Download Molecular MRI of Cerebral Venous Sinus Thrombosis Using

Molecular MRI of Cerebral Venous Sinus Thrombosis Using
a New Fibrin-Specific MR Contrast Agent
Christian P. Stracke, MD; Markus Katoh, MD; Andrea J. Wiethoff, PhD; Edward C. Parsons, PhD;
Peter Spangenberg; Elmar Spüntrup, MD
Downloaded from http://stroke.ahajournals.org/ by guest on August 11, 2017
Background and Purpose—Imaging of cerebral vein thrombosis is still challenging. Currently, diagnosis is based on CT
venography and MRI including MRA and conventional digital subtraction angiography. However, especially in chronic
cases, each method has shown its limitations. Newer strategies for MRI are found on molecular imaging using targeted
contrast agents. The aim of this study was to prove the feasibility of a novel fibrin-targeted MR contrast agent
(EP-2104R; EPIX Pharmaceuticals) for selective imaging of sinus venous thrombosis in an animal model.
Methods—Thrombosis of the superior sagittal sinus with human blood was induced in 6 pigs using a combined
microsurgical and interventional approach. MRI was then performed before and up to 120 minutes after injection of
4 ␮mol/kg body weight EP-2104R. Molecular imaging was performed with a 3-dimensional high-resolution
T1-weighted gradient echo sequence. Time courses of signal-to-noise ratio and contrast-to-noise ratio were analyzed.
Thrombi were then surgically removed and the Gadolinium concentration was assessed.
Results—In all cases the thrombosis could be successfully induced; the complete MR protocol could be performed in 5
animals. In these cases the thrombi showed selective enhancement after injection of the molecular contrast agent.
However, a continuous contrast-to-noise ratio increase was seen up to 120 minutes after contrast administration,
achieving a contrast-to-noise ratio of 14.2⫾0.7 between clot and the blood pool.
Conclusion—The novel fibrin-targeted molecular MR contrast EP-2104R allows selective and high-contrast imaging of
cerebral sinus vein thrombosis in an animal model. (Stroke. 2007;38:1476-1481.)
Key Words: cerebral venous thrombosis 䡲 molecular imaging 䡲 MR angiography 䡲 neuroradiology
䡲 venous thrombosis
C
erebral sinus vein thrombosis is a common disease with
different clinical presentations.1 The clinical presentation varies with acute, subacute, or chronic symptoms.
Symptoms vary between mild headache to severe intracranial
bleeding and ischemic infarction.2,3 The mortality ranges
between 5% and 15%.4
Since diagnostic procedures have improved, an increased
incidence of sinus vein thrombosis has been noted. Imaging
diagnosis relies on different modalities, such as CT, MRI, and
x-ray digital subtraction angiography. In clinical routine, the
first imaging modality used is usually cranial CT with and
without intravenous contrast agent. In plain scans, thrombosed sinus and veins can appear hyperdense to the surrounding brain tissue, especially in acute thrombosis. After contrast
injection, filling defects in the sinus can be observed like the
classic empty triangle sign.5 With the increased availability of
multi-row spiral CT scanners, CT venography has become a
powerful diagnostic tool for the assessment of sinus thrombosis. Complete occlusion or extensive thrombosis is usually
visible on CT venography. In patients with special anatomical
features or suspicion of chronic cerebral venous thrombosis,
the interpretation can be difficult.
MRI including MR venography are other broadly used
methods to assess the cerebral venous system.4,6 – 8 Besides
imaging with conventional T2- and T1-weighted sequences,
MRA techniques play a major role. Time of flight angiograms
can easily be obtained without contrast medium, but can lead
to false results caused by signal changes arising from methemoglobin, which can mimic flow in the vessel.9 Phase-contrast
MRA is another technique that can be applied with and without
contrast medium. This technique is highly sensitive for slow
blood flow and so excellently suitable for imaging of venous
vessels. However, limitations include vessels with very slow
flow or turbulent flow patterns.
Contrast enhanced MR venography offers the possibility
for direct thrombus visualization as a filling defect in the
contrast filled sinus or vein,10 –13 but MRA techniques have
the same problems in differentiating thrombosis from hyp-
Received December 12, 2006; accepted December 20, 2006.
From Department of Radiology (C.P.S.), University of Cologne, Cologne, Germany; Department of Diagnostic Radiology (M.K., E.S.), University
Hospital, RWTH Aachen University, Aachen, Germany; EPIX Pharmaceuticals (A.J.W., E.C.P.), Cambridge, Mass; Department of Neurosurgery (P.S.),
University Hospital, RWTH Aachen University, Aachen, Germany.
Correspondence to C.P. Stracke, Department of Radiology, University of Cologne, Joseph-Stelzmann-Strasse 9 50924 Cologne, Germany. E-mail
[email protected]
© 2007 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/STROKEAHA.106.479998
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Stracke et al
TABLE 1.
Cerebral Venous Sinus Thrombosis
1477
MR Protocols for Structural Imaging: T2 TSE and MRA
Protocol
Orientation
Field of
View
Matrix
Slice
Thickness
No. of
Slices
TR
T2 TSE
cor
230
512⫻512
Time of Flight MRA
cor
200
256⫻256
4
25
4522
100
90
5
25
23
7
40
3-dimensional PCA
sag
230
256⫻256
0.8
220
16
6.5
10
TE
Flip
TSE indicates turbo-spin-echo; TR, repetition time; TE, time to echo; PCA, phase contrast angiography.
Downloaded from http://stroke.ahajournals.org/ by guest on August 11, 2017
oplasia or aplasia of a sinus. This problem can even occur in
digital subtraction angiography, but x-ray angiograms offer
additional indirect information, eg, the pathologic flow pattern in case of venous congestion. With the available techniques of CT venography and MRI and MR venography,
cerebral venous thrombosis should be correctly diagnosed in
the majority of cases. However, in a small number of patients
the correct diagnosis remains difficult.
Consequently, it has been proposed that the incidence of
sinus thrombosis is still underestimated.14
A general solution to these limitations of all the diagnostic
modalities may be the direct and selective high-signal visualization of the thrombus itself while the surrounding blood
pool and soft tissue is signal-suppressed. Several recent
developments in MR contrast media belong to the category of
molecular imaging. These combine signal-generating gadolinium or iron oxide with tissue-specific chemical groups,
which selectively bind to different molecular targets.
One new development in this field is EP-2104R, a fibrintargeted gadolinium-based contrast agent (EPIX Pharmaceuticals). It exhibits highly specific binding to human fibrin. In
various in vivo studies, it has been used to image human thrombi
in the cardiac atrium, coronary or pulmonary vessels, or the
carotid arteries.15–20 It has the further advantage of enabling
imaging of acute, subacute, and chronic thrombi.15,19,20
The aim of this study was to investigate the potential of
EP-2104R for molecular imaging of sinus thrombosis using a
recently developed minimal invasive animal model,21 with
special consideration of the particular anatomical features of
cerebral venous and surrounding anatomy.
Methods
Sinus Thrombosis Animal Model
Sinus thrombosis was induced in a pig model with a combined
surgical and interventional procedure as previously described.21 The
experiments were approved by the government committee on animal
affairs. The animals were obtained from the Institute of Animal
Research, Aachen University, Germany.
After a cutaneous incision, a microsurgical opening of the skull
bone was performed. After transdural puncture of the sinus a
4-French sheath was introduced. Temporary distal occlusion of the
sinus was obtained with a 2-French 4-mm balloon catheter (Syntel;
Applied Medical). Simultaneous injection of human blood and
thromboplastin (Dade Behring Inc; Newark, Del) induced thrombosis. The balloon was deflated and removed after 35 minutes. To
prove thrombus formation, digital subtraction venograms were
achieved repeatedly throughout the procedure by contrast injection
through the 4-French sheath.
With only the sheath remaining, animals were transferred to the
MR scanner. After finishing the MR measurements, direct x-ray
venography was repeated to prove constancy of the clot. Subsequently, the animals were euthanized. The skull was opened and the
clots were removed and analyzed. The clots were immediately
weighed, and gadolinium content was later measured by inductively
coupled plasma mass spectroscopy.15
MR Measurements
All measurements were performed on a 1.5-T scanner (Intera;
Philips).
Animals were placed in a prone position and fixed to the MR table
unit using tapes and pillows to minimize any potential movement
artifacts. Scanning was performed using a small circular surface coil
(C1; Philips). After a short gradient echo survey scan, initial MR
examination was performed with standard structural and angiography sequences as used for imaging of the cerebral sinus in humans
with parameters shown in Table 1.
For molecular imaging, a strongly T1-weighted, fat-suppressed,
3-dimensional gradient echo sequence was used. Repetition time was
14 ms, with an echo time of 5.6 ms, and flip angle of 40°. With a 512
matrix, a field of view of 360 mm was scanned with 150 contiguous
slices of 0.5-mm thickness, resulting in a measured voxel size of
0.7⫻0.79⫻1 mm and reconstructed voxel size of 0.7⫻0.7⫻0.5 mm.
The total measurement time was 5:26 minutes. After local shimming,
a water-selective excitation pulse was applied to suppress signal
from fat.
The entire MR protocol (phase-contrast MRA, structural scans,
and the molecular imaging sequence) was performed before thrombus induction, and twice after thrombus induction, both before and
after contrast media administration. The sequence for molecular
imaging was repeated 5, 30, 60, and 90 minutes after contrast
injection for all animals, and also after 120 minutes in 4 animals.
Contrast Agent
EP-2104R is a novel fibrin-targeted contrast agent based on gadolinium. It is composed as a small peptide with 4 gadolinium chelate
moieties. It binds to fibrin, but not to circulating fibrinogen. A dose
of 4 ␮mol/kg body weight was administered with slow infusion over
3 minutes.
Data Analysis
Qualitative correlation of the clot extent in x-ray venography with
that of the MR images was performed by 2 readers. Each reader
assessed the extent of clot in the anterior, middle and posterior part
of superior sagittal sinus first for x-ray venography images, second
for the structural and angiographic MR images, and third for the
molecular imaging MRI data sets.
Quantitative analysis of molecular imaging was performed with
region-of-interest measurements. Signal time curves were measured
in the anterior superior sagittal sinus, posterior superior sagittal
sinus, an inner brain vein, the external carotid artery, the gray matter
adjacent to the superior sagittal sinus, the white matter, and the
muscle. Noise was quantified as the standard deviation of the signal
measured in air. Signal-to-noise ratios for thrombus, nonthrombosed sinus, inner brain veins, skull bone, and gray and white
brain tissue were calculated. Contrast-to-noise ratios were calculated over time for the difference between thrombus and nonthrombosed veins (blood pool) and between thrombi and the gray
matter. Difference of signal-to-noise ratios for thrombus and
nonthrombosed veins were statistically analyzed using a nonparametric Wilcoxon test (JMP software; JMP).
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May 2007
Figure 1. Left, The x-ray venogram after
successful thrombus induction shows clot
in the superior sagittal sinus (double
arrows) and the left transverse sinus
(arrowhead). Because of the impairment of
the venous flow there is retrograde filling
of several cortical veins. Right, The molecular imaging MR sequence shows
enhancement in the superior sagittal sinus
(double arrows) and strong enhancement
in the transverse sinus (arrowheads) 120
minutes after contrast injection.
Downloaded from http://stroke.ahajournals.org/ by guest on August 11, 2017
Results
In all 6 animals the thrombosis could be successfully induced
and verified by conventional x-ray venography (Figure 1).
One animal died immediately after thrombus induction,
presumably because of subdural hemorrhage. In all the
remaining 5 animals, thrombus formations in the superior
sagittal sinus were proven. In 2 animals additional thrombus
in one of the transverse sinuses was visible (Table 2, Figure 1).
Thrombi could be explanted in these 5 animals from the
superior sagittal sinus. The clot weights ranged between 57
and 560 mg (Table 2), with an average of 288 mg and SD of
186 mg. Gadolinium measurements were available only in 3
clots because of damage of 2 clots during transportation
overseas to the institution where the gadolinium measurements were performed. Gadolinium concentration ranged
between 0.3 and 0.65 mmol/L. Table 2 shows the thrombus
weights and locations in the different animals.
Structural sequences and the angiographic sequences could
be performed without any severe artifacts caused by the
model used (Figure 2). The clot extent in direct x-ray
venography correlated well to the signal changes in the MRA
protocols (Table 2). In 3 cases, thrombus formations in the
anterior superior sagittal sinus were suspected from MRI and
time-of-flight and phase-contrast MRA, where it was not
present in venography. This could be because of the fact that
very slow flow can lead to pathologic signal behavior. In the
inflow-sensitive gradient echo sequence (time-of-flight),
thrombus formations showed intermediate signal intensity,
comparable to brain tissue.
After contrast injection, signal elevation was apparent in
the external carotid artery and the internal brain veins, similar
to that seen with standard extracellular contrast agents.
Within 60 minutes, the signal in the blood pool decreased
over time. In all 5 animals, the thrombosed sinus showed
significant signal increase, which was strongest after an
average of 104 minutes (⫾23 minutes). Extension of the
contrast enhancement in the thrombi in molecular MRI
correlated strongly to the x-ray venography findings (Figure 1).
Differences in signal-to-noise ratios of the thrombosed
sinus and nonthrombosed veins reached statistical signifi-
TABLE 2. Clot Weights and Extent in Venography, Structural MRI, and MRA, and
Enhancement in Molecular Imaging Sequence
Animal
Clot
Weight, mg
Gadolinium
Concentration, mmol/L
Thrombus Extent in
Venography
Thrombus Extent in
Structural MR and
MRA
Thrombus Extent
in Molecular MRI
1
267
䡠䡠䡠
mss, pss, rt
ass, mss, pss
mss, pss, rt
2
57
mss, pss, lt
ass, mss, pss
mss, pss, lt
3
348
䡠䡠䡠
0.31
mss
ass, mss
mss
4
200
0.3
ass, mss
ass, mss
ass, mss
5
䡠䡠䡠
560
䡠䡠䡠
0.65
䡠䡠䡠
mss, pss
䡠䡠䡠
ass, mss, pss
䡠䡠䡠
mss, pss
6
ass indicates anterior superior sagittal sinus; lt, left transverse sinus; mss, middle third of superior sagittal sinus;
pss, posterior part of the superior sagittal sinus; rt, right transverse sinus.
In structural MR and MR venography (PCA and TOF), a thrombosis is suspected in the anterior sagittal sinus in 3
cases, whereas it could not be proven in digital subtraction venography.
Stracke et al
Cerebral Venous Sinus Thrombosis
1479
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Figure 2. Fat-suppressed 3-dimensioan
gradient echo sequence. Left upper, Plain
scan before surgery and interventional
thrombus induction. Right upper, After
thrombus induction there is a substance
defect visible in the area of the microsurgical access to the sinus (double arrows).
Signal in the adjacent superior sagittal
sinus is slightly hyperintense (arrowhead).
Lower row, Enhancement (arrows) in the
thrombosed superior sagittal sinus 30
minutes after contrast (left) and 90 minutes after contrast administration (right).
On both postcontrast images, the sinus
thrombus can be seen as focal signal
enhancement. However, contrast is superior after 90 minutes compared with 30
minutes after injection of the molecular
agent.
cance after 30 minutes (Figure 3). Contrast-to-noise between
thrombus and nontrombosed vessels (ie, the blood pool)
increased after contrast administration to an average of 14.21
(⫾0.76) after 120 minutes (Figure 4). Contrast-to-noise ratio
between thrombus and the adjacent gray brain tissue also
increased monotonically to 9.9 (SD ⫾3.14).
Figure 3. Signal-to-noise ratios (n⫽5) for thrombus in the sinus
(black squares) and inner brain vein (blood pool) after contrast
administration; 5 minutes after contrast administration, there is
no difference between the signal-to-noise ratio of thrombosed
sinus and an inner brain vein. After 30 minutes the difference
became statistically significant (*). SDs (n⫽4) are indicated with
the error bars.
Discussion
Cerebral venous thrombosis remains a diagnostic challenge.
Combined imaging with CT, CTA, MRI, and MRA is often
required. CT with CT venography and MRI with MR venography seem to have similar sensitivity for cerebral venous
thrombosis.22 However, some authors consider MRI with MR
venography as the imaging method of choice because of its
superior information concerning parenchymal changes and
the age of the thrombi.4 However, in a small group of patients
the diagnosis itself remains uncertain and, often, digital
Figure 4. Contrast-to-noise ratios between thrombus and blood
pool (black squares) and thrombus and gray brain tissue (open
gray squares) up to 120 minutes after contrast administration.
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May 2007
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subtraction angiography is added to the diagnostic protocol.
Molecular MRI allows for selective imaging of dedicated
targets while the surrounding tissues show no significant
enhancement. Hence, molecular imaging using a fibrinspecific contrast agent may be a new potential tool for
specific diagnosis of thrombosis and clot imaging.
The novel contrast agent EP-2104R has already shown its
potential to specifically bind to fibrin. Experimental studies
from coronary, atrial, and pulmonary clot have shown the
high-contrast achievable with this contrast agent.15–20 One
study showed superiority of EP-2104R compared with a
standard Gd-DTPA contrast agent for selective visualization
of clots in the carotid arteries and proved the enhancement of
the contrast agent in chronic clots up to 8 weeks20 The aim of
this study was to investigate the function of the contrast agent
in the cerebral venous system in a sinus thrombosis model. In
our animal model, cerebral venous thrombosis is induced in
the superior sagittal sinus, which is significantly smaller than
in humans (average maximum vessel diameter in our study:
2.6 mm [⫾0.42 mm]). Nevertheless, contrast enhancement
with EP-2104R allowed discrimination between thrombus,
blood pool, and brain tissue after 30 minutes. There was
complete qualitative correlation of the clot extent in the
superior sagittal sinus in the molecular imaging sequence as
compared with the venographic gold standard. In comparison
to structural MRI and MRA, molecular imaging additionally
showed thrombi in the transverse sinus in 2 cases and did not
bring any false-positive results, as structural and angiographic
MR showed in 3 cases (Table 2). However, this difference
can with regard to our small study not be considered as
significant.
Signal kinetics of thrombus in the sinus showed nonambiguous enhancement, according to the behavior of contrast
uptake in pulmonary and cardiac studies.17,18 Gadolinium
content was measured in 3 thrombi. Concentrations were high
and in the same range seen in previous studies. Contrasts
between thrombi and surrounding tissues were high enough
to distinguish between thrombosis and both brain and the
blood pool between 1 and 2 hours after contrast administration. However, we have only investigated acute thrombi and
no chronic thrombi, because our animal model seems not to
be suitable for a chronic evaluation of cerebral venous
thrombosis because it is rather invasive.
The molecular imaging sequence that was used is a simple
and robust T1-weighted 3-dimensiona gradient echo protocol
available on routine clinical scanners from various vendors.
Because of the sagittal slice orientation and the large field of
view/thick 3-dimensional imaging slab covering the entire
neurocranium, it shows no time-of-flight effects, so that flow
phenomena cannot mimic specific contrast enhancement.
A potential complication with this sequence may be methemoglobin in subacute thrombi. This hemoglobin breakdown product occurs after a few days in clots and has short
T1 relaxation times. Hence, it could therefore mimic contrast
enhancement with signal elevation in our molecular imaging
sequence. This pitfall should be overcome by measuring the
sequence before and after contrast injection.
The molecular imaging protocol is simple, but clinical
application may be further facilitated by other characteristics
of the EP-2104R. It has 4 gadolinium moieties per molecule,
and greater relativity when bound to fibrin. Thus, it is
effective for thrombus visualization at a dose of 4 ␮mol/kg
compared with usual Gd-DTPA in a dose of 0.1 mmol/kg.
Moreover, its relativity in the blood pool, even at a low dose,
may be sufficient to be used similarly to a standard extracellular contrast agent in a normal clinical MR examination; 60
minutes after injection, and after the wash-out, the specific
thrombus enhancement could be imaged in a brief second
examination that only includes the 3-dimensional gradient
echo sequence. In clinical routine, this second examination
could be performed in a few minutes.
Cortical vein thrombosis was not selectively induced in our
study, so no statement about contrast behavior in the smaller
cortical veins, which can be expected to be of submillimeter
size can be made. However, the high contrast between
thrombi and the blood pool may, in humans, allow us to
distinguish smaller thrombi inside the sinus from arachnoid
granulations or intrasinusoidal brain herniations, which are a
frequent source of errors.23
Our study shows the applicability of EP-2104R for selective thrombus imaging in the intracranial circulation. It would
be valuable to study certain other applications for this
contrast agent in similar anatomy. In stroke patients it may
allow differential diagnosis of emboli or acute appositional
thrombi in high-grade intracranial atherosclerotic stenoses or
chronic vessel occlusions, providing valuable information
with regard to thrombolytic therapy. In patients with intracranial or extracranial artery stenosis, EP-2104R could provide information concerning appositional clot before interventional therapy.
Conclusion
Molecular imaging with fibrin-specific EP 2104R of experimentally induced sinus thrombosis allows for high-contrast
visualization of clots in small intracranial sinus.
Sources of Funding
This study was supported in part by the German Research Council (SP
634/2-1). The study was also funded in part by EPIX Pharmaceuticals.
Disclosures
None.
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Molecular MRI of Cerebral Venous Sinus Thrombosis Using a New Fibrin-Specific MR
Contrast Agent
Christian P. Stracke, Markus Katoh, Andrea J. Wiethoff, Edward C. Parsons, Peter Spangenberg
and Elmar Spüntrup
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Stroke. 2007;38:1476-1481; originally published online March 22, 2007;
doi: 10.1161/STROKEAHA.106.479998
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