Robert
John
J. Sevick, Kucharczyk,
MD PhD
Fumio Kanda, MD, PhD #{149} Jan Mintorovitch, Jay S. Tsuruda, MD #{149}David Norman, MD
#{149}
Cytotoxic Brain Edema: with Diffusion-weighted To determine whether cytotoxic brain edema is associated with a decrease in diffusion, it was induced in rats, in the absence of ischemia, with an established model of acute hyponatremic encephalopathy. Cytotoxic brain edema secondary to acute hyponatremia was induced with intraperitoneal injections of 2.5% dextrose in water and subcutaneous injection of arginine-vasopressin. Coronal spin-echo magnetic resonance (MR) images were obtained with and without strong diffusion-sensitizing gradients before and after induction of acute hyponatremia. The apparent diffusion coefficient (ADC) was measured at two coronal section locations. In hyponatremic rats, the brain ADC was significanfly reduced (P = .0153 and 0001) and was positively correlated with increased total brain water content (P = .0011). Plots of ADC versus total brain water showed a statistically significant inverse linear relationship between ADC and increasing brain water at the anterior coronal section location. The results indicate that the ADC may be a sensitive indicator of cytotoxic brain edema and thus may enable quantitalive evaluation of such edema with diffusion-weighted MR imaging. Index
terms:
Brain, edema, 10.86 #{149}Brain, MR. 10.1214 #{149} Magnetic resonance (MR), diffusion study, 10.1214 #{149} Magnetic resonance (MR), experimental #{149} Magnetic resonance (MR), pulse sequences #{149}Magnetic resonance (MR), technology
Radiology
1992;
From M.E.M.),
185:687-690
PhD #{149} Allen I. Arieff, Michael E. Moseley,
#{149}
D
Assessment MR Imaging’
IFFUSION-WEIGHTED
nance
(MR)
magnetic resoimaging is a rela-
tively new technique diffusion-sensitizing
in which gradients
strong are
added
to conventional spin-echo (SE) The resultant images are extremely sensitive to changes in the microscopic motions of water propulse
sequences.
tons (i,2). Diffusion-weighted imaging has already demonstrated
great
utility
in detection
emic
damage
in animal
stroke.
In several
MR
of early
reported
correlates are poorly
causes decrease tissues, cellular stricted
brain
to arterial
influx
possibility
pulsa-
occlusion,
of water
(4). The
is a particularly
attrac-
evaluate edema ischemia images.
model
in acute objective
the effects not associated
of cytotoxic
was
to
of cytotoxic with cerebral
on diffusion-weighted An established rat
edema
MR brain
was
used
the Departments of Radiology, Section of Neuroradiology (R.J.S., J.M., J.K., J.S.T., D.N., and Medicine, Division of Geriatrics (F.K.), University of California, San Francisco; and San Francisco Veterans Affairs Medical Center, San Francisco (F.K., AlA.). From the 1991 RSNA scientific assembly. Received November 6, 1991; revision requested December 26; final revision received July 6, 1992; accepted July 24. R.J.S. supported in part by a clinical fellowship from the Alberta Heritage Foundation for Medical Research. J.S.T. supported in part by an RSNA Research and Education Fund Seed Grant. Address reprint requests to R.J.S., Department of Radiological Sciences and Diagnostic Imaging, MRI Centre, Foothills Provincial General Hospital, 1403 29th St NW, Calgary, Alta, Canada T2N 2T9. ,-
RSNA,
1992
rats
hyperim-
with
a body
METHODS
Sprague-Dawley
weight
of 220-250
g were
randomly assigned to one of three study groups. Eight rats in the experimental group and six control rats were imaged. Another group of six controls were not imaged. Anesthesia was induced with intraperitoneal injection of 50 mg of ket-
amine hydrochloride zine hydrochloride.
and 2.5 mg of xylaAcute hyponatremia
was induced over 2.5 hours with intrapentoneal injection of 140 mmol/L dextrose in water (12% body weight) and subcutaneous injection of 2 IU of arginine-vasopressin. This was followed 30 minutes later by an additional intraperitoneal injection of 140
mmol/L
dextrose
in water
(6%
body
weight). Body temperature was maintamed by means of a circulating warm water pad while the rats were in the magnet and by means of heat lamps when they
were out of the magnet. All MR images were obtained 2-T
unit
ischemia. of this study
AND
A total of 20 female
live explanation of the temporal sequence of changes observed on MR images The
MATERIALS
studies,
in temperature in ischemic changes in osmolality of extrafluid in the brain, and reproton motion secondary to
intracellular last
reduced
secondary
is correlated with signal intensity on diffusion-weighted ages (4). ADC
of
in acute cerebral ischunderstood. Possible
include
tion
(5-iO). To eliminate Ti and T2 relaxation effects, the apparent diffusion coefficient (ADC) was calculated both before and after the induction of brain edema. Previous studies have demonstrated that a reduction in the
isch-
models
areas of signal hyperintensity were observed on diffusion-weighted MR images well in advance of any abnormalities on T2-weighted SE images (3,4). Although the physical cause of diffusion-weighted signal hyperintensity is known to be associated with slower diffusion of water protons, its physio-
logic emia
MD PhD
#{149}
chemical
shift
(GE Medical
equipped
with
with
a
imager/spectrometer
Systems,
Milwaukee)
self-shielded
gradient
coils
(±15 C/cm, 15-cm bore) (Acustar, GE Medical Systems) (Ii). A low-pass birdcage proton imaging coil with an inner diameter of 5 cm was used to obtain multisection SE MR images in the coronal plane immediately before the induction of hyponatremia and approximately 3 hours later. The diffusion-weighted pulse sequence used was similar to the intravoxel incoherent-motion sequence devised by
Le Bihan
et al (i), which
gradient
pulses
Abbreviations: efficient, ROI
ADC =
places
on either
region
=
side
apparent
of interest,
matched of the
radio-
diffusion co= spin
SE
echo.
687
frequency-refocusing exact manner as the
180#{176} pulse in the original Stejskal-Tan-
ner pulse
The imaging
sequence.
parame-
ters were as follows: repetition time msec/ echo time msec = 1,500/80; field of view, 60 mm; 128 phase-encoding steps; section thickness, 3 mm, without intersection gap;
and four signals
averaged.
The diffusion-
sensitizing gradient was oriented in the y direction (ventral to dorsal) with a pulse duration of 20 msec, gradient separation of 40 msec, and gradient strength of 5.6 C/cm. In aggregate, these factors produce a b value of i,4i3 sec/mm2. The b value was determined by means of careful calibration of several pure liquids for which the diffusion coefficient is known at the temperature of the calibration measurement. The calibration measurements were
with
performed
exactly
the same
parame-
Figure 1. out and
Coronal SE MR images (1,500/80, (right) with strong diffusion-sensitizing
basal ganglia passed most
as well as frontal of one hemisphere,
and temporal excluding
with
four signals averaged) gradients. This anterior
cortex. The subarachnoid
obtained coronal
(left) withlevel includes
ROI used for ADC calculation spaces and ventricles.
encom-
ters as those used for the in vivo measurements. The b value used was approximately equal to the value anticipated from
integration
of the original
Stejskal-Tanner
equations with half-sine shapes for the diffusion-sensitizing gradient pulses and with consideration of potential cross-terms from the inherent MR imaging encodinggradient pulses. Separate images were obtamed with and without the application of strong diffusion-sensitizing gradients.
Region
of interest
(ROI)
performed on the same ages selected from each
before
and after
analyses
were
two coronal multisectional
im-
hyponatremia.
set
The ante-
nor section (Fig i) included the basal ganglia, as well as frontal and temporal cortex, while the posterior section (Fig 2) consisted primarily of thalamus and parietal and posterior temporal cortex. At each of the two levels, ROI measurements coyered most of one hemisphere and encompassed gray and white matter but exduded subarachnoid spaces and ventricles. ADC values were calculated according to the formula ADC
ROI signal
where
S1
fusion
gradients,
without
(lnS2
=
=
S2
=
-
intensity with difROI signal intensity
diffusion gradients, and b in b value between images 1,413 sec/mm2) and without (b
=
diffusion-sensitizing
the
=
with 0)
=
gradients.
At the conclusion of the imaging procedune, a blood sample was obtained by means of cardiac puncture for measurement of plasma sodium; then the rat was decapitated and the brain was removed, as previously described (i2). We analyzed the brain for water content by drying to constant weight triplicate samples of cerebral cortex that weighed approximately 0.2
g each,
as previously
Data were
analyzed
tistics
a paired,
and
described
with
(13).
descriptive
two-tailed
sta-
Student
significantly
plasma
sodium and total and extracellular
measurements
Radiology
#{149}
are
summarized
brain water)
wa-
with
was
increased
brain water. ADC values were consistently lower in the anterior section location (0.63 x i05 cm2/sec ± 0.04 x i0) than those in the posterior section location (0.72 x iO-5 cm2/sec ± 0.04 x 10) in both experimental and control rats. differences existed values at 0 and 3 hours
control group. On the statistically significant
creases
in ADC
values
were
at both
coronal
levels
when
posthyponatremia in Ta-
sodium
correlated
total
in the hand,
RESULTS
688
ble 1. Decreased
No significant between ADC
test.
Plasma ter (intra-
signals averaged) obtained (left) withlevel includes thalamus as well as pan-
lnS1)/b,
difference (b
Figure 2. Coronal SE MR images (i,500/80, with four out and (right) with diffusion gradients. This posterior etal and posterior temporal cortex.
pared
(Table
values
2).
Table 2 ADC Values Section 1 2
in Experimental
Before Hyponatremia 0.61 0.73
Group
After Hyponatremia
±
0.02
0.56
±
±
0.03
0.67
±
0.04 (.0153) 0.03(0001)
Note-Values are the mean x i0 cm2/sec standard deviation; numbers in parentheses are P values. I = anterior, 2 = posterior. ±
other deobserved
prewere
and com-
Figures 3 and 4 illustrate tionship between the ADC water content. Hyponatremia-in-
duced
increases
in total
brain
the and
relabrain
water
December
1992
S S
E
E
06
05
ADC
08
07
(m..n
x
ADC
3.
Os
07
cm’/s.c)
1O
(m..n
x
09
cm’/s.c)
1O.
4.
Figures
3, 4.
ADC ADC
shows versus
(3) Plot
of ADC
an inverse total brain
linear water
crease with increases was not statistically
versus total brain water in anterior coronal section location. The relationship with increasing brain water (R2 = .75). (4) Plot of in posterior coronal section location. A tendency for ADC to de-
in brain significant
water (R2
is evident. =
However,
the
multiple
correlation
change in brain intracellular pH was found, and there was normal resistance to mannitol infusion. The intactness of the blood-brain barrier was confirmed by the finding that administration of gadolinium did not produce signal intensity changes on Tiweighted MR images of the brain in the same animals. Similar results were obtained by Rymer and Fishman (10), who evaluated the integrity of the blood-brain barrier in acutely hyponatremic rats by use of tritiated mannitol. These results indicate that the blood-brain barrier is preserved in the model of acute hyponatremic encephalopathy used in our study and suggest
.16).
gray
lion was found between the ADC and brain water content at the level of the
cerebrospinal fluid into the bloodstream, may be overwhelmed with resultant cellular water expansion or cytotoxic edema. In some instances of hyponatremia, by comparison, the
posterior
intrinsic
correlated
significantly
in the
ADC
3).
statistically
No
in the
with
anterior
decreases
section
significant
section
(Fig
(Fig
correla-
4).
DISCUSSION Diffusion-weighted has
been
the
MR imaging
focus
of a number
of re-
cent studies in animal models of cerebral ischemia (3,4,14). Approximately five explanations have been proposed to account for the areas of early-onset signal hyperintensity sion-weighted MR
seen images
on diffuof acutely
ischemic brain (which appear well in advance of changes in signal intensity on T2-weighted images). One explanation is that signal hyperintensity may
be
secondary
to intracellular
ter accumulation
or cytotoxic
wa-
edema
(4).
Our ship sity
study
evaluated
the
between changes on diffusion-weighted
and cytotoxic severe acute
relation-
in signal MR
edema associated with hyponatremic encepha-
that
such
rats
are more
susceptible
hyponatremia-induced
brain
than male rats (5). Acute mia is the most common disorder among hospital has
significant
associated
to
injury
hyponatreelectrolyte patients
and
morbidity
Volume
cells (5-7,15). Adaptive mechaincluding the loss of cellular and increased movement of
185
Number
#{149}
3
in intracellular likely have
an effect as well. Many previous studies have used dilutional hyponatremia (6,7) induced with vasopressin injection and parenteral glucose in water to induce cerebral edema in rats. It is well known vasopressin
retention ponatremia,
can
increase
water
by the kidneys. In acute hysuch an increase could the
osmotic
disequilibrium
between plasma and brain cells. However, the peptide hormone is now also known to significantly increase the permeability of both brain capillaries
and mortality, which are primarily associated with dysfunction of the central nervous system (is). An acute drop in serum sodium causes osmotic disequilibrium and shift of water into brain nisms, solutes
sium pump. Changes viscosity and osmolality
sustain
lopathy. Young adult female rats were used because it has been shown
mechanisms
of the brain are able to reestablish brain cell volume without permanent brain damage (6,7). We can only speculate as to how the ADC is decreased in cytotoxic brain edema. The diffusion of water that is accumulating in cells is slowed. The cause of this slowing is unknown. It could be related to breakdown of the transmembranous sodium-potas-
that
intenimages
compensatory
and
ventricular
ependymal
that
brain water edema. A previous
coefficient
cells
to water (8,16-18), even in the absence of hyponatremia (i9). It is possible that vasopressin may be a hormonal mediator of water movement in the central nervous system. Adler et al (9) evaluated the integ-
and
the
observed
content study
white
increases
indicate has
matter
shown are
in
cytotoxic that
equally
affected by the cytotoxic edema induced in this model (10), a finding which suggests that the differences in the measured ADC values at the antenor and posterior coronal section locations
are
most
likely
attributable
to
regional variations in the relative volumes of gray and white matter in each section. ADC values are known to be substantially different in gray and white matter. For example, the cortical gray matter of cat brain has been reported to have an ADC of 0.80.9 x i0 cm2/sec, whereas ADC values in white matter ranged from 0.3 x io to 1.2 x i05 cm2/sec, depending on which diffusion gradient direction was selected (i4,20,2i). In our study, lower ADC values were consistently observed in the anterior section localion in both control and experimental rats.
In the
anterior
section,
gray
mat-
ter is primarily composed of the thin mantle of cerebral cortex and the large caudate nucleus. White matter at this level includes the corpus cabsum,
anterior
commissure,
internal
capsule, and longitudinally oriented myelinated fiber tracts. In the posterior section, the gray matter is again represented by a thin cerebral cortex but also includes large aggregations of thalamic and hypothalamic neurons that would contribute to an increase in the ADC. On this basis, it seems
possible
that
the
gray
matter!
model of acute hyponatremia induced with water and desmopressin. These workers infused 0.25% HC1 and measured brain intracellular pH by
white matter ratio is higher in the posterior section, and this might account for the higher ADC values. This explanation is speculative, however, because selective ADC measurements were not performed in gray and white matter separately. Other factors to consider regarding the observed differences in ADC be-
means
tween
rity
of the
blood-brain
of MR
spectroscopy.
barrier
in a rat
No
anterior
and
posterior
section
Radiology
689
#{149}
locations include the possibility that the ADC of gray matter and that of white matter differ in various regions of the brain. Finally, it is possible that the observation is artifactual. The results of this study do not prove conclusively that the areas of signal hyperintensity diffusion-weighted
observed MR images
may
prove
valuable
in experi-
mental studies of brain edema and ultimately (in combination with techniques of ultrafast MR imaging) in
690
Radiology
#{149}
of brain
edema
in human
11.
sub-
#{149}
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E, Lallemand
D, Gre-
nier P. Cabanis E, Laval-Jeantet imaging of intravoxel incoherent
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December
1992