Controversies in the antiphospholipid syndrome and stroke

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Abstract

Many clinicians providing care and advice to patients with antiphospholipid syndrome (APS), where the principal clinical manifestation is stroke, do so in the setting of an evidence base of mixed quality. Indeed, systematic studies have not particularly helped the practising clinician as they have been characterised by variable criteria used to select subjects, making it impossible to extrapolate to typical clinic patients. This has left us with a number of key questions, each of which attracts controversy in terms of patient management. In this review, these are posed as a series of questions with the answer, or lack of one, considered after each question. The review draws attention to the important questions that require answers for current primary and secondary prevention, as well as treatment of APS and stroke, and suggests a series of studies that are needed to clarify these issues.

Introduction

There are a substantial number of gaps in our knowledge about stroke and antiphospholipid (aPL) antibodies. Many of these were reviewed in a consensus meeting at the last Antiphospholipid Congress in Taormina, Sicily, 2002 [1]. The purpose of this paper is not to review in detail the evidence, or lack of it, in regard to the relationship between, and management of, stroke and antiphospholipid antibodies, but to pose a series of questions that, as physicians caring for patients, we need answers to. In each case, whether or not we have all or part of the answer will be assessed.

Cerebrovascular disease, stroke and transient ischaemic attacks (TIAs) are some of the most common causes of morbidity and mortality in developed nations and are rapidly growing in importance in developing countries as they adopt the worst aspects of a western lifestyle [2], [3], [4]. There are many causes of stroke, with the vast bulk being accounted for by degenerative vascular disease associated with age, hypertension, smoking, elevated serum lipids, cardiac disease and diabetes [5]. Quite frankly, this huge burden of disease may drown out the impact of uncommon potential associations with stroke—such as aPL antibodies—and makes good clinical studies difficult to perform. Furthermore, with the exception of the very young, many of the subjects that will enter any studies endeavouring to answer questions about aPL and stroke will almost certainly have one or more of these other, generally more common, risk factors.

The questions, and this is not an exhaustive list, that a physician responsible for the care of patients requires answers to include:

  • Is aPL a risk factor in a primary sense for cerebrovascular disease?

  • If so, is there evidence to support primary preventative measures?

  • How should an acute cerebrovascular event be managed in the context of aPL? Does it differ from management of a ‘conventional’ cerebrovascular event? That is, is urgent specific diagnosis required?

  • Is aPL associated with a risk of recurrent stroke?

  • If so, how should they optimally be prevented?

  • What is the relative role of embolic strokes in patients with aPL?

  • What should we advise if aPL becomes persistently negative in the course of patient follow-up?

Each of these will be dealt with in turn. As has been elegantly pointed out before, there are a number of ways of addressing most of these issues, each with the potential to give different answers because the different methods are asking slightly different questions. Firstly, patients who have already had a formal diagnosis of antiphospholipid syndrome (APS) made can be compared, according to Sapporo criteria [6], with a control population over time. Whether they have already had a stroke or not is clearly an important variable which immediately divides the group into primary and secondary risk. Secondly, a group of stroke patients can be compared with a group without stroke for the presence of aPL–anticardiolipin (aCL), lupus anticoagulant (LA) and anti-beta 2 glycoprotein-1 (β2GP1). Finally, a group without stroke can be tested for aPL and followed prospectively, potentially for a long period to determine the incidence of stroke when compared to controls. To each of these studies could be added more specific questions about whether strokes are embolic, thrombotic or both, and all could potentially act as a platform for studies on management decisions [1]. Most large series of patients exemplified by the Euro Phospholipid Project have a substantial proportion of patients presenting with stroke, generally at a young age (<55 years), indeed, stroke appears to be the most common arterial thromboembolic disorder in APS [7].

Section snippets

aPL as a primary risk factor

There are reports of patients in many series of APS who have developed a stroke as a further manifestation of their APS in the course of follow-up, when the original presentation may have been some other problem, such as a venous thrombosis. There are no studies that enable in a systematic way to put a quantitative risk on this event. Moreover, now that most people in the latter setting are treated, it is unlikely that this study will ever be done [8], [9], [10], [11]. The setting in which a

Management of acute disease

The management of acute cerebrovascular disease is subject to ongoing study in a broad sense, let alone the subset associated with aPL. Following the success of thrombolytic therapy and myocardial infarction, a number of studies have examined the role of this therapy in acute stroke. To date, the outcome has only been significantly better than alternative therapy at an acceptable cost in side effects when thrombolytic therapy has been instituted very early, within 3 h [26]. If indeed the early

Recurrent stroke

A substantial number of studies using the first method described above have provided evidence in support of aPL being a risk factor for recurrence [8], [9], [10], [11], [28], [29]. There are exceptions to this, and again, the differences appear to be due to different patient populations and the nature and range of aPL assays used in the various studies. The magnitude of the risk shows wide variation and may decline with time [11]. Not surprisingly, the magnitude appears to vary with the type of

Secondary prevention of stroke

The optimal prevention of recurrence is the question that has received most attention. While primary prevention in a very broad sense is very important for the health of the populations we serve, physicians are largely concerned with the management of disease once declared, that is, secondary prevention. Relatively small studies, taking patients who unequivocally had APS, showed that the prevention of recurrent events, including stroke, was possible and appeared to be best achieved with

The role of embolic disease

A number of reports in the early 1990s, including our own group, concluded that most patients appear to have embolic disease [34], [35]. Subsequent larger studies show that while a significant proportion of patients continue to have embolic disease, there are clearly many who do not. Our own updated experience shows up to 30% of patients may be embolic (Hawkins, C., et al., submitted, 2004). Any future studies of secondary prevention must stratify patients into embolic versus non-embolic

Disappearing aPL

Our group and others have observed patients in whom, after a variable period of time, the aPL tests become persistently negative. This is hardly a surprise as the observation has been made with a number of autoantibodies [38]. It is a minority of patients in our series, but at presentation, the patients were indistinguishable from other patients with stroke and aPL (Hawkins, C., et al., submitted, 2004). Thus, we have experienced eight patients who presented with clinical evidence of

Concluding remarks

While physicians are trained to be able to make decisions in the face of uncertainty, we are increasingly challenged to make our decisions based on evidence. In this paper, both the evidence and the lack of evidence to support decisions that we make all the time has been highlighted. I believe the Conference should encourage and facilitate the design and performance of large, appropriately stratified studies that will have to be multi-centre to produce answers to the questions posed here. Most

References (38)

  • R. Cervera et al.

    Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients

    Arthritis Rheum.

    (2002)
  • V.L. Babikian et al.

    Clinical and laboratory findings in patients with antiphospholipid antibodies and cerebral ischaemia

    Stroke

    (1990)
  • S.R Levine et al.

    Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome

    Ann. Neurol.

    (1995)
  • G. Ruiz-Irastorza et al.

    Bleeding and recurrent thrombosis in definite antiphospholipid syndrome

    Arch. Intern. Med.

    (2002)
  • P. Nencini et al.

    Lupus anticoagulant and anticardiolipin antibodies in young adults with cerebral ischaemia

    Stroke

    (1992)
  • Anticardiolipin antibodies are an independent risk factor for first ischaemic stroke

    Neurology

    (1993)
  • S. Tuhrim et al.

    Elevated anticardiolipin antibody titre is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity

    Stroke

    (1999)
  • RL. Brey et al.

    Antiphospholipid antibodies and stroke in young women

    Stroke

    (2002)
  • Anticardiolipin antibodies and the risk of recurrent thrombo-occlusive events and death

    Neurology

    (1997)
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