Journal of Autoimmune Diseases BioMed Central
Research Open Access
Cerebrovascular disease associated with antiphospholipid
antibodies: more questions than answers
Carolyn Hawkins1,3, Paul Gatenby*1,3, Roger Tuck2, Gytis Danta2 and
Colin Andrews2
Address: 1Department of Clinical Immunology, The Canberra Hospital, Garran, Australia, 2Department of Neurology, The Canberra Hospital,
Garran, Australia and 3Australian National University Medical School (ANUMS), Australian National University, Acton, Australia
Email: Carolyn Hawkins - ; Paul Gatenby* - ; Roger Tuck - ;
Gytis Danta - ; Colin Andrews -
* Corresponding author
Published: 30 March 2006 Received: 09 June 2005
Accepted: 30 March 2006
Journal of Autoimmune Diseases2006, 3:3 doi:10.1186/1740-2557-3-3
This article is available from: http://www.jautoimdis.com/content/3/1/3
© 2006Hawkins et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Neurological syndromes occur in a significant number of patients with antiphospholipid antibodies. The
optimal management for these patients however remains uncertain.
Our study is a descriptive analysis looking retrospectively at 45 patients who presented to the principal
tertiary referral centre in the Australian Capital Territory, with either cerebral arterial or venous
thrombosis for which there was no obvious cause for their presentation when initially reviewed. The
diagnosis was based on the clinical findings made by one of three neurologists attached to our centre.
Radiological findings and the presence of either IgM or IgG anticardiolipin antibodies, IgG anti-beta-2
glycoprotein 1 antibodies or a lupus anticoagulant were then documented.
In this group of patients three subgroups were identified:
1. Individuals that fulfilled the Sapporo Classification Criteria
2. Individuals with transiently positive antiphospholipid antibodies and
3. Individuals with persistently low positive antiphospholipid antibodies.
The most interesting of these three groups are those individuals with transiently positive antiphospholipid
antibodies. A potential cause for presentation was identified in only one patient of this group with
documented infective endocarditis and bacteraemia. Comparison with the other two groups suggested
that there was little in terms of clinical presentation, radiological findings or intercurrent risk factors for
thrombotic disease to distinguish between them. With disappearance of antiphospholipid antibodies, the
individuals within this group have not had further thrombotic events.
Our observations emphasise the problems that continue to exist in relation to the occurrence of
cerebrovascular disease in the context of antiphospholipid antibodies and the optimal management of
these stratified groups. Our findings also raise an as yet unanswered question as to the signficance of these
transiently positive antiphospholipid antibodies. In the absence of significant intercurrent risk factors our
findings would suggest that in the group we describe that they are likely to be of clinical significance.
Page 1 of 7
(page number not for citation purposes)
, Journal of Autoimmune Diseases 2006, 3:3 http://www.jautoimdis.com/content/3/1/3
Background Methods
The antiphospholipid syndrome (APS) is an autoimmune Patients were selected consecutively on the basis of admis-
disorder characterised by recurrent venous and arterial sion to The Canberra Hospital, the principal tertiary refer-
thromboses, recurrent foetal loss and spontaneous abor- ral hospital for the Australian Capital Territory and
tions, thrombocytopenia, and the presence of antiphos- surrounding south east New South Wales, with a total
pholipid antibodies [1,2]. While there is an association population of approximately 500,000, between January 1,
with other autoimmune diseases such as systemic lupus 1995 to May 31, 2003 inclusive, with clinical or radiolog-
erythematosus, the condition may also arise independ- ical evidence of cerebral infarction and the presence of
ently of other autoimmune disorders [1,3,4]. The pres- IgM or IgG aCL antibodies, IgG anti-β2GP1 antibodies
ence of antiphospholipid antibodies may also occur as (when this assay became routinely available at our centre
associated epiphenomena related to intercurrent infec- in 2000) and/or lupus anticoagulant. Initial events were
tions and in this setting are said to be less likely to be asso- recorded back to 1975 and therefore in some individuals
ciated with the characteristic syndrome [5]. Furthermore, the diagnosis was made retrospectively, in that aCL were
a number of individuals with high titre anticardiolipin not routinely tested for until 1986. Currently, in this insti-
antibodies do not develop APS and studies suggest that tution, patients are further investigated for the presence of
additional factors or a "second hit" are required to cause prothrombotic factors including AT-III, protein C and
endothelial dysfunction and activation of a pro-coagulant protein S deficiencies in addition to prothrombin
phenotype [6,7]. G20210A and Factor V Leiden mutations, where there are
no identifiable causes for their presentation with either
Neurological syndromes occur in a significant proportion cerebral venous or arterial thrombosis. Over the study
of individuals with antiphospholipid antibodies and period January 1, 1995 to May 31, 2003, 1729 patients
include transient ischaemic attacks, stroke (either embolic were admitted to The Canberra Hospital with cerebral inf-
or thrombotic), cerebral venous thrombosis, migraines, arction.
seizures, multi-infarct dementia and mononeuritis multi-
plex [2,8-10]. With strong evidence that appropriate treat- Following selection, clinical data were retrospectively and
ment with anticoagulant therapy is effective in prospectively reviewed. For each patient the clinical find-
minimising both arterial and venous thrombotic disease ings were confirmed by examination by one of three neu-
in these individuals [11,12], it is important to be able to rologists. A number of other parameters were assessed
identify individuals with APS at the time of presentation. including: intercurrent risk factors for vascular disease –
Classification, but not clinical diagnosis is assisted by the hypertension, hyperlipidemia, tobacco use, obstructive
Sapporo criteria, a preliminary classification formulated sleep apnoea [14] – the presence of other procoagulant
in 1999. In these criteria, venous or arterial thrombotic factors, the use of the combined oral contraceptive pill, a
vascular disease is essential. The criteria currently mandate history of previous miscarriage, intrauterine growth retar-
repeating antibody tests after 6 weeks [13]. This presents a dation or pre-eclampsia and previous arterial or venous
problem where an acute diagnosis has implications for thrombotic events. Results of cerebral imaging, including
initiating active therapy. computed tomography (CT) and magnetic resonance
imaging (MRI), in addition to echocardiography and
While a firm evidence base is accumulating for the man- carotid duplex ultrasound, were collated. Follow-up
agement of venous thrombosis and recurrent pregnancy antiphospholipid testing, ideally at least 6 weeks apart as
loss in APS, the same cannot be claimed for cerebrovascu- defined in the Sapporo criteria [13] was collected where
lar disease, which remains a problematic area with a possible. Information regarding the therapy instituted at
number of unanswered questions. the time of diagnosis and long-term follow-up was
obtained.
This study involved the descriptive analysis of all patients
presenting to a single centre with either cerebral arterial or Laboratory tests
venous thrombosis where a cause could not clearly be IgM and IgG aCL antibodies were detected by a semi-
identified at the time of presentation. The presence of IgM quantitative enzyme-linked immunoabsorbent assay
or IgG anticardiolipin (aCL) antibodies, IgG anti-beta-2- according to the manufacturer's instructions using a com-
glycoprotein1 (anti-β2GP1) antibodies and/or a lupus mercially available kit (Immuno Concepts RELISA, Sacra-
anticoagulant and results of radiological imaging were mento, CA, USA). The test system is standardised using
documented. internationally recognised reference preparations
obtained from the Antiphospholipid Standardisation
This series of patients illustrates each of the above conun- Laboratory. Results were reported semi-quantitatively
drums, and emphasises the difficulty in clear-cut decision- according to the manufacturer's instructions in standard-
making. ised units as follows: negative (IgG, <8 G phospholipid
Page 2 of 7
(page number not for citation purposes)
Research Open Access
Cerebrovascular disease associated with antiphospholipid
antibodies: more questions than answers
Carolyn Hawkins1,3, Paul Gatenby*1,3, Roger Tuck2, Gytis Danta2 and
Colin Andrews2
Address: 1Department of Clinical Immunology, The Canberra Hospital, Garran, Australia, 2Department of Neurology, The Canberra Hospital,
Garran, Australia and 3Australian National University Medical School (ANUMS), Australian National University, Acton, Australia
Email: Carolyn Hawkins - ; Paul Gatenby* - ; Roger Tuck - ;
Gytis Danta - ; Colin Andrews -
* Corresponding author
Published: 30 March 2006 Received: 09 June 2005
Accepted: 30 March 2006
Journal of Autoimmune Diseases2006, 3:3 doi:10.1186/1740-2557-3-3
This article is available from: http://www.jautoimdis.com/content/3/1/3
© 2006Hawkins et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Neurological syndromes occur in a significant number of patients with antiphospholipid antibodies. The
optimal management for these patients however remains uncertain.
Our study is a descriptive analysis looking retrospectively at 45 patients who presented to the principal
tertiary referral centre in the Australian Capital Territory, with either cerebral arterial or venous
thrombosis for which there was no obvious cause for their presentation when initially reviewed. The
diagnosis was based on the clinical findings made by one of three neurologists attached to our centre.
Radiological findings and the presence of either IgM or IgG anticardiolipin antibodies, IgG anti-beta-2
glycoprotein 1 antibodies or a lupus anticoagulant were then documented.
In this group of patients three subgroups were identified:
1. Individuals that fulfilled the Sapporo Classification Criteria
2. Individuals with transiently positive antiphospholipid antibodies and
3. Individuals with persistently low positive antiphospholipid antibodies.
The most interesting of these three groups are those individuals with transiently positive antiphospholipid
antibodies. A potential cause for presentation was identified in only one patient of this group with
documented infective endocarditis and bacteraemia. Comparison with the other two groups suggested
that there was little in terms of clinical presentation, radiological findings or intercurrent risk factors for
thrombotic disease to distinguish between them. With disappearance of antiphospholipid antibodies, the
individuals within this group have not had further thrombotic events.
Our observations emphasise the problems that continue to exist in relation to the occurrence of
cerebrovascular disease in the context of antiphospholipid antibodies and the optimal management of
these stratified groups. Our findings also raise an as yet unanswered question as to the signficance of these
transiently positive antiphospholipid antibodies. In the absence of significant intercurrent risk factors our
findings would suggest that in the group we describe that they are likely to be of clinical significance.
Page 1 of 7
(page number not for citation purposes)
, Journal of Autoimmune Diseases 2006, 3:3 http://www.jautoimdis.com/content/3/1/3
Background Methods
The antiphospholipid syndrome (APS) is an autoimmune Patients were selected consecutively on the basis of admis-
disorder characterised by recurrent venous and arterial sion to The Canberra Hospital, the principal tertiary refer-
thromboses, recurrent foetal loss and spontaneous abor- ral hospital for the Australian Capital Territory and
tions, thrombocytopenia, and the presence of antiphos- surrounding south east New South Wales, with a total
pholipid antibodies [1,2]. While there is an association population of approximately 500,000, between January 1,
with other autoimmune diseases such as systemic lupus 1995 to May 31, 2003 inclusive, with clinical or radiolog-
erythematosus, the condition may also arise independ- ical evidence of cerebral infarction and the presence of
ently of other autoimmune disorders [1,3,4]. The pres- IgM or IgG aCL antibodies, IgG anti-β2GP1 antibodies
ence of antiphospholipid antibodies may also occur as (when this assay became routinely available at our centre
associated epiphenomena related to intercurrent infec- in 2000) and/or lupus anticoagulant. Initial events were
tions and in this setting are said to be less likely to be asso- recorded back to 1975 and therefore in some individuals
ciated with the characteristic syndrome [5]. Furthermore, the diagnosis was made retrospectively, in that aCL were
a number of individuals with high titre anticardiolipin not routinely tested for until 1986. Currently, in this insti-
antibodies do not develop APS and studies suggest that tution, patients are further investigated for the presence of
additional factors or a "second hit" are required to cause prothrombotic factors including AT-III, protein C and
endothelial dysfunction and activation of a pro-coagulant protein S deficiencies in addition to prothrombin
phenotype [6,7]. G20210A and Factor V Leiden mutations, where there are
no identifiable causes for their presentation with either
Neurological syndromes occur in a significant proportion cerebral venous or arterial thrombosis. Over the study
of individuals with antiphospholipid antibodies and period January 1, 1995 to May 31, 2003, 1729 patients
include transient ischaemic attacks, stroke (either embolic were admitted to The Canberra Hospital with cerebral inf-
or thrombotic), cerebral venous thrombosis, migraines, arction.
seizures, multi-infarct dementia and mononeuritis multi-
plex [2,8-10]. With strong evidence that appropriate treat- Following selection, clinical data were retrospectively and
ment with anticoagulant therapy is effective in prospectively reviewed. For each patient the clinical find-
minimising both arterial and venous thrombotic disease ings were confirmed by examination by one of three neu-
in these individuals [11,12], it is important to be able to rologists. A number of other parameters were assessed
identify individuals with APS at the time of presentation. including: intercurrent risk factors for vascular disease –
Classification, but not clinical diagnosis is assisted by the hypertension, hyperlipidemia, tobacco use, obstructive
Sapporo criteria, a preliminary classification formulated sleep apnoea [14] – the presence of other procoagulant
in 1999. In these criteria, venous or arterial thrombotic factors, the use of the combined oral contraceptive pill, a
vascular disease is essential. The criteria currently mandate history of previous miscarriage, intrauterine growth retar-
repeating antibody tests after 6 weeks [13]. This presents a dation or pre-eclampsia and previous arterial or venous
problem where an acute diagnosis has implications for thrombotic events. Results of cerebral imaging, including
initiating active therapy. computed tomography (CT) and magnetic resonance
imaging (MRI), in addition to echocardiography and
While a firm evidence base is accumulating for the man- carotid duplex ultrasound, were collated. Follow-up
agement of venous thrombosis and recurrent pregnancy antiphospholipid testing, ideally at least 6 weeks apart as
loss in APS, the same cannot be claimed for cerebrovascu- defined in the Sapporo criteria [13] was collected where
lar disease, which remains a problematic area with a possible. Information regarding the therapy instituted at
number of unanswered questions. the time of diagnosis and long-term follow-up was
obtained.
This study involved the descriptive analysis of all patients
presenting to a single centre with either cerebral arterial or Laboratory tests
venous thrombosis where a cause could not clearly be IgM and IgG aCL antibodies were detected by a semi-
identified at the time of presentation. The presence of IgM quantitative enzyme-linked immunoabsorbent assay
or IgG anticardiolipin (aCL) antibodies, IgG anti-beta-2- according to the manufacturer's instructions using a com-
glycoprotein1 (anti-β2GP1) antibodies and/or a lupus mercially available kit (Immuno Concepts RELISA, Sacra-
anticoagulant and results of radiological imaging were mento, CA, USA). The test system is standardised using
documented. internationally recognised reference preparations
obtained from the Antiphospholipid Standardisation
This series of patients illustrates each of the above conun- Laboratory. Results were reported semi-quantitatively
drums, and emphasises the difficulty in clear-cut decision- according to the manufacturer's instructions in standard-
making. ised units as follows: negative (IgG, <8 G phospholipid
Page 2 of 7
(page number not for citation purposes)
