Combi | DK-5 4050 | Endovascular Thrombectomy and Thrombolysis for Severe

Endovascular Thrombectomy and Thrombolysis for Severe Cerebral Sinus
Thrombosis: A Prospective Study
Jan Stam, Charles B.L.M. Majoie, Otto M. van Delden, Krijn P. van Lienden and Jim
A. Reekers
Stroke 2008;39;1487-1490; originally published online Mar 13, 2008;
DOI: 10.1161/STROKEAHA.107.502658
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Endovascular Thrombectomy and Thrombolysis for Severe
Cerebral Sinus Thrombosis
A Prospective Study
Jan Stam, MD, PhD; Charles B.L.M. Majoie, MD, PhD; Otto M. van Delden, MD, PhD;
Krijn P. van Lienden, MD, PhD; Jim A. Reekers, MD, PhD
Background and Purpose—Most patients with cerebral sinus thrombosis (CST) recover after treatment with heparin, but
a subgroup has a poor prognosis. Those patients may benefit from endovascular thrombolysis.
Methods—Prospective case series. Patients with sinus thrombosis were selected for thrombolysis if they had an altered
mental status, coma, straight sinus thrombosis, or large space-occupying lesions. Urokinase was infused into the sinuses
(bolus 120 to 600!103 U; then 100!103 U/h) via a jugular catheter, in 15 cases combined with mechanical thrombus
disruption or removal.
Results—We treated 20 patients (16 women), mean age 32 years. Twelve patients were comatose and 14 had hemorrhagic
infarcts before thrombolysis. Twelve patients recovered (Rankin score 0 to 2), 2 survived with handicaps, and 6 died.
Factors associated with a fatal outcome were leukemia (3/6 versus 0/14, P"0.02) and large hemorrhagic infarcts (4/6
versus 2/14, P"0.04). Seizures were less frequent in the fatal cases (P"0.05). Patients who died had a larger mean
lesion surface than survivors (30.5 versus 13.6 cm2; P"0.03), larger midline shift (5.2 versus 1.7 mm; P"0.02), and a
more rapid course (2.7 versus 8.2 days; P"0.01). Five patients who died had large hemispheric infarcts and edema
before thrombolysis, causing herniation. Five patients had increased cerebral hemorrhage (3 minor, 2 major) after
thrombolysis.
Conclusions—Thrombolysis can be effective for severe sinus thrombosis, but patients may deteriorate because of increased
cerebral hemorrhage. Patients with large infarcts and impending herniation did not benefit. (Stroke. 2008;39:1487-1490.)
Key Words: sinus thrombosis ! intracranial ! thrombolytic therapy
C
erebral sinus thrombosis is usually treated with anticoagulation. The efficacy of conventional or fractionated
heparin showed a modestly beneficial effect in 3 small
randomized trials.1–3 Metaanalysis showed a pooled relative
risk reduction of 0.46 for the outcome death or dependency
after heparin compared to placebo (95% confidence interval
0.16 to 1.31).4 Most neurologists now use full-dose heparin
(conventional or fractionated low-molecular weight [LMW])
as standard initial treatment for patients with CVST.5
In the clinical trials 10% of the patients treated with
heparin had a poor outcome. In a large prospective study of
624 patients, the International Study on Cerebral Vein and
Dural Sinus Thrombosis (ISCVT), 13.4% had a poor outcome
(dead or dependent, Rankin 3 or worse).5 Most patients (83%)
were treated with heparin. Factors associated with a poor
outcome were age (#37 years), male sex, coma, mental status
disorder, thrombosis of the deep cerebral venous system,
intracranial hemorrhage, malignancy, and central nervous
system infection. About 30% of patients with one or more of
these risk factors had a poor outcome despite treatment with
heparin. For these patients endovascular thrombolysis might
give better results.
Endovascular thrombolysis dissolves the thrombus by infusion of a thrombolytic drug into the occluded sinuses. It is
often combined with mechanical techniques, such as thrombus disruption, thrombosuction with a rheolytic catheter, and
thrombus removal with a balloon catheter.6 The theoretical
advantage of thrombolysis for CVST is that the drug is
delivered where needed, and downstream from cerebral
venous— often hemorrhagic—infarcts. Mechanical methods
result in more rapid recanalization and increase the surface of
the thrombus exposed to thrombolytics. We treated 20 patients with severe CVST with endovascular thrombolysis in a
prospective study, analyzed the results, and compared them
with results of previous studies.
Methods
We selected patients with cerebral sinus thrombosis with an assumed
poor prognosis because of an altered mental status (cognitive
Received September 4, 2007; final revision received October 2, 2007; accepted October 10, 2007.
From the Departments of Neurology (J.S.) and Radiology (C.B.L.M.M., O.M.v.D., K.P.v.L., J.A.R.), Academic Medical Centre, University of
Amsterdam, The Netherlands.
Correspondence to Prof Dr J. Stam, Department of Neurology (H2-226), Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105
AZ, Amsterdam, The Netherlands. E-mail J.Stam@amc.uva.nl
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.107.502658
1487
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by on December 20, 2008
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Table 1.
Baseline Clinical Data of 20 Patients With CVST, Treated With Thrombolysis
Patient
No.
Cause or
Risk Factor
HI
Onset to
Diagnosis
(days)
Diagnosis to
Heparin
(days)
Heparin to
Thrombolysis
(days)
GCS
1
Sex
Age
1
M
36
ALL; L-asp.
$$
0
0
1
2
M
29
hyperthyreoidy
$
12
0
0
GCS
2
Pupils
(right/left)
Seizures
Risk
Factors
Outcome
(Rankin)
13
7
14
14
$/%
%
1,2,5,6
death
$/$
TC
4,5,6
0
0
3
F
19
OAC
%
7
0
1
13
13
$/%
%
3,4
4
M
12
head injury
%
3
0
0
7
3
$/$
TC status
2,3,5
0
5
F
27
ALL
$$
3
0
0
8
8
%/%
%
1,2,3,6
death
6
F
36
OAC
$$
1
5
0
15
10
$/$
TC
4,6
0
7
F
40
ALL; L-asp.
$$
1
0
0
10
10
$/$
TC
1,4,6
death
8
F
40
%
$$
4
1
3
8
5
$/$
TC
2,6
1
9
F
19
OAC
%
6
0
0
11
10
$/$
TC
3,4
3
10
M
57
%
$
1
0
1
7
6
$/$
TC
2,5,6
2
11
F
25
OAC
$
8
1
1
8
4
$/$
TC
2,6
1
12
F
41
severe anemia
%
8
0
9
15
8
$/$
TC
2,3
1
13
F
23
myeloprolif. disorder,
OAC
$
27
0
0
4
4
$/$
%
2,3,6
2
14
F
17
head injury
$
5
0
0
15
7
$/$
TC
2,3,6
2
15
F
39
post partum
$
2
0
0
coma
4
%/%
%
2,6
death
16
F
25
ulcerative colitis
$$
3
1
0
coma
3
%/%
%
2,6
death
17
F
31
OAC
$
5
0
0
10
9
$/$
%
3,4,6
death
18
F
43
%
$
3
0
0
11
11
$/$
F
3,4,6
1
19
F
46
%
%
4
0
0
7
7
$/$
%
2,3
4
20
F
38
OAC
%
3
0
1
12
9
$/$
%
3,4
0
ALL indicates acute lymphatic leukaemia; L-asp, L-asparaginase; OAC, oral anti-conceptive; HI, Haemorrhagic infarct on base-line CT or MRI scan ($ minor, $$
large); GCS 1, at or shortly before diagnosis; GCS 2, at or shortly before endovascular treatment; TC, tonic clonic seizure; F, focal seizures.
Risk factors for a poor outcome as found in the ISCVT5,19: 1, malignancy; 2, coma; 3, deep venous system thrombosis; 4, mental status disorder; 5, male sex; 6,
hemorrhagic infarct.
disturbances including abnormal alertness and orientation), coma,
straight sinus thrombosis, or large space occupying lesions, such as
edema or (hemorrhagic) infarcts. The diagnosis of CVST was
confirmed by MRI and MR-venography, CT venography, or conventional angiography. The pretreatment CT or MRI scans were
assessed for midline shift and lesion size, measured as the surface on
the image with the largest diameter of the lesion, on the last available
scan before thrombolysis. Any cerebral lesion with CT or MRI
signals compatible with blood was defined as hemorrhagic infarct.
Lesions #15 cm2 with more than approximately 50% of the surface
containing blood were considered large hemorrhagic infarcts.
We performed thrombolysis by introducing a catheter via the
internal jugular vein and advancing it into a frontal position in the
superior sagittal sinus while the thrombus was dissolved with
urokinase (bolus 120 to 600!103 IU). If needed and possible we also
entered the straight sinus. The catheter was left in situ, and urokinase
was infused locally for variable periods of time, usually 24 hours, at
a rate of 100.000 IU/h, depending on the degree of recanalisation.
Heparin was continued during thrombolytic therapy. In most cases
we also applied thrombosuction with a rheolytic catheter, combined
with thrombectomy with a Fogerty-catheter. Sinus recanalisation
was examined by contrast injection through the thrombolysis catheter or by intraarterial angiography. We assessed the outcome at
follow-up visits or by telephone interview, between 3 and 6 months
after treatment. Neurological impairment was expressed as a score
on the modified Rankin scale (0"complete recovery; 6"death). We
analyzed differences between patients who died and survivors with
the Mann–Whitney test for scale variables and with Fisher exact test
for nominal variables. We compared the outcome of our patients
with outcomes in previously reported case series7–12 and in a review
of published case reports.13
Results
We treated 20 patients (16 women, 4 men) with a mean age
of 32 years (range 12 to 57). Most patients (17/20) were
referred from other hospitals because of worsening CVST.
Details are given in Table 1. The median delay between onset
of symptoms and diagnosis was 3.5 days. The mean Glasgow
coma score (GCS) was 7.6 (range 3 to 14). Twelve patients
were comatose before treatment. Fourteen patients had hemorrhagic infarcts before thrombolysis. Eleven patients had
thrombosis of the deep cerebral venous system. Ten patients
had generalized tonic-clonic seizures, with an epileptic status
in one. Three patients had acute lymphatic leukemia (ALL;
treated with L-asparaginase in 2). For radiological and
treatment data see supplemental Table I, available online at
http://stroke.ahajournals.org.
All patients were treated with heparin (conventional or full
dose LMW) at the day of the diagnosis or the next day, except
for 1 in whom heparin was delayed 5 days because the
referring clinicians considered it contraindicated because of a
large hemorrhagic infarct (case 6). Two patients (8 and 12)
deteriorated and became comatose during treatment with
heparin and improved after thrombolysis. In 15 patients we
applied thrombolysis and thrombosuction, in 4 thrombolysis
only. In 1 case (patient 19) it was impossible to enter the
sinuses because of firm organized thrombus.
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Stam et al
Nine patients recovered or had minimal residual symptoms
(Rankin 0 or 1), 3 came out with a minor handicap (Rankin
2), 2 had a moderate or severe handicap (Rankin 3 and 4), and
6 died. Patients who died more frequently had leukemia (3/6)
and large hemorrhagic infarcts (4/6) as compared to survivors
(0/14 and 2/14, respectively; P"0.02 and 0.04). Seizures
occurred less frequently in the fatal cases (1/6) than in the
surviving patients (10/14; P"0.05). Patients who died had a
larger mean lesion size than the survivors (30.5 versus 13.6
cm2; P"0.03), larger mean midline shift (5.2 versus 1.7 mm;
P"0.02), and a shorter delay between onset and diagnosis
than those who survived (2.7 versus 8.2 days; P"0.01). Other
potential risk factors (age, coma, straight sinus thrombosis)
were not associated with a fatal outcome.
Death was caused by transtentorial herniation in all patients, confirmed by autopsy in one. Five patients who died
were already in early or advanced stages of herniation before
thrombolysis, consistent with their large unilateral infarcts
with midline shift (patients 1, 5, 7), large bilateral lesions
(patients 15 and 16), obliterated basal cisterns, and fixed and
dilated pupils (one unilaterally, three bilaterally), all before
thrombolysis. Patients 15 and 16 were in a very bad clinical
condition, and thrombolysis was performed as a last therapeutic option with very little hope for recovery. Four of the
patients who died (5, 7, 15, 17) had an increased amount of
intraventricular or parenchymal blood on the CT scan after
thrombolysis. Patient 17 had a relatively small left temporal
hemorrhagic infarct, which became larger and more hemorrhagic after thrombolysis and caused fatal herniation. In one
surviving patient (14) thrombolysis was followed by a hemorrhagic infarct and a large local hemorrhage in the neck from
the jugular puncture. She recovered with minor residual
symptoms.
Discussion
Twelve patients had excellent recovery or minor handicaps.
Eight had a poor outcome, of whom 6 patients died despite
maximally supportive treatment. A number of factors contributed to the poor results in these patients. The most
conspicuous feature of the patients who died was their
significantly larger midline shift, caused by large unilateral
hemorrhagic infarcts, or the presence of large bilateral lesions
at baseline, all causing herniation. This agrees with a previous
study, which showed that the most frequent cause of early
death in CVST is cerebral herniation.14 The delay between
onset and diagnosis was 2.7 days for the patients who died,
significantly shorter than for the survivors, which is compatible with a rapid deterioration attributable to early large
hemorrhagic infarcts. The fact that 5 patients had mildly (3)
or evidently (2) increased cerebral hemorrhage after
thrombolysis, of whom 4 died, indicates that the procedure
might be unacceptably hazardous in some cases. The number
of increased hemorrhages in our series is larger than in
previous studies. This may be related to the higher number of
pretreatment hemorrhagic infarcts in our patients (Table 2).
Nevertheless, we believe that in only 1 of these cases (patient
17) the increased hemorrhage may have contributed to the
fatal outcome. The other patients were already in a very
serious condition before thrombolysis.
Thrombolysis for Cerebral Sinus Thrombosis
1489
Table 2. Comparison of Previously Published Case Series,
a Review of Cases Reports, and the Present Study of
Thrombolysis for CVST
Previous Case
Series11–16
No. of cases
82
Coma
Cases Reviewed
up to 20017
142
Present
Study
20
4%
32%
60%
18%
33%
70%
New or increased cerebral
hemorrhage
7%
5%
25%
Death
5%
9%
30%
Baseline hemorrhagic
infarcts
Three patients who died suffered from ALL. Sinus thrombosis is a well known complication of ALL.15,16 The combination of ALL and sinus thrombosis has a worse prognosis
than each condition separately.16 Factors that contribute to
poor outcome are effects of chemotherapy (L-aspariginase)
and thrombocytopenia. Two patients with ALL (5 and 7) had
some increased intraventricular blood on their CT scan after
thrombolysis and low thrombocyte counts of 131 and
43!109/L, respectively. Remarkably, the surviving patients
more often had seizures than the patients who died. A
possible explanation is that patients with multiple seizures in
acute sinus thrombosis can be severely ill with impaired
consciousness between seizures, even in the absence of
severe infarcts or hemorrhages. The presence of seizures may
have caused recruitment of some patients with small cerebral
lesions and a good prognosis despite their impaired consciousness, in whom standard treatment with heparin and
antiepileptics might have been sufficient for a good outcome.
The first case reports of thrombolysis for CVST were
published around 1990, initially by neurosurgeons who introduced a catheter via a burr hole into the superior sagittal sinus
or applied open thrombectomy, followed by reports of endovascular treatment. A systematic review of all published cases
of thrombolysis for CVST up to July 2001 identified 146
patients in 72 publications of single case reports or uncontrolled case series.13 Six larger series have been published,7–12
the largest containing 20 patients.11 Some baseline data and
results from these studies are compared with our study in
Table 2. This shows that the outcomes of endovascular
treatment probably depend strongly on case mix. The best
results were obtained in the 6 case series, in patients with the
best baseline conditions, followed by the cases reviewed by
Canha˜o. In comparison, in our study more patients were
comatose; they more often had hemorrhagic infarcts before
treatment, and had the highest death rate.
The main rationale for endovascular thrombolysis is earlier
recanalization of the sinuses. In 2 of our patients this seems to
have reversed a relentless deterioration in spite of heparin.
However, thrombosed cortical veins are probably not opened
by thrombolysis of the sinuses. Also, thrombolysis apparently
comes too late for patients with impending herniation. Based
on this experience, we changed our policy to hemicraniectomy for such patients. Some promising results have been
reported.17,18
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In conclusion, our results of endovascular treatment for
severe CVST are less favorable than the results of earlier
studies, which may be explained in part by publication bias
and differences in case mix. A randomized clinical trial to
compare endovascular treatment with standard treatment
(heparin) in selected patients is needed, but will be difficult to
realize in this rare condition.
Disclosures
None.
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