(Stroke. 1997;28:2363-2369.)
© 1997 American Heart Association, Inc.
Articles |
Cerebral Venous Thrombosis and Anticardiolipin Antibodies
From the Center for Stroke Research, Department of Neurology and Henry Ford Stroke Program, Henry Ford Hospital and Health Sciences Center, Detroit, Mich (Detroit Campus of Case Western Reserve University).
Correspondence to Steven R. Levine, MD, Center for Stroke Research, Department of Neurology, K-11, Henry Ford Hospital and Health Sciences Center, 2799 W Grand Blvd, Detroit, MI 48202-2689. E-mail stevel{at}neuro.hfh.edu
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Abstract |
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Background and Purpose The association of cerebral venous thrombosis (CVT) with a variety of pathological states is well established. However, there are only rare isolated reports of CVT associated with anticardiolipin antibodies (aCL).
Methods To clarify the clinical and neuradiological features as well as outcome of patients with CVT associated with aCL, we reviewed the records of all patients with CVT evaluated at our institution between 1989 and 1996 (retrospective and prospective) and systematically reviewed the pertinent literature.
Results We identified 8 aCL+ and 7 aCL- patients with CVT. No patients with lupus anticoagulant (LA) were identified. The mean age was 23±11.01 (range, <1 to 36) years in the aCL+ and 38±9.30 (range, 25 to 54) years in the aCL- patients (P=.016). Six of 8 aCL+ and 5 of 7 aCL- patients were women. The dural sinuses were involved in all aCL+ and in 6 of 7 aCL- patients, while deep venous system thrombosis occurred in 5 of 8 (63%) aCL+ and 1 of 7 (14%) aCL- patients. In the aCL+ patients CVT was associated with puerperium or oral contraceptive use (n=6) and sickle cell trait (n=1), and in the aCL- patients CVT was associated with systemic lupus erythematosus (n=1), myelodysplastic syndrome (n=1), colonic cancer (n=1), oral contraceptive use or puerperium (n=3), and dehydration (n=1). Seven aCL+ patients received either intrasinus urokinase or intravenous heparin sulfate, and 1 received aspirin. Four aCL+ patients developed new onset or worsening of preexisting migraine, 2 developed recurrent peripheral venous thrombosis, and 1 went on to have intracranial hypertension. Twenty additional patients with CVT associated with antiphospholipid antibodies (aPL) were found reported in the literature. The overall mean age was 36±11.6 (range, 21 to 62) years, and 14 (70%) were women. LA was present in 11 of 18 tested, aCL in 7 (35%), LA and aCL in 1, and the type of aPL was not reported in 3. The mean age for the aCL+ only group was 28 years and for the LA+ (with or without aCL+) was 34 years. Only 1 patient, whose aPL type was not specified, had thrombosis of the deep venous system in addition to involvement of the dural sinuses.
Conclusions Our series and review suggest that aCL may be an important factor contributing to development of CVT even in the presence of other potential etiologies or risk factors. Onset of aCL+ CVT occurs at a relative young age and with relatively more extensive superficial and deep cerebral venous system involvement than aCL- CVT.
Key Words: antibodies, antiphospholipid • sinus thrombosis • anticoagulants • cerebral veins • lupus inhibitor • venous thrombosis • lupus anticoagulant
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Introduction |
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Antiphospholipid antibodies are predominantly acquired serum immunoglobulins with affinity for anionic and neutral phospholipid-containing moieties, such as cellular membranes of vascular endothelium. The two most extensively studied aPL are the aCL and the LA.1 2 In the past decade a syndrome—the antiphospholipid syndrome—has been described in which systemic and cerebral venous and arterial occlusions are seen at a relatively young age and with a relatively high risk of recurrent thrombo-occlusive events.3 4 5 6
CVT is a rare disorder carrying a relatively high mortality (10% to 15%).7 8 With the advent of MRI and MR angiography and digital subtraction angiography, the prevalence and natural history of CVT are being refined.9 10 11 Risk factors for CVT include systemic noninfectious conditions such as pregnancy and puerperium, hyperviscosity syndromes, Behçet's disease, coagulopathies including activated protein C resistance and factor V Leiden mutation,12 13 14 and collagen vascular diseases.15 16 17 The presence of aPL (aCL or LA) has been suggested as a risk factor for CVT,18 19 20 21 22 23 but the clinical, radiological, and outcome profiles have not been determined or systematically studied, mainly because of the scarcity of the reported cases. Whether the presence or absence of aPL in patients with CVT has clinical relevance remains unknown. Furthermore, the exact mechanism by which aPL promotes thrombosis and the therapy of choice also remain largely unknown. To help clarify the significance of aCL in CVT, we systematically analyzed the clinical, radiological, treatment, and outcome information of patients with CVT tested for aCL immunoreactivity (no systematic LA screening) at our institution and systematically reviewed the pertinent literature.
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Subjects and Methods |
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Subjects
We performed a computerized search for the International Classification of Diseases, 9th Revision, Clinical Modification code for intracranial venous sinus thrombosis (325.0) and reviewed the records of patients consecutively evaluated at our institution over a period of 5.75 years (April 1989 to December 1996). In the second part of the study we prospectively searched for patients evaluated at our institution with the diagnosis of cerebral venous thrombosis in the period January 1995 to January 1997.
We included patients with (1) an appropriate clinical syndrome (raised intracranial pressure, focal neurological deficit, seizures, headache) at the onset of the disease; (2) CVT demonstrated by appropriate neuroimaging studies; and (3) testing for aCL seroreactivity.
We excluded patients with CVT directly related to neurosurgical procedures (n=2), head or facial infections (n=2), and those not tested for aCL seroreactivity during admission (n=2). An additional patient with isolated cerebral cortical vein thrombosis and acute, severe necrotizing cervical myelitis presented with quadriplegia and ventilatory failure. She was recently diagnosed with SLE and central nervous system lupus erythematosus associated with LA. Because of her extensive neurological deficit, primarily related to the myelopathy, we decided not to include this patient in our analysis.
We systematically collected demographic, epidemiological, clinical, radiological, laboratory, treatment (dextran, antiplatelet agents, anticoagulation, or thrombolysis) and outcome data. We paid particular attention to risk factors relevant for cerebral arterial ischemia and venous thrombosis, history of previous cerebral or systemic venous occlusive events, topography of involved cerebral venous structures, and laboratory evidence of inflammatory or autoimmune conditions. CVT-related headache and migraine were defined according to the classification criteria of the International Headache Society.24
Diagnostic Investigations
Screening with automated serum chemistries, complete blood count
and differential, platelet count, prothrombin time, and aPTT was
performed. In the majority of the patients, serological studies
including rheumatoid factor, Westergren erythrocyte sedimentation rate,
VDRL serology for syphilis, antinuclear antibodies, anti-DNA
antibodies, serum complement (C3, C4, and
CH50), serum protein electrophoresis, protein C activity
and antigen, protein S antigen, antithrombin III, and coagulation
factor activity and concentration were available. Selected patients
were tested with cerebrospinal fluid analysis and
electroencephalographic recordings.
All patients underwent neuroimaging studies, including head CT (General Electric 8800 or 9800 series scanner, with intravenous contrast administration when needed), MRI (1.5-T General Electric) and MR angiography, MR venography, intracranial dural sinus venography, and cerebral digital subtraction angiography; the type of study depended on the judgment of the caring physician. Ultrasonographic studies of the peripheral veins were done when clinically indicated.
Antiphospholipid Antibody Assay
Anticardiolipin Antibody
A solid-phase enzyme-linked immunosorbent assay (as developed
initially by Gharavi et al25 and later modified and
standardized by an international workshop report26 ) was
used. The aCL results were expressed in GPL (for IgG aCL) and MPL (for
IgM aCL) units, defined as the cardiolipin binding activity of one
microgram per milliliter of an affinity-purified IgG or IgM preparation
from a standard serum. Negative was <10 GPL (<7.5 MPL), low positive
was 10 to 20 GPL (7.5 to 15 MPL), positive was 20 to 100 GPL (15 to 60
MPL), and high positive was >100 GPL (>60 MPL).
Lupus Anticoagulant
aPTT was routinely tested on admission. Patients with prolonged
aPTT in the absence of anticoagulation therapy were screened for LA
with mixing studies, and its presence was confirmed with kaolin
clotting time27 and modified Russell viper venom
time.28 This algorithm identifies approximately 85% of
LAs.
Clinical Outcome
The information was obtained from the inpatient record, the
follow-up notes of the patient's primary care physician or
neurologist, and by telephone interview when possible.
Statistical Analysis
The comparison of age distribution of the aCL+ and aCL- groups
was analyzed by Student's t test. No statistical
analysis of the remaining data was performed because of the
small size of the study population and increased probability of a type
II error.
Literature Review
We systematically reviewed the English language literature (1985
to January 1997) via Medline using key words for cerebral venous
thrombosis, dural sinus thrombosis, cerebral sinus thrombosis,
antiphospholipid antibodies, anticardiolipin antibodies, and lupus
anticoagulant. We also reviewed all potential references cited by these
articles.
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Results |
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Demographics
Eight aCL+ and 7 aCL- patients were identified. The mean age at the onset of disease was 23 years (range, 3 weeks to 36 years; SD, ±11.01 years) for the aCL+ patients in contrast with the mean age of 38 years for the aCL- group (range, 25 to 54 years; SD, ±9.30 years; P=.016). Six patients (75%) in the aCL+ and 5 (71%) in the aCL- group were women.
Clinical Features
Puerperium or use of OC was associated with CVT in 6 aCL+ patients
and in 3 aCL- patients. In the aCL- group, other associated
conditions in single patients included systemic lupus
erythematosus, myelodysplastic syndrome, colonic
adenocarcinoma, and dehydration. History of migraine or spontaneous
miscarriages was reported by 4 aCL+ but none of the aCL- patients. One
aCL+ patient (13%) had a false-positive VDRL. In the aCL- group,
history of illicit drug use (1 patient), ischemic stroke (1
patient), and hypertension (3 patients) was obtained.
Cognitive abnormalities such as aphasia, apraxia, visual agnosia, and
abulia at presentation were seen in 2 aCL+ and 4 aCL-
patients. Depressed level of consciousness was present in 2 aCL+
and 1 aCL- patients, while hemiparesis or hemisensory loss
was present in 4 aCL+ and 3 aCL- patients. The clinical
characteristics are summarized in Table 1
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Laboratory Features
Six patients had IgG aCL and 2 had IgM aCL positivity. IgG titers
ranged from 14.48 to 52.56 GPL. The aCL+ patients were tested for other
serological features of antiphospholipid syndrome: Only the aCL+
patient 7 had a false-positive VDRL, while none had positive
antinuclear antibodies, thrombocytopenia, or a prolonged aPTT. None of
the patients included in this study were screened for activated
protein C resistance at the time of the study.
Neuroradiological Features
In 7 aCL+ patients and 6 aCL- patients, the neuroradiological
studies were available for review. The CT and digital subtraction
angiography studies of patient 1 were unobtainable for review, and only
radiology written reports were available. For this reason we decided
not to include this information in the analysis. In the 7 aCL+
(100%) and 5 of 6 aCL- patients (83%) there was involvement of the
superficial venous system, while 5 aCL+ patients (71%) and only 1
aCL- patient (17%) demonstrated simultaneous thrombosis
of the superficial and deep venous systems (Figs 1 and 2). Brain
infarction was evident on head CT or MRI in 3 aCL+ (43%) patients and
in 1 patient (17%) in the aCL- cohort. The neuroradiological data are
summarized in Table 2.
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Treatment
Four of the aCL+ and none of the aCL- patients received acute
intervention (within the first 72 hours from symptom onset), consisting
of intrasinus urokinase administration followed by
intravenous heparin in 2 of them. Intravenous
heparin alone was given to 3 aCL+ and 5 aCL- patients. Long-term oral
anticoagulation was given to 5 aCL+ and 5 aCL- patients.
Outcome
The only patient with deep venous system involvement in the aCL-
group died, while no case fatalities were observed in the aCL+ cohort.
New onset or worsening of preexisting migraine (4 patients), recurrent
peripheral venous thrombosis (2 patients), and pseudotumor
cerebri (1 patient) were seen in the aCL+ cohort only. One aCL-
patient developed epilepsy.
Review of the Literature
We identified 20 patients with CVT associated with aCL or LA: mean
age was 36 years (median, 32 years) (range, 21 to 62 years; SD, ±11.6
years), and 14 (70%) were women. Nine developed CVT associated with LA
only, 7 had aCL, and 1 had both aCL and LA; in 3 patients the type of
aPL was not specified. The only patient (patient 11 in Table 3) with combined superficial and deep
cerebral venous system thrombosis had a history of antiphospholipid
syndrome and protein C deficiency. Her specific type aPL
immunoreactivity was not specified. From the patients with available
outcome information, this case represented the only case
fatality. Other pertinent information is summarized in Table 3.
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Discussion |
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The LA has been considered as a possible risk factor for CVT in previous case reports.18 19 21 23 24 To our knowledge, there are only six previously reported cases of CVT associated with aCL in the absence of SLE.13 19 22 30 31 This paucity of information prompted us to design the present study. It was primarily retrospective; however, the two cohorts were obtained through a search of consecutive, unselected patients admitted with the diagnosis of CVT to our institution. We found an unexpectedly high prevalence of aCL immunoreactivity (53%) in patients with CVT tested for aCL. These results could be interpreted as possible selection bias (the systematic investigation for aPL in a stroke research center as well as exclusion of patients who were not tested for aCL), but an alternative hypothesis is that aCL antibodies may be more common than previously realized risk factor for CVT. No patients in our series had a detectable LA, although, based on a less than 100% detection rate with the use of our LA testing algorithm, some of our patients may have had an LA.
In 6 of the 8 aCL+ patients (75%), its presence was associated with OC use, pregnancy, or puerperium. A similar coexistence of risk factors such as protein S deficiency, OC use, or puerperium in patients with peripheral venous thrombosis or CVT carrying the factor V point mutation (factor V Leiden mutation) is being recognized with increased frequency.13 31 32 33 34 35 Hence, the pathogenesis of CVT is multifactorial, and a diagnosis of idiopathic CVT is generally made when a thorough diagnostic evaluation does not reveal any potential factors. Conditions such as activated protein C resistance12 13 14 unrelated or due to the factor V Leiden mutation12 13 and even aCL seem to become clinically apparent in the presence of an exogenous factor that inclines an already challenged hemostatic mechanism further toward a prothrombotic state. Known triggering factors are pregnancy and puerperium, estrogen-containing preparations, and recognized coagulopathies such as protein C deficiency, protein S deficiency, and antithrombin III deficiency. Additionally, in patients with aCL, whether these conditions act synergistically as procoagulants or whether aCL is marker of antigenic endothelial exposure is currently under investigation.36 It is unclear whether pregnancy can induce aCL immunoreactivity. It is reasonable to suggest screening for aCL and LA even in CVT cases in which traditional risk factors for CVT are apparent. The yield of seropositivity may be even higher in young women, since these two factors were more common in the aCL+ group. In contrast, the aCL- patients tended to present later in life, and their underlying conditions associated with CVT were systemic medical illnesses and hypertension.
Correlations between the clinical presentation and the
topography of the thrombotic process were made by Crawford et
al36 in a review of cases of deep CVT. The relatively small
number of patients in our study does not allow definitive conclusions
to be reached. However, several observations deserve further study:
First, the superficial dural system was involved in the aCL+ and aCL-
groups with approximately equal frequency, thus explaining the similar
incidence of cortical signs observed in the two cohorts. Second, long
tract signs and altered consciousness were slightly more common in the
aCL+ patients, which may correspond to the more frequent compromise of
the deep cerebral venous system (71%) in the aCL+ cohort. The
relatively frequent involvement of the straight sinus, torcular
Herophili, vein of Galen, and the internal cerebral veins has, to our
knowledge and literature review, not been previously noted. aCL may
produce a generalized thrombotic diathesis and therefore a more diffuse
venous system involvement and may be why aCL+ patients with deep
cerebral venous system disease also developed simultaneous
superficial dural thrombosis as well as recurrent systemic venous
thrombosis during the follow-up period. In contrast to our results, a
review of the literature (Table 3
) revealed that patients with CVT and
aCL or LA (LA in 11 of 18 of the reported cases) developed preferential
superficial venous system compromise. Whether different aPL types
have different biological activity is currently unknown and should be
investigated further. Alternatively, the LA might represent a
more specific marker of an already existing vasculopathy, as occurs in
SLE. Third, the more frequent observation of cerebral infarction on
neuroimaging studies in the aCL+ patients may similarly suggest a more
severe venous flow compromise due to the more extensive
thrombotic process because severe venous stasis should be expected to
increase the likelihood of tissue ischemia and necrosis.
The outcome of the two groups of patients was difficult to analyze because the treatments administered were empiric and therefore did not follow a systematic or uniform set of criteria. Some authors advocate therapy with intravenous heparin sulfate, intrasinus urokinase, or tissue plasminogen activator in patients with CVT,38 39 even in the setting of hemorrhagic venous infarcts and deep venous thrombosis. In patients with CVT, aPL deficiency, and acquired functional proteins deficiency, coumadin can be associated with skin necrosis.40 More patients in the aCL+ group received intravenous anticoagulant therapy and showed a reasonably favorable outcome during follow-up compared with historical controls7 8 41 (not optimal, but the only available data).
The clinical aspects of the patients with CVT and
aCL or LA previously reported in the literature (Table 3), as a group,
shared similar features with the presentation of patients
with dural sinus thrombosis as reported in other large
series7 as well as with our aCL- cohort. A mean age at
presentation of 36±11.6 years, a predominant involvement
of the dural sinuses in all 20 patients (100%), and thrombosis of the
deep venous system present in 1 patient (5%) were observed. The
mean age of the aCL+ only group was 28 years, and the mean age of the
LA+ group (with or without aCL+) was 34 years. Of the patients with
aCL+ only (ie, LA-), 75% were female. Of the patients who were LA+
(with or without aCL+), 55% were female. Headache in 17 patients
(85%), long tract signs in 7 (35%), cognitive signs in 5 (25%), and
visual dysfunction in 8 (40%) were salient features. Since only 7
patients were aCL+ and in an additional 3 patients the subtype of aPL
was not specified, it is not possible to reach conclusions about
specific clinical features in patients with CVT associated with each of
the two types of aPL. Nevertheless, it seemed evident that the deep
venous system was not a preferential target of the thrombotic
processes, especially in the LA+ group. Whether this represents
a manifestation of different biological properties between aCL and LA
is a matter of speculation at this time and therefore should be further
investigated.
Our study and review suggest that aCL or LA may be an important associated condition or factor promoting CVT. However, the presence of aPL was identified in approximately 20 patients among some 1600 reports of CVT published since 1985. Although the true incidence of aCL positivity in patients with CVT is unlikely to be as high as 50%, as suggested by our series, it is likely to be higher than previously appreciated because many patients with CVT are not being evaluated for aPL. The presence of aCL appears to predispose patients to develop CVT at a relatively younger age and to have more extensive cerebral venous system involvement and more frequent thrombosis of the deep venous system.
A large, prospective study is necessary to determine the significance of both aCL and LA in the context of CVT and to identify the most appropriate therapeutic modalities of both the acute and the subsequent phases of this condition.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Institutes of Health (National Institute of Neurological Disorders and Stroke) grants NS-R01–30896 and NS-P01–23393.
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Footnotes |
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Presented in part at the 48th Annual American Academy of Neurology meeting, San Francisco, Calif, March 23-30, 1996.
Received July 24, 1997; revision received September 5, 1997; accepted September 5, 1997.
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 G. Sanna, M. L. Bertolaccini, M. J. Cuadrado, M. A. Khamashta, and G. R. V. Hughes Central nervous system involvement in the antiphospholipid (Hughes) syndrome Rheumatology, February 1, 2003; 42(2): 200 - 213. [Abstract] [Full Text] [PDF]
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F. G. I. Jennekens and L. Kater The central nervous system in systemic lupus erythematosus. Part 1. Clinical syndromes: a literature investigation Rheumatology, June 1, 2002; 41(6): 605 - 618. [Abstract] [Full Text] [PDF]
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F. G. I. Jennekens and L. Kater The central nervous system in systemic lupus erythematosus. Part 2. Pathogenetic mechanisms of clinical syndromes: a literature investigation Rheumatology, June 1, 2002; 41(6): 619 - 630. [Abstract] [Full Text] [PDF]
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 R. L. Bick State-of-the-Art Review: Antiphospholipid Thrombosis Syndromes Clinical and Applied Thrombosis/Hemostasis, October 1, 2001; 7(4): 241 - 258. [PDF]
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 F. J. Kirkham, M. Prengler, D. K.M. Hewes, and V. Ganesan Risk Factors for Arterial Ischemic Stroke in Children J Child Neurol, May 1, 2000; 15(5): 299 - 307. [Abstract] [PDF]
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