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EXPERIENCE AND REASON |
Department of Neurology
Panagiotis and Aglaïa Kyriakou Children’s Hospital
Athens, 11527 Greece
Second State Department of Pediatrics
Panagiotis and Aglaïa Kyriakou Children’s Hospital
Athens, 11527 Greece
Immunology Department
General Hospital of Athens
Athens, Greece
Second State Department of Pediatrics and Outpatient Pediatric Rheumatology Clinic
Panagiotis and Aglaïa Kyriakou Children’s Hospital
Athens, 11527 Greece
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTDISCUSSIONREFERENCES |
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Key Words: anti-ß2GPI • stroke • antiphospholipid syndrome • children
Abbreviations: aPLs, antiphospholipid antibodies • aCLs, anticardiolipin antibodies • LA, lupus anticoagulant • anti-ß2GPI, anti-ß2-glycoprotein I antibodies • MRI, magnetic resonance imaging • IgM, immunoglobulin M • IgG immunoglobulin G • ELISA, enzyme-linked immunosorbent assay • APS, antiphospholipid syndrome
The reported incidence of cerebral ischemic accidents in children has increased over time because of improvements in imaging techniques. Although they have been associated with a variety of conditions including congenital heart disease, prothrombotic abnormalities, homocystinuria, and infections, most events remain idiopathic.1
Over the last decade the association between cerebral infarction and antiphospholipid antibodies (aPLs) has been found to be important in children and adults.2–4 aPLs constitute a heterogeneous group of autoantibodies that include anticardiolipin (aCL), lupus anticoagulant (LA) and anti-ß2-glycoprotein I (anti-ß2GPI). Recently it has been shown that anti-ß2GPI antibodies may be more specific than aCL in predicting thrombosis, especially in systemic lupus erythematosus (SLE) adult patients.5,6 However, there are no reported cases of childhood cerebral infarction in the presence of anti-ß2-GPI antibodies, while aCL and LA are negative.
We report a case of childhood ischemic stroke with antibodies to ß2-glycoprotein I, but no antibodies detectable in standard antiphospholipid assays.
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CASE REPORT |
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TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
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On admission, hemiparesis with hyperreflexia and a central seventh cranial nerve deficit was verified on the right side. No other aberration in the physical examination was observed. Magnetic resonance imaging (MRI) showed an increased signal on T2 images of the left basal ganglia (lentiform nucleus and caudate nucleus), findings consistent with prior infarction (Fig 1). An ultrasound Doppler of both carotid systems was normal, as was cardiac evaluation including electrocardiogram and echocardiogram. Magnetic resonance and digital substraction angiography of the head were normal with no evidence of thrombus, vessel wall dissection, aneurysm, or angiitis.
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Metabolic evaluation—including serum glucose, cholesterol, triglycerides, lipoprotein(a), methylenetetrahydrofolate reductase gene mutation, total plasma homocysteine, thyroid gland hormones, arterial blood gases, serum and urine amino acids, blood lactic acid, and pyruvic acid—disclosed no abnormalities. Borrelia burgdorferi, Chlamydia, Mycoplasma, and viral titers were negative for an ongoing infection while cerebrospinal fluid cells, protein, and glucose were normal. Gram stain and cultures revealed no pathogenic agent.
Immunologic tests for Venereal Disease Research Laboratory (test), antinuclear antibody, perinuclear antineutrophil cytoplasmic antibody, and antineutrophil cytoplasmic antibody were negative. LA profile as detected by dilute Russell viper venom test and platelet-neutralizing procedure and anticardiolipin antibodies (aCLs) were normal (immunoglobulin M [IgM]: 50 U; immunoglobulin G [IgG]: 89 U, normal range: 0–100 U). Initial anti-ß2GPI values were IgM: 30 U and IgG: 132 U (normal range: 0–100 U), while an examination 6 weeks later revealed a highly positive IgG of 350 U with negative IgM (60 U). The aPLs study in both parents was negative. The determination of aCL was performed with aCL-ß2GPI-dependent enzyme-linked immunosorbent assay (ELISA) (Gull Diagnostics, Bad, Hombürg, Germany) while anti-ß2GPI were detected by ELISA (Inova Diagnostics, San Diego, CA) using human ß2-glycoprotein I coated in 
-irradiated plates in the absence of phospholipid. In both assays a number of 20 sera from blood donors were used as normal controls and the results of the patients were evaluated as the mean of controls + 3SD.
During the next 2.5 years of follow-up, the boy has had numerous determinations of aCLs and LA activity, all of which have been negative. Anti-ß2GPI antibodies have remained elevated; 6 months after the stroke the IgG titer was 164 U, while an examination 2 years later revealed a highly positive IgG titer of 216 U. A follow-up MRI of the brain in September 2002 revealed the old infarct in the left basal ganglia and, additionally, mild dilatation of the left frontal ventricular horn and the body of the lateral ventricle.
Aspirin therapy was initiated at 4 mg/kg/day. The child exhibited significant improvement in function in the first 2 weeks, recovered completely in 4 weeks, and has not had a recurrent event for 2.5 years. He is still receiving treatment with low-dose aspirin.
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DISCUSSION |
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TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
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Our patient had a documented left cerebral infarct without other evidence of thromboembolism. No inherited disorders of coagulation or metabolic abnormalities were present. His echocardiogram revealed no structural or valvular disease and imaging of his cerebrovascular supply illustrated no signs of vasculitis or anatomic disruption. The presence of anti-ß2GPI was not associated with an underlying autoimmune disease or the presence of other autoantibodies in the serum.
The term "antiphospholipid/cofactor syndrome" has been used to define the syndrome in which clinical manifestations akin to those of the APS occur in the absence of "Sapporo" laboratory criteria,12 but in the presence of anti-ß2GPI.13 Cabiedes et al5 found 16 SLE adult patients with manifestations of APS and only anti-ß2GPI in their sera, and Picillo et al14 reported 4 patients with thrombosis and only anti-ß2GPI. Possible explanations for the antibody reactivity against human ß2GPI-based ELISAs may be the species specificity found in anti-ß2GPI or that the epitope recognized by antibodies is not expressed when ß2GPI is bound to phospholipids.15 On the basis of these findings, many investigators recommend searching for anti-ß2GPI in patients with negative results for standard aPL tests and strong suspicion for APS.
Although most studies have been in adults, there are now several cases of aPL-related cerebral ischemia in children.4,16–18 In a study evaluating the importance of various thrombopilia markers in pediatric patients, aPL was found to be significant risk factor for ischemic stroke in children.19 Recently, in the first report on the prevalence of anti-ß2GPI in a pediatric cohort, Von Scheven et al20 reported 4 children suffering from stroke who were all anti-ß2GPI-positive, but none of them had only this autoantibody in the serum. Furthermore, it was concluded that with the exception of stroke, anti-ß2GPI detection does not improve identification of pediatric APS over that of traditional aPL assays.
In the present case, the lower levels of anti-ß2GPI at the time of thrombosis, as opposed to 6 weeks later, is particularly interesting since Gomez-Pacheco et al21 have described the fall of the anti-ß2GPI titer during the thrombotic event with the subsequent increase in many SLE adult patients. This observation may indicate the consumption of anti-ß2GPI antibodies and thus a causal relationship between them and clinical manifestations. More studies are needed to confirm the usefulness and importance of anti-ß2GPI antibody determination in the evaluation of children with clinical manifestations of APS and its potential role in the pathogenesis of central nervous system thrombosis.
Treatment of children with cerebral infarction attributable to APS has been directed toward the prevention of recurrent thrombosis. Aspirin is a relatively low-risk option in these patients, although there are no studies that indicate it is an adequate therapy. Long-term treatment with warfarin is indicated in children with >1 event.22 Recently, in a large prospective study,23 including a subgroup of patients with thrombosis and aPL, warfarin showed no significant superiority over aspirin for the prevention of recurrent stroke. Nevertheless, the treatment of childhood stroke associated with aPLs remains to be determined and studies are needed to discover whether the risk of recurrence outweighs the risk of treatment with aspirin or oral anticoagulation.1
To our knowledge, this is the first report of childhood ischemic stroke with isolated anti-ß2GPI in the serum. Based on recent data, we underline the importance of screening for these antibodies in children with thrombotic events, especially when they do not fulfill the "classic" criteria for the diagnosis of the APS.
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FOOTNOTES |
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Reprint requests to (E.K.) Department of Neurology, Panagiotis and Aglaïa Kyriakou Children’s Hospital, 3 Thivon and Levadias St, Athens, 11527 Greece. E-mail: pectasid{at}otenet.gr
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TOPABSTRACTCASE REPORTDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  M.-C. Boffa and E. Lachassinne Review: Infant perinatal thrombosis and antiphospholipid antibodies: a review Lupus, August 1, 2007; 16(8): 634 - 641. [Abstract] [PDF]
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