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.

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.

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.

Focal and/or lateralized polymorphic delta activity. Association with either 'normal' or 'nonfocal' computed tomographic scans.

Focal continuous polymorphic delta activity (PDA) is classically taught to be associated with destructive lesions of cerebral white matter. One hundred patients with focal or lateralized continuous PDA recorded by an electroencephalogram who also had computed tomographic (CT) scans of the head performed at approximately the same time were studied. Thirty-three percent had normal or "nonfocal" abnormalities on their CT scans. Most of these had a history of either seizures (51%) or transient cerebral ischemia/stroke (27%); however, a wide variety of causes were possible. This high percentage of patients with focal continuous PDA without corresponding CT scan lesions supports the concept that the electroencephalogram is a physiologic study that is complementary to anatomic imaging techniques.

Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection.

This report summarizes the results of neurologic and cerebrospinal fluid (CSF) study findings in over 400 of the 649 human immunodeficiency virus-infected US Air Force personnel, evaluated as of Dec 31, 1987. Eighty percent of these patients were entirely asymptomatic and immunologically normal, 13% had low T-helper lymphocyte counts and/or cutaneous anergy, and only 7% had opportunistic infection. Sixty-three percent of all patients had some CSF abnormality. Sixty percent of the asymptomatic group had at least one abnormal result, over 25% had three or four CSF abnormalities, and over 7% had five or six abnormal values. When patients with evidence of blood-brain barrier leak were excluded, significant differences were seen between disease groups with regard to CSF glucose, CSF IgG levels, and CSF IgG synthesis. No human immunodeficiency virus-related central nervous system abnormalities were found on neurologic examination in immunologically intact asymptomatic patients regardless of CSF findings. No clear-cut predictor of impending central nervous system complications has, as yet, been identified from the CSF parameters studied.

Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals.

Although individuals with acquired immunodeficiency syndrome (AIDS) are often impaired on a variety of neuropsychological tasks, questions remain as to when neuropsychological decline can be reliably detected during the course of human immunodeficiency virus (HIV) infection. Detailed neuropsychological testing was accomplished on a cohort of 83 immunologically and neurologically intact asymptomatic HIV-infected individuals drawn from a larger pool of 649 US Air Force personnel with HIV antibodies. These asymptomatic subjects were compared with a group of HIV-negative subjects, and no significant differences in neuropsychological functioning were found. No significant neuropsychological differences were found as a function of cerebrospinal fluid abnormalities in these asymptomatic subjects. When data from 13 subjects with immune compromise were included in the analyses, those with abnormal cerebrospinal fluid values performed significantly poorer on a task of verbal memory, suggesting that cognitive dysfunction is antedated by immunological decline. Methodological problems that inhibit specification of the incidence, prevalence, and natural history of HIV-related cognitive impairment are discussed, as are data suggesting that previously published high estimates of the frequency of HIV-related dementia may not be representative of all HIV-infected populations.

Cerebrospinal fluid anti-cardiolipin antibodies in patients with HIV-1 infection.

Both cerebrospinal fluid (CSF) immunologic abnormalities and serum anti-cardiolipin antibodies (aCL) have been reported in patients with HIV-1 infection. The antibody specificity of only a small amount of the total CSF IgG in these patients is known, and is directed against a variety of HIV-1 antigens. The specificity of the remaining CSF IgG is unknown. We report the results of the first study of CSF aCL in an HIV-1-infected population. We measured aCL IgG and IgM in the CSF of 21 HIV-1-infected patients without nervous system symptoms or AIDS, and in four HIV-1-negative controls. Twelve HIV-1-infected patients had an abnormal serum aCL value and CSF immunologic abnormalities and 9 HIV-1-infected patients had either abnormal serum aCL or CSF immunologic abnormalities but not both, or were normal in both regards. There was no difference between any HIV-1-infected patient and controls for CSF aCL IgM. Nine of 12 patients with an abnormal serum aCL and CSF immunologic abnormalities had CSF aCL IgG values that were at least 5 SD above normal control values, whereas none of the remaining patients had abnormal CSF aCL IgG values. All patients with abnormal CSF aCL IgG values had an intact blood-brain barrier as evidenced by an albumin index of less than 9, and all had nonreactive CSF VDRL tests. These data demonstrate that aCL IgG is produced intrathecally in some HIV-1-infected patients.

CSF changes in a longitudinal study of 124 neurologically normal HIV-1-infected U.S. Air Force personnel.

Over a 2 year period, 124 neurologically normal HIV-1-infected patients had three successive cerebrospinal fluid (CSF) examinations approximately 1 year apart. Immunological status as measured by absolute CD4 counts in the blood identified two groups of patients over time: (a) a group with progressive CD4 decline (66 patients), and (b) a group with stable CD4 counts (58 patients). These two study groups provided us the opportunity to compare CSF changes (cells, protein, albumin index, IgG, IgG index, and IgG synthesis rate) in neurologically normal individuals with respect to immunological status over time. We found significantly increased intrathecal cellular response and IgG production over time independent of CD4 group. We conclude that any clinical study comparing CSF findings in neurologically symptomatic HIV-infected individuals must recognize and control for these CSF changes in neurologically asymptomatic patients.

Lack of cerebrospinal fluid myelin basic protein in HIV-infected asymptomatic individuals with intrathecal synthesis of IgG.

We evaluated 130 consecutive HIV-infected neurologically asymptomatic individuals for intrathecal IgG production and myelin basic protein (MBP) levels. Although 56.7% of immunologically normal and 68.8% of immunocompromised patients had some CSF abnormality, no patient had an abnormal MBP level. The lack of MBP elevation in the CSF of these patients suggests that the production of intrathecal IgG is not related to active demyelination.

Antiphospholipid antibodies and cerebral ischemia in young people.

The importance of a prothrombotic state as a cause of ischemic stroke in young adults is ill defined. We examined 46 unselected patients under age 50 years with cerebral ischemia for anticardiolipin antibody (aCL) and lupus anticoagulants (LA), over a 3-year-period. Age- and sex-matched patients with other neurologic diseases served as a noncerebral ischemia comparison group to test whether (1) stroke/transient ischemic attacks (TIA) in young people is associated with aCL and/or LA, and (2) their presence is specific to cerebral ischemia. In the stroke/TIA group, 21 patients had aCL or LA and 25 had neither, whereas in the control group, 2 patients had aCL and 24 had neither. Equal numbers of stroke/TIA patients with and without antiphospholipid antibodies (aPL) had other stroke risk factors. Patients with aPL and cerebral ischemia, however, had a more frequent history of multiple events than those without them. These antibodies occur with undue frequency in young patients with stroke/TIA and are not associated with a concurrent diagnosis of systemic lupus in most cases. A coexistent aPL-associated prothrombotic state may be a key determinant of whether patients with atherosclerosis, mitral valve prolapse, or other structural lesions experience recurrent ischemia.

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.

Accuracy of anticardiolipin antibodies in identifying a history of thrombosis among patients with systemic lupus erythematosus.

OBJECTIVE: To measure the accuracy of anticardiolipin antibodies (aCL) in identifying a history of thrombosis among patients with systemic lupus erythematosus (SLE) or the primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: Patients with SLE or PAPS who attended our rheumatology clinic between April 1992 and March 1994 were included in a retrospective analysis of the relationship between thrombotic events and aCL. All aCL measurements were performed in the same laboratory by enzyme-linked immunosorbent assay, blinded as to the presence or absence of thrombosis. The diagnostic accuracy of IgG, IgM, and IgA aCL was quantified by means of the receiver operating characteristic area under the curve (ROC AUC) for each isotype. Stratum-specific likelihood ratios and their 95% confidence intervals were calculated to define strata with optimal discriminant power. RESULTS: During the period of study, aCL was measured in 117 patients (113 SLE and 4 PAPS), of whom 24 (20.5%) had experienced thrombotic events. The ROC AUC +/- the standard error for IgG aCL was 0.81 +/- 0.05, signifying an 81% accuracy in the identification of a history of thrombosis. In contrast, the accuracy of the IgM and IgA aCL was significantly lower (0.60 +/- 0.08 and 0.54 +/- 0.07, respectively, P < 0.05). Using stratum-specific likelihood ratios, we defined three strata in the IgG aCL scale that discriminate between patients with low, indeterminate, and high probabilities of thrombosis. For IgG aCL levels below 21.4 IgG phospholipid (GPL) U/mL, the posttest probability of thrombosis was 0.07, whereas for IgG aCL levels > or = 65.1 GPL U/mL, the posttest probability of thrombosis was 0.75. For IgG aCL values between 21.4 and 65.0 GPL U/mL, the probability of thrombosis was 0.20, equivalent to the entire cohort. CONCLUSIONS: The IgG aCL determinations perform well in the identification of thrombosis in SLE or PAPS, while the IgM and IgA aCL have poor diagnostic accuracy. These findings may have implications for management of these patients.

Effects of repeated freeze-thaw cycles on anticardiolipin antibody immunoreactivity.

The effect of repeated freeze-thaw cycles on anticardiolipin antibody levels was evaluated using an enzyme-linked immunosorbent assay. Normal human serum was spiked with known quantities of freeze-dried human polyclonal anticardiolipin antibody IgG and IgM (19 samples each) or IgA (11 samples). Each spiked sample was split into four identical aliquots; one aliquot was never frozen, and the remaining three were taken through successive freeze-thaw cycles. All aliquots from each sample were evaluated on the same day using the same plate and reagents. A significant decline in mean anticardiolipin IgG levels occurred between the aliquot which had never been frozen and the one which had been through three freeze-thaw cycles (Student's t-test, P = .04). Although mean IgM and IgA values declined as well, the differences were not significant. When individual samples were evaluated the decline appeared to occur most often between the second and third freeze-thaw cycle. Eight anticardiolipin IgG and three IgM-containing samples which had been positive initially became negative by the third freeze-thaw cycle. These data show that handling and storage of serum used to perform anticardiolipin antibody assays are important potential sources of assay variability.

Neurologic complications of antiphospholipid antibodies.

Antibodies directed against phospholipids are highly associated with venous and arterial thrombotic episodes, which are often recurrent. There seems to be a skewed frequency of cerebral and ocular events when the arterial circulation is affected. Other neurologic syndromes, including dementia, migraine, chorea, transverse myelopathy, Guillain Barré syndrome, transient global amnesia, seizures, motor neuron disease, myasthenia gravis, and depression, have also been described in association with aPL. Although some of them (for example, dementia, chorea, seizures, and transient global amnesia) could well be the result of aPL-related cerebrovascular disease, the relationship of aPL to the underlying pathophysiology of these syndromes is less clear. Clues that should lead one to consider evaluating for these antibodies include recurrent thrombosis (especially in young people), recurrent fetal loss, and thrombocytopenia. Associated laboratory abnormalities may include a biologically false-positive VDRL test, abnormal ANA or anti-DNA titers, and a high ESR. If the APTT is positive on routine screening and does not correct with mixing studies, a LA should be highly suspected. More sensitive and specific tests are usually necessary to detect aPL, however. Many in vitro and, more recently, in vivo systems strongly suggest that aPL may be directly implicated in the pathogenesis of thrombosis, as opposed to being markers of a procoagulant state. The management of patients with aPL-associated thrombosis can be difficult. Prospective studies are needed to determine the optimal treatment strategies for this group of patients.

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.

Antiphospholipid antibodies and complement activation in patients with cerebral ischemia.

Antiphospholipid antibodies (aPL) have been linked to stroke and TIA. The mechanism for aPL-associated thrombosis is uncertain, but could be related to complement-mediated membrane damage. Indirect evidence for complement activation (low C4 levels) has been associated with aPL, with variable correlation with disease manifestations. We measured complement activation directly using an ELISA for SC5b-9 in 26 patients with stroke/TIA; 13 with and 13 without aPL. Patient plasma levels of SC5b-9 were measured along with standard positive and 5 normal control samples. Nine patients with, whereas only one without, aPL had an abnormal SC5b-9 level (p = 0.0018, Fisher's Exact Test). These data confirm a relationship between aPL and complement activation, which argues for an active autoimmune process in aPL-associated thrombosis and suggests that complement activation may play a pathogenic role.

The role of antiphospholipid antibodies in stroke.

Antiphospholipid antibodies may be found in about 10% of all subjects with acute stroke but probably are present in as many as 50% of young persons with stroke and perhaps even in high prevalence in persons who have coexisting rheumatologic diseases such as SLE. In these latter groups, the association may be as high as 50%. Probably the best related syndrome is Sneddon's syndrome, which has a high prediction to dementia. Furthermore, vascular dementia may be a prominent feature of the aPL syndrome in subjects under age 55. The cause and mechanism by which aPL are related to stroke remain unknown. Likewise, there is a dearth of information about prognosis, morbidity, and stroke recurrence in subjects who have these immunoglobulin markers. Thus therapy remains very problematic, but current strategies include the use of antiaggregate therapy, warfarin, and limited implementation with prednisone and plasmaphoresis. Data that demonstrate clear cut benefit of any of these therapies are lacking. Ultimately, unraveling these crucial problems concerning the aPL syndrome may provide great insight into certain stroke mechanisms.

Soluble terminal complement components in human myasthenia gravis.

The loss of membrane acetylcholine receptor (AChR) leading to muscle weakness and impaired neuromuscular junction (NMJ) transmission in human myasthenia gravis (MG) is in part due to complement mediated muscle membrane damage. This has been supported by the histologic finding of C9 at the NMJ in human MG. We evaluated for evidence of terminal complement components in plasma by using an ELISA for SC5b-9 in 42 separate plasma samples from 31 patients with MG and from healthy controls. Abnormal elevations of SC5b-9 was found in 18 of 31 patients (58%) at one or more time points when plotted on a standard positive dilution curve. Multiple samples were available from 8 patients over time. Clinical deterioration in some, but not all, was accompanied by an increase in SC5b-9 values. There was no clear distinction in the group as a whole between MG severity or AChR antibody levels and SC5b-9 values. This supports the potential role of complement-mediated muscle membrane damage in the pathogenesis of human MG, but also demonstrates that plasma levels as measured by ELISA do not always correlate with disease activity.