Antiphospholipid antibodies and the brain: a consensus report.

This report discusses the difference between antiphospholipid antibodies (aPL) as a predictor for first and recurrent ischemic stroke, whether or not concomitant systemic lupus erythematosus (SLE) increases aPL-associated risk, and the association of aPL with other neurological manifestations. The neurological manifestations covered in this report were selected because they are among the most common, including cognitive dysfunction, headache, multiple sclerosis and seizures/epilepsy. Recommendations are made regarding further research that is needed to clarify remaining uncertainties.

International consensus for a definition of disease flare in lupus.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: "A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment." The LFA proposes this definition for lupus flare on the basis of its high face validity.

Antiphospholipid syndrome and the brain in pediatric and adult patients.

The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.

Neurological manifestations of the antiphospholipid syndrome: risk assessments and evidence-based medicine.

The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterised by autoantibody production and vascular thrombosis or pregnancy morbidity. Autoantibodies generated against phospholipid and phospholipid-binding proteins often impair phospholipid-dependent clotting assays (lupus anticoagulants). These autoantibodies activate endothelial cells, platelets and biochemical cascades and can exist in autoimmune disorders such as lupus. Consistently positive antibodies may worsen the severity of thrombo-occlusive disease. The most common neurological manifestations of APS include stroke and transient ischaemic attacks due to arterial thromboses. Antiphospholipid antibodies may cause additional neurological impairments through both vascular and immune mechanisms. Antiaggregant or anticoagulant therapies are indicated for APS-related ischaemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory disease remain controversial. There is scant literature on neurological APS manifestations in paediatric patients. Assessment of traditional cardiovascular and inherited thrombophilia risk factors is essential in patients with APS. Modifiable risk factors and valvular heart disease may worsen thrombotic and cerebrovascular outcomes. Alternative therapies such as statins, anti-malarials, angiotensin-converting enzyme inhibitors and thrombin inhibitors warrant further research.

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).

New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.

Predictors of cognitive dysfunction in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate predictors of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). METHODS: The authors evaluated 123 patients enrolled in the San Antonio Lupus Study of Neuropsychiatric Disease (SALUD) who had completed at least 3 years of follow-up. Study visits occurred every 4 months and included a standard medical history, physical examination, and cognitive testing. Blood was obtained at each study visit for autoantibody testing. RESULTS: There were 116 (94.3%) women and 7 (5.7%) men (mean age = 41.5 [+/-12.0] years). Patients had the following vascular risk factors: hypercholesterolemia (17.1%), diabetes (21.1%), and hypertension (48.0%). Consistent medication use included aspirin (21.1%), prednisone (65.0%), nonsteroidal anti-inflammatories (42.3%), and hydroxychloroquine (58.5%). The numbers of patients with consistently positive autoantibody levels were as follows: antiphospholipid, 54%; anti-beta-2-glycoprotein 1, 73%; and anti-ribosomal P, 17%. Factors significantly associated with declining cognitive function were consistently positive antiphospholipid antibodies, consistent prednisone use, diabetes, higher depression scores, and less education. The association of prednisone and poorer cognitive function was seen primarily in the middle age group and could not be totally explained by SLE-associated disease activity. Consistent aspirin use was associated with improved cognitive function, primarily in the oldest age group, especially if diabetes was also present. CONCLUSIONS: Regular aspirin use is associated with improved cognitive function in older patients with systemic lupus erythematosus (SLE) in conjunction with the presence of other vascular risk factors. Regular prednisone use is associated with decreased cognitive functioning in middle-aged patients with SLE. Although this prednisone effect was independent of measures of SLE-associated disease activity, the authors cannot exclude the possibility that consistent prednisone use is a surrogate for more severe disease.

Validating a computerized neuropsychological test battery for mixed ethnic lupus patients.

Patients with systemic lupus erythematosus (SLE) often show cognitive impairment on traditional neuropsychological tests; however, many of these tests are unsuitable for use with mixed ethnic populations. Computer-administered cognitive tests are promising, but have not been validated against traditional tests or with predominantly Hispanic samples. We gave 67 lupus patients a computer-administered test battery (Automated Neuropsychological Assessment Metrics--ANAM) and a battery of traditional neuropsychological tests. The two batteries were compared using correlation and multiple regression analyses. All patients were fluent in English, 54% were Hispanic and 13% were bilingual. Non-Hispanic patients were predominantly European American (37%). About 80% of patients were rated as impaired on traditional tests. Hispanics were younger, had less education and more current SLE disease activity than non-Hispanics; but did not differ in lifetime SLE-related organ damage or current steroid use. Hispanics and younger patients were more impaired on many of the traditional tests, while ANAM was not affected by Hispanic ethnicity or education. ANAM tests were moderately correlated with analogous traditional tests. Age and selected ANAM scores accounted for about 60% of the variance in the traditional battery. These results replicate the high prevalence of cognitive deficits in SLE found by others and suggest that computer-administered tests like ANAM may be useful for assessment of cognitive impairment in mixed-ethnic samples. Confounding variables such as age, education, English language fluency and prior experience with tests were identified and need to be controlled statistically or with comparison groups in future studies.

Stroke and the antiphospholipid syndrome: consensus meeting Taormina 2002.

Ischaemic stroke is the only neurological manifestation accepted as a clinical diagnostic criterion for the antiphospholipid syndrome (APS). This association is reasonably well established in patients first diagnosed with APS but is less clear in randomly selected stroke patients who test positive on one occasion for antiphospholipid antibodies and who have no other evidence of systemic autoimmune disease. We propose a grading system that posits stroke to be definitely, likely or possibly associated with antiphospholipid antibodies (aPL). Further, there are limited prospective data to determine appropriate treatment. There is controversy as to whether the presence of aPL even increases risk of a recurrent stroke or other thromboembolic event, although data point to persistent medium-high titre aCL and/or LA as risk factors for recurrence. In the absence of data to guide clinicians on the best treatment, we cannot make strong recommnendations as to optimal therapy, nor can we propose clear consensus treatment guidelines.

Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental studies.

Although many types of neurological disorders and events have been described in association with antiphospholipid antibodies (aPL) and the antiphospholipid syndrome (APS), only ischaemic stroke is reasonably well established and accepted as a diagnostic criterion for the syndrome. We propose to evaluate, classify and rank the association of other neurological manifestations as possible, probable, or definite according to the data available from clinical studies and animal models. By these criteria, none of the neurological disorders or events such as epilepsy, psychiatric disease, dementia, transverse myelitis, multiple sclerosis-like disease, chorea, migraine, Guillian-Barrè syndrome, and sensory-neural hearing loss, can be definitely associated with aPL or APS.

Neuropsychiatric syndromes in lupus: prevalence using standardized definitions.

OBJECTIVE: The San Antonio Lupus Study of Neuropsychiatric Disease is a longitudinal study designed to characterize the spectrum of and important risk factors for specific neuropsychiatric systemic lupus erythematosus (NPSLE) syndromes. METHODS: Subjects must meet criteria for SLE and must be at least 18 years of age. A standardized medical history, neurologic, rheumatologic, and psychiatric examinations, computerized neuropsychological evaluation, and serologic testing are performed. RESULTS: This report is based on the first 128 subjects (120 women and 8 men) who completed the initial study visit. Data from this initial study visit were evaluated for the prevalence of NPSLE using the American College of Rheumatology case definitions for 19 NPSLE syndromes. One or more NPSLE syndromes were present in 80% of subjects: cerebrovascular disease (2, 2%; ischemic stroke); headaches (73, 57%); mononeuropathy (9, 8%; median 8, ulnar 1); movement disorder (1, 1%; chorea); neuropathy, cranial (2, 2%; trigeminal); polyneuropathy (29, 22%; sensorimotor); seizures (21, 16%; partial); anxiety disorder (27, 24%); major depressive-like episode (37, 28%); mood disorder with depressive features (21, 19%); mood disorder with manic features (3, 3%); mood disorder with mixed features (1, 1%); psychosis (6, 5%). In a subset of 67 patients who received standardized neuropsychological testing, 21% had normal results. In the remainder, the following levels of impairment were seen: 43% mild, 30% moderate, and 6% severe. CONCLUSIONS: The prevalence of NPSLE was high in this cohort of unselected patients with SLE. Headaches, cognitive dysfunction, and psychiatric disorders were the most common NPSLE syndromes seen. These results will be easily comparable to other studies also using standardized diagnostic criteria. However, the lack of ethnicity and language-matched normative neuropsychological data may make comparisons of cognitive dysfunction in SLE populations difficult.

beta(2)-Glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program.

BACKGROUND: It has been hypothesized that immunoreactivity to beta(2)-glycoprotein 1 (beta2GP1)-dependent anticardiolipin antibody (aCL), but not beta2GP1-independent aCL, is associated with increased risk of ischemic stroke and myocardial infarction (MI). METHODS: We performed a nested case-control study examining aCL as a risk factor for ischemic stroke and MI by using stored frozen sera obtained from subjects enrolled in the Honolulu Heart Program and followed for up for 20 years. We measured beta2GP1-dependent and beta2GP1-independent aCL and anti-beta2GP1 immunoreactivity in 259 men who developed an ischemic stroke, in 374 men who developed an MI, and in a control group of 1360 men who remained free of both conditions. RESULTS: Only beta2GP1-dependent aCL of the IgG class was significantly associated with both incident ischemic stroke and MI. This association was attenuated in the last 5 years of the 20-year follow-up. For stroke, the risk factor-adjusted relative odds for men with a positive versus a negative beta2GP1-dependent aCL of the IgG class were 2.2 (95% CI 1.5 to 3.4) at 15 years and 1.5 (95% CI 1.0 to 2.3) at 20 years. For MI, the adjusted relative odds were 1.8 (95% CI 1.2 to 2.6) at 15 years and 1.5 (95% CI 1.1 to 2.1) at 20 years. CONCLUSIONS: These data suggest that aCL IgG, particularly the beta2GP1-dependent variety, is an important predictor of future stroke and MI in men.

Differential diagnosis of central nervous system manifestations of the antiphospholipid antibody syndrome.

Anti-phospholipid antibodies (aPL) have been associated with a variety of neurologic manifestations. The evidence for an association between aPL and most of these is weak because (1) no association actually exists, (2) the manifestation is rare or (3) sufficiently powered studies have not been performed. The only neurologic manifestation that is considered to have sufficient evidence to justify it being a part of the criteria for the diagnosis of Anti-phospholipid Antibody Syndrome (APS) is cerebral ischemia. In this mini-review, most of the neurologic syndromes with an actual or suspected association with aPL are considered. The role of aPL in the differential diagnosis of these syndromes is considered as well.

Neurological manifestations of antiphospholipid antibody syndrome.

Thrombosis, thrombocytopenia, recurrent fetal loss and a variety of non-thrombotic neurological disorders have all been associated with antiphospholipid antibodies (aPL). Cerebral ischemia associated with aPL is the most common arterial thrombotic manifestation. Depression, cognitive dysfunction, depression and psychosis have all been associated with aPL. The presumed pathophysiologic mechanism underlying these manifestations is thought to be a result of cerebral ischemia in some, but not all cases. Seizures, chorea and transverse myelitis all appear to be associated with aPL. An interaction between aPL and central nervous system cellular elements rather than aPL-associated thrombosis seems to be a more plausible mechanism for these clinical manifestations. Migraine on the other hand, does not appear to be associated with aPL in either lupus or non-lupus populations. Neuroimaging studies show an increased frequency of brain abnormalities in patients with aPL, but none appear to be specific. The best treatment strategy for preventing neurological manifestations of aPL is not fully defined. For thrombotic manifestations, both antiplatelet and anticoagulant therapies have been suggested. In some patients, immunosuppressant therapy has been used. For non-thrombotic manifestations, some combination of immunosuppressant therapy and symptomatic treatment may be warranted.

Animal models for nervous system disease in systemic lupus erythematosus.

Animal models have much to teach us about nervous system dysfunction in SLE. It should be stressed that the murine strains described in this review have variable expression in the onset and severity of clinical and serological features, perhaps making them more like a heterogeneous human population with SLE. With this in mind, studies involving animal models like those involving human subjects should use a sample size that ensures adequate power. It is not surprising that studies that use sample sizes as low as four to five animals per group would find discrepant results, especially in outcomes that are measured prior to the terminal phases of the disease. Similar to human SLE patients, murine models have systemic autoimmune as well as neurological manifestations. Studies with murine models must continue to consider some type of SLE disease activity measures in order to control for the effects of systemic disease on nervous system dysfunction. Because of the short time window between the earliest evidence of neurologic dysfunction and severe autoimmune disease manifestations, especially in MRL/lpr mice, the disease acceleration model may allow a more careful dissection of how immunological events are related to nervous system dysfunction. Alternatively, the study of MRL/lpr mice ultraearly (e.g., 3 weeks of age) could also provide invaluable information about the first events leading to nervous system dysfunction in SLE. Both approaches promise to identify predictors of specific nervous system manifestations that may suggest novel and more specific therapeutic interventions.

Anti-intercellular adhesion molecule-1 (ICAM-1) antibody treatment prevents central and peripheral nervous system disease in autoimmune-prone mice.

Abnormal neurological functioning similar to that seen in systemic lupus erythematosus (SLE) patients is detectable in an SLE-prone murine strain (MRL/lpr) by 8-10 weeks and is severe by 18 weeks of age. The purpose of this study was to evaluate the effectiveness of murine antiintercellular adhesion molecule-1 (ICAM-1) in suppressing neurological disease in MRL/lpr mice. Beginning at 6 weeks of age, five MRL/lpr mice received 5 weekly intraperitoneal injections of anti-ICAM-1-containing culture supernatant in phosphate-buffered saline (PBS) whereas four animals were treated with non-anti-ICAM-1 containing supernatant in PBS. A decline in neurological functioning began in control mice by 10 weeks, but anti-ICAM-1 treated mice remained normal throughout the study. All control mice had vasculitic skin lesions by 14 weeks of age whereas none of the anti-ICAM-1 treated mice ever developed skin lesions. Nerve conduction studies performed on all mice prior to sacrifice showed sciatic compound motor action potentials of anti-ICAM-1 treated mice that were of higher amplitude and shorter latency than those of controls. Inflammation in the sciatic nerve was more common in control mice. Brain histology revealed a similar degree of choroid plexus inflammation in both groups. Our study demonstrated that anti-ICAM-1 was effective in suppressing neurological abnormalities in MRL/lpr mice and may potentially be useful therapy in human SLE.

Neurological aspects of antiphospholipid antibody syndrome.

Antiphospholipid antibodies (aPL) have been associated with a variety of neurological disorders, mostly linked to focal neuroparenchymal ischemia or infarction. Cerebral ischemia associated with the antiphospholipid syndrome (APS) occurs at a younger age than typical atherothrombotic cerebrovascular disease, is often recurrent, and high positive GPL values are usually linked to the presence of a lupus anticoagulant. When other features of the syndrome are not present and cerebral ischemia occurs only associated with anticardiolipin immunoreactivity, there appears to be no discerning features of these patients unless GPL > 40 for which recurrent thrombo-occlusive events appear to occur more frequently. Other neurological manifestations associated with aPL include cerebral venous sinus thrombosis, ocular ischemia, dementia, including ischemic encephalopathy, and chorea. The role of aPL in migrainous events is controversial and may not play a role in recent, large case-controlled studies. Most seizures in patients harboring aPL are associated with focal brain infarction.