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(Stroke. 1998;29:2245-2253.)
© 1998 American Heart Association, Inc.

Original Contributions

Cerebrovascular Ischemic Events With High Positive Anticardiolipin Antibodies

Piero Verro, MD; Steven R. Levine, MD; Gretchen E. Tietjen, MD

From the Center for Stroke Research, Department of Neurology, Henry Ford Health Science Center (Detroit Campus of Case Western University), Detroit, Mich.

Correspondence to Steven R. Levine, MD, DMC/WSU Stroke Program, Department of Neurology, WSU School of Medicine, University Health Center 6E, 4201 St Antoine, Detroit, MI 48201-2153. E-mail slevine{at}med.wayne.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Background and Purpose—The aim of our study was to characterize the patient profile and prognostic value associated with high positive IgG (>100 GPL) anticardiolipin antibodies (aCL).

Methods—We studied the clinical, laboratory, radiological, and prospective historical features of ischemic cerebrovascular disease in patients with >100 GPL titers. From our neurology department, 27 consecutive patients were prospectively identified and followed up (mean follow-up time, 34 months).

Results—The mean age of our cohort was 41 years. Lupuslike illness occurred in 3; 23 had primary antiphospholipid syndrome, including 3 who met criteria for Sneddon's syndrome; 1 patient had progressive systemic sclerosis. Cerebral infarcts occurred in 74% and were recurrent in 37%. Systemic ischemic events, most commonly deep vein thrombosis, occurred in 37%. Tobacco use was documented in 85%, hyperlipidemia in 74%, hypertension in 44%, and diabetes mellitus in 7% of patients. A prominent headache history was present in 67%. Lupus anticoagulant (LA) was present in 72%, approximately one half had positive antinuclear antibodies and thrombocytopenia, and one quarter had a false-positive VDRL. We compared mean GPL levels in patients testing positive for specific laboratory features of antiphospholipid syndrome with those testing negative for these parameters. Only the LA(+) group had a significantly higher mean GPL than the LA(-) group (P=0.006). Brain imaging showed nonlacunar infarcts in 73% and lacunes in 12%. Of 19 cerebral angiograms, 5 (26%) showed large-vessel occlusive disease and 6 (32%) branch obstruction. Echocardiograms were abnormal in 75%: thickened left-sided valves in 33% and vegetations in 12%. Recurrent cerebrovascular ischemic events were observed in 96%, with transient events (mean rate, 25%/y) occurring 5 times more frequently than strokes (mean rate, 5%/y). Using a standardized disability scale blinded to aCL titer, neurological impairment was severe in 7%, moderate in 30%, and mild or nonexistent in 63%, and unrelated to mean GPL value (P=0.567). Titers fluctuated greatly for individual patients, and most did not consistently test as highly positive. An analysis of fluctuation in symptom severity with concurrent GPL values did not show a statistically significant correlation. Compared with historical controls having a wide range of positive titers, the presence of high IgG aCL titers did not confer a worse prognosis for disability and recurrent ischemic events.

Conclusions—Our data suggest that cerebrovascular events associated with high positive GPL are frequently multiple and minor (with no disability-titer correlation), present in relatively young patients, and often associated with tobacco abuse, hyperlipidemia, LA, systemic ischemic events, and occult cardiac disease.

Key Words: antibodies, anticardiolipin • antibodies, antiphospholipid • anticoagulants, lupus • antiphospholipid syndrome • cerebral ischemia, transient • cerebrovascular disorders • stroke • thrombosis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Anticardiolipin antibodies (aCL) are primarily acquired antibodies against neutral and anionic phospholipids that are found in cell membranes and components of coagulation. They have been associated with thrombosis in both the venous and arterial circulations, including the cerebral vasculature.^{1 2 3 4 5 6 7 8} The exact mechanism of thrombosis is uncertain. Mechanisms for venous thrombosis may differ from mechanisms of arterial thrombo-occlusion. aCL have been suggested to be associated with disrupted endothelium, platelet aggregation, acquired APC resistance, complement activation, and disruption of coagulation. Involvement of the endothelium of the cardiac valve may predispose to cardiac embolism as well.⁹ The antiphospholipid syndrome (APS) consists of recurrent venous and arterial thrombotic events or recurrent fetal loss in the presence of a positive test for a lupus anticoagulant (LA) or aCL, independent of the presence of any single disease entity, such as systemic lupus erythematosus.⁵ Accumulating data suggest that the IgG isotype of aCL is predominantly associated with the thrombotic complications of the APS.¹⁰ There is also literature to support antiphospholipid antibodies (aPL) of other specificities, such as antibodies to ß₂-glycoprotein 1, phosphatidylserine, or phosphatidylinositol, as being equally or even more important.⁶

There is, however, uncertainty regarding degree of IgG aCL immunoreactivity that should be considered "positive," (ie, that confers pathogenicity) and whether the specific IgG aCL titer correlates with the severity of APS.^{11 12 13 14 15 16 17 18 19 20} To characterize the clinical, laboratory, and radiological profile of patients with very high titers of these antibodies and to investigate their prognostic implications, we studied a cohort of patients with aCL IgG titer >100 GPL units, a value that is considered high positive by even the most conservative standard.²¹ We followed up this cohort for an average of 3 years to ascertain whether a temporal relationship existed between thrombo-occlusive events and elevations in aCL titer and whether the degree of disability correlated with the mean titer.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Patient Population
We prospectively identified and followed consecutive patients who presented with cerebrovascular ischemic symptoms (cerebral infarct, transient ischemic attack (TIA), or ocular ischemia) and who were found to have high positive aCL levels of the IgG isotype on 1 or more occasions. Patients were recruited from the Department of Neurology outpatient stroke clinic and the inpatient neurology service, an urban as well as referral-based tertiary-care setting. Routine screening for aCL in all patients presenting to our institution with cerebrovascular ischemic events occurred as part of an ongoing research protocol for 4 years.²⁶ In addition, patients from surrounding communities who are found to be positive for aCL are frequently referred to our clinic for further evaluation. Patients meeting American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE)²² were excluded from the study. Also excluded were patients with a history of syphilis or HIV infection. We excluded patients with SLE, syphilis, and HIV infection because these disorders are associated with aCL immunoreactivity and we were trying to identify patients with the primary APS, not SLE with secondary APS or infections associated with aCL immunoreactivity.

Patients were followed up by 1 of the authors for a mean of 34 months. Clinical data were obtained by personal and telephone interviews, general physical and neurological examinations, and systematic review of inpatient and outpatient medical records for all patients in the cohort.

aCL Assay
Antibody levels were obtained by a standardized, validated ELISA.²³ A high-positive IgG level was defined as >100 GPL units, which represents 28 SDs above the mean for normal, asymptomatic subjects. IgM isotype was also measured by the same ELISA.

Clinical and Radiological Definitions
Ischemic strokes were defined by clinical criteria as focal neurological deficits of sudden onset lasting 24 hours, most with confirmatory CT or MRI studies showing lesions in appropriate locations. TIAs were similarly defined, with symptoms lasting <24 hours and negative brain imaging. Transient visual disturbances (TVDs) were frequent though poorly characterized visual complaints, such as visual blurring or dimming of vision, which did not fit clinical criteria for amaurosis fugax. Many patients experienced negative visual phenomena (eg, total "graying") as opposed to the positive visual phenomena typically described in migraine. Diplopia was occasionally described. Both monocular and binocular symptoms were described.

All head CT, MRI, and cerebral angiographic films were reviewed by 1 or more of the authors, except for 2 CT studies which were unavailable. (Data from these 2 CT scans were based on the official clinical report from the medical record.)

GPL-Disability Correlation
A Modified Rankin Scale (MRS)²⁴ score was assigned to each patient at the time of the final follow-up visit (blinded to GPL values) and correlated with the mean GPL value. In addition, during the follow-up period we scored changes in disability caused by ischemic events (blinded to GPL values) through the use of the Acute Disability Scale (ADS) (see the Appendix). This scale was based on the MRS, with additional points assigned for acute exacerbations, allowing for consideration of overall disability as well as acute fluctuations in severity of symptoms. Fluctuations in aCL titer were correlated with the ADS score to test the hypothesis that increases in aCL titer are temporally related to clinical ischemic events. The ADS was not formally validated, although its basic structure is derived from the validated MRS.

Statistical Analysis
The Wilcoxon rank sum test was used to compare mean GPL values between groups having strokes or TIAs, and between groups positive for LA or VDRL, and those patients negative for these parameters. The Kruskall-Wallis test was used to compare mean GPL values for patients with varying levels of neurological disability and for varying degrees of tobacco use. Fisher's exact test was used to compare event rates for different treatment groups. Weighted group correlation coefficients were used to correlate symptom fluctuation with changes in the ADS score. Statistical significance was defined as P<0.05, or in the case of correlation analysis, a 95% confidence interval (CI) that did not include 0.0.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Demographics and Stroke Risk Factors
Over the period of enrollment, 27 patients meeting study criteria were identified and were followed up for a mean of 34 months (median, 20 months). Three patients were seen only 1 time; the remainder were seen repeatedly. There were 10 female patients (37%); 1 patient (4%) was African-American, and the remainder were Caucasian. Age at time of index event ranged from 20 to 68 years, with a mean of 41 years (SD=12 years). Three of the patients had lupuslike illness (ie, demonstrating some characteristics of SLE without meeting full ARA criteria), 1 patient had progressive systemic sclerosis (scleroderma), and 3 had Sneddon's syndrome (stroke plus livedo reticularis). Conventional stroke risk factors (Table 1) for cerebrovascular disease were found in 24 patients (89%). Hyperlipidemia and cigarette smoking were more commonly identified in our cohort than hypertension or diabetes mellitus. Mean GPL values were not higher in those who smoked tobacco heavily (>20 cigarettes/d) when compared with those with moderate (<20 cigarettes/d) or no use of tobacco, nor between active and previous smokers.

View this table: [in this window] [in a new window]   Table 1. Conventional Risk Factors for Cerebrovascular Disease

Only 3 patients (11%) had no conventional risk factors for cerebrovascular disease, and 30% had 3 or more conventional risk factors.

Clinical Events
The specific types of cerebrovascular ischemic events are summarized in Table 2. The mean GPL value for the 20 patients who had 1 or more strokes was not significantly different from that of the 4 patients with TIAs only. Most strokes caused minor to moderate deficits: for 13 patients for whom such information was available, mean disability was measured 24 hours after stroke onset with the MRS scale. The mean acute increase in disability was 1.5 points on the MRS scale (with 5 points maximum indicating severe disability). Twenty-four patients were seen repeatedly at our facilities, with a mean follow-up time of 38.1 months. During this time strokes occurred in 4 patients, for a rate of 5%/y. Two of these patients were not taking medications regularly at the time of their stroke. TIAs or TVDs occurred in 19 patients, a rate of 25%/y. The data as they pertain to individual patients, plus laboratory and radiological findings, are summarized in Table 3.

View this table: [in this window] [in a new window]   Table 2. Cerebrovascular Ischemic Events

View this table: [in this window] [in a new window]   Table 3. Individual Subject Data

A prominent history of recurrent, migrainelike headaches was found in 18 patients (67%). These headaches were concurrent with cerebrovascular ischemic events in 10 patients (37%). Ten patients (37%) had systemic thrombo-occlusive events, including deep venous thrombosis (in 4), premature coronary artery disease (3), pulmonary embolus (1), brachial artery thrombosis (1), adrenal infarct (1), and testicular infarct (pathologically proven) (1).

Neuroradiology
Neuroimaging (brain CT, MRI, or both) was performed in 26 patients (Table 4), and 24 were available for review. One infarct was minimally hemorrhagic and the rest had no visible blood. The infarcts showed a wide range of size, with 11 (58%) >3 cm and 7 <1.5 cm in diameter, although 4 of the smallest infarcts were not in locations typical of lacunes. There were nonlacunar large infarcts in 19 studies, and in 10 they involved different arterial territories.

View this table: [in this window] [in a new window]   Table 4. Neuroradiologic Results

Conventional catheter angiography was performed in 19 patients (Table 4). One patient with a normal angiogram on initial examination showed occlusion of the extracranial internal carotid artery (ICA) on repeat angiogram 1 year later. One patient with obstruction of the intracranial ICA showed resolution on a repeat angiogram 6 months later.

Cardiac Investigations
Twenty-four patients underwent echocardiographic evaluation, 10 with transesophageal studies and 14 with transthoracic studies only. Three quarters of the studies were abnormal, and these results are summarized in Table 5. One third of the cohort undergoing echocardiography had mitral or aortic valve thickening, and 3 patients had nonbacterial, thrombotic vegetations.

View this table: [in this window] [in a new window]   Table 5. Echocardiographic Results (n=2)

Laboratory Investigations
The mean aCL titers of patients with laboratory abnormalities frequently associated with APS (LA, antinuclear antibody, false-positive VDRL, and thrombocytopenia) were compared with the aCL titers of those with normal serological results (Table 6). Although there was a trend toward higher GPL values in persons with a false-positive VDRL (P=0.075), only in the presence of the LA, another aPL, were the GPL values significantly higher.

View this table: [in this window] [in a new window]   Table 6. Laboratory Abnormalities

Prospective History/Prognosis
Over the follow-up period (mean, 34 months), the average number of aCL titers determined per patient was 4.4 (range, 1 to 13). There were wide fluctuations in consecutive antibody levels. Individual values ranged from 9 to 399 GPL, and mean GPL values for each patient ranged from 73 to 179. Only 5 of 21 patients (24%) who had more than 1 GPL value drawn remained high positive at all times. Three patients (11%) had negative titers (<20 GPL) recorded at some time. The greatest fluctuation recorded was in 1 patient who had a GPL value of 9 followed 1 month later by a value of 166. Disability at last follow-up was measured by the MRS for the 5 patients who remained high positive and compared with the group that fluctuated in GPL values. Median MRS for both groups was 1 (P=NS by Wilcoxon rank sum test). All 5 of the consistently high aCL patients were LA (+), whereas in the patients who fluctuated the LA was present in only 9 of 14 patients (64%) who were tested for it (P=0.257 by Fisher's exact test).

No correlation between symptom severity (as measured by the ADS) and GPL value was found for the 15 patients for whom sufficient data were available for analysis (weighted group correlation coefficient was 0.15, with a 95% CI of -0.447 to 0.655). Disability was scored by MRS at the last patient visit (Table 7): no significant difference was found between mean GPL values for the 3 grades of disability.

View this table: [in this window] [in a new window]   Table 7. Final Disability

Therapy
Two patients received intravenous immunoglobulin therapy and 8 were on intermittent tapering doses of prednisone, either alone or in combination with antiplatelet agents or warfarin. In general, however, patients were treated with antiplatelet agents initially but switched to warfarin if ischemic events (minor or otherwise) recurred. A comparison of stroke rates on aspirin and warfarin yielded the following observations: 7 of 18 patients (39%) treated with aspirin alone suffered a stroke, whereas 1 of 7 (14%) on warfarin suffered a retinal infarct and none had a stroke (P=0.362). Of the entire cohort, 13 patients suffered subsequent TIAs without TVDs, 8 had further TIAs and TVDs, and 1 had only subsequent TVDs. Five patients did not have transient events on follow-up.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
Our cohort of consecutively identified patients with ischemic cerebrovascular disease with high positive aCL titers is, to our knowledge, the largest group of such patients reported, and the only group of such patients systematically and prospectively studied with respect to risk of recurrent ischemic events and long-term disability. Therefore, it allows further clarification of the clinical features, laboratory and neurological investigations, natural history, and prognosis in this group of patients with the highest levels of IgG aCL. The average age of 41 years is more than 2 decades younger than the general stroke population and similar to the young age reported in other series.^{1 2 7 25 26} Our patients were nearly all Caucasian, despite the fact that >50% of the patients admitted to our institution with stroke are African American (Henry Ford Hospital Stroke Center Data Base, unpublished data), and routine screening for aCL has been ongoing as part of a research protocol for 4 years. A referral bias may be at least partially responsible for this, as many patients are referred from the surrounding, mostly Caucasian, communities. A similarly high prevalence of aCL in Caucasians was present in a study of aCL in the SLE population.²⁷

All but 1 patient in our study experienced multiple cerebrovascular ischemic events, and these continued during follow-up and treatment. Similar findings have been noted in other studies.^{1 2 28 29 30} The clinical nature of the cerebrovascular events experienced by these patients changed over time: the 13% stroke incidence during prospective follow-up was much less than the 74% stroke incidence found when considering the patients' entire neurological history. In contrast, the incidence of TIAs and TVDs during follow-up (79%) continued to be high, although somewhat lower than the 93% seen over their entire history. Thus, these patients experienced strokes early in the history of their disease, with transient symptoms predominating during subsequent treatment. This may reflect, in part, the impact of therapy, particularly since 2 of the 4 patients who experienced strokes during follow-up were not taking medications regularly at the time of their stroke.

The 5%/y mean stroke rate during follow-up seen in our population was much lower than reported in other studies of aCL-positive patients: Brey et al¹ and Nencini et al³¹ noted a 14%/y stroke recurrence rate, while the Antiphospholipid and Stroke Study Group (APASS) noted a 9.4%/y rate in 1 retrospective analysis² and an 18.7%/y rate in a second, prospective analysis.³⁰ Coull et al,⁸ in a review of the literature, cite a stroke recurrence rate of 13% to 14% per year in aPL-positive patients of all types and ages. The reason for the lower rate in our cohort is unclear. However, it may be that a single high-positive aCL level alone does not necessarily predict a more ominous subsequent course over the ensuing several years. Further, as our data show, levels of IgG aCL change over time, and most patients did not remain high positive. The 5 patients who did remain high positive over time had a clinical course that appeared not to differ from those who fluctuated, although the sample size is small and raises the possibility of a type II statistical error. The LA was more frequently associated with a persistent high aCL titer, although this difference did not reach statistical significance in this small sample.

It is difficult to know how best to classify or stratify patients with aCL immunoreactivity. The present study would suggest that stratification by the presence of 1 or more high-positive values may not be prognostically meaningful, although the sample size was small and these data should be considered preliminary and hypothesis generating.

The strokes suffered by these patients were usually slight to moderate, as reflected by the high percentage of patients (63%) with no or minimal disability at last follow-up and the relatively small change in disability immediately following each stroke. We acknowledge, however, that the MRS that was used to rate disability underestimated the contribution of cognitive impairment. Nonetheless, despite their frequent strokes, the outcome in this population was not uniformly poor and was often relatively good, as also reported by Montalban et al.³²

The prospective APASS study of aCL in first ischemic stroke supported aCL as an independent risk factor for first ischemic stroke³³ and only the IgG isotype as statistically significantly associated with stroke. In the high-positive IgG aCL population that we studied, we frequently found other stroke risk factors, including a predominance of cigarette smoking and hyperlipidemia. Other investigators^{1 3 29 34 35 36} have reported similar findings. It has been hypothesized that endothelial injury caused by the presence of conventional stroke risk factors may lead to exposure of antigens that are normally secluded within the phospholipid bilayer, thus stimulating an aCL antibody response.³⁷

Our patients frequently reported severe, migrainelike headaches, which were often temporally associated with cerebrovascular ischemic events. Similar phenomena have been reported by others.^{3 8 38 41} The relationship of complicated migraine to aCL remains unclear and controversial.^{39 40}

In our series, brain CT/MRI frequently revealed multiple infarcts in the distribution of pial branches of different arteries as well as angiographic evidence of vascular occlusion of the ICA or its distal branches. These findings, similar to those reported previously,^{3 4 29} suggest hypercoagulability or cardioembolism. Our relatively frequent finding of left-sided cardiac valve abnormalities lends support to a potential cardioembolic stroke mechanism.⁴²

The presence of LA was the only laboratory abnormality associated with a significantly elevated titer of aCL. However, the small number of patients raises the possibility of type II error, so these results should be interpreted with caution. If borne out, this implies that production of various aPL may be stimulated under certain conditions. Harris et al^{12 18} reported similar findings. Despite the fact that patients meeting ARA criteria for SLE were excluded from the study, antinuclear antibody positivity (generally low titer) was another relatively frequent finding.

Within this subgroup of patients, the titer of aCL did not have prognostic significance with regard to the nature of the ischemic event or degree of disability. This is in contrast to other studies that have found a higher frequency of ischemic events in patients with higher aCL titers, although rather than restricting their subjects to those testing in the high-positive range, they included patients over the entire range of aCL titers and may thus represent a different population in which it may be easier to test the significance of a change in titer.

The aCL titer of individual patients fluctuated widely over time, as has been reported by some studies^{20 27 43 44} and not found by others.^{18 45} The etiology and significance of these marked fluctuations in titers is presently unknown. We did not find a consistent reduction in IgG aCL titer with the use of corticosteroids (n=9). Only 1 patient underwent plasmapheresis, and 2 were treated with intravenous immunoglobulin therapy; both therapies tended to reduce the GPL levels for a period of weeks to months. The fact that we did not find an aCL titer correlation with recurrence of ischemic events serves to diminish the prognostic significance of aCL titers once patients surpass 100 GPL units. Our findings support a similar conclusion made in previous reports.^{20 45} It is also possible that other aPL having differing specificities (such as antibodies to ß₂-glycoprotein 1, antiphosphatidylserine, antiphosphatidylinositol, or only cofactor-dependent IgG aCL) may be better predictive markers of thrombosis and prognosis.^{6 46 47 48 49 50 51 52 53 54}

Further prospective evaluations of follow-up on standardized treatment in larger numbers of patients, including those with moderate as well as high titers of aCL (including all isotypes), are needed and are currently underway.⁵⁵

Regarding treatment, the unblinded and nonrandomized methods of determining patient therapy makes it difficult to draw conclusions about medication effects from a small study such as ours.

In summary, our data suggest that cerebrovascular events associated with high-positive IgG aCL (>100 GPL) are present in relatively young adults and are frequently multiple and relatively minor in nature. There is no correlation of physical disability to aCL IgG titer. High positive IgG aCL are also associated with tobacco use, hyperlipidemia, systemic thrombosis, occult cardiac disease, and the presence of the LA. Severe disability is not common, and the short-term, several-year natural history after the first event is not uniformly poor, although subsequent transient cerebrovascular events are common.

View this table: [in this window] [in a new window]   Table 8. Comparison of Modified Rankin Scale and Acute Disability Scale Levels

	Appendix 1

Top Abstract Introduction Subjects and Methods Results Discussion Appendix 1 References

 
The Acute Disability Scale (ADS) was designed to rank the degree of overall disability as well as identify recent exacerbations. Six basic disability levels are used in the ADS; these are identical to those of the Modified Rankin Scale (MRS) (24 levels). Each of these disability levels (except asymptomatic) was further subdivided into 3 possible scores in the ADS, with higher scores reflecting recent exacerbations. The 6-point MRS was thus expanded into the 15-point ADS, as shown in Table 8.

At each evaluation the patient was first assigned to 1 of the MRS disability levels, based on the actual degree of handicap present at that time. An ADS score was then derived by adding points to the MRS score as follows: no points were added if no exacerbations occurred in the last month. One additional point was added if infrequent (ie, <1 per week) TIAs had occurred within 1 month. Two additional points were assigned if frequent TIAs (ie, >1 per week), or a major cerebrovascular ischemic event (eg, stroke) had occurred within 1 month. Thus, the patient's actual disability score as expressed by the MRS could be increased by a maximum of 2 points, reflecting recent exacerbations. (A comparison of the MRS and ADS is shown in Table 8.)

	Acknowledgments

 
Supported in part by NIH grants NS-23393 and NS-30896 and a Grant-in-Aid from the American Heart Association, Michigan Affiliate. We thank Shirley Sian and Lalaine Castillo for expert assistance in the preparation of this manuscript.

Received May 7, 1998; revision received July 30, 1998; accepted August 25, 1998.

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