusion.
The signal intensity
(SI) of a voxel of tissue is calculated as follows: where
SI0 is the signal
intensity on the T2-weighted (or b = 0
sec/mm2) image, the diffusion
sensitivity factor b is equal to γ2G2δ2(Δ − δ/3),
and D is the
diffusion coefficient. γ is the gyromagnetic ratio; G is the magnitude of, δ the width of, and Δ the
time between the two balanced DW gradient pulses.
According to Fick’s law, true diffusion is the
net movement of molecules due to a concentration gradient. With MR imaging,
molecular motion due to concentration gradients cannot be differentiated from
molecular motion due to pressure gradients, thermal gradients, or ionic
interactions. Also, with MR imaging we do not correct for the volume fraction
available or the increases in distance traveled due to tortuous pathways.
Therefore, when measuring molecular motion with DW imaging, only the apparent
diffusion coefficient (ADC) can be calculated. The signal intensity of a DW
image is best expressed as
With the development
of high-performance gradients, DW imaging can be performed with an echo-planar
spin-echo T2-weighted sequence. With the original spin-echo T2-weighted
sequence, even minor bulk patient motion was enough to obscure the much smaller
molecular motion of diffusion. The substitution of an echo-planar spin-echo
T2-weighted sequence markedly decreased imaging time and motion artifacts and
increased sensitivity to signal changes due to molecular motion. As a result,
the DW sequence became clinically feasible to perform. Other methods of
performing DW MR imaging without echo-planar gradients have also been developed.
These include DW sequences based on a single-shot gradient and spin-echo or
single-shot fast spin-echo techniques. “Line-scan” DW and spiral DW sequences have also
been developed.
In the brain, apparent
diffusion is not isotropic (the same in all directions); it is anisotropic
(varies in different directions), particularly in white matter. The cause of
the anisotropic nature of white matter is not completely understood, but
increasing anisotropy has also been noted in the developing brain before T1-
and T2-weighted imaging or histologic evidence of myelination becomes evident . It is likely that in addition to axonal direction
and myelination, other physiologic processes, such as axolemmelic flow,
extracellular bulk flow, capillary blood flow, and intracellular streaming, may
contribute to white matter anisotropy. The anisotropic nature of diffusion in
the brain can be appreciated by comparing images obtained with DW gradients
applied in three orthogonal directions (Fig 1). In each of the images, the signal intensity is
equal to the signal intensity on echo-planar T2-weighted images decreased by an
amount related to the rate of diffusion in the direction of the applied
gradients. Images obtained with gradient pulses applied in one direction at a
time are combined to create DW images or ADC maps. The ADC is actually a tensor
quantity or a matrix:
Figure 1.
Anisotropic
nature of diffusion in the brain. Transverse DW MR images (b = 1,000 sec/mm2; effective gradient,
14 mT/m; repetition time, 7,500 msec; minimum echo time; matrix,
128 × 128; field of view, 200 × 200 mm; section thickness,
6 mm with 1-mm gap) with the diffusion gradients applied along the x (Gx, left), y (Gy, middle),
and z (Gz, right)
axes demonstrate anisotropy. The signal intensity decreases when the white
matter tracts run in the same direction as the DW gradient because water
protons move preferentially in this direction. Note that the corpus callosum
(arrow on left image) is hypointense when the gradient is applied in the x
(right-to-left) direction, the frontal and posterior white matter (arrowheads)
are hypointense when the gradient is applied in the y (anterior-to-posterior)
direction, and the corticospinal tracts (arrow on right image) are hypointense
when the gradient is applied in the z (superior-to-inferior) direction.
The diagonal elements
of this matrix can be combined to give information about the magnitude of the
apparent diffusion: (ADCxx + ADCyy + ADCzz)/3.
The off-diagonal
elements provide information about the interactions between the x, y, and z
directions. For example, ADCyx gives information about the correlation
between displacements in the x and y directions (4). Images displaying the magnitude of the ADC are used
in clinical practice.
DW gradient pulses are
applied in one direction at a time. The resultant image has information about
both the direction and the magnitude of the ADC (Fig 1). To create an image
that is related only to the magnitude of the ADC, at least three of these
images must be combined. The simplest method is to multiply the three images
created with the DW gradient pulses applied in three orthogonal directions. The
cube root of this product is the DW image (Fig 2). It is important to
understand that the DW image has T2-weighted contrast as well as contrast due
to differences in ADC. To remove the T2-weighted contrast, the DW image can be
divided by the echo-planar spin-echo T2-weighted (or b = 0 sec/mm2) image to give an
“exponential image” (Fig 3). Alternatively, an ADC map, which is an image whose
signal intensity is equal to the magnitude of the ADC, can be created (Fig 4).
Figure 2.
Calculation
of signal intensity on an isotropic DW image (b = 1,000 sec/mm2; effective gradient,
14 mT/m; repetition time, 7,500 msec; minimum echo time; matrix,
128 × 128; field of view, 400 × 200 mm; section thickness,
6 mm with 1-mm gap). The signal intensities of the three transverse images (Gx, Gy, and Gz), each with a diffusion gradient applied in one of
three orthogonal directions, are multiplied together. Here the DW gradients
were applied along the x, y, and z axes. The signal intensity of the isotropic
DW image (bottom) is essentially the cube root of the signal intensities of
these three images multiplied together. Note that both T2-weighted contrast and
the rate of diffusion contribute to the signal intensity of the isotropic DW
image.
Figure 3.
Removal
of T2-weighted contrast. To remove the T2-weighted contrast in the isotropic
transverse DW image (b = 1,000
sec/mm2; effective gradient,
14 mT/m; repetition time, 7,500 msec; minimum echo time; matrix,
128 × 128; field of view, 200 × 200 mm, section thickness,
6 mm with 1-mm gap), the transverse DW image (DWI) is divided by the transverse echo-planar
spin-echo T2-weighted (EP SET2) image. The
resultant image is called the exponential image because its signal intensity is
exponentially related to the ADC.
Figure 4.
Creation
of an ADC map. One method of creating an ADC map is to mathematically
manipulate the exponential (Exp.) image. The
appearances on the transverse DW image (DWI),
exponential image, and ADC map, as well as the corresponding mathematic
expressions for their signal intensities, are shown. Image parameters are b = 1,000 sec/mm2; effective gradient,
14 mT/m; repetition time, 7,500 msec; minimum echo time; matrix,
128 × 128; field of view, 200 × 200 mm; section thickness,
6 mm with 1-mm gap. SI = signal
intensity, SIo = signal
intensity on T2-weighted image.
Instead of obtaining
images with b = 0
sec/mm2 and with b = 1,000 sec/mm2 and solving for
ADC using Equation , one usually determines the ADC graphically. This is
accomplished by obtaining two image sets, one with a very low but nonzero b value and one with b = 1,000 sec/mm2. By plotting the
natural logarithm of the signal intensity versus b for these twob values,
the ADC can be determined from the slope of this line.
For our clinical
studies, the DW image, exponential image, ADC map, and echo-planar spin-echo
T2-weighted images are routinely available for review (Fig 4). Because the ADC values of gray and white matter
are similar, typically there is no contrast between gray and white matter on
the exponential image or ADC map. The contrast between gray and white matter
seen on the DW image is due to T2-weighted contrast. This residual T2 component
on the DW image makes it important to view either the exponential image or ADC
map in conjunction with the DW image. In lesions such as acute stroke, the
T2-weighted and DW effects both cause increased signal intensity on the DW
image. Therefore, we have found that we identify regions of decreased diffusion
best on DW images. The exponential image and ADC maps are used to exclude “T2
shine through” as the cause of increased signal intensity on DW images. The
exponential image and ADC map are useful for detecting areas of increased
diffusion that may be masked by T2 effects on the DW image.
CLINICAL APPLICATIONS
Ischemic Stroke
Theory of restricted diffusion in acute stroke.—Within minutes after the onset of ischemia, a profound
restriction in water diffusion occurs in affected brain tissue . The biophysical basis of this change
is not completely clear. One likely important contributor is cytotoxic edema.
Cytotoxic edema induced with acute hyponatremic encephalopathy (without
ischemia) is associated with restricted diffusion . Furthermore, when decreased ADCs
were present in early ischemia in rat brain tissue, there was a reduction in Na+/K+ adenosine
triphosphatase activity without a significant increase in brain water . In addition, ouabain, an inhibitor
of Na+/K+ adenosine
triphosphatase, was associated with a reduction in ADC in rat cortex . These findings have led to the
predominant theory for the restriction of water diffusion in stroke: Ischemia
causes disruption of energy metabolism, leading to failure of the Na+/K+ adenosine
triphosphatase pump and other ionic pumps. This leads to loss of ionic
gradients and a net translocation of water from the extracellular to the
intracellular compartment, where water mobility is relatively more restricted.
There are additional factors. With cellular swelling, there is a
reduction in the volume of extracellular space . A decrease in the diffusion of
low-molecular-weight tracer molecules has been demonstrated in animal models ,
which suggests that the increased tortuosity of extracellular space pathways
contributes to restricted diffusion in acute ischemia. Furthermore, there are
substantial reductions in ADCs in intracellular metabolites in ischemic rat
brain Proposed explanations are increased intracellular viscosity due to
dissociation of microtubules and fragmentation of other cellular components or
increased tortuosity of the intracellular space and decreased cytoplasmic
mobility. It is worth bearing in mind that the normal steady-state function of these
structures requires energy and uses adenosine triphosphate. Other factors such
as temperature and cell membrane permeability play a minor role in explaining
the reduction in ADC in acutely ischemic tissue.
Time course of lesion evolution in acute stroke.—In animals, restricted diffusion associated with acute ischemia
has been detected as early as 10 minutes to 2 hours after vascular occlusion.
The ADCs measured at these times are approximately 16%–68% below those of
normal tissue. In animals, ADCs pseudonormalize (ie, are similar to those of
normal brain tissue, but the tissue is infarcted) at approximately 2 days and
are elevated thereafter.
In adult humans, the time course is more prolonged.We have
observed restricted diffusion associated with acute ischemia 30 minutes after a
witnessed ictus. The ADC continues to decrease and is most reduced at 8–32
hours. The ADC remains markedly reduced for 3–5 days. This decreased diffusion
is markedly hyperintense on DW images (which are generated with a combination
of T2-weighted and DW imaging) and hypointense on ADC images. The ADC returns
to baseline at 1–4 weeks. This most likely reflects persistence of cytotoxic
edema (associated with decreased diffusion) and development of vasogenic edema
and cell membrane disruption, leading to increased extracellular water
(associated with increased diffusion). At this point, an infarction is usually
mildly hyperintense due to the T2 component on the DW images and is isointense
on the ADC images. Thereafter, diffusion is elevated as a result of continued
increase in extracellular water, tissue cavitation, and gliosis. This elevated
diffusion is characterized by slight hypointensity, isointensity, or
hyperintensity on the DW images (depending on the strength of the T2 and diffusion
components) and increased signal intensity on ADC maps.
Figure 5.
Time course of an ischemic infarction.
Images demonstrate the evolution of an ischemic infarction involving the left
cerebellar hemisphere and left middle cerebellar peduncle. Both transverse DW
images (DWI;b = 1,000
sec/mm2; effective gradient, 14 mT/m; repetition time msec/echo time msec,
6,000/108; matrix, 256 × 128; field of view, 400 × 200 mm;
section thickness, 6 mm with 1-mm gap) and transverse ADC maps are displayed.
The patient underwent MR imaging 6 hours after the onset of acute neurologic
symptoms. At 6 hours, the lesion (arrows) is hyperintense on the DW images and
hypointense on the corresponding ADC map. The lesion becomes progressively more
hyperintense on DW images, reaching its maximum hyperintensity at the 58-hour
time point, when it also reaches its maximum hypointensity on ADC maps. At 7
days, there is ongoing resolution of the lesion on both DW images and ADC maps.
By 134 days, there is subtle hypointensity on the DW image and hyperintensity
on the ADC images.
The time course does not always conform to the aforementioned
outline. With early reperfusion, pseudonormalization (return to baseline of the
ADC reduction associated with acute ischemic stroke) may occur at a much
earlier time—as early as 1–2 days in humans given intravenous recombinant
tissue plasminogen activator less than 3 hours after stroke onset .Furthermore,
Nagesh et al demonstrated that although the mean ADC of an ischemic lesion is
depressed within 10 hours, different zones within an ischemic region may
demonstrate low, pseudonormal, or elevated ADCs, suggesting different temporal
rates of tissue evolution toward infarction. Despite these variations, tissue
characterized by an initial reduction in ADC nearly always undergoes infarction
in humans.
DW and perfusion-weighted MR imaging for assessment of stroke
evolution.—The combination of
perfusion-weighted and DW MR imaging may provide more information than would
either technique alone. Perfusion-weighted imaging involves the detection of a
decrease in signal intensity as a result of the susceptibility or T2* effects
of gadolinium during the passage of a bolus of a gadolinium-based contrast
agent through the intracranial vasculature .A variety of hemodynamic images may
be constructed from these data, including relative cerebral blood volume,
relative cerebral blood flow, mean transit time, and time-to-peak maps.
In the context of arterial occlusion, brain regions with decreased
diffusion and perfusion are thought to represent nonviable tissue or the core
of an infarction The majority of stroke lesions increase in volume on DW
images, with the maximum volume achieved at 2–3 days.
When most patients with acute stroke are evaluated with both DW
and perfusion-weighted MR imaging, their images usually demonstrate one of
three patterns A lesion is smaller on DW images than the same lesion is on
perfusion-weighted images; a lesion on DW images is equal to or larger than
that on perfusion-weighted images; or a lesion is depicted on DW images but is
not demonstrable on perfusion-weighted images. In large-vessel stroke lesions
(such as in the proximal portion of the middle cerebral artery), the
abnormality as depicted on perfusion-weighted images is frequently larger than
the lesion as depicted on DW images. The peripheral region, characterized by
normal diffusion and decreased perfusion, usually progresses to infarction
unless there is early reperfusion. Thus, in the acute setting,
perfusion-weighted imaging in combination with DW imaging helps identify an
operational “ischemic penumbra” or area at risk for infarction
Figure 6.
Diffusion-perfusion mismatch after left
middle cerebral artery stroke. The patient was imaged 3.8 hours after a
witnessed sudden onset of a right hemiparesis. Transverse DW images (DWI;b = 1,000
sec/mm2; effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128;
field of view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap)
demonstrate hyperintensity in the subcortical region, including in the
lenticular nucleus and corona radiata (arrowheads, right-hand image in top
row). Transverse cerebral blood volume (CBV) images
(spin-echo echo-planar technique; 0.2 mmol/kg gadopentetate dimeglumine
[Magnevist; Berlex Laboratories, Wayne, NJ]; 51 images per section; 1,500/75;
matrix, 256 × 128; field of view, 400 × 200 mm; section
thickness, 6 mm with 1-mm gap) demonstrate decreased dynamic cerebral blood
volume in the region of hyperintensity on the DW images. However, there are
areas of abnormal cerebral blood volume (arrows) that appear relatively normal
on the DW study. Follow-up study performed 10 hours after the onset of symptoms
demonstrates an increase in the size of the DW imaging abnormality (arrowheads,
right-hand image in fifth row) as it extends into the region of brain that was
previously normal on DW images but abnormal on cerebral blood volume images.
On
the other hand, in small-vessel infarctions (perforator infarctions and distal
middle cerebral artery infarctions), the initial lesion volumes on
perfusion-weighted and DW images are usually similar, and the
diffusion-weighted image lesion volume increases only slightly with time. A lesion
larger on DW images than on perfusion-weighted images or a lesion visible on DW
images but not on perfusion-weighted images usually occurs with early
reperfusion. In this situation, the lesion on DW images usually does not change
substantially over time.
In animals treated with neuroprotective agents after occlusion of
the middle cerebral artery, the increase in stroke lesion volume on serial DW
images is reduced. This effect has not been convincingly demonstrated in
humans.
Reversibility of ischemic lesions on DW images.—In animal models of ischemia, both a time threshold and an ADC
threshold for reversibility have been demonstrated. In general, when the middle
cerebral artery in animals is temporarily occluded for an hour or less, the
diffusion lesion size markedly decreases or resolves; however, when the middle
cerebral artery is occluded for 2 hours or more, the lesion size remains the
same or increases Hasegawa et al demonstrated that after 45 minutes of
temporary occlusion of the middle cerebral artery in rats, diffusion lesions
are partially or completely reversible when the difference in ADC values
between the ischemic region and a contralateral homologous nonischemic region
is not greater than a threshold of −0.25 × 10−5 cm2/sec. When the ADC difference
is greater than this threshold, the lesion nearly always becomes completely
infarcted. Similarly Dardzinski et al demonstrated a threshold ADC of
0.55 × 10−3 mm2/sec at 2 hours in a permanent-occlusion rat model.
In humans, reversibility of ischemic lesions is rare. To our
knowledge, only one case has been reported in the literature and we have
observed reversibility of only one ischemic lesion in over 2,000 patients
imaged in our clinical practice That patient was treated with intravenous recombinant
tissue plasminogen activator 2 hours after symptom onset, and the initial ADC
was approximately 20% below that of contralateral homologous nonischemic brain
tissue. In humans, neither a threshold time nor a threshold ADC for
reversibility have been established.
Figure 7.
Reversible ischemic lesion. Top: The patient
was imaged approximately 2 hours after the onset of a witnessed acute
neurologic deficit. Top left: Transverse DW image (DWI; b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap) shows an
area of hyperintensity (arrow) in the left posterior frontal and anterior
parietal lobes. Top middle: A region of hypointensity (arrow) corresponding to
this area is seen on the transverse ADC image (arrow). Top right: No definite
abnormality is seen on the transverse fast spin-echo T2-weighted MR image
(4,000/104; echo train length, eight; matrix, 256 × 192; field of
view, 200 × 200 mm; section thickness, 5 mm with 1-mm gap; one signal
acquired). The patient was treated with intravenous recombinant tissue
plasminogen activator, with resolution of the neurologic symptoms. Bottom:
Follow-up images obtained 3 days later demonstrate near interval resolution of
the abnormalities on the 2-hour DW image and ADC map. No definite lesion was
identified on the follow-up T2-weighted image. Of note, the decrease in ADC was
approximately 20% of the normal value. Lesions that become confirmed
infarctions typically demonstrate a 50% reduction in ADC.
DW imaging reliability in acute stroke.—Conventional computed tomography (CT) and MR imaging cannot be
used to reliably detect infarction at the earliest time points. The detection
of hypoattenuation on CT scans and hyperintensity on T2-weighted MR images
requires a substantial increase in tissue water. For infarctions imaged within
6 hours after stroke onset, reported sensitivities are 38%–45% for CT and
18%–46% for MR imaging. For infarctions imaged within 24 hours, the authors of
one study reported a sensitivity of 58% for CT and 82% for MR imaging.
DW images are very sensitive and specific for the detection of
hyperacute and acute infarctions, with a sensitivity of 88%–100% and a
specificity of 86%–100% A lesion with decreased diffusion is strongly
correlated with irreversible infarction. Acute neurologic deficits suggestive
of stroke but without restricted diffusion are typically due to transient
ischemic attack, peripheral vertigo, migraine, seizures, intracerebral
hemorrhage, dementia, functional disorders, amyloid angiopathy, and metabolic
disorders .
Although, after 24 hours, infarctions usually can be detected as
hypoattenuating lesions on CT and hyperintense lesions on T2-weighted and
fluid-attenuated inversion recovery MR images, DW imaging is useful in this
setting, as well. Older patients commonly have hyperintense abnormalities on
T2-weighted images that may be indistinguishable from acute lesions. However,
acute infarctions are hyperintense on DW images and hypointense on ADC maps,
whereas chronic foci are usually isointense on DW images and hyperintense on
ADC maps due to elevated diffusion (Fig 8). In one study in which there were indistinguishable acute and
chronic white matter lesions on T2-weighted images in 69% of patients, the
sensitivity and specificity of DW imaging for detection of acute subcortical
infarction were 94.9% and 94.1%, respectively.
Figure 8.
Differentiation of acute white matter
infarction from nonspecific small-vessel ischemic changes. This patient had
onset of symptoms 2 days prior to imaging. Top: Transverse DW images (DWI;b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap) in the top
row clearly demonstrate the acute infarction (arrowheads) in the putamen and
corona radiata. Bottom: Fluid-attenuated inversion recovery (FLAIR)
images (10,000/141; inversion time, 2,200 msec; echo train length, eight;
matrix, 256 × 192; field of view, 240 × 240 mm; section thickness,
5 mm with 1-mm gap; one signal acquired) demonstrate multiple white matter
lesions in which acute (arrowhead) and chronic lesions (arrows) cannot be
differentiated.
False-negative DW images have been reported in patients with very
small lacunar brainstem or deep gray nuclei infarction Some of these lesions
were seen on follow-up DW images, and others were presumed to be present on the
basis of clinical deficits. False-negative DW images also occur in patients
with regions of decreased perfusion (increased mean transit time and decreased
relative cerebral blood flow), which are hyperintense on follow-up DW images;
in other words, these patients initially had regions characterized by ischemic
but viable tissue that progressed to infarction. These findings stress the
importance of obtaining early follow-up images in patients with normal DW
images and persistent strokelike deficits, so that infarctions or areas at risk
for infarction are identified and treated as early as possible.
False-positive
DW images have been reported in patients with a diagnosis other than acute
infarction. These include cerebral abscess (with restricted diffusion on the
basis of viscosity) and tumor (with restricted diffusion on the basis of dense
cell packing). When these lesions are viewed on DW images in combination with
other routine T1- and T2-weighted MR images, they can usually be differentiated
from acute infarctions.
Correlation of DW MR imaging with clinical outcome.—DW MR imaging findings may reflect the severity of clinical
neurologic deficits and help predict clinical outcome. Statistically
significant correlations between the acute DW MR lesion volume and both acute
and chronic neurologic assessment results, including those of the National
Institutes of Health Stroke Score Scale, the Canadian Neurologic Scale, the
Barthel Index, and the Rankin Scale, have been demonstrated This correlation is
stronger in cases of cortical stroke and weaker in cases of penetrator artery
stroke. Lesion location likely explains the variance; for example, a lesion in
a major white matter tract may produce a more profound neurologic deficit than
would a cortical lesion of the same size. There also is a weaker correlation
between initial lesion volume and National Institutes of Health Stroke Score
Scale measures in patients with a prior infarction. In addition, there is a
significant correlation between the acute ADC ratio (lesion ADC to normal
contralateral brain ADC) and chronic neurologic assessment scale scores.
Perfusion-weighted image volumes also correlate with acute and chronic
neurologic assessment test results In one study , patients who had lesion
volumes on perfusion-weighted images that were larger than volumes on DW images
(perfusion-diffusion mismatches) had worse outcomes and larger final infarct
volumes. In another study , patients with early reperfusion had smaller final
infarct volumes and better clinical outcomes. Because DW and perfusion-weighted
MR imaging can help predict clinical outcome at very early time points, these
techniques may prove to be valuable for the selection of patients for
thrombolysis or administration of neuroprotective agents.
Neonatal hypoxic ischemic brain injury.—DW MR imaging is rapidly improving the evaluation of neonatal
hypoxic ischemic encephalopathy and focal infarctions. Animal models of
neonatal ischemia have demonstrated lesions on DW MR images as early as 1 hour
after ligation of the carotid artery . In humans, within 1 day of birth, acute
ischemic lesions not seen on routine CT or MR images are identified on DW MR
images . When lesions are identified on conventional images, lesion conspicuity
is increased and lesion extent is seen to be larger on DW MR images. In
addition, lesions identified on the initial DW MR images are identified on follow-up
conventional images and, therefore, help accurately predict the extent of
infarction. This correlates with the finding in animals that areas of
restricted diffusion correlate with areas of injury at autopsy.
Animal models have also demonstrated the evolution of neonatal
hypoxic ischemic injury over time. In a rabbit model , ischemic lesions were
seen first in the cortex, followed by the subcortical white matter, the
ipsilateral basal ganglia, and the contralateral basal ganglia.
Thus,
DW MR imaging is helping increase our understanding of the pathophysiology of
neonatal ischemia. It allows timing of ischemic onset, provides earlier and
more reliable detection of acute ischemic lesions, and allows differentiation
of focal infarctions from more global hypoxic ischemic lesions. This
information may provide a better early assessment of the long-term prognosis
and may be important in the evaluation of new neuroprotective agents.
Transient ischemic attacks.—Nearly 50% of patients with transient ischemic attacks have
lesions characterized by restricted diffusion . These lesions are usually small
(<15-mm diameter), are almost always in the clinically expected vascular
territory, and are thought to represent markers of more widespread reversible
ischemia. In one study , 20% of the lesions were not seen at follow-up; the
lesions could have been reversible or, owing to atrophy, too small to see on
conventional MR images. The information obtained from DW MR imaging changed the
suspected localization of an ischemic lesion, as well as the suspected
etiologic mechanism, in more than one-third of patients . In another study ,
statistically significant independent predictors for identification of these
lesions on DW MR images included previous nonstereotypic transient ischemic
attack, cortical syndrome, or an identified stroke mechanism, and the authors
suggested an increased stroke risk in patients with these lesions. Early
identification of patients with transient ischemic attack with increased risk
of stroke and better identification of etiologic mechanisms is changing acute
management and may affect patient outcome.
Other clinical stroke mimics.—These syndromes generally fall into two categories: (a)
nonischemic lesions with no acute abnormality on routine or DW MR images or (b)
vasogenic edema syndromes that mimic acute infarction on conventional MR
images. Nonischemic syndromes with no acute abnormality identified on DW or
conventional MR images and reversible clinical deficits include peripheral
vertigo, migraines, seizures, dementia, functional disorders, amyloid
angiopathy, and metabolic disorders . When a patients with these syndromes
present, we can confidently predict that they are not undergoing infarction;
they are spared unnecessary anticoagulation treatment and a stroke work-up.
Syndromes with potentially reversible vasogenic edema include
eclampsia, hypertensive encephalopathy, cyclosporin toxicity, other posterior
leukoencephalopathies, venous thrombosis, human immunodeficiency virus
encephalopathy, and hyperperfusion syndrome after carotid endarterectomy .
Patients with these syndromes frequently present with neurologic deficits that
are suggestive of acute ischemic stroke or with neurologic deficits such as
headache or seizure that are suggestive of vasogenic edema, but ischemic stroke
is still a strong diagnostic consideration. Conventional MR imaging cannot help
differentiate vasogenic edema from the cytotoxic edema associated with acute
infarction. Cytotoxic edema produces high signal intensity in gray and/or white
matter on T2-weighted images. Although vasogenic edema on T2-weighted images
typically produces high signal intensity in white matter, the hyperintensity
can involve adjacent gray matter. Consequently, posterior leukoencephalopathy
can sometimes mimic infarction of the posterior cerebral artery. Hyperperfusion
syndrome after carotid endarterectomy can resemble infarction of the middle
cerebral artery. Human immunodeficiency virus encephalopathy can produce
lesions in a variety of distributions, some of which have a manifestation
similar to that of arterial infarction. Deep venous thrombosis can produce
bilateral thalamic hyperintensity that is indistinguishable from “top of the
basilar” syndrome arterial infarction.
Figure 9.
Hyperperfusion syndrome after carotid
endarterectomy. The patient developed neurologic symptoms referable to the left
hemisphere several days after undergoing a left carotid endarterectomy. The CT
scan was abnormal, and the question of infarction was raised. Left: Transverse
fast spin-echo T2-weighted MR image (4,000/104; echo train length, eight;
matrix, 256 × 192; field of view, 200 × 200 mm, section
thickness, 5 mm with 1-mm gap; one signal acquired) demonstrates numerous areas
of abnormal high signal intensity (arrow) in the left hemisphere. Infarctions
remained in the differential diagnosis. Middle: Transverse DW MR image (b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap) reveals
predominant isointensity in the left hemisphere with small areas of slight
hypointensity and slight hyperintensity (arrow). ADC images (not shown)
demonstrated no areas of restricted diffusion. Right: Transverse
three-dimensional time-of-flight MR angiogram (49/6.9; 20° flip angle; matrix,
256 × 192; field of view, 200 × 200 mm; section thickness,
1 mm) demonstrates excellent flow-related enhancement (arrow) in the left
hemisphere. A diagnosis of hyperperfusion syndrome with vasogenic edema was
established on the basis of DW imaging findings. The patient was treated
conservatively and recovered fully.
DW MR imaging can be used to reliably distinguish vasogenic from
cytotoxic edema. Whereas cytotoxic edema is characterized by restricted
diffusion, vasogenic edema is characterized by elevated diffusion due to a
relative increase in water in the extracellular compartment, where water is
more mobile . On DW MR images, vasogenic edema may be hypointense to slightly
hyperintense, because these images have both T2 and diffusion contributions.
When vasogenic edema is hyperintense on DW MR images, it can mimic hyperacute
or subacute infarction. On ADC images, cytotoxic edema due to ischemia is
always hypointense for 1–2 weeks, and vasogenic edema is always hyperintense.
Therefore, DW MR images should always be compared with ADC images.
Correct
differentiation of vasogenic from cytotoxic edema affects patient care.
Misdiagnosis of vasogenic edema syndrome as acute ischemia could lead to
unnecessary and potentially dangerous use of thrombolytics, antiplatelet
agents, anticoagulants, and vasoactive agents. Furthermore, failure to correct
relative hypertension could result in increased cerebral edema, hemorrhage,
seizures, or death. Misinterpretation of acute ischemic infarction as vasogenic
edema syndrome would discourage proper treatment with anticoagulants,
evaluation for an embolic source, and liberal blood pressure control, which
could increase the risk of recurrent brain infarction.
Masses
Extraaxial masses: arachnoid cyst versus epidermoid tumor.—Conventional MR images cannot be used to reliably distinguish
epidermoid tumors from arachnoid cysts; both lesions are very hypointense
relative to brain parenchyma on T1-weighted MR images and very hyperintense on
T2-weighted images. Epidermoid tumors are solid masses, however, which demonstrate
ADCs similar to those of gray matter and lower than those of CSF . With the
combination of T2 and diffusion effects, epidermoid tumors are markedly
hyperintense compared with CSF and brain tissue on diffusion MR images.
Conversely, arachnoid cysts are fluid filled, demonstrate very high ADCs, and
appear similar to CSF on DW MR images. Furthermore, on conventional MR images
obtained after resection of an epidermoid tumor, the resection cavity and
residual tumor may be similarly hypointense on T1-weighted images and
hyperintense on T2-weighted images. On DW MR images, the hypointense
CSF-containing cavity can easily be differentiated from the residual
hyperintense epidermoid tumor (Fig 10).
Figure 10.
Postoperative residual epidermoid tumor. The
patient underwent resection of a large left middle cranial fossa epidermoid
tumor that extended into the posterior fossa. Transverse T1-weighted (left)
(650/16; matrix, 256 × 192; field of view, 200 × 200 mm;
section thickness, 5 mm with 1-mm gap; one signal acquired) and fast spin echo
T2-weighted (middle) (4,000/104; echo train length, eight; matrix,
256 × 192; field of view, 200 × 200 mm; section thickness,
5 mm with 1-mm gap, one signal acquired) MR images do not allow clear
differentiation of residual mass from the resection cavity. Right: Transverse
DW MR image (b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap) clearly
demonstrates a hyperintense mass (black arrow) adjacent to the left pons and a
smaller amount of mass (white arrow) in the left middle cranial fossa,
consistent with residual epidermoid tumor. CSF (arrowhead) in the resection
cavity is markedly hypointense.
Intraaxial masses.—A
number of investigators have evaluated DW MR imaging of intraaxial tumors
(predominantly gliomas) in animals and humans. It has been demonstrated that
tumor and edema have higher ADCs than does normal brain tissue and that central
necrosis has a higher ADC than do tumor, edema, or normal brain tissue. Tien et
al demonstrated that enhancing tumors have significantly lower ADCs than does
adjacent edema, but Brunberg et al found that there is no significant
difference between ADCs of enhancing tumor and edema. Both concluded that the ADC
alone cannot be used to differentiate a nonenhancing tumor from adjacent edema.
Brunberg et al suggested that both enhancing and nonenhancing tumors can be
distinguished from edema because edema has significantly higher indices of
diffusion anisotropy when compared with adjacent tumor, presumably due to
intact myelin within the edema. Demarcation of tumor from surrounding vasogenic
edema with DW MR imaging may be important in determining radiation ports,
surgical margins, and biopsy sites. A number of investigators have demonstrated
that DW MR imaging cannot be used to differentiate between high- and low-grade
gliomas or between tumor types.
DW
MR imaging is also valuable in the assessment of tumor resections that are
complicated, in the immediate postoperative period, by acute neurologic
deficits. Although both extracellular edema and infarction are hyperintense on
spin-echo T2-weighted images, cytotoxic edema is characterized by a low ADC,
and vasogenic edema is characterized by a high ADC, relative to brain
parenchyma. Thus, an acute infarction can easily be differentiated from
postoperative edema.
Intracranial Infections
Pyogenic infection.—Abscess
cavities and empyemas are homogeneously hyperintense on DW MR images (Fig 11), with signal intensity ratios of abscess cavity
to normal brain tissue that range from 2.5 to 6.9 and with ADC ratios that
range from 0.36 to 0.46 In one study the ADC of the abscess cavity in vivo was
similar to that of pus aspirated from the cavity in vitro. In another study the
ADC ratio of empyema compared with CSF was 0.13 in one patient. The relatively
restricted diffusion most likely results from the high viscosity and
cellularity of pus.
Figure 11.
Pathologically proved cerebral abscess.
Left: A complex signal intensity pattern is visible in the right occipital and
temporal lobes on the fast spin-echo T2-weighted MR image (4,000/104; echo
train length, eight; matrix, 256 × 192; field of view,
200 × 200 mm; section thickness, 5 mm with 1-mm gap; one signal acquired).
Middle: Ring-enhancing lesion (arrows) in the right occipital lobe is
demonstrated on the gadolinium-enhanced T1-weighted MR image (650/16; matrix,
256 × 192; field of view, 200 × 200 mm; section thickness,
5 mm with 1-mm gap; one signal acquired). Right: DW MR image (b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap)
demonstrates the characteristic restricted diffusion of pyogenic abscess
(arrows). Note the hyperintensity (arrowhead) in the left occipital horn due to
a loculated collection of pus in this location.
Although intracranial abscesses and intracranial neoplasms may
appear similar on images obtained with conventional MR sequences, the signal
intensity of the abscess cavity is markedly higher and the ADC ratios are lower
than those of necrotic tumors on DW MR images Bacterial meningitis may be
complicated by subdural effusions or subdural empyemas, which are difficult to
differentiate on conventional MR images. Empyemas are hyperintense on DW MR
images and have a restricted ADC, whereas sterile effusions are hypointense and
have an ADC similar to that of CSF. Thus, DW MR images may be important when
deciding whether to drain or conservatively manage extraaxial collections
associated with meningitis.
Herpes encephalitis.—Herpes
encephalitis lesions are characterized by marked hyperintensity on DW MR images
, with ADC ratios of these lesions to normal brain parenchyma ranging from 0.48
to 0.66. On follow-up conventional T1-weighted and T2-weighted MR images, these
areas demonstrate encephalomalacic change. The restricted diffusion is
explained by cytotoxic edema in tissue undergoing necrosis. DW MR imaging may
aid in distinguishing herpes lesions from infiltrative temporal lobe tumors
because the ADCs of herpes lesions are low while the ADCs of various tumors are
elevated or in the normal range .
Figure 12.
Herpes encephalitis proved with results of
polymerase chain reaction test. DW MR images (DWI; b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap).
demonstrate restricted diffusion bilaterally in the temporal lobes (short
arrows), inferior frontal lobes (long arrows), and insulae (arrowheads), which
is a typical distribution for herpes encephalitis.
Creutzfeldt-Jakob disease.—DW
MR images in patients with Creutzfeldt-Jakob disease have demonstrated
hyperintense lesions in the cortex and basal ganglia . ADCs in lesions in five
patients were significantly lower than those of normal brain parenchyma , while
ADCs in lesions in two patients were normal or mildly elevated . The variable
ADCs are likely related to variable amounts of spongiform change, neuronal
loss, and gliosis.
Figure 13.
Pathologically proved Creutzfeldt-Jakob
disease. Top: Transverse T2-weighted MR images (4,000/104; echo train length,
eight; matrix, 256 × 192; field of view, 200 × 200 mm;
section thickness, 5 mm with 1-mm gap; one signal acquired) demonstrate
hyperintensity of the basal ganglia. Bottom: Transverse DW MR images (DWI;
b = 1,000 sec/mm2; effective gradient, 14 mT/m; 6,000/108; matrix,
256 × 128; field of view, 400 × 200 mm; section thickness,
6 mm with 1-mm gap) show marked hyperintensity involving the basal ganglia
bilaterally (arrowheads) and portions of the bilateral cortical ribbon
(arrows).
Whereas Creutzfeldt-Jakob disease is classically characterized by
progressive dementia, myoclonic jerks, and periodic sharp-wave
electroencephalographic activity, these features frequently are absent, and
Creutzfeldt-Jakob disease cannot be clinically distinguished from other
dementing illnesses . Furthermore, conventional MR images may be normal in as
many as 21% of patients . Thus, DW MR imaging may be useful for help in the
diagnosis of Creutzfeldt-Jakob disease and in the differentiation from
Alzheimer disease.
Trauma
Results of an experimental study
of head trauma have demonstrated that moderate fluid-percussion injury
leads to increased diffusion, reflecting increased extracellular water, in rat
cortex and hippocampus. This correlates with a report that moderate
fluid-percussion injury does not reduce cerebral blood flow enough to induce
ischemia. Ito et al demonstrated no significant change in brain ADCs when rats
are subjected to impact acceleration trauma alone. However, when trauma is
coupled with hypoxia and hypotension, the ADCs in rat cortex and thalami
decrease significantly and neuronal injury was observed histologically. They
concluded that brain ischemia associated with severe head trauma leads to
cytotoxic edema. Barzo et al demonstrated a reduction in rat brain ADCs hours
to weeks after an impact acceleration injury. They concluded that cerebral
blood flow does not decrease enough to cause ischemic edema and that neurotoxic
edema causes the reduced ADCs and neuronal injury.
DW MR imaging in 116 diffuse axonal injury lesions in humans
demonstrated changes similar to those in animal models: ADCs were reduced in
64% of lesions, were elevated in 34%, and were similar to ADCs of normal brain
tissue in 12%. In addition, most lesions were more conspicuous on DW MR images
than on conventional T2-weighted images . Thus, DW MR imaging may be important
for the prospective determination of the extent of traumatic injury, the degree
of irreversible injury (number of lesions characterized by low ADCs indicative
of cytotoxic edema), and the long-term prognosis.
Figure 14.
Severe head trauma resulting in diffuse
axonal injury. Top: Transverse T2-weighted MR images (4,000/104; echo train
length, eight; matrix, 256 × 192; field of view, 200 × 200
mm; section thickness, 5 mm with 1-mm gap; one signal acquired) demonstrate
multiple white matter hyperintensities (arrows). Bottom: Transverse DW MR
images (DWI;
b = 1,000 sec/mm2; effective gradient, 14 mT/m; 6,000/108; matrix,
256 × 128; field of view, 400 × 200 mm; section thickness,
6 mm with 1-mm gap) demonstrate the lesions (arrows) with increased
conspicuity. The hyperintensity is consistent with restricted diffusion. Note
abnormalities (arrowheads) that extend to the cortex posteriorly.
Hemorrhage
The appearance of hemorrhage on DW MR images is complex and
involves many factors, including the relative amounts of different hemorrhagic
products and the pulse sequence used . Oxyhemoglobin is hyperintense on DW
images and has a lower ADC than does normal brain tissue; this may indicate the
relative restriction of water movement inside the red blood cell .
Extracellular methemoglobin has a higher ADC than does normal brain tissue,
which indicates that the mobility of water in the extracellular space is
increased. The prolongation of the T2 component of fluid with extracellular
methemoglobin results in hyperintensity on DW images. Hemorrhage containing
deoxyhemoglobin, intracellular methemoglobin, and hemosiderin are hypointense
on DW images because of magnetic susceptibility effects. Because these products
of hemorrhage have very low signal intensity on T2-weighted images, ADCs cannot
be reliably calculated for them.
Figure 15.
Hematoma in a patient with a right
hemisphere glioblastoma who had undergone prior resection and who had developed
a hematoma in the right frontal lobe. The patient was hospitalized for
progression of symptoms and development of fever. A ring-enhancing lesion at
the site of the prior hematoma was seen on a gadolinium-enhanced T1-weighted MR
image (not shown) in the right frontal lobe. Left: DW MR image (b = 1,000
sec/mm2;
effective gradient, 14 mT/m; 6,000/108; matrix, 256 × 128; field of
view, 400 × 200 mm; section thickness, 6 mm with 1-mm gap) demonstrates
a hyperintense lesion (arrow) in the right frontal lobe. Right: On the ADC
image, the lesion is hypointense (arrow), which is consistent with restricted
diffusion. The lesion was drained, and old hemorrhage was demonstrated. There
was no evidence of infection.
Demyelination
Multiple sclerosis.—In
animals with experimental allergic encephalomyelitis (a model of multiple
sclerosis) and in patients with multiple sclerosis, most plaques demonstrate
increased diffusion (. In humans, acute plaques have significantly higher ADCs
than do chronic plaques . The elevated diffusion may result from an increase in
the size of the extracellular space due to edema and demyelination acutely and
to axonal loss and gliosis chronically. In rare instances, acute plaques have
restricted diffusion. This may result from increased inflammatory cellular
infiltration with little extracellular edema. Of interest, normal-appearing
white matter has a mildly increased ADC . This correlates with histologic
results in which multiple sclerosis was shown to diffusely affect white matter
.
In monkeys with experimental allergic encephalomyelitis, Heide et
al demonstrated that diffusion anisotropy decreased over time. We have also
observed this phenomenon in humans. Furthermore, Verhoye et al demonstrated a
significant positive correlation between the degree of ADC elevation in the
external capsule and severity of clinical disease in rats with experimental
allergic encephalomyelitis. However, this relationship has not been confirmed
in humans. Horsfield et al (demonstrated that benign multiple sclerosis lesions
have ADCs similar to those of secondary progressive multiple sclerosis.
Furthermore, the degree of ADC elevation within individual lesions did not
correlate with the degree of patient disability.
Acute disseminated encephalomyelitis.—Acute disseminated encephalomyelitis lesions have ADCs higher
than those of normal white matter, likely as a result of demyelination and
increased extracellular water. DW MR imaging cannot help distinguish between
multiple sclerosis and acute disseminated encephalomyelitis lesions because
both usually have elevated diffusion. Because acute infarctions are
characterized by restricted diffusion, however, DW MR imaging should be
reliable for help in the differentiation between demyelinating lesions and
stroke.
CONCLUSION
The
DW MR pulse sequence is a valuable technique. It provides information on the
physiologic state of the brain and is particularly sensitive to ischemic
infarction. We recommend its use when there is an acute neurologic deficit. As
DW imaging improves and becomes more widespread, it is expected to play a
greater role in the diagnosis of hyperacute and acute stroke and in the
differentiation of stroke from other disease processes that manifest with acute
neurologic deficits. DW MR imaging will also play a greater role in the
management of stroke and may be helpful in the selection of patients for
thrombolysis and in the evaluation of new neuroprotective agents. It may prove
to be valuable in the evaluation of a wide variety of other disease processes,
as described in this review.
The Physics and
Representation of Diffusion
Molecular diffusion, or
brownian motion, was first formally described by Einstein in 1905 . The
term molecular diffusion refers to the
notion that any type of molecule in a fluid (eg, water) is randomly displaced
as the molecule is agitated by thermal energy .In a glass of water, the motion
of the water molecules is completely random and is limited only by the
boundaries of the container. This erratic motion is best described in
statistical terms by a displacement distribution. The displacement distribution
describes the proportion of molecules that undergo displacement in a specific
direction and to a specific distance.To illustrate this idea, we can perform an
imaginary experiment. Let us imagine that we launch, at time t = 0, a given number N of labeled water
molecules in water, and we measure their individual displacement after a given
time interval Δ (hereafter, diffusion time interval). For each displacement
distance r, we count the number n of labeled water molecules that are displaced that distance.
We use the resultant data to plot a histogram of the relative number of labeled
molecules (n/N) versus displacement
distance (r) in a single direction. Most of the molecules
travel short distances, and only a few travel farther . Typically, the
displacement distribution for free water molecules is a Gaussian (bell-shaped)
function. At 37°C, with a diffusion time interval of Δ = 50 msec, the
characteristic distance (standard deviation of the Gaussian distribution)
typically is 17 μm, which means that about 32% of the molecules have moved at
least this far, whereas only 5% of them have traveled farther than 34 μm (
Diffusion in a homogeneous medium is well described as having a
Gaussian distribution. Depending on the type of molecule, the temperature of
the medium, and the time allowed for diffusion, the distribution will be wider
or narrower. The spread of the Gaussian distribution is controlled by a single
parameter: variance (σ2). Variance, in turn, depends on two
variables, so that σ2 = 2 · D · Δ, where D, the diffusion
coefficient, characterizes the viscosity of the medium or the ease with which
molecules are displaced. The diffusion coefficient for water at 37°C is
approximately D = 3 · 10−9 m2/sec. The longer the diffusion time
interval, the larger the variance, because there is more time in which
molecules may be displaced.
Molecular Displacement,
Diffusion, and Flux
To describe the global
behavior of a population of water molecules contained in an imaging voxel, we
use the term displacement distribution. Equivalent terms to
the latter are displacement probability density function and image of molecular displacement. In the present article, these terms are
used interchangeably. When molecules are agitated by thermal energy alone (ie,
when molecular displacement takes place through the process of diffusion), the
displacement distribution is centered. This means that the average or net
displacement of the molecular population is zero. Factors other than heat also
may contribute to molecular displacement. For example, a pressure gradient in a
pipe may affect molecular displacement. In an ideal setting with no turbulence
and no friction, all molecules undergo the same nonzero displacement r. Such a setting produces a very different displacement
distribution, in which the histogram is zero everywhere except in the
position r, which has the value N/N = 1 because all the molecules have been
displaced the same distance. This type of displacement is called flux. In flux,
molecules are displaced over a nonzero average distance. Although diffusion and
flux may occur together, for the sake of simplicity we have chosen in the
present article to focus on diffusion only. Therefore, the word displacement is often replaced with the more specific term diffusion.
Diffusion Contrast
Encoding
To depict the displacement
distribution, diffusion must be linked to the signal intensity measured at MR
imaging. As previously mentioned, water molecules move randomly in the presence
of thermal energy. In 1950, Hahn noted that the motion of spins (ie, hydrogen
protons of the water molecule) in the presence of a heterogeneous magnetic
field led to a decrease in signal intensity . In 1956, Torrey established the
fundamental equations used to describe the magnetization of spins in an MR
spectroscopy experiment . Since then, these equations have come to be regarded
as the most fundamental equations in diffusion imaging.
The results of the first
MR spectroscopy experiment specifically designed to measure diffusion were
reported in 1965 by Stejskal and Tanner . In their experiment, the
investigators used a pulsed gradient spin-echo (SE) sequence, a technique based
on the observation that spins moving in the magnetic field gradient direction
are exposed to different magnetic field strengths depending on their position
along the gradient axis. As is well known in MR imaging, an adequately applied
magnetic field influences the phase of the spins, with the degree of influence
depending on the strength of the field. Compared with a classic SE sequence,
the pulsed gradient SE sequence includes two additional diffusion gradient
pulses . The first of the two gradient pulses in this sequence introduces a phase
shift that is dependent on the strength of the gradient at the position of the
spin at t = 0. Before the application of the second
gradient pulse, which induces a phase shift dependent on the spin position
at t = Δ, a 180° RF pulse is applied to reverse
the phase shift induced by the first gradient pulse. Since the
diffusion-encoding gradient causes the field intensity (ie, phase shift) to
vary with position, all spins that remain at the same location along the gradient
axis during the two pulses will return to their initial state. However, spins
that have moved will be subjected to a different field strength during the
second pulse and therefore will not return to their initial state but will
experience a total phase shift that results in decreased intensity of the
measured MR spectroscopic signal. The longer the displacement distance is, the
higher the phase shift and the greater the decrease in signal will be. Hence,
the resultant image shows low signal intensity in regions where diffusion along
the applied diffusion gradient is high.
Diffusion
Spectrum Imaging
Diffusion spectrum imaging may be described as the reference
standard of diffusion imaging because it is the practical implementation of the
principles derived earlier and is the diffusion imaging technique that has a
sound basis in physical theory . Suitable for in vivo application, it provides
a sufficiently dense q-space signal sample from which to derive a displacement
distribution with the use of the Fourier transform. The technique was first
described by Wedeen et al .
If established practice is followed, 515 diffusion-weighted images
are acquired successively, each corresponding to a different q vector,
that are placed on a cubic lattice within a sphere with a radius of five
lattice units. The lattice units correspond to different b (or q)
values, from b = 0 (which corresponds to the centerpoint of
the sphere) to, typically, b = 12,000
sec/mm2 (which
is a very high b value). The Fourier transform is computed over
the q-space data. If the imaging matrix size is 128 × 128 × 30, the same number
of Fourier transform operations will be necessary as the diffusion probability
density function is computed for every brain location.
Traditionally, 515 images were considered necessary to obtain data
of good quality, although the acquisition of that number of images is very time
consuming. With improvements in MR imaging hardware and techniques in recent
years, and in view of additional very recent experience, fewer sampling points
seem to be necessary; the probability density function can be reconstructed
with approximately 257 or even 129 images by sampling only one hemisphere in
q-space. Of course, the signal-to-noise ratio and angular resolution may change
accordingly. The time for imaging of both brain hemispheres thus can be reduced
from approximately 45–60 minutes to as little as 10–20 minutes, an acquisition
time that makes the technique feasible in a clinical setting .
With the application of the Fourier transform over q-space in
every brain position, a 6D image of both position and displacement is obtained.
Diffusion at each position is described by the displacement distribution or the
probability density function, which provides a detailed description of
diffusion and excellent resolution of the highly complex fiber organization,
including fiber crossings. Since diffusion spectrum imaging is mostly used for
fiber tractography, in which only directional information is needed, the
probability density function is normally reduced to an orientation distribution
function by summing the probabilities of diffusion in each direction .
Technique
Diffusion-weighted MR Imaging
Diffusion-weighted MR imaging is the simplest form of diffusion
imaging. A diffusion-weighted image is one of the components needed to
reconstruct the complete probability density function as in diffusion spectrum
imaging. A diffusion-weighted image is the unprocessed result of the
application of a single pulsed gradient SE sequence in one gradient direction,
and it corresponds to one point in q-space. Even though such an image is rather
simple, it does contain some information about diffusion. In Figure 13, the left splenium of the corpus callosum
appears bright, whereas the right splenium appears dark. In regions such as the
right splenium, where the main diffusion direction is aligned with the applied
diffusion gradient, the intensity of the signal is markedly decreased, and the
region therefore appears darker on the image. In the ventricles, diffusion is
free and substantial in all directions, including the applied gradient
direction, and therefore the entirety of the ventricles appears dark. Despite
its simplicity, diffusion-weighted imaging is routinely used in investigations
of stroke . Indeed, in acute stroke, the local cell swelling produces increased
restriction of water mobility and hence a bright imaging appearance due to high
signal intensity in the area of the lesion. The benefit of diffusion-weighted
imaging is that the acquisition time is short, since only one image is needed.
ADC and Trace
The problem of diffusion-weighted imaging is that the
interpretation of the resultant images is not intuitive. To resolve this
problem, let us assume that the diffusion has no restrictions and that its
displacement distribution therefore can be described with a free-diffusion
physical model, which is a 3D isotropic Gaussian distribution. In this model,
the physical diffusion coefficient D is replaced
by the ADC, which is derived from the equation ADC = − b ln(DWI/b0), where DWI is the
diffusion-weighted image intensity for a specific b value
and diffusion gradient direction, defined as in the previous section, and b0 is a reference
image without diffusion weighting. Thus, to obtain an image of the ADC values,
two acquisitions are necessary.
The
ADC is very dependent on the direction of diffusion encoding. To overcome this
limitation, one can perform three orthogonal measurements and average the
result to obtain a better approximation of the diffusion coefficient. This
method is equivalent to the derivation of the trace from the diffusion tensor,
described in more detail in the next section.
Diffusion Tensor Imaging and Derived Scalars
For ADC imaging, we have assumed that diffusion follows a
free-diffusion physical model and is described by an isotropic Gaussian
distribution. This model often is too simplistic, especially if we are
interested in the orientation of axonal bundles in which diffusion is expected
to be anisotropic (ie, not the same in all directions). For purposes of
discussion, then, let us assume that diffusion remains Gaussian but may be
anisotropic. In other words, diffusion may be cigar or disc shaped but also may
be spherical, as in isotropic diffusion. Anisotropic Gaussian distributions
have six degrees of freedom instead of one. Therefore, to fit our model, we
must sample at least six points in q-space with q ≠
0 (diffusion-weighted images) and one point with q =
0 (reference image) . In general, a b value of
approximately 1000 sec/mm2 is used. To fit the resultant data to the model, we must
solve a set of six equations like the equation given earlier. The result is a
diffusion tensor (instead of a diffusion coefficient) that is proportional to
the Gaussian covariance matrix (instead of the Gaussian variance) .This diffusion tensor is a 3 ×
3 matrix that fully characterizes diffusion in 3D space, assuming that the
displacement distribution is Gaussian. The diffusion tensor is usually
represented by an ellipsoid or an orientation distribution function
Diffusion Tensor Imaging
and Diffusion Spectrum Imaging
Because of the limited
number of applied diffusion gradients and degrees of freedom, the diffusion
tensor model is incapable of resolving fiber crossings. In contrast, diffusion
spectrum imaging is not predicated on any particular hypothesis concerning
diffusion. Accordingly, its capability to resolve the diffusion probability
density function depends only on the resolution in q-space, and its capability
to resolve fiber crossings depends only on the related angular resolution.
In Figure 17, images
obtained with the two methods are juxtaposed. The regions in which the most
striking difference can be seen are the pons, where the corticospinal tract and
middle cerebellar peduncle cross, and the centrum semiovale, where the
corticospinal tract crosses the corpus callosum and the arcuate fasciculus.
Diffusion
MR Tractography
Brain fiber tractography is a
rendering method for improving the depiction of data from diffusion imaging of
the brain. Although a detailed discussion of tractography is beyond the scope
of this article, a short introduction is necessary because tractography is one
of the most powerful tools developed to aid image interpretation. The primary
purpose of tractography is to clarify the orientational architecture of tissues
by integrating pathways of maximum diffusion coherence. Fibers are grown across
the brain by following from voxel to voxel the direction of the diffusion
maximum. The fibers depicted with tractography are often considered to
represent individual axons or nerve fibers, but they are more correctly viewed
in physical terms as lines of fast diffusion that follow the local diffusion
maxima and that only generally reflect the axonal architecture. This
distinction is useful because, for a given imaging resolution and
signal-to-noise ratio, lines of maximum diffusion coherence (ie, the
computer-generated fibers) may differ from the axonal architecture in some
brains. Tractography adds information and interest to the MR imaging depiction
of the human neuronal anatomy.
The
connectivity maps obtained with tractography vary according to the diffusion
imaging modality used to obtain the diffusion data. For example, diffusion
tensor imaging provides a Gaussian approximation of the actual displacement
distribution, and since the representation of that distribution is restricted
to variations of an ellipsoid, this method creates various biases in the
tractography result. In contrast, diffusion spectrum imaging with tractography
overcomes many of those biases and allows more realistic mapping of
connectivity. The tractography result also depends on the tracking algorithm
used. Deterministic fiber tracking from diffusion tensor imaging uses the
principal direction of diffusion to integrate trajectories over the image but
ignores the fact that fiber orientation is often undetermined in the diffusion
tensor imaging data. To overcome this limitation of the data, Hagmann and
colleagues, as well as other investigators, investigated statistical fiber
tracking methods based on consideration of the tensor as a probability
distribution of fiber orientation .
The
application of fiber tractography to data such as those obtained with diffusion
spectrum imaging or q-ball imaging results in the depiction of a large set of
fiber tracts with a more complex geometry . The greater complexity obtained
with this method, compared with that from tractography with diffusion tensor MR
imaging data, is due to the consideration of numerous intersections between
fibers that can be resolved or differentiated.
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